The health and psychological consequences of cannabis use

National Drug Strategy

Monograph Series No. 25

Wayne Hall, Nadia Solowij and Jim Lemon, National Drug and Alcohol Research Centre

Prepared for the National Task Force on Cannabis

CONTENTS

Acknowledgments

The authors would like to acknowledge the assistance of the following people in the preparation of this manuscript:

Dr Robert Ali, Chairman of the National Task Force on Cannabis, for his encouragement and support at all stages of the project, and the members of the Task Force for their feedback on earlier drafts of the document.

Dr Mario Argandona (WHO Programme on Substance Abuse), Dr Greg Chesher, (National Drug and Alcohol Research Centre), Paul Christie, (Project Officer, National Task Force on Cannabis), Dr Bill Corrigal (Senior Scientist, Addiction Research Foundation, Toronto), Emeritus Professor Harold Kalant (Department of Pharmacology, University of Toronto), and Dr Jean-Marie Ruel (Bureau of Dangerous Drugs, Health and Welfare Canada) for their useful comments on the whole manuscript.

The following persons are acknowledged for their expert comments on specific sections of the manuscript: Dr Peter Fried (Carleton University, Ottawa, Ontario) for his comments on reproductive effects; Dr Richard Mattick (National Drug and Alcohol Research Centre) for his comments on the dependence syndrome; Dr Peter Nelson (Southern Cross University, New South Wales) for his comments on psychological effects); Dr Mehdi Paes (Department of Psychiatry, University of Rabat, Morocco) and Professor S.M. Channabasavanna (Director, National Institute of Mental Health and NeuroSciences, Bangalore, India) for their comments on psychiatric disorders; and Professor Donald Tashkin (Division of Pulmonary and Critical Care Medicine, University of California, Los Angeles Medical School) for his comments on cardiovascular and respiratory effects.

Eva Congreve, the Archivist at the National Drug and Alcohol Research Centre, performed above and beyond the call of duty in uncomplainingly and efficiently dealing with a plethora of requests for obscure publications in esoteric journals. Without her assistance, this review would not have been half as comprehensive as we hope it has been. Peter Congreve and Keith Warren collected articles and books which made the task of reading and writing easier.

Acknowledgment is given to the Centre's secretaries, Libby Barron, Margaret Eagers and Gail Merlin, who undertook the thankless task of checking the referencing and proof reading the manuscript.

Executive summary

The following is a summary of the major adverse health and psychological effects of acute and chronic cannabis use, grouped according to the degree of confidence in the view that the relationship between cannabis use and the adverse effect is a causal one.

Acute effects

• anxiety, dysphoria, panic and paranoia, especially in naive users;

cognitive impairment, especially of attention and memory, for the duration of intoxication;

psychomotor impairment, and probably an increased risk of accident if an intoxicated person attempts to drive a motor vehicle, or operate machinery;

an increased risk of experiencing psychotic symptoms among those who are vulnerable because of personal or family history of psychosis;

an increased risk of low birth weight babies if cannabis is used during pregnancy.

Chronic effects

The major health and psychological effects of chronic heavy cannabis use, especially daily use over many years, remain uncertain. On the available evidence, the major probable adverse effects appear to be:

• respiratory diseases associated with smoking as the method of administration, such as chronic bronchitis, and the occurrence of histopathological changes that may be precursors to the development of malignancy.

• development of a cannabis dependence syndrome, characterised by an inability to abstain from or to control cannabis use;

• subtle forms of cognitive impairment, most particularly of attention and memory, which persist while the user remains chronically intoxicated, and may or may not be reversible after prolonged abstinence from cannabis.

The following are the major possible adverse effects of chronic, heavy cannabis use which remain to be confirmed by further research:

• an increased risk of developing cancers of the aerodigestive tract, i.e. oral cavity, pharynx, and oesophagus;

• an increased risk of leukemia among offspring exposed while in utero;

• a decline in occupational performance marked by underachievement in adults in occupations requiring high level cognitive skills, and impaired educational attainment in adolescents;

• birth defects occurring among children of women who used cannabis during their pregnancies.

High risk groups

Adolescents

• Adolescents with a history of poor school performance may have their educational achievement further limited by the cognitive impairments produced by chronic intoxication with cannabis.

• Adolescents who initiate cannabis use in the early teens are at higher risk of progressing to heavy cannabis use and other illicit drug use, and to the development of dependence on cannabis.

Women of childbearing age

• Pregnant women who continue to smoke cannabis are probably at increased risk of giving birth to low birth weight babies, and perhaps of shortening their period of gestation.

• Women of childbearing age who smoke cannabis at the time of conception or while pregnant possibly increase the risk of their children being born with birth defects.

Persons with pre-existing diseases

Persons with a number of pre-existing diseases who smoke cannabis are probably at an increased risk of precipitating or exacerbating symptoms of their diseases. These include:

• individuals with cardiovascular diseases, such as coronary artery disease, cerebrovascular disease and hypertension;

• individuals with respiratory diseases, such as asthma, bronchitis, and emphysema;

• individuals who are dependent on alcohol and other drugs, who are probably at an increased risk of developing dependence on cannabis.

The health risks of alcohol, tobacco and cannabis use

Acute effects

Alcohol. The major risks of acute cannabis use are similar to the acute risks of alcohol intoxication in a number of respects. First, both drugs produce psychomotor and cognitive impairment. The impairment produced by alcohol increases risks of various kinds of accident. It remains to be determined whether cannabis intoxication produces similar increases in accidental injury and death, although on balance it probably does. Second, substantial doses of alcohol taken during the first trimester of pregnancy can produce a foetal alcohol syndrome. There is suggestive but far from conclusive evidence that cannabis used during pregnancy may have similar adverse effects. Third, there is a major health risk of acute alcohol use that is not shared with cannabis. In large doses alcohol can cause death by asphyxiation, alcohol poisoning, cardiomyopathy and cardiac infarct whereas there are no recorded cases of fatalities attributable to cannabis.

Tobacco. The major acute health risks that cannabis share with tobacco are the irritant effects of smoke upon the respiratory system, and the stimulating effects of both THC and nicotine on the cardiovascular system, both of which can be detrimental to persons with cardiovascular disease.

Chronic effects

Alcohol. Chronic cannabis use may share some of the risks of heavy chronic alcohol use. First, heavy use of either drug increases the risk of developing a dependence syndrome in which users experience difficulty in stopping or controlling their use. There is strong evidence for such a syndrome in the case of alcohol and reasonable evidence in the case of cannabis. Second, there is reasonable clinical evidence that the chronic heavy use of alcohol can produce psychotic symptoms and psychoses in some individuals. There is suggestive evidence that chronic heavy cannabis use may produce a toxic psychosis, precipitate psychotic illnesses in predisposed individuals, and exacerbate psychotic symptoms in individuals with schizophrenia. Third, there is good evidence that chronic heavy alcohol use can indirectly cause brain injury - the Wernicke-Korsakov syndrome - with symptoms of severe memory defect and an impaired ability to plan and organise. Chronic cannabis use does not produce cognitive impairment of comparable severity but there is suggestive evidence that chronic cannabis use may produce subtle defects in cognitive functioning, that may or may not be reversible after abstinence. Fourth, there is reasonable evidence that chronic heavy alcohol use produces impaired occupational performance in adults and lowered educational achievements in adolescents. There is at most suggestive evidence that chronic heavy cannabis use produces similar, albeit more subtle impairments in occupational and educational performance of adults. Fifth, there is good evidence that chronic, heavy alcohol use increases the risk of premature mortality from accidents, suicide and violence. There is no comparable evidence for chronic cannabis use, although it is likely that dependent cannabis users who frequently drive while intoxicated with cannabis increase their risk of accidental injury or death. Sixth, alcohol use has been accepted as a contributory cause of cancer of the oropharangeal organs in men and women. There is suggestive evidence that chronic cannabis smoking may also be a contributory cause of cancers of the aerodigestive tract (i.e. the mouth, tongue, throat, oesophagus, lungs).

Tobacco. The major adverse health effects shared by chronic cannabis and tobacco smokers are chronic respiratory diseases, such as chronic bronchitis, and probably, cancers of the aerodigestive tract. The increased risk of cancer in the respiratory tract is a consequence of the shared route of administration by smoking. It is possible that chronic cannabis smoking also shares the cardiotoxic properties of tobacco smoking, although this possibility remains to be investigated.

1. Summary of report

Introduction

This review of the literature on the health and psychological effects of cannabis was undertaken at the initiative of the former Federal Justice Minister, Senator Michael Tate, who requested a review of knowledge relating to cannabis, to inform policy decisions. At Senator Tate's urging, a National Task Force on Cannabis was established on 25 May 1992. The Task Force commissioned this review of the evidence on the health and psychological effects of cannabis use. A new and independent review was thought necessary because there has not been any major international review of the literature on the health and psychological effects of cannabis since 1981, when the Addiction Research Foundation and World Health Organization jointly reviewed the literature. The purpose of this review was to update the conclusions of earlier reviews in the light of research undertaken during the past decade.

Our approach to the literature

Our review of the literature was not intended to be as comprehensive as the major review undertaken by the Addiction Research Foundation and the World Health Organization. The literature is too large, and the diversity of relevant disciplines represented in it beyond the expertise we had available for the task. Unavoidably, we have relied upon expert opinion in the areas that lie outside the authors' collective expertise which is primarily in areas of epidemiology, psychiatry, psychopharmacology, neurophysiology and neuropsychology.

In order to minimise the effects of our lack of expertise in certain areas we have relied upon the consensus views expressed in the literature by experts in the relevant fields. When there has been controversy between the experts we have explicitly acknowledged areas of disagreement. We have checked our understanding and representation of these expert views by asking Australian and overseas researchers with expertise in the relevant fields to critically review what we have written.

Our approach to assessing the health effects of cannabis

The evaluation of the health hazards of any drug is difficult for a number of reasons. First, causal inferences about the effects of drugs on human health are difficult to make, especially when the interval between use and alleged ill effects is a long one. It takes time for adverse effects to develop and for research to identify such effects.

Second, in making causal inferences there is a tension between the rigour and relevance of the evidence. The most rigorous evidence is provided by laboratory investigations using animals or in vitro preparations (e.g. cell preparations in a test tube) in which well controlled drug doses are related to precisely specified biological outcomes. The relevance of this evidence to human disease is uncertain, however, because many inferences have to be made in linking the occurrence of specific biological effects in laboratory animals to the likely effects of human use. Epidemiological studies of relationships between drug use and human disease are of greater relevance to the appraisal of the health risks of human drug use, but their relevance is purchased at the price of reduced rigour. Doses of illicit drugs over periods of years are difficult to quantify because of the varied dosages of blackmarket drugs and the stigma in admitting to illicit drug use. Interpretation is further complicated by correlations between cannabis use and alcohol, tobacco and other illicit drug use.

Third, appraisals of the hazards of drug use are affected by the social approval of the drugs in question. The countercultural symbolism of cannabis use in the late 1960s has introduced an unavoidable sociopolitical dimension to the debate about the severity of its adverse health effects. Politically conservative opponents of cannabis use justify continued prohibition by citing evidence of the personal and social harms of cannabis use. When the evidence is uncertain they resolve uncertainty by assuming that the drug is unsafe until proven safe. Complementary behaviour is exhibited by proponents of cannabis use. Evidence of harm is discounted and uncertainties about the ill-effects of chronic cannabis use resolved by demanding better evidence, arguing that until such evidence is available individuals should be allowed to choose whether or not they use the drug.

Such evidential standards are rarely applied consistently. The politically conservative would reject a similar approach to the appraisal of the health hazards of industrial processes. Similarly, proponents of cannabis liberalisation rarely apply the principles used in their risk assessment of cannabis to the appraisal of the health effects of pharmaceutical drugs, industrial processes, and pesticides. To guard against such double evidential standards we will be as explicit as possible about the evidential standards we have used, and attempt to be as even-handed as we can in their application.

Evidential desiderata

The burden of proof concerns who bears the responsibility for making a case: those who make a claim of adverse health effects of cannabis, or those who doubt it. If the burden falls on those who claim that it is safe, uncertainty will be resolved by assuming that it is unsafe until proved otherwise; conversely, if the burden falls on those who claim that the drug is unsafe, then it will be assumed to be safe until proven otherwise.

It is by no means agreed who bears the burden of proof in the debate about the health effects of cannabis use. Proponents of continued prohibition appeal to established practice, arguing that since the drug is illegal the burden of proof falls upon those who want to legalise it; opponents of existing policies argue that the burden of proof falls upon those who wish to use the criminal law to prevent adults from freely choosing to use a drug.

We will vary the burden of proof depending upon the state of the evidence and argument. Once a prima facie case of harm has been made, positive evidence of safety is required rather than the simple absence of any evidence of ill effect. We will assume that a prima facie case has been made when there is either direct evidence that the drug has ill effects in humans or animals (e.g. from a case-control study), or there is a compelling argument that it could, e.g. since tobacco smoking causes lung cancer, and since cannabis and tobacco smoke are similar in their constituents, it is probable that heavy cannabis smoking also causes lung cancer.

Standard of proof reflects the degree of confidence required in an inference that there is a causal connection between drug use and harm. In courts of law, the standard of proof demanded depends upon the seriousness of the offence at issue and the consequences of a verdict, with a higher standard of proof, "beyond reasonable doubt", being demanded in criminal cases, and the "balance of probabilities" being acceptable in civil cases. Scientists generally require something closer to the standard of "beyond reasonable doubt" than the balance of probabilities before they draw confident conclusions of harm. However, since there are few adverse health effects of cannabis use which meet this standard, we will indicate when the evidence permits an inference to be made on the balance of probabilities.

The criteria for causal inference that we will use are standard ones. These are: (1) evidence that there is a relationship between cannabis use and a health outcome provided by one of the accepted types of research design (namely, case-control, cross-sectional, cohort, or experiment); (2) evidence provided by a statistical test or confidence interval that the relationship is unlikely to be due to chance; (3) good evidence that drug use precedes the adverse effect (e.g. from a cohort study); and (4) evidence either from experiment, or observational studies with statistical or other form of control, which makes it unlikely that the relationship is due to some other variable which is related to both cannabis use and the adverse health effect.

In the trade-off between relevance and rigour, our preference will be for human evidence, both experimental and epidemiological, over animal and in vitro studies. In the absence of human evidence, in vitro and animal experiments will be regarded as raising a suspicion that drug use has an adverse effects on human health, with the degree of suspicion being in proportion to the number of such studies, the consistency of their results across different species and experimental preparations, and the degree of expert consensus on the trustworthiness of the inferences from effects in vitro and in vivo to adverse effects on human health under existing patterns of usage.

Ideally, it would be desirable to quantify the magnitude of risk posed by cannabis use by estimating both the relative and attributable risks of specific health effects. However, since there is generally insufficient evidence to estimate these risks for many putative adverse effects of cannabis, the magnitude of a health risk posed by cannabis use will be qualitatively assessed by a comparison of its probable health effects with those of two other widely used recreational drugs, alcohol and tobacco. The motive for such a comparison is to minimise double standards in the appraisal of the health effects of cannabis use by providing some kind of common standard, however approximate, for making societal decisions about cannabis use.

Cannabis the drug

Cannabis is a generic name for a variety of preparations derived from the plant Cannabis sativa. A sticky resin which covers the flowering tops and upper leaves, most abundantly in the female plant, contains more than 60 cannabinoid substances. Laboratory research on animals and humans has demonstrated that the primary psychoactive constituent in cannabis is the cannabinoid, delta-9-tetrahydrocannabinol or THC.

The cannabinoid receptor

Cannabis resembles the opioid drugs in acting upon specific receptors in the brain. In this respect it differs from alcohol, cocaine and other illicit drugs which act by disrupting brain processes. The determination and characterisation of a specific cannabinoid receptor has made it possible to map its distribution in the brain, and to demonstrate that its well-known psychoactive effects are receptor mediated. Very recently an endogenous brain molecule has been discovered which binds to the cannabinoid receptor and mimics the action of cannabinoids. It has been called "anandamide", from the Sanskrit word for bliss. Its discovery promises to stimulate a great deal of research which will improve our understanding of the role played by a cannabinoid-like system of the brain, and elucidate the mechanism of action of cannabis.

Forms of cannabis

The concentration of THC varies between the three most common forms of cannabis: marijuana, hashish and hash oil. Marijuana is prepared from the dried flowering tops and leaves of the harvested plant. The potency of the marijuana depends upon the growing conditions, the genetic characteristics of the plant and the proportions of plant matter. The flowering tops and bracts are highest in THC concentration, with potency descending through the upper leaves, lower leaves, stems and seeds. The concentration of THC in a batch of marijuana containing mostly leaves and stems may range from 0.5-5 per cent, while the "sinsemilla" variety with "heads" may have THC concentrations of 7-14 per cent.

Hashish or hash consists of dried cannabis resin and compressed flowers. The concentration of THC in hashish generally ranges from 2-8 per cent, although it can be as high as 10-20 per cent. Hash oil is a highly potent and viscous substance obtained by extracting THC from hashish (or marijuana) with an organic solvent, concentrating the filtered extract, and in some cases subjecting it to further purification. The concentration of the THC in hash oil is generally between 15 per cent and 50 per cent.

Routes of administration

Almost all possible routes of administration have been used, but by far the most common method is smoking (inhaling). Marijuana is most often smoked as a hand-rolled "joint", the size of a cigarette or larger. Tobacco is often added to assist burning, and a filter is sometimes inserted. Hashish may also be mixed with tobacco and smoked as a joint, but it is probably more frequently smoked through a pipe, with or without tobacco. A water pipe known as a "bong" is a popular implement for all cannabis preparations because the water cools the hot smoke before it is inhaled and there is little loss of the drug through sidestream smoke. Hash oil is used sparingly because of its extremely high psychoactive potency; a few drops may be applied to a cigarette or a joint, to the mixture in the pipe, or the oil may be heated and the vapours inhaled. Whatever method is used, smokers inhale deeply and hold their breath for several seconds in order to ensure maximum absorption of THC by the lungs.

Hashish may also be cooked or baked in foods and eaten. When ingested orally the onset of the psychoactive effects is delayed by about an hour. The "high" may be of lesser intensity but the duration of intoxication is longer by several hours. It is easier to titrate the dose and achieve the desired level of intoxication by smoking than by ingestion, since the effects from smoking are more immediate. Crude aqueous extracts of cannabis have been very rarely injected intravenously, but this route is unpopular since THC is insoluble in water, and hence, little or no drug is actually present in these extracts. Moreover, the injection of tiny undissolved particles may cause severe pain and inflammation at the site of injection, and a variety of toxic systemic effects.

Dosage

A typical joint contains between 0.5g and 1.0g of cannabis plant matter, which may vary in THC content between 5mg and 150mg (i.e. typically between 1 per cent and 15 per cent). The actual amount of THC delivered in the smoke has been estimated at 20-70 per cent, the rest being lost through combustion or sidestream smoke. The bioavailability of THC (the fraction of THC in the cigarette which reaches the bloodstream) from marijuana cigarettes in human subjects has been reported to range from 5-24 per cent. Given all of these variables, the actual dose of THC absorbed when cannabis is smoked is not easily quantified.

In general, only a small amount of cannabis (e.g. 2-3mg of available THC) is required to produce a brief pleasurable high for the occasional user, and a single joint may be sufficient for two or three individuals. A heavy smoker may consume five or more joints per day, while heavy users in Jamaica, for example, may consume up to 420mg THC per day. In clinical trials designed to assess the therapeutic potential of THC, single doses have ranged up to 20mg in capsule form. In human experimental research, THC doses of 10mg, 20mg and 25mg have been administered as low, medium and high doses.

Patterns of use

Cannabis is the most widely used illicit drug in Australia, having been tried by a third of the adult population, and by the majority of young adults between the ages of 18 and 25. The most common route of administration is by smoking, and the most widely used form of the drug is marijuana. In the majority of cases cannabis use is "experimental", that is, most users use the drug on a small number of occasions, and either discontinue their use, or use intermittently and episodically after first trying it. Even among those who continue to use the drug over longer periods, the majority discontinue their use in their mid to late 20s.

Only a small proportion of those who ever use cannabis use it on a daily basis over an extended period such as several years. Because of uncertainties about the dose received, there is no good information on the amount of THC ingested by such regular users. "Heavy" use is consequently defined approximately in terms of frequency of use rather than the estimated average dose of THC received. The daily or near daily use pattern over a period of years is the pattern that probably places cannabis users at greatest risk of experiencing long-term health and psychological consequences of use. Daily cannabis users are more likely to be male and less well educated; they are also more likely to regularly use alcohol and to have experimented with a variety of other illicit drugs, such as, amphetamines, hallucinogens, psychostimulants, sedatives and opioids.

Metabolism of cannabinoids

Different methods of ingesting cannabis give rise to differing pharmacokinetics, i.e. patterns of absorption, metabolism and excretion of the active agent. Upon inhalation, THC is absorbed from the lungs into the bloodstream within minutes. After oral administration absorption is much slower, taking one to three hours for THC to enter the bloodstream, and delaying the onset of psychoactive effects. When cannabis is smoked, the initial metabolism of THC takes place in the lungs, followed by more extensive metabolism by liver enzymes, with the transformation of THC to a number of metabolites. The most rapidly produced metabolite is 9-carboxy-THC, which is detectable in blood within minutes of smoking. Another major metabolite produced is 11-hydroxy-THC, which is approximately 20 per cent more potent than THC, and penetrates the blood-brain barrier more rapidly. It is present at very low concentrations in the blood after smoking, but at high concentrations after the oral route. THC and its hydroxylated metabolites account for most of the observed effects of the cannabinoids.

Peak blood levels of THC are usually reached within 10 minutes of smoking, and decline rapidly thereafter to about 5-10 per cent of their initial level within the first hour. This initial rapid decline reflects both rapid conversion to its metabolites, as well as the distribution of unchanged THC to lipid-rich tissues, including perhaps the brain.

THC and its metabolites are highly fat soluble and may remain for long periods in the fatty tissues of the body, from which they are slowly released back into the bloodstream. The terminal half-life of THC (the time required to clear half of the administered dose from the body) is significantly shorter for experienced or daily users (19-27 hours) than for inexperienced users (50-57 hours). Since tissue distribution is similar for both users and non-users, it is the immediate and subsequent metabolism that occurs more rapidly in experienced users. Given the slow clearance of THC, repeated administration results in the accumulation of THC and its metabolites in the body. Because of its slow release from fatty tissues back into the bloodstream, THC and its metabolites may be detectable in blood for several days, and traces may persist for several weeks. Several studies have examined measures of cannabinoids in fat, confirming that THC may be stored for at least 28 days.

Detection of cannabinoids in body fluids

Cannabinoid levels in the body depend on both the dose given and the smoking history of the individual, but are subject to a vast degree of individual variability. Plasma levels of THC in man may range between 0-500ng/ml, depending on the potency of the cannabis ingested and the time since smoking. The detection of THC in blood above 10-15ng/ml provides evidence of recent consumption of the drug, although how recent is not possible to determine. A more precise estimate of time of consumption may be obtained from the ratio of THC to 9-carboxy-THC: similar concentrations of both in blood indicate very recent use (in the vicinity of 20-40 minutes) and a high probability of intoxication. When the levels of 9-carboxy-THC are substantially higher than those of THC itself, ingestion could be estimated to have occurred more than half an hour ago. It is very difficult to determine the time of administration from blood concentrations even if the smoking habits of the individual and the exact dose consumed were known. Therefore, the results of blood analyses are not easily interpreted and, at best, only confirm the "recent" use of cannabis.

Intoxication and levels of cannabinoids

Since there is evidence that cannabis intoxication adversely affects skills required to drive a motor vehicle (see below), it would be desirable to have a reliable measure of impairment due to cannabis intoxication that was comparable to the breath test of alcohol intoxication. However, there is no clear relationship between blood levels of THC or its metabolites and degree of either impairment or subjective intoxication. A general consensus of forensic toxicologists is that blood concentrations associated with impairment after smoking cannabis have not been sufficiently established to provide a basis for legal testimony in cases concerning driving a motor vehicle while under the influence of cannabis.

Acute psychological and health effects

The major reason for the widespread recreational use of cannabis is that it produces a "high", an altered state of consciousness which is characterised by mild euphoria, relaxation, and perceptual alterations, including time distortion and the intensification of ordinary sensory experiences, such as eating, watching films, and listening to music. When used in a social setting the high is often accompanied by infectious laughter, and talkativeness. Cognitive effects are also marked. They include impaired short-term memory, and a loosening of associations, which make it possible for the user to become lost in pleasant reverie and fantasy. Motor skills and reaction time are also impaired, so skilled activity of various kinds is frequently disrupted.

Not all the acute psychological effects of cannabis are welcomed by users. The most common unpleasant psychological effects are anxiety, sometimes producing frank panic reactions, or a fear of going mad, and dysphoric or unpleasant depressive feelings. Psychotic symptoms such as delusions and hallucinations may be more rarely experienced at very high doses. These effects are most often reported by naive users who are unfamiliar with the drug's effects, and by patients who have been given oral THC for therapeutic purposes. More experienced users may occasionally report these effects after oral ingestion of cannabis, when the effects may be more pronounced and of longer duration than those usually experienced after smoking cannabis. These effects can usually be prevented by adequately informing users about the type of effects they may experience, and once developed can be readily managed by reassurance and support.

The inhalation of marijuana smoke, or the ingestion of THC has a number of bodily effects. Among these the most dependable is an increase in heart rate of 20-50 per cent over baseline, which occurs within a few minutes to a quarter of an hour, and lasts for up to three hours. Changes in blood pressure also occur, which depend upon posture: blood pressure is increased while the person is sitting, and decreases while standing. In healthy young users these cardiovascular effects are unlikely to be of any clinical significance because tolerance develops to the effects of THC, and young, healthy hearts will only be mildly stressed.

The acute toxicity of cannabis, and cannabinoids more generally, is very low. There are no confirmed cases of human deaths from cannabis poisoning in the world medical literature. This is unlikely to be due to a failure to detect such deaths, because animal studies indicate that the dose of THC required to produce 50 per cent mortality in rodents is extremely high by comparison with other commonly used pharmaceutical and recreational drugs. The lethal dose also increases as one moves up the phylogenetic tree, suggesting by extrapolation that the lethal dose in humans could not be achieved by either smoking or ingesting the drug.

Psychomotor effects and driving

The major potential health risk from the acute use of cannabis arises from its effects on psychomotor performance. Intoxication produces dose-related impairments in a wide range of cognitive and behavioural functions that are involved in skilled performances like driving an automobile or operating machinery. The negative effects of cannabis on the performance of psychomotor tasks is almost always related to dose. The effects are generally larger, more consistent and of increased persistence in difficult tasks which involve sustained attention. The acute effects of doses of cannabis which are subjectively equivalent to or higher than usual recreational doses on driving performance in laboratory simulators and over standardised driving courses, are similar to those of doses of alcohol that achieve blood alchol concentrations between 0.07 per cent and 0.10 per cent.

While cannabis impairs performance in laboratory and simulated driving settings, it is difficult to relate the magnitude of these impairments to the risk of being involved in motor vehicle accidents. Studies of the effects of cannabis on on-road driving performance have found at most modest impairments. Cannabis intoxicated persons drive more slowly, and generally take fewer risks, than alcohol intoxicated drinkers, probably because they are more aware of their level of psychomotor impairment.

There is no controlled epidemiological evidence that cannabis users are at increased risk of being involved in motor vehicle or other accidents. This is in contrast to the case of alcohol use and accidents, where case-control studies have shown that persons with blood alcohol levels indicative of intoxication are over-represented among accident victims. All that is available are studies of the prevalence of cannabinoids in the blood of motor vehicle and other accident victims, which have found that between 4 per cent and 37 per cent of such blood samples have contained cannabinoids, typically in association with blood alcohol levels indicative of intoxication. These studies are difficult to evaluate for a number of reasons.

First, in the absence of information on the prevalence of cannabinoids in the blood of non-accident victims, we do not know whether persons with cannabinoids are over-represented among accident victims. Second, the presence of cannabinoids in blood indicates only recent use, not necessarily intoxication at the time of the accident. Third, there are also serious problems of causal attribution, since more than 75 per cent of drivers with cannabinoids in their blood also have blood levels indicative of alcohol intoxication.

Attempts have been made to circumvent the first difficulty by using NIDA Household survey data (from the United States) to estimate what proportion of drivers might be expected to have cannabinoids in their blood and urine. These suggest that cannabis users are two to four times more likely to be represented among accident victims than non-cannabis users; cannabis users who also use alcohol, rather than cannabis only users, are even more likely to be over-represented among accident victims. Other indirect support for an increased risk of accidental death associated with cannabis use comes from surveys of self-reported accidents among adolescent drug users, and from epidemiological studies of the relationships between cannabis use and mortality, and health service utilisation.

The known effects of interactions between cannabis and other drugs on psychomotor performance are what would be predicted from their separate effects. The drug most often used in combination with cannabis is alcohol. The separate effects of alcohol and cannabis on psychomotor impairment and driving performance are approximately additive.

The effects of chronic cannabis use

Cellular effects and the immune system

There is reasonably consistent evidence that some cannabinoids, most especially THC, can produce a variety of cellular changes, such as alterations to cell metabolism, and DNA synthesis, in vitro (i.e. in the test tube). There is stronger and more consistent evidence that cannabis smoke is mutagenic in vitro, and in vivo (i.e. in live animals), and hence, that it is potentially carcinogenic. If cannabis smoke is carcinogenic then it is probably for the same reasons that cigarette smoke is, rather than because it contains cannabinoids. Hence, if chronic cannabis smoking causes cancer, it is most likely to develop after long-term exposure at those sites which receive maximum exposure, namely, the lung and upper aerodigestive tract (see below).

There is reasonably consistent evidence that cannabinoids impair both the cell-mediated and humoral immune systems in rodents. Humoral immune suppression is seen in decreased antibody formation responses to antigens, and decreased lymphocyte response to B-cell mitogens. Cell-mediated immune suppression is revealed by a reduction in lymphocyte response to T-cell mitogens. These changes have produced decreased resistance to infection by a bacteria and a virus. There is also evidence that the non-cannabinoid components of cannabis smoke impair the functioning of alveolar macrophages, the first line of the body's defence system in the lungs. The clinical relevance of these findings is uncertain, however. The doses required to produce these effects have generally been very high, and the problem of extrapolating to the effects of doses used by humans is complicated by the possibility that tolerance may also develop to such effects.

The limited experimental and clinical evidence in humans is mixed, with a small number of studies suggesting adverse effects that have not been replicated by others. At present, there is no conclusive evidence that consumption of cannabinoids predisposes man to immune dysfunction, as measured by reduced numbers or impaired functioning of T-lymphocytes, B-lymphocytes or macrophages, or reduced immunoglobulin levels. There is suggestive evidence that THC impairs T-lymphocyte responses to mitogens and allogenic lymphocytes.

The clinical and biological significance of these possible immunological impairments in chronic cannabis users is uncertain. To date there has been no epidemiological, or even anecdotal, evidence of increased rates of disease among chronic heavy cannabis users, such as was seen among young homosexual men in the early 1980s when the Acquired Immune Deficiency Syndrome was first recognised. There is one large prospective study of HIV-positive homosexual men which indicates that continued cannabis use did not increase the risk of progression to AIDS. Given the duration of large-scale cannabis use by young adults in Western societies, the absence of any epidemics of infectious disease makes it unlikely that cannabis smoking produces major impairments in the immune system.

It is more difficult to exclude the possibility that chronic heavy cannabis use produces a minor impairment in immunity. Such an effect would be manifest in small increases in the rate of occurrence of common bacterial and viral illnesses among chronic users which could have escaped detection in the few studies that have attempted to address the issue. Such an increase could nonetheless be of public health significance because of the increased expenditure on health services, and the loss of productivity that it would cause among the young adults who are the heaviest users of cannabis.

The possibility that cannabinoids may produce minor impairments in the immune system would also raise doubts about the therapeutic usefulness of cannabinoids in immunologically compromised patients, such as those undergoing cancer chemotherapy, or those with AIDS. AIDS patients may provide one of the best populations in which to detect any such effects. If it was ethical to conduct clinical trials of cannabinoids to improve appetite and well-being in AIDS patients, then studies of the impact of cannabis use on their compromised immune systems would provide one way of evaluating the seriousness of this concern.

The cardiovascular system

There is insufficient new evidence to change the conclusions reached by the Institute of Medicine in 1982, namely, that although the smoking of marijuana "causes changes to the heart and circulation that are characteristic of stress ... there is no evidence ... that it exerts a permanently deleterious effect on the normal cardiovascular system..." (p72). The situation may be less benign for patients with hypertension, cerebrovascular disease and coronary atherosclerosis, in which case there is evidence that marijuana poses a threat because it increases the work of the heart. The "magnitude and incidence" of the threat remains to be determined as the cohort of chronic cannabis users of the late 1960s enters the age of maximum risk for complications of atherosclerosis in the heart, brain and peripheral blood vessels. In the interim, because any such effects could be life threatening in patients with significant occlusion of the coronary arteries or other cerebrovascular disease, patients with cardiovascular disease should be advised not to consume cannabis, and perhaps not to use THC therapeutically.

The respiratory system

Chronic heavy cannabis smoking impairs the functioning of the large airways, and probably causes symptoms of chronic bronchitis such as coughing, sputum production, and wheezing. Given the adverse effects of tobacco smoke, which is qualitatively very similar in composition to cannabis smoke, it is likely that chronic cannabis use predisposes individuals to develop chronic bronchitis and respiratory cancer. There is reasonable evidence for an increased risk of chronic bronchitis, and evidence that chronic cannabis smoking may produce histopathological changes in lung tissues of the kind that precede the development of lung cancer.

More recently, concern about the possibility of cancers being induced by chronic cannabis smoking has been heightened by case reports of cancers of the aerodigestive tract in young adults with a history of heavy cannabis use. Although these reports fall short of providing convincing evidence because many of the cases concurrently used alcohol and tobacco, they are clearly a major cause for concern, since such cancers are usually rare in adults under the age of 60, even among those who smoke tobacco and drink alcohol. The conduct of case-control studies of these cancers should be a high priority for research which aims to identify the possible adverse health effects of chronic cannabis use.

Reproductive effects

Chronic cannabis use probably disrupts the male and female reproductive systems in animals, reducing testosterone secretion, and sperm production, motility, and viability in males, and disrupting the ovulatory cycle in females. It is uncertain whether it is likely to have these effects in humans, given the inconsistency in the limited literature on human males, and the lack of research in the case of human females. There is also uncertainty about the clinical significance of these effects in normal healthy young adults. They may be of greater concern among young adolescents, and among males with fertility impaired for other reasons.

Cannabis use during pregnancy probably impairs foetal development, leading to smaller birthweight, perhaps as a consequence of shorter gestation, and probably by the same mechanism as cigarette smoking, namely, foetal hypoxia. There is uncertainty about whether cannabis use during pregnancy produces a small increase in the risk of birth defects as a result of exposure of the foetus in utero. Prudence demands that until this issue is resolved, women should be advised not to use cannabis during pregnancy, or when attempting to conceive.

There is not a great deal of evidence that cannabis use can produce chromosomal or genetic abnormalities in either parent which could be transmitted to offspring. Such animal and in vitro evidence as exists suggests that the mutagenic capacities of cannabis smoke are greater than those of THC, and are probably of greater relevance to the risk of users developing cancer than to the transmission of genetic defects to children.

There is suggestive evidence that infants exposed in utero to cannabis may experience transient behavioural and developmental effects during the first few months after birth. There is a single study which suggests an increased risk of childhood leukemia occurring among the children born to women who used cannabis during their pregnancies. Its replication is of some urgency.

Psychological effects of chronic cannabis use

Adolescent development

There is strong continuity of development from adolescence into early adult life in which many indicators of adverse development which have been attributed to cannabis use precede its use, and increase the likelihood of using cannabis. These include minor delinquency, poor educational performance, nonconformity, and poor adjustment. A predictable sequence of initiation into the use of illicit drugs was identified among American adolescents in the 1970s, in which the use of licit drugs preceded experimentation with cannabis, which preceded the use of hallucinogens and "pills", which in turn preceded the use of heroin and cocaine. Generally, the earlier the age of initiation into drug use, and the greater the involvement with any drug in the sequence, the greater the likelihood of progression to the next drug in the sequence.

The causal significance of these findings, and especially the role of cannabis in the sequence of illicit drug use, remains controversial. The hypothesis that the sequence of use represents a direct pharmacological effect of cannabis use upon the use of later drugs in the sequence is the least compelling. A more plausible and better supported explanation is that it reflects a combination of two processes: the selective recruitment into cannabis use of nonconforming and deviant adolescents who have a propensity to use illicit drugs; and the socialisation of cannabis users within an illicit drug using subculture which increases the exposure, opportunity, and encouragement to use other illicit drugs.

Although strong conclusions cannot be drawn, on the evidence from cross-sectional and longitudinal studies of cohorts of American adolescents in the 1970s and 1980s, there are suggestions that chronic heavy cannabis use can adversely affect adolescent development in a number of ways.

There has been suggestive support for the hypothesis that heavy adolescent use of cannabis impairs educational performance. In cross-sectional surveys, cannabis use is related to an increased risk of failing to complete a high school education, and of job instability in young adulthood. These relationships in cross-sectional studies are exaggerated because those who are most likely to use cannabis have lower pre-existing academic aspirations and high school performance than those who do not use it. When pre-existing academic aptitude and interest are taken into account, the relationship between cannabis use and educational and occupational performance is much more modest. Even though modest, the suggestive adverse effects of cannabis and other drug use upon educational performance are important because they may cascade throughout young adult life, affecting choice of occupation, level of income, choice of mate, and quality of life of the user and his or her children.

There is weaker but suggestive evidence that heavy cannabis use has adverse effects upon family formation, mental health, and involvement in drug-related (but not other types of) crime. In the case of each of these outcomes, the apparently strong associations revealed in cross-sectional data are much more modest in longitudinal studies, after statistically controlling for associations between cannabis use and other variables which predict these adverse outcomes.

On balance, there are sufficient indications that cannabis use in adolescence probably adversely affects adolescent development to conclude that it is desirable to discourage adolescent cannabis use, and especially regular cannabis use.

Adult adjustment

The evidence that chronic heavy cannabis use produces an amotivational syndrome among adults is equivocal. The positive evidence largely consists of case histories, and observational reports. The small number of controlled field and laboratory studies have not found compelling evidence for such a syndrome, although their evidential value is limited by the small sample sizes and limited sociodemographic characteristics of the field studies, and by the short periods of drug use, and the youthful good health and minimal demands made of the volunteers observed in the laboratory studies. If there is such a syndrome, it is a relatively rare occurrence, even among heavy, chronic cannabis users.

A dependence syndrome

A cannabis dependence syndrome like that defined in DSM-III-R probably occurs in heavy, chronic users of cannabis. There is good experimental evidence that chronic heavy cannabis users can develop tolerance to its subjective and cardiovascular effects, and there is suggestive evidence that some users may experience a withdrawal syndrome on the abrupt cessation of cannabis use. There is clinical and epidemiological evidence that some heavy cannabis users experience problems in controlling their cannabis use, and continue to use the drug despite experiencing adverse personal consequences of use. There is limited evidence in favour of a cannabis dependence syndrome analogous to the alcohol dependence syndrome. If the estimates of the community prevalence of drug dependence provided by the Epidemiologic Catchment Area study are correct, then cannabis dependence is the most common form of dependence on illicit drugs.

Recognition of the cannabis dependence syndrome has been delayed by a number of factors. First, heavy daily cannabis use has been relatively uncommon, and there have been few individuals who have requested assistance in stopping their cannabis use. Second, an overemphasis on evidence of tolerance and a withdrawal syndrome has hindered the recognition of the syndrome among individuals who have presented for treatment. Third, the occurrence of cannabis dependence has probably been overshadowed because it is most common among persons who are dependent on alcohol and opioids, forms of drug dependence which have understandably been given higher treatment priority.

Given the widespread use of cannabis, and its continued reputation as a drug free of the risk of dependence, the clinical features of cannabis dependence deserve to be better defined. This would enable the prevalence of a dependence syndrome to be better estimated and individuals who are dependent on cannabis to be better recognised and treated. Treatment should probably be on the same principles as other forms of dependence, although this issue is also in need of research.

Although cannabis dependence is likely to be a larger problem than previously thought, we should be wary of over-estimating its social and public health importance. Estimates of the risk of users becoming dependent suggest that it may be similar to that of alcohol, that it will be highest among the minority of daily cannabis users, and that even in this group the prevalence of drug-related problems may be relatively low by comparison with those of alcohol dependence. There is likely to be a high rate of remission of cannabis dependence without formal treatment. While acknowledging the existence of the syndrome, we should avoid exaggerating its prevalence and the severity of its adverse effects on individuals. Better research on the experiences of long-term cannabis users should provide more precise estimates of the risk.

Cognitive effects

The weight of the available evidence suggests that the long-term heavy use of cannabis does not produce any severe impairment of cognitive function. There is reasonable clinical and experimental evidence, however, that the long-term use of cannabis may produce more subtle cognitive impairment in the higher cognitive functions of memory, attention and organisation and integration of complex information. While subtle, these impairments may affect everyday functioning, particularly in adolescents with marginal educational aptitude, and among adults in occupations that require high levels of cognitive capacity. The evidence suggests that the longer the period that cannabis has been used, the more pronounced is the cognitive impairment. It remains to be seen whether the impairment can be reversed by an extended period of abstinence from cannabis.

There is a need for research to identify the specific cognitive functions affected by long-term cannabis use, to identify the precise mechanisms that produce impairment and to relate them to biological mechanisms, including the cannabinoid receptors and the endogenous cannabinoid, anandamide. Such research also needs to investigate individual differences in susceptibility to such effects, and the impact of long-term cannabis use on adolescents and young adults. Appropriate treatment programs for long-term dependent cannabis users will also need to address the subtle cognitive impairments likely to be found in this population.

Brain damage

A suspicion that chronic heavy cannabis use may cause gross structural brain damage was provoked by a single poorly controlled study using an outmoded method of investigation, which reported that cannabis users had enlarged cerebral ventricles. This finding was widely and uncritically publicised. Since then a number of better controlled studies using more sophisticated methods of investigation have consistently failed to demonstrate evidence of structural change in the brains of heavy, long-term cannabis users. These negative results are consistent with the evidence that any cognitive effects of chronic cannabis use are subtle, and hence unlikely to be manifest as gross structural changes in the brain. They do not exclude the possibility that chronic, heavy cannabis use may cause ultrastructural changes at the receptor level.

Psychotic disorders

There is suggestive evidence that heavy cannabis use can produce an acute toxic psychosis in which confusion, amnesia, delusions, hallucinations, anxiety, agitation and hypomanic symptoms predominate. The evidence for an acute toxic cannabis psychosis comes from laboratory studies of the effects of THC on normal volunteers and clinical observations of psychotic symptoms in heavy cannabis users which seem to resemble those of other toxic psychoses, and which remit rapidly following abstinence.

There is less support for the hypothesis that cannabis use can cause either an acute or a chronic functional psychosis which persists beyond the period of intoxication. Such a possibility is difficult to study because of the rarity of such psychoses, and the near impossibility of distinguishing them from schizophrenia and manic depressive psychoses occurring in individuals who also abuse cannabis.

There is strongly suggestive evidence that chronic cannabis use may precipitate a latent psychosis in vulnerable individuals. This is only strongly suggestive because in the best study conducted to date, the use of cannabis was not documented at the time of diagnosis, there was a possibility that cannabis use was confounded by amphetamine use, and there are doubts about whether the study could reliably distinguish between schizophrenia and acute cannabis-induced, or other drug-induced, psychoses. Even if this relationship is causal, its public health significance should not be overstated: the estimated attributable risk of cannabis use is small (less than 10 per cent), and even this seems an overestimate, since the incidence of schizophrenia declined over the period when cannabis use increased among young adults.

Therapeutic effects of cannabinoids

There is reasonable evidence that THC is an effective anti-emetic agent for patients undergoing cancer chemotherapy, especially those whose nausea has proven resistant to the anti-emetic drugs that were widely used in the late 1970s and early 1980s, when most of the research was conducted. It is uncertain whether THC is as effective as newer anti-emetic drugs. Uncertainty also exists about the most optimal method of dosing and the advantages and disadvantages of different routes of administration. Nonetheless, there is probably sufficient evidence to justify THC being made available in synthetic form to cancer patients whose nausea has proven resistant to conventional treatment.

There is also reasonable evidence for the potential efficacy of THC and marijuana in the treatment of glaucoma, especially in cases which have proved resistant to existing anti-glaucoma agents. Further research is required to establish the effectiveness and safety of long-term use, but this should not prevent its use under medical supervision in individuals with poorly controlled glaucoma.

There is sufficient suggestive evidence of the potential usefulness of various cannabinoids as anti-spasmodic, and anti-convulsant agents to warrant further clinical research into their effectiveness. There are other potential therapeutic uses which require more basic pharmacological and experimental investigation, e.g. cannabinoids as possible analgesic and anti-asthma agents.

There is a need for further research into the effectiveness of cannabis and its derivatives in assisting patients with HIV/AIDS-related conditions, and in particular, their value in counteracting weight loss associated with these conditions, improving mood and easing pain. Case reports have suggested that synthetic THC may be effective in reducing nausea and stimulating appetite in symptomatic AIDS patients. While there is a potential concern that possible effects of cannabinoids on the immune system may have more serious consequences for HIV positive individuals and AIDS patients, a recent study has failed to find a relationship between the use of cannabis, or any other psychoactive drugs, and the rate at which HIV positive people progress to clinical AIDS.

Despite the basic and clinical research work which was undertaken in late 1970s and early 1980s, the cannabinoids have not been widely used therapeutically, nor has further investigation been conducted along the lines suggested by the Institute of Medicine in 1982. This seems attributable to the fact that, in the United States, where most cannabis research has been conducted, clinical research on cannabinoids has been discouraged by regulation and a lack of funding. The discouragement of clinical cannabis research, in turn, derives from the fact that THC, the most therapeutically effective cannabinoid, is the one that produces the psychoactive effects sought by recreational users. An unreasonable fear that the therapeutic use of THC would send "mixed messages" to youth has motivated the discouragement of research into the therapeutic effects of cannabinoids.

The recent discovery of a specific cannabinoid receptor and the endogenous cannabinoid-like substance anandamide may change this situation by encouraging more basic research on the biology of cannabinoids which may have therapeutic consequences. It may prove possible to separate the psychoactive and therapeutic effects of cannabis, fulfilling the ancient promise of "marijuana as medicine".

Overall appraisal of the health and psychological risks of cannabis use

The following is a summary of the major adverse health and psychological effects of acute and chronic cannabis use, classified by the degree of confidence about the relationship between cannabis use and the adverse effect.

Acute effects

The major acute adverse psychological and health effects of cannabis intoxication are:

• anxiety, dysphoria, panic and paranoia, especially in naive users;

• cognitive impairment, especially of attention and memory;

• psychomotor impairment, and possibly an increased risk of accident if an intoxicated person attempts to drive a motor vehicle;

• an increased risk of experiencing psychotic symptoms among those who are vulnerable because of personal or family history of psychosis; and

• an increased risk of low birth weight babies if cannabis is used during pregnancy.

Chronic effects

The major health and psychological effects of chronic heavy cannabis use, especially daily use, over many years, remain uncertain. On the available evidence, the major probable adverse effects appear to be:

• respiratory diseases associated with smoking as the method of administration, such as chronic bronchitis, and the occurrence of histopathological changes that may be precursors to the development of malignancy;

• development of a cannabis dependence syndrome, characterised by an inability to abstain from or to control cannabis use; and

• subtle forms of cognitive impairment, most particularly of attention and memory, which persist while the user remains chronically intoxicated, and may or may not be reversible after prolonged abstinence from cannabis.

The following are the major possible adverse effects of chronic, heavy cannabis use which remain to be confirmed by further research:

• an increased risk of developing cancers of the aerodigestive tract, i.e. oral cavity, pharynx, and oesophagus;

• an increased risk of leukemia among offspring exposed in utero;

• a decline in occupational performance marked by underachievement in adults in occupations requiring high level cognitive skills, and impaired educational attainment in adolescents; and

• birth defects occurring among children of women who used cannabis during their pregnancies.

High risk groups

A number of groups can be identified as being at increased risk of experiencing some of these adverse effects.

Adolescents

• Adolescents with a history of poor school performance may have their educational achievement further limited by the cognitive impairments produced by chronic intoxication with cannabis.

• Adolescents who initiate cannabis use in the early teens are at higher risk of progressing to heavy cannabis use and other illicit drug use, and to the development of dependence on cannabis.

Women of childbearing age

• Pregnant women who continue to smoke cannabis are probably at increased risk of giving birth to low birth weight babies, and perhaps of shortening their period of gestation.

• Women of childbearing age who smoke cannabis at the time of conception or while pregnant possibly increase the risk of their children being born with birth defects.

Persons with pre-existing diseases

Persons with a number of pre-existing diseases who smoke cannabis are probably at an increased risk of precipitating or exacerbating symptoms of their diseases. These include:

• individuals with cardiovascular diseases, such as coronary artery disease, cerebrovascular disease and hypertension;

• individuals with respiratory diseases, such as asthma, bronchitis and emphysema;

• individuals with schizophrenia who are at increased risk of precipitating or of exacerbating schizophrenic symptoms; and

• individuals who are dependent on alcohol and other drugs, who are probably at an increased risk of developing dependence on cannabis.

Two special concerns

Storage of THC

There is good evidence that with repeated dosing of cannabis at frequent intervals, THC can accumulate in fatty tissues in the human body where it may remain for considerable periods of time. The health significance of this fact is unclear. The storage of cannabinoids would be serious cause for concern if THC were a highly toxic substance which remained physiologically active while stored in body fat. The evidence that THC is a highly toxic substance is weak and its degree of activity while stored has not been investigated. One potential health implication of THC storage is that stored cannabinoids could be released into blood, producing a "flashback", although this is likely to be a very rare event, if it occurs at all. Whatever the uncertainties about health implications of THC storage, all potential users of cannabis should be aware that it occurs.

Increases in the potency of cannabis?

It has been claimed that the existing medical literature on the health effects of cannabis underestimates its adverse effects, because it was based upon research conducted on less potent forms of marijuana than became available in the USA in the past decade. This claim has been repeated and interpreted in an alarmist fashion in the popular media on the assumption that an increase in the THC potency of cannabis necessarily means a substantial increase in the health risks of cannabis use.

It is far from established that the average THC potency of cannabis products has substantially increased over recent decades. If potency has increased, it is even less certain that the average health risks of cannabis use have materially changed as a consequence, since users may titrate their dose to achieve the desired effects. Even if the users are inefficient in titrating their dose of THC, it is not clear that the probability of all adverse health effects will be thereby increased. Given the existence of these concerns about THC potency, it would be preferable to conduct some research on the issue rather than to rely upon inferences about the likely effects of increased cannabis potency. Studies of the ability of experienced users to titrate their dose of THC would contribute to an evaluation of this issue.

A comparative appraisal of health risks: alcohol, tobacco and cannabis use

The probable and possible adverse health and psychological effects of cannabis need to be placed in comparative perspective to be fully appreciated. A useful standard for such a comparison is what is known about the health effects of alcohol and tobacco, two other widely used psychoactive drugs. Cannabis shares with tobacco, smoking as the usual route of administration, and resembles alcohol in being used for its intoxicating and euphoriant effects. Although allowance has to be made for the very different prevalence of use of the two drugs, and for the fact that we know a great deal more about the adverse effects of alcohol and tobacco use, the comparison serves the useful purpose of reminding us of the risks we currently tolerate with our favourite psychoactive drugs.

Acute effects

Alcohol. The major risks of acute cannabis use are similar to the acute risks of alcohol intoxication in a number of respects. First, both drugs produce psychomotor and cognitive impairment, especially of memory and planning. The impairment produced by alcohol increases risks of various kinds of accident, and the likelihood of engaging in risky behaviour, such as dangerous driving, and unsafe sexual practices. It remains to be determined whether cannabis intoxication produces similar increases in accidental injury and death, although on the balance of probability it does.

Second, there is good evidence that substantial doses of alcohol taken during the first trimester of pregnancy can produce a foetal alcohol syndrome. There is suggestive but far from conclusive evidence that cannabis used during pregnancy may have similar adverse effects.

Third, there is a major health risk of acute alcohol use that is not shared with cannabis. In large doses alcohol can cause death by asphyxiation, alcohol poisoning, cardiomyopathy and cardiac infarct, whereas there are no recorded cases of fatalities attributable to cannabis.

Tobacco. The major acute health risks that cannabis share with tobacco are the irritant effects of smoke upon the respiratory system, and the stimulating effects of both THC and nicotine on the cardiovascular system, both of which can be detrimental to persons with cardiovascular disease.

Chronic effects

Alcohol. There are a number of risks of heavy chronic alcohol use, some of which may be shared by chronic cannabis use. First, heavy use of either drug increases the risk of developing a dependence syndrome in which users experience difficulty in stopping or controlling their use. There is strong evidence for such a syndrome in the case of alcohol and reasonable evidence in the case of cannabis. A major difference between the two is that it is uncertain whether a withdrawal syndrome reliably occurs after dependent cannabis users abruptly stop their cannabis use, whereas the abrupt cessation of alcohol use in severely dependent drinkers produces a well defined withdrawal syndrome which can be potentially fatal.

Second, there is reasonable clinical evidence that the chronic heavy use of alcohol can produce psychotic symptoms and psychoses in some individuals. There is suggestive evidence that chronic heavy cannabis use may produce a toxic psychosis, precipitate psychotic illnesses in predisposed individuals, and exacerbate psychotic symptoms in individuals with schizophrenia.

Third, there is good evidence that chronic heavy alcohol use can indirectly cause brain injury - the Wernicke-Korsakov syndrome - with symptoms of severe memory defect and an impaired ability to plan and organise. With continued heavy drinking, and in the absence of vitamin supplementation, this injury may produce severe irreversible cognitive impairment. There is good reason for concluding that chronic cannabis use does not produce cognitive impairment of comparable severity. There is suggestive evidence that chronic cannabis use may produce subtle defects in cognitive functioning, that may or may not be reversible after abstinence.

Fourth, there is reasonable evidence that chronic heavy alcohol use produces impaired occupational performance in adults, and lowered educational achievements in adolescents. There is at most suggestive evidence that chronic heavy cannabis use produces similar, albeit more subtle impairments in occupational and educational performance of adults.

Fifth, there is good evidence that chronic, heavy alcohol use increases the risk of premature mortality from accidents, suicide and violence. There is no comparable evidence for chronic cannabis use, although it is likely that dependent cannabis users who frequently drive while intoxicated with cannabis increase their risk of accidental injury or death.

Sixth, alcohol use has been accepted as a contributory cause of cancer of the oropharangeal organs in men and women. There is suggestive evidence that chronic cannabis smoking may also be a contributory cause of cancers of the aerodigestive tract (i.e. the mouth, tongue, throat, oesophagus, lungs).

Tobacco. The major adverse health effects shared by chronic cannabis and tobacco smokers are chronic respiratory diseases, such as chronic bronchitis, and probably, cancers of the aerodigestive tract. The increased risk of cancer in the respiratory tract is a consequence of the shared route of administration by smoking. It is possible that chronic cannabis smoking also shares the cardiotoxic properties of tobacco smoking, although this possibility remains to be investigated.

Implications for harm reduction

Anyone who wishes to avoid the probable acute and chronic adverse health effects of cannabis should abstain from using the drug. This advice is especially pertinent for persons with any of the diseases (e.g. cardiovascular) or conditions (e.g. pregnancy) which would make them more vulnerable to the adverse effects of cannabis.

Current cannabis users should be aware of the following risks of using the drug. First, the risk of being involved in a motor vehicle accident is likely to be increased when cannabis users drive while intoxicated by cannabis. The combination of alcohol and cannabis intoxication will substantially increase this risk. Second, the chronic smoking of cannabis poses significant risks to the respiratory system, apart from any specific effects of THC. Third, the respiratory risks of cannabis smoking are amplified if deep inhalation and breath-holding are used to maximise the absorption of THC in the lungs. This technique greatly increases the delivery and retention of particulate matter and tar. Fourth, daily or near daily use of cannabis is to be avoided, as it has a high risk of producing dependence.

2. Introduction

This review of the literature on the health and psychological effects of cannabis was undertaken at the initiative of the former Federal Justice Minister, Senator Michael Tate, who requested a review of knowledge relating to cannabis, to inform policy decisions. At Senator Tate's urging, a National Task Force on Cannabis was established on 25 May 1992. The Task Force commissioned this review of the evidence on the health and psychological effects of cannabis use. A new and independent review was thought necessary because there has not been any major international review of the literature on the health and psychological effects of cannabis since 1981, when the Addiction Research Foundation and World Health Organization jointly reviewed the literature. The purpose of this review was to update the conclusions of earlier reviews in the light of research undertaken during the past decade (ARF/WHO, 1981; Fehr and Kalant, 1983).

2.1 Our approach to the literature

Our review of the literature was not intended to be, and could not hope to be, as comprehensive as the major review undertaken by the Addiction Research Foundation and the World Health Organization. The literature is too large, and the diversity of relevant disciplines represented in it beyond the expertise we had available for the task. Unavoidably, we have relied upon published expert opinion in the very many areas which lie outside the authors' collective expertise, which is primarily in epidemiology, psychopharmacology, neurophysiology and neuropsychology. This fact is inevitably reflected in the relative attention given to the literatures that lie within and beyond our expertise. The literatures on the psychological consequences of acute and chronic cannabis use, for example, are much more comprehensively and critically reviewed than those pertaining to effects on the reproductive and immune systems. In reviewing the literature that lies outside our expertise, we have relied upon the consensus views expressed in the literature by experts in the relevant fields. When there has been controversy between the experts we have explicitly acknowledged it. We have checked our understanding and representation of these expert views by asking Australian and international researchers with expertise in the relevant fields to critically review what we have written.

3. Evidential principles

3.1 Issues in appraising health hazards

The evaluation of the health hazards of any drug is difficult for a variety of scientific and sociopolitical reasons. First, causal inferences about the effects of drugs on human health are not easy to make (ARF/WHO, 1981). Even inferences about the relatively direct and transient effects of acute drug use may be complicated by individual variability in response to a standard dose of a drug, and by the fact that serious adverse effects are relatively rare. Inference becomes more difficult the longer the interval between use and alleged ill effects: it takes time for such effects to develop, and it may take considerably longer for the research technology to be developed that enables these effects to be identified and confidently attributed to the drug use rather than some other factor (Institute of Medicine, 1982). In the case of chronic tobacco use, for example, it has taken over three hundred years to discover that it increases premature mortality from cancer, and heart disease. Moreover, new health hazards of tobacco use, such as passive smoking, continue to be discovered.

Second, in making causal inferences about drug use and its consequences there is a tension between the rigour and relevance of the evidence. The most rigorous evidence is provided by laboratory investigations using experimental animals, or in vitro preparations of animal cells and micro-organisms in which well controlled drug doses are related to precisely measured biological outcomes. The relevance of such research to human disease, however, is often problematic. A great many inferences have to be made in linking the occurrence of specific biological effects in laboratory animals or cell cultures to the likely effects of the drug under existing patterns of human use.

Epidemiological studies of relationships between drug use and human disease have manifestly greater relevance to the appraisal of the health risks of human drug use, but this is purchased at the price of reduced rigour. Doses of drugs over periods of years are difficult to quantify in the best of circumstances. The vagaries of human memory which make quantification of consumption difficult in the case of tobacco and alcohol are magnified in the case of illicit drugs by the non-standard doses and contaminants in blackmarket drugs, and the reluctance of users to report illicit drug use. The fact that different patterns of drug use and other life-style factors are often correlated (e.g. alcohol and tobacco), makes attribution of ill-effects to particular drugs even more difficult (Task Force on Health Risk Assessment, 1986).

Third, appraisals of the hazards of recreational drug use are unavoidably affected by the societal approval or disapproval of the drug in question. As Room (1984) has observed, when evaluating the impact of alcohol on non-industrialised societies, anthropologists have often engaged in problem deflation in response to the problem inflation of missionaries and colonial authorities. In our own culture, the economic interests of tobacco and alcohol industries provide a potent reason for problem deflation with these drugs. Such problem deflationists often discount the adverse effects of alcohol use, either by contesting the evidence for adverse effects, or by denying that there is a causal connection between alcohol use and particular adverse health effects.

Similar processes have been at work in the appraisal of the health effects of recreational cannabis use. The countercultural symbolism of cannabis use in the late 1960s has introduced a strong sociopolitical dimension to the debate about the adverse health effects of cannabis. Politically conservative opponents of cannabis use, for example, justify its continued prohibition by citing evidence of the personal and social harms of its use. When the evidence is uncertain, as it is with many of the alleged effects of chronic use, they resolve the uncertainty by assuming that the cannabis is unsafe until proven safe. Complementary behaviour is exhibited by some proponents of decriminalisation. Evidence of harm is discounted or discredited, and uncertainties about the ill-effects of chronic cannabis use are resolved by demanding more and better evidence, arguing that until this uncertainty is resolved individuals should be allowed to exercise their free choice about whether or not they use the drug.

Such approaches to the appraisal of evidence have not always been consistently applied. Both sides of the debate would reject the application of their own approaches to the appraisal of cannabis to the appraisal of the health hazards of alcohol, pesticides, herbicides, or chemical residues in food. While we do not claim to be unaffected by these processes, we will be as explicit as possible about the evidential standards that we have used, and as even-handed as we can in their application.

3.2 Evidential desiderata

The following issues must be addressed in specifying what we have taken to be the evidential desiderata in our appraisal of the health risk of cannabis use: the burden of proof; standard of proof; criteria for causal inference; preference for relevance or rigour; approaches to estimating the magnitude of risk; and the desirability of a comparative appraisal of the risks.

The burden of proof concerns who bears the responsibility for making a case; those who make a claim of adverse health effects, or those who doubt it (see Rescher, 1977, chapter XII). Who bears the burden of proof determines the way in which an issue is decided in the face of uncertainty: if the burden falls on those who claim that the drug is safe, uncertainty will be resolved by assuming that it is unsafe until proved otherwise; conversely, if the burden falls on those who claim that the drug is unsafe, then it will be assumed to be safe until proven otherwise.

It is by no means agreed who bears the burden of proof in the debate about the health effects of cannabis use. Proponents of continued prohibition appeal to established practice (Whately, 1846), arguing that since the drug is illegal, the burden of proof falls upon those who want to legalise it. Some proponents of its legalisation counter that this begs the question, since there was no evidence, they argue, that cannabis was harmful when its use was first made a criminal offence. Others argue that the burden of proof falls upon those who wish to use the criminal law to prevent adults from freely choosing to use a drug (e.g. Husak, 1992).

We will vary the burden of proof on the basis of the state of the evidence and argument. Once a prima facie case of harm has been made, positive evidence of safety will be required rather than the simple absence of any evidence of ill effect. We will assume that a prima facie case has been made either when there is direct evidence that the drug has ill effects in animals or humans (e.g. from a case-control study), or when there is some compelling argument that it could, e.g. the inference that since tobacco smoking causes lung cancer and cannabis and tobacco smoke are similar in their constituents, it is probable that heavy cannabis smoking also causes lung cancer.

The standard of proof reflects the degree of confidence required in an inference that there is a causal connection between drug use and harm. In courts of law, the standard of proof demanded depends upon the seriousness of the offence at issue and the consequences of a verdict, with a higher standard of proof, "beyond reasonable doubt", being demanded in criminal cases, while the "balance of probabilities" is acceptable in civil cases. Although these legal standards are not directly translatable into scientific practice, scientists generally require something closer to the standard of "beyond reasonable doubt" than the balance of probabilities before drawing confident conclusions that a drug causes harm.

If we were to demand that such a standard be met for the health effects of cannabis, this review would be exceedingly brief. Consequently, we will relax the criteria and indicate when the evidence permits a causal inference to be made on the balance of probabilities. We will take this standard to be exemplified in the consensus of informed scientific opinion that sufficient evidence has been provided to infer a probable causal connection between drug use and a harm (e.g. Fehr and Kalant, 1983; Institute of Medicine, 1982).

In the trade-off between relevance and rigour, our preference will be for human evidence, both experimental and epidemiological, rather than animal and in vitro studies. In the absence of human evidence, in vitro and animal experiments will be taken as raising a suspicion that drug use has an adverse effects on human health. The degree of suspicion raised will be in proportion to the number of such animal studies, the consistency of their results across different species and experimental preparations (Task Force on Health Risk Assessment, 1986), and the degree of expert consensus that the inferences from effects in vitro and in vivo to adverse effects under existing patterns of human use are valid. The degree of consensus on the latter point will be indicated by the views expressed in authoritative reviews in peer reviewed journals or contributions to international consensus conferences (e.g. Fehr and Kalant, 1983; Institute of Medicine, 1982).

The criteria for causal inference that we will use are standard ones (see Hall, 1987), namely:

1. Evidence that there is a relationship between drug use and a health outcome provided by one of the accepted types of epidemiological research design (namely, case-control, cross-sectional, cohort, or experiment).

2. Evidence (usually provided by a statistical significance test or the construction of a confidence interval) that the relationship is unlikely to be due to chance.

3. Good evidence that drug use precedes the adverse effect (e.g. a cohort study).

4. Evidence either from experiment, or statistical or other form of control, which makes it unlikely that the relationship is due to some other variable which is related to both drug use and the adverse effect.

In appraising a body of literature as a whole we determine the extent to which the evidence meets the criteria outlined by Hill (1977).

Ideally, once a strong case has been made for a causal connection between drug use and an adverse health effect, the magnitude of risk needs to be estimated so the seriousness of the risk can be quantified. For example, the consumption of large amounts of water over a short period of time can kill human beings, but this is not a good reason for counselling people against drinking water. The quantities required to produce intoxication and death are so large (e.g. 30 or more litres) that only diseased or psychotic individuals consume them.

The standard epidemiological measures of risk magnitude are relative risk and population attributable risk. The relative risk is the increase in the odds of experiencing an adverse health outcome among those who use the drug compared to those who do not (that is, the number of times greater the risk of experiencing an effect is among those who use the drug compared with those who do not). The population attributable risk represents that proportion of cases with an adverse outcome which is attributable to drug use. The two measures of risk magnitude have different uses and implications. Relative risk is of greatest relevance to individuals attempting to estimate the increase in their risk of experiencing an adverse outcome if they use a drug. Attributable risk is of most relevance to a societal appraisal of the harms of drug use.

The importance of the two measures of risk magnitude depends upon the prevalence of drug use and the base rate of the adverse outcome. An exposure with a low relative risk may have a large public health impact if a large proportion of the population is exposed (e.g. cigarette smoking and heart disease). Conversely, an exposure with a high relative risk may have little public health importance because very few people are exposed to it. Accordingly, an appraisal of the public health importance of illicit drug use must take some account not only of the relative risk of harm, but also the prevalence of use and the base rate of the adverse effect. As will become apparent in the course of this review, it is very difficult to estimate either relative or attributable risk of any probable adverse health effects of cannabis use because few epidemiological studies have been conducted.

A different way of assessing the health risk posed by cannabis use has had to be used: a comparative qualitative appraisal of its risks with those of other widely used recreational drugs such as alcohol and tobacco (ARF/WHO, 1981). The motive for such comparisons is that they reduce the operation of double-standards in the health appraisal of drug use by reminding us that the drugs we currently tolerate pose major health risks. They also help to put the risk of newer drugs into perspective, so that we can use a common standard when making societal decisions about whether or not to tolerate such drug use. The task of comparison, however, is more difficult than it seems at first.

First, we know much more about the quantitative risks of acute and chronic tobacco and alcohol use than we know about the health risks of currently illicit drugs. This is largely because the legal drugs have been consumed by substantial proportions of the population, over centuries in the case of tobacco, and millennia in the case of alcohol, and there have been more than 40 years of scientific studies of the health consequences of their use. The contemporary illicit drugs, by contrast, have been much less widely used in Western society, and for a shorter period, primarily by healthy young adults; there have also been few studies of their adverse health effects, and there have been even fewer attempts to quantify the risks of their use.

Second, the prevalence of use of currently legal and illegal drugs is so different that any comparison based upon existing patterns of use will disadvantage the legal drugs (Peterson, 1980). In principle, this problem could be addressed by estimating what the health risks of cannabis use might be if its prevalence was to approach that of alcohol and tobacco. This approach has not been adopted here because in the absence of good data on the quantitative risks of cannabis use, a large number of contestable assumptions would have to be made to permit such estimates to be made.

These obstacles provide strong reasons for cautiously interpreting comparisons of the health hazards of cannabis with those of alcohol and tobacco. They do not, however, provide insurmountable objections to such comparisons. We will accordingly make some qualitative comparisons with the health risks of alcohol and tobacco after we have considered the evidence on the adverse health effects of cannabis.

References

Addiction Research Foundation/World Health Organization (1981) Report of an ARF/WHO Scientific Meeting on the Adverse Health and Behavioral Consequences of Cannabis Use. Toronto: Addiction Research Foundation, .

Fehr, K.O. and Kalant, H. (1983) (eds) Cannabis and Health Hazards. Toronto: Addiction Research Foundation.

Hall, W. (1987) A simplified logic of causal inference. Australian and New Zealand Journal of Psychiatry, 1987, 21, 507-513.

Hill, A.B. (1977). A Short Textbook of Statistics. London: Hodder and Stoughton.

Husak, D.N. (1992) Drugs and Rights. Cambridge: Cambridge University Press.

Institute of Medicine. (1982) Marijuana and Health. Washington DC: National Academy Press.

Peterson, R (1980) (ed) Marijuana Research Findings: 1980 National Institute on Drug Abuse Research Monograph Number 31. Rockville, MD: U.S. Department of Health and Human Services.

Rescher, N. (1977) Methodological Pragmatism. Oxford, Blackwell.

Room, R. (1984) Alcohol and ethnography: A case of problem deflation? Current Anthropology, 25, 169- 191.

Task Force on Health Risk Assessment, United States Department of Health and Human Services (1986) Determining Risks to Health: Federal Policy and Practice. Dover, MA: Auburn House Publishing Company.

Whately, R. (1846) Elements of Rhetoric. Originally published 1846. (ed) D. Ehninger. Carnondale, Illinois: Illinois University Press, 1963.

4. Cannabis the drug

4.1 Cannabis the drug

Cannabis is the material derived from the herbaceous plant Cannabis sativa, which grows vigorously throughout many regions of the world. It occurs in male and female forms, with both sexes having large leaves which consist of five to 11 leaflets with serrated margins. A sticky resin which covers the flowering tops and upper leaves is secreted most abundantly by the female plant and this resin contains the active agents of the plant. While the cannabis plant contains more than 60 cannabinoid compounds, such as cannabidiol and cannabinol, the primary psychoactive constituent is delta-9-tetrahydrocannabinol or THC (Gaoni and Mechoulam, 1964), the concentration of which largely determines the potency of the cannabis preparation. Most of the other cannabinoids are either inactive or only weakly active, although they may increase or decrease potency by interacting with THC (Abood and Martin, 1992).

Cannabis has been erroneously classified as a narcotic, as a sedative and most recently as an hallucinogen. While the cannabinoids do possess hallucinogenic properties, together with stimulant and sedative effects, they in fact represent a unique pharmacological class of compounds. Unlike many other drugs of abuse, cannabis acts upon specific receptors in the brain and periphery. The discovery of the receptors and the naturally occurring substances in the brain that bind to these receptors is of great importance, in that it signifies an entirely new pathway system in the brain.

4.2 The cannabinoid receptor

The desire to identify a specific biochemical pathway responsible for the expression of the psychoactive effects of cannabis has prompted a prodigious amount of cannabinoid research (Martin, 1986). Early studies found that radioactively labelled THC would non-specifically attach to all neural surfaces, suggesting that it produced its effects by perturbing cell membranes (Martin, 1986). However, the work of Howlett and colleagues (Howlett et al 1986; 1987; 1988) showed that cannabinoids inhibit the enzyme that synthesizes cyclic AMP in cultured nerve cells, and that the degree of inhibition was correlated with the potency of the cannabinoid. Since many receptors relay their signals to the cell interior by changing cellular cyclic AMP, this finding strongly suggested that cannabinoids were not just dissolving non-specifically in membranes. After eliminating all the known receptors that act by inhibiting adenylate cyclase, it was concluded that cannabinoids acted through their own receptor. The determination and characterisation of a specific cannabinoid receptor in brain followed soon after (Devane et al, 1988), paving the way for its distribution in brain to be mapped (Bidaut-Russell et al, 1990; Herkenham et al, 1990).

It is now accepted that cannabis acts on specific cannabinoid receptors in the brain, conclusive evidence for which was provided by the cloning of the gene for the cannabinoid receptor in rat brain (Matsuda et al, 1990). A cDNA which encodes the human cannabinoid receptor was also cloned (Gerard et al, 1991) and the human receptor was found to exhibit more than 97 per cent identity with the rat receptor. Cannabinoid receptors have also been found in the nervous system of lower vertebrates, including chickens, turtles and trout (Howlett et al, 1990) and there is preliminary evidence that they exist in low concentration in fruit flies (Bonner quoted in Abbott, 1990; Howlett, Evans and Houston, 1992). This phylogenetic distribution suggests that the gene must have been present early in evolution, and its conservation implies that the receptor serves an important biological function.

The localisation of cannabinoid receptors in the brain has elucidated the pharmacology of the cannabinoids. Herkenham and colleagues (Herkenham, et al 1990; 1991a; 1991b; 1992) used autoradiography to localise receptors in fresh cut brain sections of a number of species, including humans. Dense binding was detected in the cerebral cortex, hippocampus, cerebellum and in outflow nuclei of the basal ganglia, particularly the substantia nigra pars reticulata and globus pallidus. Few receptors were present in the brainstem and spinal cord. Bidaut-Russell and colleagues (Bidaut-Russell et al, 1990) located cannabinoid receptors in greatest abundance in the rat cortex, cerebellum, hippocampus and striatum, with smaller but significant binding in the hypothalamus, brainstem and spinal cord.

High densities of receptors in the hippocampus and cortex suggest roles for the cannabinoid receptor in cognitive functions. This is consistent with evidence in humans that the dominant effects of cannabis are cognitive: loosening of associations, fragmentation of thought, and confusion on attempting to remember recent occurrences (Hollister, 1986; Miller and Branconnier, 1983). High densities of receptors in the basal ganglia and cerebellum suggested a role for the cannabinoid receptor in movement control, a finding which is also consistent with the ability of cannabinoids to interfere with coordinated movements.

Cannabis has a mild effect on cardiovascular and respiratory function in humans (Hollister, 1986) which is consistent with the observation that the lower brainstem area has few cannabinoid receptors. The absence of sites in the lower brainstem may in fact explain why high doses of THC are not lethal. Cannabinoid receptors do not appear to reside in the dopaminergic neurons or the mesolimbic dopamine cells that have been suggested as a possible "reward" system in the brain.

These mappings of receptors have been broadly confirmed in recent work by Matsuda and colleagues (1992, 1993) using a histochemistry technique to neuroanatomically localise cannabinoid receptor mRNA. Labelling intensities were highest in forebrain regions (olfactory areas, caudate nucleus, hippocampus) and in the cerebellar cortex. Clear labelling observed in the rat forebrain suggests several potential sites in the human brain that could mediate an impairment of memory function (Miller and Branconnier, 1983), such as the hippocampus, medial septal complex, lateral nucleus of the mamillary body, and the amygdaloid complex. Similarly, labelling was detected clearly in rat forebrain regions that correspond to those that could mediate cannabis-induced effects on human appetite and mood (namely, the hypothalamus, amygdaloid complex, and anterior cingulate cortex). It should be borne in mind that the regions where cannabinoid receptors occur may have long projections to other areas, contributing to the multiplicity of effects of the cannabinoids.

Since THC is not a naturally occurring substance within the brain, the existence of a cannabinoid receptor implied the existence of a naturally occurring or "endogenous" cannabinoid-like substance. Devane and colleagues (1992) recently identified a brain molecule which binds to the receptor and mimics the action of cannabinoids. The molecule, arachidonylethanolamide, which is fat soluble like THC, has been named "anandamide" from a Sanskrit word meaning "bliss". Anandamide has been found to act on cells that express the cannabinoid receptor, but it has no effect on identical cells which lack the receptor. Further research is necessary to determine which neurons are responsible for producing anandamide molecules and to determine what their role is.

The unique psychoactivity of cannabinoids may be described as a composite of numerous effects which would not arise from a single biochemical alteration, but rather from multiple actions (Martin, 1986). Thus, the diverse pharmacological actions of the various cannabinoids implies the existence of receptor subtypes. Cannabinoid receptor cDNA can be used to search for other members of the hypothesised receptor family (Snyder, 1990). If the receptors with the potential for mediating the therapeutic uses of cannabis are different from those responsible for their psychoactive effects, cannabinoid receptor cDNA cloning and new synthetic cannabinoids modelled on anandamide may help to uncover the receptor subtypes and develop drugs to target them, thus fulfilling the ancient promise of "marijuana as medicine". If, however, it were the case that there was only one type of cannabinoid receptor, then the psychoactive and therapeutic effects would be inseparable. The evidence against this proposition mounts with the recent cloning of a cannabinoid receptor in spleen that does not exist in brain (Munro et al, 1993).

4.3 Forms of cannabis

The concentration of THC varies with the forms in which cannabis is prepared for ingestion, the most common of which are marijuana, hashish and hash oil. Marijuana is prepared from the dried flowering tops and leaves of the harvested plant. Its potency depends upon the growing conditions, the genetic characteristics of the plant and the proportions of plant matter. The flowering tops and bracts (known as "heads") are highest in THC concentration, with potency descending through the upper leaves, lower leaves, stems and seeds. Some varieties of the cannabis plant contain little or no THC, such as the hemp varieties used for making rope, while others have been specifically cultivated for their high THC content, such as "sinsemilla".

Marijuana may range in colour from green to grey or brown, depending on the variety and where it was grown, and in texture from a dry powder or finely divided tea-like substance to a dry leafy material. The concentration of THC in a batch of marijuana containing mostly leaves and stems may range from 0.5-5 per cent, while the "sinsemilla" variety with "heads" may result in concentrations from 7-14 per cent. The potency of marijuana preparations being sold has probably increased in the past decade (Jones, 1987), although the evidence for this has been contested (Mikuriya and Aldrich, 1988).

Hashish or hash consists of dried cannabis resin and compressed flowers. It ranges in colour from light blonde/brown to almost black, and is usually sold in the form of hard chunks or cubes. The concentration of THC in hashish generally ranges from 2-8 per cent, although it can be as high as 10-20 per cent. Hash oil is a highly potent and viscous substance obtained by using an organic solvent to extract THC from hashish (or marijuana), concentrating the filtered extract, and, in some cases, subjecting it to further purification. The colour may range from clear to pale yellow/green, through brown to black. The concentration of the THC in hash oil is generally between 15 per cent and 50 per cent, although samples as high as 70 per cent have been detected.

4.4 Routes of administration

Almost all possible routes of administration have been used, but by far the most common method is smoking (inhaling). Marijuana is most often smoked as a hand-rolled "joint" the size of a cigarette or larger, and usually thicker. Tobacco is often added to marijuana to assist burning and "make it go further", and a filter may be inserted. Hashish may be mixed with tobacco and smoked as a joint, but is more often smoked through a pipe, either with or without tobacco. A water pipe known as "bong" is a popular implement for all cannabis preparations, because the water cools the hot smoke before it is inhaled and there is little loss of the drug through sidestream smoke. Hash oil is used sparingly because of its extremely high psychoactive potency; a few drops may be applied to a cigarette or a joint, to the mixture in the pipe, or the oil may be heated and the vapours inhaled. Whatever method is used, smokers usually inhale deeply and hold their breath for several seconds in order to ensure maximum absorption of THC by the lungs.

Hashish may also be cooked or baked in foods and eaten. When ingested orally the onset of the psychoactive effects is delayed by about an hour. In clinical and experimental research, THC has often been prepared in gelatine capsules and administered orally. In India, a popular method of ingestion is in the form of a tea-like brew of the leaves and stems, known as "bhang". The "high" is of lesser intensity but the duration of intoxication is longer by several hours. It is easier to titrate the dose and achieve the desired level of intoxication by smoking than by oral ingestion since the effects are more immediate.

Crude aqueous extracts of cannabis have on very rare occasions been injected intravenously. THC is insoluble in water, so little or no drug is actually present in these extracts, and the injection of tiny undissolved particles may cause severe pain and inflammation at the site of injection and a variety of toxic systemic effects. Injection should not be considered as a route of cannabis administration, but has been used in research to investigate pharmacokinetics.

Since different routes of administration give rise to differing pharmacokinetics (see below), the reader should assume for the remainder of this document that the method of ingestion is smoking unless stated otherwise.

4.5 Dosage

A typical joint contains between 0.5g and 1.0g of cannabis plant matter, which varies in THC content between 5mg and 150mg (i.e. typically between 1 per cent and 15 per cent THC). Not all of the available THC is ingested; the actual amount of THC delivered in the smoke has been estimated at 20 per cent to 70 per cent of that in the cigarette (Hawks, 1982), with the rest being lost through combustion or escaping in sidestream smoke. The bioavailability of THC from marijuana cigarettes (the fraction of THC in the cigarette which reaches the bloodstream) has been reported to range between 5 per cent and 24 per cent (mean 18.6 per cent) (Ohlsson et al, 1980). For all these reasons, the actual dose of THC that is absorbed when cannabis is smoked is not easily estimated.

In general, only a small amount of smoked cannabis (e.g. 2mg to 3mg of available THC) is required to produce a brief pleasurable high for the occasional user, and a single joint may be sufficient for two or three individuals. A heavy smoker may consume five or more joints per day, while heavy users in Jamaica, for example, may consume up to 420mg THC per day (Ghodse, 1986). In clinical trials designed to assess the therapeutic potential of THC, single doses have ranged up to 20mg in capsule form. In human experimental research, THC doses of 10mg, 20mg and 25mg have been administered as low, medium and high doses (Barnett et al 1985; Perez-Reyes et al 1982).

Perez-Reyes et al (1974) determined the amount of THC required to produce the desired effects by slow intravenous administration. They estimated that the threshold for perception of an effect was 1.5mg while a peak social "high" required 2-3mg THC. These levels did not differ between frequent and infrequent users, so Perez-Reyes et al concluded that tolerance or sensitivity to the perceived high does not develop.

4.6 Patterns of use

Cannabis is the most widely used illicit drug in Australia, having been tried by a third of the adult population, and by the majority of young adults between the ages of 18 and 25 (see Donnelly and Hall, 1994). The most common route of administration is by smoking, and the most widely used form of the drug is marijuana.

The majority of cannabis use in Australia and elsewhere is "recreational". That is, most users use the drug to experience its euphoric and relaxing effects rather than for its recognised therapeutic effects. Unless explicitly stated to the contrary (as in chapter 8) it should be assumed that the phrase "cannabis use" is a short-hand term for the recreational use of cannabis products.

The majority of cannabis use is also "experimental" in that most of those who have ever used cannabis either discontinue their use after a number of uses, or if they continue to use, do so intermittently and episodically whenever the drug is available. Only a small proportion of those who ever use cannabis become regular cannabis users. The best estimate from the available survey data is that about 10 per cent of those who ever use cannabis become daily users, and a further 20-30 per cent use on a weekly basis (see Queensland Criminal Justice Commission, 1993; Donnelly and Hall, 1994). Among those who continue to use cannabis, the majority discontinue their use in their mid to late 20s.

Because of uncertainties about the dose of THC contained in illicit marijuana, there is no information on the amount of THC ingested by regular Australian cannabis users. "Heavy" cannabis use is typically defined in terms of the frequency of use rather than average dose of THC received. Although it is possible that daily users could use small quantities per day, this is unlikely to be true of the majority of regular users because of the tolerance to drug effects which develops with regular use. Evidence collected on chronic long-term users at the National Drug and Alcohol Research Centre (Solowij, 1994), indicated that they typically used more potent forms of cannabis (namely, "heads" and hashish).

The daily or near daily use pattern is the pattern that probably places users at greatest risk of experiencing long-term health and psychological consequences of use. Such users are more likely to be male and less well educated, and are more likely to regularly use alcohol, and to have experimented with a variety of other illicit drugs, such as amphetamines, hallucinogens, psychostimulants, sedatives and opioids.

4.7 Metabolism of cannabinoids

"Cannabinoids" is the collective term for a variety of compounds which can be extracted from the cannabis plant or are produced within the body after ingestion and metabolism of cannabis. Some of these compounds are psychoactive, that is, they have an effect upon the mind of the users; others are pharmacologically or biologically active, that is, have an effect upon cells or the function of other bodily tissues and organs, but are not psychoactive. Animal and human experimentation indicates that delta-9-tetrahydrocannabinol (THC) is the major psychoactive constituent of cannabis.

THC is rapidly and extensively metabolised in humans. Different methods of ingesting cannabis give rise to different patterns of absorption, metabolism and excretion of THC. Upon inhalation, THC is absorbed within minutes from the lungs into the bloodstream. Absorption of THC is much slower after oral administration, entering the bloodstream within one to three hours, and delaying the onset of psychoactive effects.

After smoking, the initial metabolism of THC takes place in the lungs, followed by more extensive metabolism by liver enzymes which transform THC to a number of metabolites. The most rapidly produced metabolite is 9-carboxy-THC (or THC-COOH) which is detectable in blood within minutes of smoking cannabis. It is not psychoactive. Another major metabolite of THC is 11-hydroxy-THC, which is approximately 20 per cent more potent than THC, and which penetrates the blood-brain barrier more rapidly than THC. 11-hydroxy-THC is only present at very low concentrations in the blood after smoking, but at high concentrations after the oral route (Hawks, 1982). THC and its hydroxylated metabolites account for most of the psychoactive effects of the cannabinoids.

Peak blood levels of THC are reached very rapidly, usually within 10 minutes of smoking and before a joint is fully smoked, and decline rapidly to about 5-10 per cent of their initial level within the first hour. This initial rapid decline reflects the rapid conversion of THC to its metabolites, as well as the distribution of THC to lipid-rich tissues, including the brain (Fehr and Kalant, 1983; Jones, 1980; 1987). THC and its metabolites are highly fat soluble and may remain for long periods of time in the fatty tissues of the body, from which they are slowly released back into the bloodstream. This phenomenon slows the elimination of cannabinoids from the body.

The time required to clear half of the administered dose of THC from the body has been found to be shorter for experienced or daily users (19-27 hours) than for inexperienced users (50-57 hours) (Agurell, et al 1986; Hunt and Jones, 1980; Lemberger et al, 1970; 1978; Ohlsson, et al, 1980). Recent research using more sensitive detection techniques suggests that the half-life in chronic users may be closer to three to five days (Johansson et al, 1988). It is the immediate and subsequent metabolism of THC that occurs more rapidly in experienced users (Blum, 1984). Given the slow clearance, repeated administration of cannabis results in the accumulation of THC and its metabolites in the body. Because of its slow release from fatty tissues into the bloodstream, THC and its metabolites may be detectable in blood for several days, and traces may persist for several weeks.

While blood levels of THC peak within a few minutes, 9-carboxy-THC levels peak approximately 20 minutes after commencing smoking and then decline slowly. The elimination curve for THC crosses the 9-carboxy-THC curve around the time of the peak of the latter and subjective intoxication also peaks around this time (i.e., 20-30 minutes later than peak THC blood levels), with acute effects persisting for approximately two to three hours.

4.8 Detection of cannabinoids in body fluids

Cannabinoid levels in the body, which depend on both the dose given and the smoking history of the individual, are subject to substantial individual variability. Plasma levels of THC in man may range between 0-500ng/ml, depending on the potency of the cannabis ingested and the time since smoking. For example, blood levels of THC may decline to 2ng/ml one hour after smoking a low potency cannabis cigarette, a level that may be achieved only nine hours after smoking a high potency cannabis cigarette. In habitual and chronic users such levels may persist for several days after use because of the slow release of accumulated THC.

The detection of THC in blood above 10-15ng/ml provides presumptive evidence of "recent" consumption of cannabis, but it is not possible to determine how recently it was consumed. A somewhat more precise estimate of the time of consumption may be obtained from the ratio of THC to 9-carboxy-THC: similar concentrations of each in blood could be an indication of use within the last 20-40 minutes, and would predict a high probability of the user being intoxicated. When the levels of 9-carboxy-THC are substantially higher than those of THC, ingestion can be estimated to have occurred more than half an hour ago (Hawks, 1982; Perez-Reyes et al, 1982). However, such an interpretation probably applies only to the naive users who have resting levels of zero. Background levels of cannabinoids (particularly 9-carboxy-THC) in habitual users make the estimation of time of ingestion almost impossible. It is very difficult to determine the time of administration from blood concentrations of THC and its metabolites, even if the smoking habits of the individual and the exact dose consumed are known. The results of blood analyses indicate, at best, the "recent" use of cannabis.

Urinary cannabinoid levels provide an even weaker indicator of current cannabis intake. In general, the greater the level of cannabinoid metabolites in urine, the greater the possibility of recent use, but it is impossible to be precise about how "recent" use has been (Hawks, 1982). Only minute traces of THC itself appear in the urine due to its extensive metabolism, and most of the administered dose is excreted in the form of metabolites in faeces and urine (Hunt and Jones, 1980). 9-carboxy-THC is detectable in urine within 30 minutes of smoking. This and other metabolites may be present for several days in first time or irregular cannabis users, while frequent users may continue to excrete metabolites for weeks or months after last use because of the accumulation and slow elimination of these compounds (Dackis et al, 1982; Ellis et al, 1985). As with blood levels, there is substantial human variability in the metabolism of THC, and no simple relationship between urinary levels of THC metabolites and time of consumption. Hence, urinalyses results cannot be used to distinguish between use within the last 24 hours and use more than a month ago.

Several studies have examined measures of cannabinoids in fat and saliva. Analyses of human fat biopsies confirm storage of the drug for at least 28 days (Johansson, et al, 1987). Detection of cannabinoids in saliva holds more promise for forensic purposes, since it has the capacity to reduce the time frame of "recent" use from days and weeks to hours (Hawks, 1982; Gross et al 1985; Thompson and Cone, 1987). Salivary THC levels have also been shown to correlate with subjective intoxication and heart rate changes (Menkes et al, 1991).

4.9 Intoxication and levels of cannabinoids

Ingestion of cannabis produces a dose related impairment of a wide range of cognitive and behavioural functions. Since there is evidence that cannabis intoxication adversely affects skills required to drive a motor vehicle (see below), it would be desirable to have a reliable measure of impairment due to cannabis intoxication that was comparable to the breath test of alcohol intoxication. For this reason, a reliable measure for determining the degree of impairment due to cannabis has been particularly sought after.

While the degree of impairment from alcohol can be determined from a single blood alcohol estimate, a clear relationship between blood levels of THC or its metabolites and degree of either impairment or subjective intoxication has not been demonstrated (Agurell et al, 1986). The estimation of the degree of intoxication from a single value of blood THC level is difficult, not only because of the time delay between subjective high and blood THC, but also because of large individual variations in the effects experienced at the same blood levels. The difficulty is compounded by the distribution of THC to body tissues, and its metabolism to other psychoactive compounds.

Blood levels of THC metabolites, such as 11-hydroxy-THC, correlate temporally with subjective effects but are not readily detectable in blood after smoking cannabis, while blood levels of THC correlate only modestly with cannabis intoxication, in part because of its lipid solubility (Barnett et al, 1985; McBay 1988; Ohlsson et al 1980). The level of intoxication could only realistically be related to the total sum of all the psychoactive cannabinoids present in body fluids and in the brain and various tissues.

Due to large human variability, no realistic limit of cannabinoid levels in blood has been set which can be related to an undesirable level of intoxication. Tolerance also develops to many of the effects of cannabis. Hence, a given dose consumed by a naive individual may produce greater impairment on a task than the same dose consumed by a chronic heavy user. THC may also be active in the nervous system long after it is no longer detectable in the blood, so there may be long-term subtle effects of cannabis on the cognitive functioning of chronic users even in the unintoxicated state. To date, there is no consistently demonstrated correlation between blood levels of THC and its effect on human mind and performance. Thus, no practical method has been developed as a forensic tool for determining levels of intoxication based on detectable cannabinoids. A consensus conference of forensic toxicologists has concluded that blood concentrations of THC which cause impairment have not been sufficiently established to provide a basis for legal testimony in cases concerning driving a motor vehicle while under the influence of cannabis (Consensus Report, 1985).

4.10 Passive inhalation

In the United States, urine testing for drug traces and metabolites is increasingly used to identify illicit drug users in the workplace (Hayden, 1991). A technical concern raised by the opponents of this practice has been the possibility of a person having a urine positive for cannabinoids as the result of the passive inhalation of marijuana smoke at a social event immediately prior to the provision of the urine sample. A number of research studies have attempted to determine the relationship between passive inhalation of marijuana smoke and consequent production of urinary cannabinoids (Hayden, 1991).

In one of the first studies on passive inhalation, Perez-Reyes and colleagues (1983) found that non-smokers who had been confined for over an hour in a very small unventilated space containing the smoke of at least eight cannabis cigarettes over three consecutive days had insignificant amounts of urinary cannabinoids. Law and colleagues (1984) and Mule et al (1988) also showed that passive inhalation produced urinary cannabinoid concentrations well below the detection limit of 20ng/ml 9-carboxy-THC used in workplace drug screens.

Morland et al (1985) produced urinary cannabinoid levels above 20ng/ml in non-smokers but the conditions were extreme, namely, confinement in a space the size of a packing box with exposure to the smoke of six cannabis cigarettes. The studies of Cone and colleagues (1986; 1987a, 1987b) confirmed the necessity to apply extreme experimental conditions, which they claimed non-smokers were unlikely to submit themselves to for the long periods of time required to produce urinary metabolites above 20ng/ml. They also showed that non-smokers with significant amounts of cannabinoids in their urine experienced the subjective effects of intoxication.

References

Abbott, A. (1990) The switch that turns the brain on to cannabis. New Scientist, 11 Aug, 19.

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5. The acute effects of cannabis intoxication

5.1 Psychological and physical effects

Any attempt to summarise the acute effects of cannabis, or of any psychoactive drug, is necessarily an oversimplification. The effects experienced by the user will depend upon: the dose, the mode of administration, the user's prior experience with the drug, any concurrent drug use, and the "set" - the user's expectations, mood state and attitudes towards drug effects - and "setting" - the social environment in which the drug is used (Jaffe, 1985). The following descriptions of the typical effects of cannabis are made with this qualification in mind.

The major motive for the widespread recreational use of cannabis is the experience of a subjective "high", an altered state of consciousness which is characterised by: emotional changes, such as mild euphoria and relaxation; perceptual alterations, such as time distortion, and; intensification of ordinary sensory experiences, such as eating, watching films, listening to music, and engaging in sex (Jaffe, 1985; Tart, 1970). When used in a social setting, the "high" is often accompanied by infectious laughter, talkativeness, and increased sociability.

Cognitive changes are usually marked during a "high". These include an impaired short-term memory, and a loosening of associations, which make it possible for the user to become lost in pleasant reverie and fantasy, while making it difficult for the user to sustain goal-directed mental activity. Motor skills, reaction time and motor coordination are also affected, so many forms of skilled psychomotor activity are impaired while the user is intoxicated (Jaffe, 1985).

Not all the effects of cannabis intoxication are welcomed by users. Some users report unpleasant psychological reactions, ranging from a feeling of anxiety to frank panic reactions, and a fear of going mad to depressed mood (Smith, 1968; Weil, 1970; Thomas, 1993). These effects are most often reported by naive users who are unfamiliar with the effects of cannabis, and by some patients given THC for therapeutic purposes. More experienced users may also report these effects on occasion, especially after the oral ingestion of cannabis when the effects may be more pronounced and of longer duration than those usually experienced after smoking cannabis. These effects can usually be successfully prevented by adequate preparation of users about the type of effects they may experience. If these effects develop they can be managed by reassurance and support (Smith, 1968; Weil, 1970). Psychotic symptoms, such as delusions and hallucinations, are very rare experiences that occur at very high doses of THC, and perhaps in susceptible individuals at lower doses (Smith, 1968; Thomas, 1993; Weil, 1970).

The inhalation of marijuana smoke, or the ingestion of THC, the psychoactive derivative of cannabis, has a number of bodily effects. Among these the most dependable are the effects on the heart and vascular system. The most immediate effect of cannabis use by all routes of administration is an increase in heart rate of 20-50 per cent over baseline which occurs within a few minutes to a quarter of an hour and lasts for up to three hours (Huber et al, 1988; Jones, 1984). Changes in blood pressure also occur which depend upon posture: blood pressure is increased while the person is sitting, and decreases while standing. A sudden change from a recumbent posture may produce postural hypotension and fainting, an effect which may explain the feeling of "light-headedness" and faintness that is often the earliest indication of intoxication in naive users (Maykut, 1984). Increases are also observed in the production of the catecholamine norepinephrine, although these lag behind the cardiovascular changes, and their mechanisms are not well understood (Hardman and Hosko, 1976).

In healthy young users these cardiovascular effects are unlikely to be of any clinical significance. They may, however, magnify anxiety in naive users. The cannabis-induced tachycardia and postural hypotension may contribute to the panic attacks sometimes experienced by naive users (Weil, 1970) who may mistakenly interpret the palpitations, and the feeling of faintness, as symptoms of serious misadventure, magnifying pre-existing anxiety in a positive feedback cycle that leads to a panic attack.

5.2 Toxic dose levels

THC appears to be the component of cannabis which has the highest direct toxicity in all animals so far tested. The toxic effects of cannabis are mediated through its effects on neural systems. The cause of death in experimental animals is almost invariably apnoea or cardiac arrest, if apnoea is prevented (Rosencrantz, 1983). Due to the development of tolerance, toxic doses depend upon the amount by which they exceed the customary dose. In contrast to the increase in toxic dose typical of many drugs when moving from primates to lower animals, it appears that phylogenetically higher animals are less susceptible to the acute toxicity of THC. Thus, the dose of THC which kills 50 per cent of animals (LD50) when administered intravenously is 40mg/kg in the rat but 130mg/kg in the dog and monkey (Rosencrantz, 1983).

For obvious ethical reasons there is no experimental evidence to determine a lethal dose in humans. Nor is there any clinical evidence, since there have been no reported cases of death attributable to cannabis in the world medical literature (Blum, 1984; Nahas, 1984). Extrapolation from the animal evidence suggests that the lethal human dose of THC is at least as high as, and probably higher than, that observed in the monkey. If this is so, then the toxic dose of THC in a 65kg adult would be 8.45kg.

A number of non-fatal toxic reactions occur in humans with higher than normal doses. The tachycardia almost invariably produced in acute intoxication, combined with the sensory alterations and increased tremor commonly reported, probably contribute to the affective components of these reactions. CNS and respiratory depression are noted with high doses, which in severe overdose may be life-threatening (Rosencrantz, 1983). These effects are, of course, more dangerous to those with pre-existing cardiac irregularities. Because of the large effective to lethal dose ratio in humans (probably in excess of 1:1000 in non-tolerant users) the risk of experiencing severe toxic effects of cannabis is limited by the aversive psychotropic effects of high doses, which usually lead to cessation of use before the onset of dangerous physical consequences.

5.3 Tolerance to acute effects

In animals, tolerance develops to the lethal, hypothermic and some of the behavioural effects of cannabinoids. This has been attributed to functional or pharmacodynamic adaptations of the CNS rather than to a more rapid metabolic disposition (Jaffe, 1985). Laboratory studies in humans involving daily dosing at high levels over periods of weeks have demonstrated tolerance to mood effects, tachycardia, decrease in skin temperature, increased body temperature, and impaired performance on psychomotor tests. Abrupt discontinuation in these studies usually produces a mild withdrawal syndrome (see below pp111-113).

5.4 Psychomotor effects

A major societal concern about cannabis intoxication is its potential to impair psychomotor performance in ways which may directly affect the well-being of non-users of cannabis. The prototype outcome is an automobile accident caused by a cannabis user driving while intoxicated. It is well known that individuals who drive while intoxicated with alcohol are dangerous to others in proportion to their level of intoxication. Is there evidence that intoxication with cannabis produces impaired psychomotor performance of a nature and degree sufficient to warrant restrictions upon its use by automobile drivers? To what extent has cannabis intoxication contributed to road accidents?

Psychoactive substances typically have both acute and chronic effects on performance of a variety of tasks. Given the fact that most tasks of interest to researchers require effort and concentration, only those substances which enhance these very general abilities typically improve performance. Recreational drugs are usually valued for effects which remove the user from mundane concerns, produce relaxation, and enhance experiences which would normally interfere with concentration on a skilled task. Consequently, many societies enact restrictions on the use of such drugs, either during specific tasks such as motor vehicle driving, or at any time, as is the case with cannabis in most Western societies, and with alcohol in many Islamic societies.

The subjective effects of cannabis include feelings of well-being and relaxation, and sensory and temporal distortions which might be expected to decrease performance in situations where perceptual accuracy and attention are important. In deciding whether the recreational use of cannabis presents a danger to the user and others we need to consider two things: (1) the extent to which its use disrupts the performance of potentially dangerous tasks such as motor vehicle driving or the operation of machinery, and (2) the effect that the drug has on the user's compliance with restrictions upon its use. The second point refers to any disinhibitory effects of the drug which might predispose users to ignore prohibitions on driving, or may increase their willingness to take risks while intoxicated.

The risks of cannabis intoxication and driving will be assessed in the following way. First, laboratory evidence on the effects of cannabis on various psychomotor tasks will be reviewed. In the following review of this evidence, when a number of studies have produced similar results, only the most typical studies will be cited. (For a more complete review of such studies see Chait and Pierri, 1992). Second, the possible mechanisms of the psychomotor effects of cannabis will be briefly discussed. Third, the literature on the effects of cannabis on performance in driving and flying simulators will be briefly reviewed. Fourth, the experimental literature on the effects of cannabis intoxication on on-road driving will be reviewed. Finally, the limited epidemiological evidence on the contribution of cannabis to motor vehicle accidents will be considered.

5.4.1 Effects of cannabis on psychomotor tasks

Muscle control. Standing steadiness (Kiplinger et al, 1971) and hand steadiness (Klonoff et al, 1973) are both adversely affected by cannabis. Finger or toe tapping speed does not appear to be reliably affected (Weckowicz et al, 1975; Evans et al, 1976; Milstein et al, 1975; Dalton et al, 1975), as only one study (Klonoff et al, 1973) found a decrement in finger tapping.

Reaction time. Simple reaction time does not appear to be reliably affected by cannabis. Some studies have reported decrements in mean reaction time (Borg et al, 1975; Dornbush et al, 1971), or the variability of reaction time (Braden et al, 1974), while others have found no difference (Evans et al, 1973). Choice reaction time tasks, in which the response is conditional not only upon the occurrence of a stimulus, but also the presence of some other discriminant (such as the pitch of a tone or the colour of a visual stimulus), have been administered to determine the effect of cannabis. In a number of these studies, reaction time was indeed slower after cannabis use (Borg et al, 1975; Block & Wittenborn, 1984; 1986), although there were some studies which found no change (Peeke et al, 1976; Block & Wittenborn, 1984). With only one exception (Low et al, 1973), errors in choice reaction time were not increased by cannabis.

Single tasks of manual dexterity. Pursuit rotor tasks, in which the subject attempts to follow a rotating target with a pointer, are generally performed worse after cannabis use (Manno et al, 1971; Manno et al, 1970), although studies employing regular users (Salvendy & McCabe, 1975; Carlin et al, 1972) have found no effect, suggesting that the regular users developed tolerance to the effects of cannabis. Other tracking tasks are generally not affected (Zacny & Chait, 1991; Heishman et al, 1989). Tests in which the subject must manipulate and accurately place small items (Dalton et al, 1975; 1976; Evans et al, 1973) are usually affected, while sorting tasks may (Chait et al, 1985) or may not (Kelly et al, 1990) be performed less well.

Concurrent tasks. Most concurrent task studies use one task which requires almost continuous attention, typically tracking, and one in which significant stimuli occur sporadically, often within a larger number of non-significant stimuli. The tasks are often referred to as the central and peripheral tasks respectively. The performance of concurrent tasks is almost always affected negatively by cannabis, although the effects on the component tasks are not consistent. Number or proportion of peripheral targets missed (MacAvoy & Marks, 1975; Marks & MacAvoy, 1989; Casswell & Marks, 1973; Moskowitz et al, 1972), proportion of hits (Moskowitz, Sharma & McGlothlin, 1972), false alarms (Chait et al, 1988, MacAvoy & Marks, 1975; Moskowitz & McGlothlin, 1974) or reaction time to peripheral targets (Perez-Reyes et al, 1988; Evans et al, 1976; Moskowitz et al, 1976) may suffer, but no interpretable pattern of decrements has emerged. It may be the case that while overall performance on concurrent tasks is decreased during cannabis intoxication, differences in the tasks used produce various patterns of effect. While there has been some speculation as to whether the effects of cannabis in concurrent tasks might be concentrated on the central or peripheral tasks (Moskowitz, 1985), no observed pattern has emerged to clearly support these conjectures.

5.4.2 Possible mechanisms of psychomotor effects

Sensory disturbances. Reports of the subjective experience of cannabis intoxication include altered experience in all sensory modalities, as well as in the perception of space and time (Tart, 1970). Since almost all tasks of psychomotor performance include important visual and auditory components, sensory disturbances might well affect the ability to perform such tasks. Studies of the ability to discover embedded figures within complex designs have shown that this is impaired by cannabis (Carlin et al, 1972; Carlin et al, 1974; Pearl et al, 1973). Performance decrements due to cannabis in the Stroop colour naming test have been reported (Carlin et al, 1972; 1974), although it is not clear whether disturbed perception has any significant effect upon this task.

Central Nervous System depression. Both the toxic and behavioural effects of cannabis indicate that it acts as a CNS depressant, at least in moderate to high doses. It might seem reasonable to hypothesise that this general effect might contribute to slowed reaction times, inability to maintain concentration, and lapses in attention. This is certainly the case with alcohol and other CNS depressants. When compared to the relatively large and reliable depressant effects of moderate doses of alcohol, it is clear that this effect of cannabis is not the primary mediator of performance changes. It must be stressed, however, that high doses of cannabis would make this aspect of its action on psychomotor skills more important.

Motivational changes. A great deal has been written about the supposed effects of cannabis on human motivation. Hypotheses concerning the motivational effects of chronic cannabis use have been reviewed separately (see chapter 7.2). Cannabis users routinely report reduced desire for physical activity and increased difficulty of concentrating on intellectually demanding tasks such as reading for study (Tart, 1970). Studies designed to test the effect of cannabis on the willingness to perform laboratory "work" have found no striking decrements (Mendelson, 1983). This is consistent with comparisons of manual workers who used cannabis with those who did not (Rubin & Comitas, 1975; Stefanis et al, 1977). Indeed, the counter-argument that cannabis users can voluntarily compensate for some of the impairing effects of the drug has received experimental support (Cappell & Pliner, 1973; Robbe & O'Hanlon, 1993). As discussed below, motivational changes are surely important in decisions made outside the laboratory, but there appears to be no reliable evidence that motivational changes are responsible for any major proportion of the psychomotor effects of cannabis.

5.4.3 Effects of cannabis on simulated driving and flying

Simulated driving tasks. As the previous sections have shown, there is considerable evidence that cannabis intoxication has some negative effects upon performance which become more pronounced with increasing task difficulty. Motor vehicle driving is a complex task, especially in conditions of heavy traffic or poor road or weather conditions, and as such, it might be expected to be adversely affected by cannabis. Simulated driving tasks require skills which are similar to those involved in driving, which can be performed under controlled laboratory conditions. When special efforts are made to simulate the performance characteristics of a car, simulations have two major advantages (Smiley, 1986). First, cannabis users an be tested after taking doses of cannabis which it would be unethical to use on the road. Second, they can be placed in simulated emergency situations which test their level of impairment in ways that would be impermissible on the road. The disadvantage of simulator studies derives from the difficulty of achieving sufficient fidelity to on-road driving tasks.

One of the earliest studies by Crancer et al, (1969) found only that "speedometer errors" increased in simulated driving after cannabis use. In one of the more influential studies, Dott (1972) reported an apparent decrease in the willingness to take risks in simulated passing of another vehicle after cannabis use, while alcohol had the opposite effect. Alcohol also tended to hamper the subjects' response to stimuli signalling an emergency condition, while cannabis had little effect on this response. Both, however, increased reaction time to a more routine signal. A similar dissociation of the effects of alcohol and cannabis was reported by Ellingstad, et al, (1973) who found that cannabis did not appear to increase risk-taking, whereas alcohol did. Cannabis affected the ability to judge the time taken to pass another vehicle, while alcohol did not. Moskowitz et al (1976) found that alcohol altered the visual search patterns of subjects performing a simulated driving task, while cannabis did not. The alterations found with alcohol were, in theory, consistent with a reduced ability to scan for hazardous events, but no reliable difference in task performance was found with either drug.

Smiley (1986) critically reviewed the research on the effects of cannabis intoxication on simulated driving. She argued that the earlier studies which showed fewer effects on car control than later studies suffered because of their unrealistic car dynamics. Later studies which used driving simulators with more realistic car dynamics have shown impairments of lane control after cannabis use. Some of the studies have also shown reductions in risk-taking as manifested in slower speeds, and maintenance of a larger distance from the car in front in following tasks (Smiley, 1986).

Simulated flying. Janowsky et al (1976) found substantial increases in the number and magnitude of errors during a simulated flight after taking cannabis. These were principally in keeping the plane at the proper altitude and heading. Yesavage et al (1985) originally reported negative effects of cannabis on some components of a simulated flying task up to 24 hours after smoking, but this study did not include a control group. A later study (Leirer et al, 1989) which attempted to replicate this result with a control group found only an effect one to four hours after smoking. A third study which also included a control group (Leirer et al, 1991) again demonstrated decrements in the composite performance score up to 24 hours after smoking cannabis. Much has been made of these findings by critics of cannabis use, but the effects are very small and of uncertain significance for flying safety. Jones (1987) has argued that the use of cannabis by pilots in the 24 hours preceding flying may be more an indicator of poor judgment, rather than a cause for concern about the residual psychomotor effects of cannabis.

5.4.4 Effects of cannabis on on-road driving

It is often remarked that the activity most often cited as dangerous when performed under the influence of recreational drugs - motor vehicle driving - is one of the least studied. Given the concern about the safety of the experimental subject in drug and driving experimentation, it is understandable that such studies have been relatively uncommon. A review by Nichols (1971) found that there were no well controlled observations of the effects of cannabis on driving performance. This situation changed with research commissioned by the Canadian Commission of Inquiry into the Non-Medical use of Drugs. A comprehensive report published by Hansteen et al (1976) showed that a moderate dose of alcohol (approximately 0.07 BAC) or THC (5.9mg) impaired driving on a traffic-free course (as measured by the number of times the lane-defining cones ("witch's hats") were struck). Driving speed was decreased after cannabis but not after alcohol use.

Smiley et al (1975), using a different type of course, found that reaction time to signal stimuli was increased with the combination of cannabis and alcohol. Klonoff (1974) studied driving on a closed course, and in city traffic, after a placebo and two doses of smoked cannabis (4.9mg and 8.4mg THC). Closed course driving was scored by the number of cones hit on a precisely laid out path. Driving in traffic was scored by observation of eleven categories of driving skill, similar to those used in some driving tests. Driving on the closed course was impaired by both doses, as indicated by a higher proportion of subjects whose performance declined after cannabis use. Driving in traffic, however, while showing a trend toward poorer performance, was not significantly affected, and the effects of cannabis were much more variable. Sutton (1983) also found that cannabis had little effect on actual driving performance. Peck et al (1986) recorded performance on a range of driving tasks on a closed circuit on four occasions after the administration of placebo, up to 19mg of smoked THC, 0.84g/kg of alcohol, and the combination of both drugs. On most individual and derived composite measures, cannabis impaired performance. This study is important in that there was a high degree of concordance between objective performance measures (e.g. number of traffic markers hit during manoeuvres), subjective estimates of performance by the drivers, and ratings by police observers. However, the conclusion reached was that the effects of cannabis on driving performance were somewhat less than those of alcohol. Robbe and O'Hanlon (1993), have reported the methodology, but not the detailed results, of a study of driving in traffic. Their brief report suggests that their results also indicated little impairment of actual driving skills after cannabis. They speculated that since drivers were aware of their intoxication, they had successfully attempted to counter the impairment.

Overall, the effects of cannabis use on on-road driving have been smaller than the comparable effects of intoxicating doses of alcohol in the same settings (Smiley, 1986). The most consistent cannabis effect has been that drivers reduce their risk by slowing down; a finding that contrasts with the consistent finding that subjects typically increase their speed when intoxicated with alcohol. It is probably this compensatory behaviour by cannabis users that explains the comparatively small effects of cannabis intoxication in on road studies. For ethical reasons such studies have not been able to adequately test the response of cannabis intoxicated drivers to situations that require emergency decision, in which there is less opportunity to compensate for impairment. The few studies which have attempted to simulate this situation (e.g. by using subsidiary reaction tasks in addition to driving) have shown that cannabis intoxication impairs emergency decision-making (Smiley, 1986).

The small effects of cannabis on driving performance seem at odds with its effects on laboratory tasks requiring divided attention. Peck et al (1986) have pointed out, however, that the subtle performance effects of drugs in laboratory divided attention tasks may be poor predictors of driving performance. While the combination of performance abilities which is tapped by the typical divided attention task, such as concurrent pursuit tracking and visual discrimination, is plausibly related to driving, the tracking task is usually a much more difficult task than driving under normal conditions. Much more attention must be allocated to the central task in most divided attention tests, for example, leading to a substantial decrease in performance when drugs such as cannabis are taken. In addition, in the laboratory the subject is unable to vary a key task parameter, such as driving speed, in order to compensate for any perceived impairment. Hence, while laboratory divided attention tasks may be ideal for detecting small drug effects, they may over-estimate the effects of drugs on actual driving. It is not surprising then that many studies which have used both types of test have reported less effect on actual driving than on laboratory tasks or simulated driving.

5.4.5 Studies of cannabis use and accident risk

While cannabis produces decrements in psychomotor performance in laboratory and controlled settings, it does not necessarily follow that these decrements will increase the risk of being involved in accidents. It may be, for example, that cannabis users are less likely to drive than drinkers because they are more aware of their intoxication. The survey evidence suggests that this is not the case. Several surveys (e.g. Dalton et al, 1975; Thompson, 1975; Klonoff, 1974; Robbe & O'Hanlon, 1993) have found that cannabis users are generally aware that their driving is impaired after using cannabis but the majority had driven, or would drive, after using cannabis, despite this recognition of impairment (Klonoff, 1974). This finding is consistent with observations on the recreational use of alcohol when driving (Smart, 1974).

Even if cannabis users drive when intoxicated it does not necessarily follow that they will be over-represented among drivers involved in accidents. It could be, for example, that cannabis users take special care and avoid risk-taking when driving while intoxicated. This possibility is difficult to investigate because there have been no controlled epidemiological studies conducted to establish whether cannabis users are at increased risk of being involved in motor vehicle or other accidents. This is in contrast to the instance of alcohol use and accidents, where case-control studies have shown that persons with blood alcohol levels indicative of intoxication are over-represented among accident victims (Holman et al, 1988).

In the case of cannabis, all that is available are studies of the prevalence of cannabinoids in the blood of motor vehicle and other accident victims (see McBay, 1986 for a review). Most often these have been retrospective studies of the prevalence of cannabinoids in blood tested post-mortem, which have found that between 4 per cent and 37 per cent of blood samples have contained cannabinoids, typically in association with blood alcohol levels indicative of intoxication (e.g. Cimbura et al, 1982; Mason and McBay, 1984; Williams et al, 1985). Zimmerman et al (1983) have reported similar prevalence data on blood cannabinoid levels among Californian motorists tested because of suspicion of impairment by the Highway patrol. Soderstrom et al (1988) have conducted one of the few prospective studies among trauma patients rather than accident fatalities, which showed a high prevalence of bloods positive for cannabinoids (35 per cent).

These studies are difficult to evaluate for a number of reasons. First, in the absence of information on the prevalence of cannabinoids in the blood of non-accident victims, we do not know whether persons with cannabinoids are over-represented among accident victims (Terhune, 1986). Although a prevalence of 35 per cent may seem high, this is of the order of the prevalence of cannabis use among young males who are at highest risk of involvement in motor vehicle and other accidents (Soderstrom et al, 1988). Second, there are major problems in using cannabinoid blood levels to determine whether a driver or pedestrian was intoxicated with cannabis at the time of an accident (Consensus Development Panel, 1985). The simple presence of cannabinoids indicates only recent use, not necessarily intoxication at the time of the accident (see above pp35-36). Third, there are also serious problems of causal attribution, since more than 75 per cent of drivers with cannabinoids in their blood also have blood levels indicative of alcohol intoxication (McBay, 1986). On the basis of the available evidence, it is accordingly difficult to draw any conclusions about the contribution that cannabis intoxication may make to the occurrence of motor vehicle accidents (Terhune, 1986).

One approach that has been used in an attempt to get around the absence of data on the prevalence of cannabis use among drivers not involved in accidents has been to perform "culpability analyses" (Terhune, 1986). In such analyses, decisions are made as to which drivers killed in fatal accidents are culpable (i.e. responsible for the accident). Drivers with no alcohol or other drugs in their blood are then used as the control group in analyses of the relationship between the presence of drugs in blood and degree of culpability. These studies have their problems: the culpability of the drug-free drivers is usually high thereby reducing the ability to detect an increase in culpability among drivers with alcohol and cannabis; different studies use different criteria for deciding that when a driver was intoxicated with cannabis; and as a consequence, different studies have produced very different estimates of the relationship between cannabinoids in blood and driver culpability (although most have shown an increased culpability for drivers with intoxicating levels of alcohol in their blood). As Simpson (1986) concluded after reviewing the culpability literature: "the results are mixed and inconclusive" (p28).

Gieringer (1988) used a different approach to circumvent the absence of data on the prevalence of cannabinoids in drivers not involved in accidents. He used data from a National Institute of Drug Abuse (NIDA) household survey of drug abuse in the United States to estimate the proportion of all drivers who might be expected to have blood and urine samples positive for cannabinoids. On the basis of these data, he estimated that cannabis users are two to four times more likely to be represented among accident victims than non-cannabis users, and that cannabis users who also used alcohol were even more likely to be over-represented among the victims of motor vehicle accidents.

Gieringer's inference about the risks of combining alcohol and cannabis when driving receive some support from the studies of Mason and McBay (1984) and Williams et al (1985). Mason and McBay estimated that at most one driver in their series of 600 drivers killed in single-vehicle accidents was significantly impaired by cannabis use alone, compared with between nine and 28 drivers who were impaired by marijuana and alcohol, and 476 drivers who had blood alcohol contentrations (BACs) greater than 0.10. Williams et al (1985) investigated the relationship between alcohol and cannabis use and driver responsibility for fatal accidents (as judged from police investigations of each accident) involving young men in California. Using the small drug-free group as the comparison, they found that both alcohol (OR=4.7 [95 per cent CI: 2.1, 10.3]) and alcohol and marijuana in combination (OR=8.6 [95 per cent CI: 3.3, 22.2]) significantly increased the odds of the driver being adjudged to be responsible for the accident. Marijuana-only drivers, however, were less likely to be adjudged responsible for their accident (OR=0.5 [95 per cent CI: 0.2, 1.3]), although numbers were small (N=19).

There is also indirect evidence that cannabis use produces an increase in the risk of accidents, from surveys of self-reported accidents among adolescent drug users. Two such surveys have found a statistically significant relationship between marijuana use and self-reported involvement in accidents, with marijuana smokers having approximately twice the risk of being involved in accidents of non-marijuana smokers (Hingson et al, 1982; Smart and Fejer, 1976).

More direct evidence of an association between cannabis use and accidents is provided by two epidemiological studies, one of cannabis use and mortality (Andreasson and Allebeck, 1990), and the other of cannabis use and health service utilisation (Polen et al, 1993). Andreasson and Allebeck reported a prospective study of mortality over 15 years among 50,465 Swedish military conscripts. They found an increased risk of premature mortality among men who had smoked cannabis 50 or more times by age 18 (RR=4.6, 95 per cent CI: 2.4, 8.5). Violent deaths were the major cause of death contributing to this excess mortality, with 26 per cent of deaths being motor vehicle and 7 per cent other accidents (e.g. drownings and falls). The increased risk was no longer statistically significant (RR=1.2 [95 per cent CI: 0.7, 1.9]) after multivariate statistical adjustment for confounding variables such as anti-social behaviour, and alcohol and other drug use in adolescence (Andreasson and Allebeck, 1990), reinforcing Gieringer's suggestion that the combination of cannabis and alcohol may be the important risk factor for accidents.

Polen et al (1993) compared health service utilisation by non-smokers (N=450) and daily cannabis-only smokers (N=450) screened at Kaiser Permanente Medical centres between July, 1979 and December, 1985. They reported an increased rate of medical care utilisation by cannabis-only smokers for respiratory conditions and accidental injury over a one to two-year follow-up. There was also an interaction between cannabis and alcohol use, in which cannabis users who were the heaviest alcohol users showed the highest rates of utilisation. This result is suggestive but minimally informative about the risks of motor vehicle accidents, because all forms of accidental injury were aggregated.

5.4.6 Conclusions on cannabis and driving

There is no doubt that cannabis adversely affects the performance of a number of psychomotor tasks, an effect which is related to dose, and which is larger, more consistent and persistent in difficult tasks involving sustained attention. The acute effects on performance of typical recreational doses of cannabis are similar to, if smaller than, those of intoxicating doses of alcohol. Alcohol and cannabis differ in their effects on the apparent willingness of intoxicated users to take risks when driving, with persons intoxicated by cannabis engaging in less risky behaviour than persons intoxicated by alcohol.

5.5 Interactions between cannabis and other drugs

Cannabis is often taken in combination with other drugs. This is most likely among those who use it frequently and in large quantities (Tec, 1973). The predominant drug of choice for use with cannabis is alcohol (e.g. Carlin & Post, 1971; Hochhauser, 1977; McGlothlin et al, 1970; Norton and Colliver, 1988) which supports the popular notion that this combination enhances the degree of intoxication. Barbiturates, in contrast, appear to produce an aversive intoxication when combined with cannabis (Johnstone et al, 1975). The interactions of cannabis with each type of drug will be considered in three ways; interactions of toxicity, psychotropic effects and psychomotor impairment.

5.5.1 Other cannabinoids

There are slight interactions of THC with other cannabinoids found in cannabis preparations. The two major cannabinoids other than THC which have been extensively tested for interactions with THC and other drugs are cannabidiol and cannabinol. Both of these compounds have been found to have little psychoactivity when administered alone (Hollister, 1986). In rather high doses (15-60mg), cannabidiol has been reported to abolish the effects of 30mg of oral THC (Karniol et al, 1975), whereas cannabinol had no apparent effect (Hollister & Gillespie, 1975). Comparisons of smoked THC and smoked cannabis, the latter containing the usual small amounts of cannabinol and cannabidiol, indicate that there is, if anything, a slightly greater psychoactive effect from the cannabis than from THC (Galanter et al, 1973; Lemberger et al, 1976). The psychotropic effects of THC also appear to be slightly enhanced by the minor constituent cannabinoids found in natural products when smoked (Galanter et al, 1973). No such differences have been reported in the behavioural effects of smoked cannabis.

5.5.2 Alcohol

Alcohol and cannabis have a number of effects in common, although the mechanisms of these actions appear to be different. The recent identification of the cannabinoid receptor (Howlett et al, 1990), and an endogenous ligand for that receptor, have confirmed the hypothesis that the central activity of cannabis is receptor-mediated (see pp 29-31 above). While the mechanism of action of alcohol is still in question, most explanations are concerned with the effects of alcohol upon the structure and chemistry of the cell membrane. Both drugs are considered to be CNS depressants, especially in high doses, and both have substantial analgesic properties. Since these effects of the two drugs appear to be approximately additive (Siemens, 1980) it is possible that the toxicity of high doses of Æ9-tetrahydrocannabinol (THC) (Rosencrantz, 1983) may be potentiated by alcohol, although there is very little evidence to support this conjecture. Neither the metabolism of alcohol nor that of THC appears to be altered by the presence of the other drug (Siemens & Khanna, 1977).

Alcohol and THC also appear to have similar psychotropic effects. The perceived stimulation and euphoria at low doses are common effects, as well as a tendency toward behavioural disinhibition over a range of doses (Hollister & Gillespie, 1970). This interaction is generally perceived by users as enhancing the intoxication produced by either drug alone (Chesher et al, 1976), although contrary results have been reported (Manno et al, 1971). However, larger doses in combination are often reported to be aversive (Sulkowski & Vachon, 1977; Chesher et al, 1986).

The effects of alcohol and cannabis combinations on psychomotor performance are more complex. The majority of studies have reported that both drugs produce impairment on a variety of psychomotor tasks, and that the interaction is approximately additive. However, a number of studies have reported that at low doses there is less than an additive effect. Chesher et al (1976, 1977) found a reduction in impairment late in intoxication after a combination of oral THC (0.14-0.21mg/kg) and alcohol (0.5-0.6g/kg). A further study in which the THC (0.32mg/kg) was administered one hour before the alcohol (0.54g/kg) found no apparent antagonism (Belgrave et al, 1979). Another study using three doses of smoked marijuana in combination with alcohol showed a lower-than-expected impairment in the group which received the lowest dose of THC (5mg) and the lowest dose of alcohol (0.54g.kg) (Chesher et al, 1986). Peck et al (1986) also reported an apparent antagonism, but only on a composite "stopping" variable derived from driving performance. In most of their measures, the combination of alcohol and cannabis produced additive impairments.

Siemens (1980) has proposed that alcohol may reduce the availability of THC through a pharmacokinetic interaction demonstrated in animals (Siemens & Khanna, 1977). Given that there is substantial evidence for cross-tolerance between alcohol and THC (Newman et al, 1972), it is possible that low doses of THC and alcohol in combination may enhance the acute tolerance to alcohol (Hurst & Bagley, 1972) late in intoxication.

5.5.3 Psychostimulants

The most characteristic effect of psychostimulants such as amphetamine and cocaine is their activation of the sympathetic branch of the autonomic nervous system, as indicated by increases in arousal, blood pressure and respiratory rate. There are few actions which appear to be common between cannabis and stimulants. The few effects on the cardiovascular system, such as amphetamine-induced hypertension, and THC-induced tachycardia, seem to occur independently (Zalcman et al, 1973). It is in the combined effect upon cardiac action that toxic interactions of THC and stimulants could be dangerous, but there are no clear indications in the literature for humans, and the evidence from animal studies is mixed (Siemens, 1980).

The psychotropic effects of the combination of 0.14mg/kg amphetamine and 0.05mg/kg THC have been reported as a longer and more intense "high" (Evans et al, 1976), although a similar study using only 0.025mg/kg THC found no effect of the combination (Forney et al 1976). While the concurrent use of cannabis and cocaine is often reported (Miller et al, 1990), systematic study of their interaction is lacking.

There is some evidence that amphetamine may antagonise the behavioural impairments produced by cannabis (Zalcman et al, 1973), as a number of stimulants appear to do in some animals (Consroe et al, 1976). The infrequency of stimulant/cannabis combinations in recreational use (Hollister, 1986) may be due to as yet unspecified negative interactions experienced by users. It may be, for example, that stimulants increase the probability of occurrence, or severity of the acute panic reaction which sometimes occurs after cannabis use.

5.5.4 Depressants

A great deal of experimentation in animals has shown that cannabis in general increases the depressant action of drugs such as the barbiturates over a range of doses (Siemens, 1980). This is also the case with oxymorphone (Johnstone et al, 1975) and diazepam (Smith & Kulp, 1976). As with alcohol, it is likely that interactions between these acute effects of depressant drugs would lead to the greatest danger of acute toxicity. There is little human evidence at present, however, to support this speculation.

The psychotropic effects produced by combinations of barbiturates with cannabis appear to be additive (Dalton et al, 1975). As mentioned previously, this intoxication is more likely to be aversive to the user (Johnstone et al, 1975). The behavioural effects of the interaction of depressant drugs with cannabis are, in almost all reports, also additive.

5.5.5 Miscellaneous drugs

A number of other substances have been reported to antagonise various effects of cannabis in animals, including phenitrone (Kudrin & Davydova, 1968), pemoline (Howes, 1973) and even tamarind (Hollister, 1986). Only pemoline is acknowledged to counter the reduced motor activity and hypoalgesia due to THC. Physostigmine has shown a complex interaction which includes increasing the motor depression produced by THC and antagonising the tachycardia (Freemon et al, 1975). Propanolol, which would be expected to antagonise the tachycardia characteristic of cannabis intoxication, also appears to abolish the reduction in learning capacity produced by cannabis (Sulkowski et al, 1977), although an earlier study using smaller, spaced doses found no effect (Drew et al, 1972). Recently, it has been reported that indomethacin, a non-steroidal anti-inflammatory, reduced or eliminated a number of physiological effects of THC, and attenuated the "high", but did not affect the acute memory impairment (Perez-Reyes et al, 1991).

5.5.6 Conclusions on drug interactions

At present, the interactions between the effects of cannabis and other drugs are what would be predicted from their separate actions, and are generally relatively innocuous in recreational doses. There have been a number of reports in which cannabis use has accompanied serious consequences, typically when used in combination with one or more other drugs in high doses, or over extended periods of intoxication. However, there appears to be no evidence that cannabis is particularly implicated in cases of heavy intoxication with other drugs. The concurrent intoxication with alcohol and cannabis, which is the most common combination of drugs, may have greatest relevance in motor vehicle accidents. The separate impairments induced by the two drugs appear to be approximately additive, and there are indications that users of both drugs are over-represented among motor vehicle accidents.

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6. The chronic effects of cannabis use on health

Cellular and immunological effects

The possible effects of chronic cannabis use on cellular processes and the immune system are considered together because both effects may influence a cannabis user's susceptibility to diseases. If cannabis use affects cellular processes then users may be at increased risk of developing various types of cancer, and if it affects the immune system then cannabis users may be at increased risk of contracting infectious diseases and developing cancer.

6.1 Mutagenicity and carcinogenicity

A major reason for research into the effects of cannabinoids on cellular processes is to discover whether cannabinoids are mutagenic, i.e. whether they may produce mutations in the genetic material in the somatic and germ cells of users. If cannabinoid exposure affects the genetic material of a user's somatic or bodily cells (such as those of the lung, for example) then chronic cannabis use may cause cancer. If it affects the genetic material of germ cells (the sperm and ova), then genetic mutations could be transmitted to the children of cannabis users.

There is experimental evidence from in vitro studies of animal cells that some cannabinoids, including THC, can produce a variety of changes in cellular processes in vitro (i.e. in the test tube). These include alterations to cell metabolism, DNA synthesis, and cell division (Nahas, 1984). The potential for cannabinoids to produce genetic change in humans or animals is unclear. There is, at most, mixed evidence that THC and other cannabinoids are mutagenic in standard microbial assays, such as the Ames test, and there is contradictory evidence on whether the cannabinoids are clastogenic, i.e. produce breaks in chromosomes. According to Bloch (1983) who reviewed the literature for the World Health Organisation: "in vivo and in vitro exposure to purified cannabinoids or cannabis resin failed to increase the frequency of chromosomal damage or mutagenesis" (p412). Nahas (1984) reviewed the same evidence and concluded that "cannabinoids and marihuana may exert a weak mutagenic effect" (p117). More recently, Zimmerman and Zimmerman (1990/1991) concluded that "cannabis mutagenicity remains unclear", but argued that there was evidence that "cannabinoids induce chromosome aberrations in both in vivo and in vitro studies" (p19).

There is stronger and more consistent evidence that cannabis smoke, like smoke produced by most burning plant material, is mutagenic in vitro, and hence, is potentially carcinogenic (Leuchtenberger, 1983). According to Bloch (1983) "marijuana smoke exposure has been reported to be associated with chromosomal aberrations ... [such as] hypoploidy, mutagenicity in the Ames test ... " (Bloch, 1983, p413). This is consistent with research indicating that cannabis smoke contains many of the same carcinogens as cigarette smoke (Institute of Medicine, 1982; Leuchtenberger, 1983), suggesting that if cannabis smoke is carcinogenic it is more likely to be because of the carcinogens it shares with cigarette smoke rather than because of the cannabinoids it contains. If it is the non-cannabinoid components of cannabis smoke that are mutagenic, then any cancers caused by cannabis smoking are most likely to develop after long-term exposure to cannabis smoke, and they are most likely to develop at sites which have had the maximum exposure to that smoke, namely, the upper aerodigestive tract and lung. This possibility is considered in more detail below (see pp49-50).

6.2 Immunological effects

The possibility that cannabis reduces immune system function is important for several reasons. First, tobacco smoking suppresses both the humoral and cell-mediated immune systems. Given the similarities between the constituents of cigarette and cannabis smoke (Institute of Medicine, 1982; Leuchtenberger, 1983) it is reasonable to suspect that cannabis may also be an immunosuppressant (Nahas, 1984). Second, even a modest reduction in immunity caused by cannabis use could have public health significance because of the relatively large number of young adults who have used the drug (Munson and Fehr, 1983). Third, if cannabinoids have immunosuppressive effects, then this would have mixed implications for their therapeutic use. On the one hand, they could be therapeutically useful as immunosuppressant drugs in patients undergoing organ transplants. On the other hand, their therapeutic use for other purposes would be limited in patients with impaired immune systems, a restriction which would potentially preclude their use as anti-emetic agents in cancer chemotherapy, or as appetite stimulants and mood enhancers in patients with AIDS.

There are a number of difficulties in deciding whether cannabis impairs the functioning of the immune system. First, the majority of studies that have been conducted have been either in vitro studies in which animal and human cell cultures have been exposed to cannabis smoke or cannabinoids, or in vivo animal studies in which the effects of cannabis and cannabinoid exposure on immune system function have been assessed in live animals. The usual problems of extrapolation from in vivo and in vitro studies to human users are complicated by the fact that many of the effects of cannabinoids on the immune system of animals are only obtained at very high doses which are rarely taken by human beings. Second, the difficulties in interpreting these studies are exacerbated because the results of the small number of human in vivo studies have been conflicting. Third, there have been very few epidemiological studies of immune system functioning and disease susceptibility in heavy chronic cannabis users.

Given that the majority of the in vitro and in vivo animal work was undertaken in the 1970s, we have relied upon the summary of findings provided in the authoritative reviews of this literature undertaken by the Addiction Research Foundation and World Health Organization (Leuchtenberger, 1983; Munson and Fehr, 1983). This enables the present review to focus upon on the clinical and public health significance of the immunological effects observed in the experimental studies. Before doing so, a brief and schematic review will be provided of the components of the human immune system.

6.2.1 The immune system

The immune system in mammals is "an adaptive and a protective mechanism against noxious foreign materials including pathogens and cancer cells" (Munson and Fehr, 1983). Its multiple components include: lymphoid tissues such as the spleen and lymph nodes; the bone marrow and thymus, where lymphocytes and other important cells in the immune system are manufactured; and the recirculating lymphocytes that mediate cellular and humoral immunity (see Grossman and Wilson, 1992; and Nossal, 1993).

Immunity may be either innate or acquired. Innate immunity consists of those responses to foreign substances that do not require sensitisation from previous exposure, such as the ingestion of bacteria by macrophages, and the killing of tumour cells by natural killer cells. Acquired immunity is that form of immunity in which the recognition and destruction of foreign material depends upon processes produced by a previous exposure to the material. It is mediated by the cooperative functioning of two major systems of lymphocyte cells: the B-cells (Thymus-independent lymphocytes) which control humoral immunity, and T-cells (Thymus-dependent lymphocytes) the activity of which controls cell-mediated immunity.

Humoral immunity involves the production of antibodies in response to antigens, usually proteins, which are attached to the surface of foreign cells. Antigens are recognised by the B-cells which proliferate and differentiate into two types of cells, the first of which synthesises and releases antibody, and the second of which remains as antigen-sensitised cells that are able to respond to subsequent exposure to the antigen by rapidly releasing large amounts of antibody. The antibodies can act directly to inactivate the pathogens or toxins by damaging cell membranes, or they can work cooperatively with the cell-mediated immune system by enabling cells called macrophages to recognise and destroy the foreign cells, either by ingesting those cells which have antibodies attached, or by releasing toxins which kill the cells. Cell-mediated immunity is directed against foreign cells including many bacteria, viruses and fungi. Macrophages are intimately involved in the early removal of foreign materials directly by ingestion, or indirectly by altering their antigens and presenting them to the T- and B-cells for the further development of the immune response. They work in concert with the humoral immune system to protect the organism from all pathogens in its environment.

6.2.2 Effects of cannabinoids on lymphoid organs

A non-specific indication of an effect of cannabinoids on the immune system would be a reduction in the weight of lymphoid organs, such as the thymus and spleen, or a decrease in the number of circulating lymphocytes. A substantial body of anatomical and histological studies in animals bearing upon this possibility has been reviewed by Munson and Fehr (1983). These studies reveal that cannabinoids in high doses can affect the function of the stem cells which produce lymphocytes, and can reduce the size of the spleen in rodents. It is uncertain what the implications are for immune system competence because these effects all occur after acute exposure, typically in response to very high doses of cannabinoids. It is also unknown whether these effects occur as the direct result of cannabinoids acting upon the lymphoid cells, or whether they are an indirect effect of cannabinoids acting on the adrenal-pituitary axis to increase the release of corticosteroids which in turn shrink the spleen.

6.2.3 Effects of cannabinoids on humoral immunity

The effect of cannabinoids on humoral immunity has been assessed in vitro by measuring the effect of cannabinoids on the number and functioning of animal and human B-cells produced in response to the presence of sheep red blood cells. Cannabinoids do not consistently alter the number or percentage of B-cells (Munson and Fehr, 1983).

B-cell function has also been assessed in vitro by measuring the proliferation of B-cells in response to chemicals which stimulate the cells to divide, and by assessing antibody production in B-cells that have previously been exposed to cannabinoids. While cannabinoids have been consistently shown to impair the B-cell responses in mice, no such effects have been consistently observed in humans, and the few positive studies have produced results which are still within the normal range (Munson and Fehr, 1983).

Antibody formation to THC has been demonstrated in animals. There are also clinical reports in humans that cannabinoids can exacerbate existing allergies, and there are several reports of demonstrated allergy to cannabinoids in humans (e.g. Freeman, 1983). Munson and Fehr (1983) concluded that: "it appears that cannabinoids can elicit the formation of specific antibodies ... [and that THC] or a metabolite is probably acting as a hapten, combining with a protein to form an antigenic complex" (p289).

Hollister (1992), however, has questioned the clinical significance of this evidence, arguing that:

While it is possible that a few persons may become truly allergic to cannabinoids, it is far more likely that allergic reactions, which have been extremely rare following the use of marijuana, are due to contaminants .. (e.g. bacteria, fungi, molds, parasites, worms, chemicals) that may be found in such field plants. That such impure material, when smoked and inhaled into the lungs, causes so little trouble is really a marvel (p163).

6.2.4 Effects of cannabinoids on cell-mediated immunity

Researchers have examined the effects of cannabinoids on both the numbers and functioning of T-cells and macrophages. There are considerable inconsistencies in the results of studies on the effects of cannabinoids on T-cell numbers in humans, with some studies showing reductions (e.g. Nahas et al, 1974) while others have not (e.g. Dax et al, 1989). There is also mixed evidence on the effect of cannabinoids on T-cell functioning as assessed by response to allogenic cells and mitogens, chemicals which stimulate the cells to divide. A number of the earliest studies suggested that T-cells from chronic cannabis users showed a decreased responsiveness to such stimulation, but later studies, including laboratory studies of chronic heavy dosing in humans (e.g. Lau et al, 1976), have failed to replicate these results. Studies of in vitro exposure of T-cells to cannabinoids have also produced mixed results, while animal studies have showed a decreased T-cell response to mitogens (Munson and Fehr, 1983).

Interpretations of this literature differ. Munson and Fehr (1983) concluded that the fact that cannabinoids can affect T-cell function in several species of animals "suggests that the same effects could occur in humans given exposure to these substances" (pp306-307). Nahas (1984) concluded that "there is only suggestive" evidence that cannabinoids "exert an immunodepressive effect" (p156). Hollister (1986) argued that even if there were such effects, they were of limited clinical significance because they were probably transient effects in healthy young adults, and there was no evidence of increased susceptibility to disease in cannabis smokers. More recently, Hollister (1992) has concluded that "... the effects of cannabinoids on cell-mediated immunity are contradictory. Such evidence as has been obtained to support such an effect has usually involved doses and concentrations that are orders of magnitude greater than those obtained when marijuana is used by human subjects. (p161)"

6.2.5 Effects of cannabinoids on host resistance

It is one thing to decide that in vitro exposure of the immune system to high doses of cannabinoids impairs its functioning in various ways; it is much more difficult to decide whether the small impairments in immunity predicted by in vitro studies is likely to impair host resistance to pathogens and infection with micro-organisms among human cannabis users. There is a very small animal, and almost no human, literature on which to make such a decision.

A small number of studies in rodents (mice and guinea pigs) has suggested that high doses (200mg/kg) of cannabinoids decrease resistance to infection (Friedman, 1991), e.g. with Lysteria monocytogenes (Morahan et al, 1979), and herpes simplex type 2 virus (Cabral et al, 1986; Mishkin and Cabral, 1985; Morahan et al, 1979). A reasonably consistent finding in humans has been that exposure to cannabis smoke adversely affects alveolar macrophages, cells in the respiratory system that constitute a first line of bodily defence against many pathogens and micro-organisms which enter the body via the lungs (Leuchtenberger, 1983). Studies of these cells obtained from cannabis smokers have demonstrated ultrastructural abnormalities (Tennant, 1980), and studies of the in vitro exposure of alveolar macrophages to cannabis smoke have demonstrated that their ability to inactivate Staphylococcus aureus (Leuchtenberger, 1983; Munson and Fehr, 1983), and more recently the fungus Candida albicans (Sherman et al, 1991) has been impaired. In this case, however, it seems to be the non-cannabinoid components of cannabis smoke that produce the effect (Leuchtenbeger, 1983).

6.2.6 Human significance of immunological effects of cannabinoids

The animal evidence is reasonably consistent that cannabinoids produce impairments of the cell-mediated and humoral immune systems, and in several studies these changes have been reflected in decreased resistance to bacteria and viruses. There is also evidence that the non-cannabinoid components of cannabis smoke can impair the functioning of alveolar macrophages, the first line of the body's defence system. However, the doses required to produce these immunological effects have varied from the behaviourally relevant to very high doses. This raises the issue of whether their findings can be extrapolated to the doses used by humans.

The possibility of tolerance developing to any immunological effects of cannabinoids also makes the human significance of the results of in vitro studies uncertain. If immunological tolerance develops with chronic use, then the possibility of observing even the small effects projected from the in vitro studies would be substantially reduced. There have been no demonstrations that such tolerance occurs in animals, in part because most studies have used short duration, high dosing schedules rather than chronic high dosing required for tolerance to be demonstrated. Given the large number of cannabinoid effects to which tolerance has been shown to develop, it would not be surprising if this were also true of its immunological effects.

The very limited human evidence from experimental studies of immune function is mixed, with a small number of studies suggesting immunosuppressant effects that have not been replicated by others. As Munson and Fehr (1983) concluded: "At present, there is no conclusive evidence that consumption of cannabinoids predisposes man to immune dysfunction" (p338), as measured by reduced numbers or impaired functioning of T-lymphocytes, B-lymphocytes or macrophages, or reduced immunoglobulin levels. There was "suggestive evidence" of impaired T-lymphocyte functioning reflected in an impaired reaction to mitogens and allogenic lymphocytes (Munson and Fehr, 1983). More recently, Wallace et al (1988, 1993 in press) have failed to find any impairment of lymphocyte function in alveolar macrophages in marijuana smokers, although they did find such impairment in tobacco smokers.

The clinical significance of these possible immunological impairments in chronic cannabis users is uncertain. There have been sporadic reports of ill health, including decreased resistance to disease, among chronic heavy cannabis users in Asia and Africa (Munson and Fehr, 1983). These reports are difficult to evaluate because of the confounding effects of poor living conditions and nutritional status, although it may be that the small human immunological impairment predicted from the animal literature is most likely to be seen among such populations (Munson and Fehr, 1983).

Three field studies of the effects of chronic cannabis use in Costa Rica (Carter et al, 1980), Greece (Stefanis et al, 1977), and Jamaica (Rubin and Costas, 1975), have failed to demonstrate any evidence of increased susceptibility to infectious diseases among chronic cannabis users. However, these negative findings are not very convincing. Less than 100 users were studied overall, which is too small a sample in which to detect a small increase in the incidence of common infectious and bacterial diseases. While it is difficult to detect a small increase in the incidence of infections in an individual or among a small sample of people, such an increase may have great public health significance. The type of large-scale epidemiological studies that are needed to explore this issue have not been conducted until very recently.

A recent study by Polen et al (1993) compared health service utilisation by non-smokers and daily cannabis only smokers enrolled in a health maintenance organisation. Their results provided the first suggestive evidence of an increased rate of presentation for respiratory conditions among cannabis-only smokers, although its significance remains uncertain because infectious and non-infectious respiratory conditions were aggregated. Nevertheless, further studies of this type may enable a more informed decision to be made about the seriousness of the risk that chronic heavy cannabis smoking poses to the immune and respiratory systems.

Hollister (1992) has expressed a sceptical attitude towards the human health implications of the literature on the immunological effects of cannabis, arguing that:

... Clinically, one might assume that sustained impairment of cell-mediated immunity might lead to an increased prevalence of malignancy. No such clinical evidence has been discovered or has any direct epidemiological data incriminated marijuana use with the acquisition of human immunodeficiency virus or the clinical development of AIDS. (p161)

Given the duration of large-scale cannabis use by young adults in Western societies, the absence of an epidemic of infectious disease is arguably sufficient to rule out the hypothesis that cannabis smoking produces major impairments in the immune systems of users comparable to those caused by AIDS. The absence of such epidemics among cannabis users does not, however, exclude the possibility that chronic heavy use may produce minor impairments in immunity, since this would produce small increases in the rate of occurrence of common bacterial and viral illnesses (Munson and Fehr, 1983) that would have escaped the notice of clinical observers. Such an increase could nonetheless be of public health significance because of the increased expenditure on health services, and the loss of productivity among the young adults who are the heaviest users of cannabis.

Clinical studies of patients with immune systems compromised by AIDS may provide one of the best ways of detecting any adverse immunological effects of cannabinoids. AIDS patients and gay advocacy groups have proposed that cannabinoids should be used therapeutically to improve appetite and well-being in AIDS patients (see below p195). If it was ethical to conduct trials of the therapeutic use of cannabinoids in AIDS patients, then monitoring the impact on immune functioning would provide one way of evaluating the seriousness of the immunological effects of cannabinoids, not only for AIDS patients, but also for other immunologically compromised patients using cannabinoids for therapeutic purposes. If there were no effects in patients with compromised immune systems, it would also be a reasonable to infer that there was little risk of immunological effects in long-term recreational users.

An epidemiological study of predictors of progression to AIDS among HIV positive homosexual men suggests that the risks may be sufficiently small in the case of HIV positive patients to warrant further research. Kaslow et al (1989) conducted a prospective study of progression to AIDS among HIV positive men in a cohort of 4,954 homosexual and bisexual men. Among the predictor variables studied were licit and illicit drug use, including cannabis use. Illicit drug use predicted an increased risk of infection with HIV, as has been consistently found in studies of risk factors for HIV infection. However, neither cannabis use, nor any other psychoactive drug use, predicted an increased rate of progression to AIDS among men who were HIV positive. Nor was cannabis use related to changes in a limited number of measures of immunological functioning.

6.2.7 Conclusions

There is reasonable evidence that cannabis smoke is mutagenic, and hence, potentially carcinogenic, because of the many mutagenic and carcinogenic substances it shares with tobacco smoke. THC is at most weakly mutagenic. This suggests that the major cancer risk from cannabis use is the development of cancers of the respiratory tract arising from smoking as a route of administration, rather than from the mutagenicity of the psychoactive components of cannabis.

There is reasonably consistent animal evidence that THC can impair both the cell-mediated and humoral immune systems, producing decreased resistance to infection by bacteria and viruses. The relevance of these findings to human health is uncertain: the doses required to produce these effects are often very high, and the problem of extrapolating from the effects of these doses to those used by humans is complicated by the possibility that tolerance develops to the effects on the immune system.

The limited experimental evidence on immune effects in humans is conflicting, with the small number of studies producing adverse effects not being replicated. Even studies that have produced evidence of adverse effects observe small changes that are still within the normal range. The clinical and biological significance of even the small positive effects in chronic cannabis users is uncertain. There has not been any evidence of increased rates of disease among chronic heavy cannabis users analogous to that seen among homosexual men in the early 1980s. Given the duration of large-scale cannabis use by young adults in Western societies, the absence of such epidemics makes it unlikely that cannabis smoking produces major impairments in the immune system.

It is more difficult to exclude the possibility that chronic heavy cannabis use produces minor impairments in immunity. Such effects would produce small increases in the rates of infectious diseases of public health significance, because of the increased expenditure on health services, and the loss of productivity among the young adults who are the heaviest users. There is one large prospective study of HIV-positive homosexual men which indicates that continued cannabis use did not increase the risk of progression to AIDS (Kaslow et al, 1989). A recent epidemiological study by Polen et al (1993) which compared health service utilisation by non-smokers and daily cannabis-only smokers provided the first suggestive evidence of an increased rate of medical care utilisation for respiratory conditions among cannabis smokers. This remains suggestive, however, because infectious and non-infectious respiratory conditions were not distinguished. The most sensitive assay of any small immunological effects of cannabis may come from studies of the therapeutic usefulness of cannabinoids in immunologically compromised patients, such as those undergoing cancer chemotherapy, or those with AIDS.

6.3 Cardiovascular effects

Both the inhalation of marijuana smoke and the ingestion of THC reliably produces an increase in heart rate of 20 per cent to 50 per cent over baseline (Huber et al, 1988; Jones, 1984). When cannabis is smoked, the heart rate increases within two to three minutes, peaks within 15 to 30 minutes, and may remain elevated for up to two hours. When ingested, these effects are delayed for several hours, and last for four to five hours (Maykut, 1984). There are also complex changes in blood pressure which depend upon posture: blood pressure is increased while the person is sitting or lying, but decreases on standing, so that a sudden change from a recumbent to an upright position may produce postural hypotension and, in extreme cases, fainting (Maykut, 1984).

Young, healthy hearts are likely to be only mildly stressed by these acute effects of cannabis (Tennant, 1983). The clinical significance of the repeated occurrence of these effects in chronic heavy cannabis users remains uncertain, because there is evidence from clinical and experimental studies (Benowitz and Jones, 1975; Jones and Benowitz, 1976; Nowlan and Cohen, 1977) that tolerance develops to the acute cardiovascular effects of cannabis. Clinical studies employing chronic dosing over periods of up to nine weeks show that the increased heart rate all but disappears, while the blood pressure increase is much attenuated. Tolerance to the cardiovascular effects develops within seven to 10 days in persons receiving high daily doses by the oral route (Jones, 1984).

The field studies of chronic heavy users in Costa Rica (Carter et al, 1980), Greece (Stefanis et al, 1977), and Jamaica (Rubin and Costas, 1975) failed to disclose any evidence of cardiac toxicity, even in those subjects with heart disease that was unrelated to their cannabis use. The findings of the field studies have been supported by the fact that electrocardiographic studies in conditions of both acute and prolonged administration have rarely revealed pathological changes (Benowitz and Jones, 1975; Jones, 1984). It seems reasonable to conclude then that among healthy young adults who use cannabis intermittently, cannabis use is not a major risk factor for life-threatening cardiovascular events in the way that the use of cocaine and other psychostimulants can be (Gawin and Ellinwood, 1988). There is suggestive evidence of a small risk, however, since there have been a number of case reports of myocardial infarction in young men who were heavy cannabis smokers and had no personal history of heart disease (Tennant, 1983; Choi and Pearl, 1989; Pearl and Choi, 1992; Podczeck et al, 1990). Such cases deserve close investigation to exclude the role of other cardiotoxic drugs.

The possibility remains that chronic heavy cannabis smoking may have more subtle effects on the cardiovascular system. Jones (1984) has suggested, for example, that there is a possibility that "after years of repeated exposure" there may be "lasting, perhaps even permanent, alterations of the cardiovascular system function" (p331). Arguing by analogy with the long-term cardiotoxic effects of tobacco smoking, he suggests that there are "enough similarities between THC and nicotine cardiovascular effects to make the possibility plausible" (p331). Moreover, since many cannabis smokers are also cigarette smokers, there is the possibility that there may be adverse interactions between nicotine and cannabinoids in their effects on the cardiovascular system.

6.3.1 Effects on patients with cardiovascular disease

The cardiovascular effects of cannabis may adversely affect patients with pre-existing cardiovascular disease. As the Institute of Medicine observed:

the possibility is great that the abnormal heart and circulation will not be as tolerant of an agent that speeds up the heart, sometimes unpredictably raises or drops blood pressure, and modifies the activities of the autonomic nervous system (pp69-70).

There are a number of concerns about the potentially deleterious effects of cannabis use on patients with ischaemic heart disease, hypertension, and cerebrovascular disease (Jones, 1984; National Academy of Science, 1982). First, THC appears to increase the production of catecholamines which stimulate the activity of the heart, thereby increasing the risk of cardiac arrhythmias in susceptible patients. Second, THC increases heart rate, thereby producing chest pain (angina pectoris) in patients with ischaemic heart disease, and perhaps increasing the risk of a myocardial infarction. Third, THC also has analgesic properties (see below p194) which may attenuate chest pain, delaying treatment seeking, and thereby perhaps increasing the risk of fatal arrhythmias. Fourth, marijuana smoking increases the level of carboxyhaemoglobin, thereby decreasing oxygen delivery to the heart, increasing the work of the heart and, perhaps, the risk of atheroma formation. Moreover, the reduced delivery of oxygen to the heart is compounded by a concomitant increase in the work of the heart - and therefore its oxygen requirements - because of the tachycardia induced by THC. Fifth, patients with cerebrovascular disease may be put at risk of experiencing strokes by unpredictable changes in blood pressure, and patients with hypertension may experience exacerbations of their disease for the same reason.

After considering the known cardiovascular effects of THC, and their likely interactions with cardiovascular disease, the Institute of Medicine (1982) concluded that it: " ... seems inescapable that this increased work, coupled with stimulation by catecholamines, may tax the heart to the point of clinical hazard" (p70). Despite the plausibility of the reasoning, there is very little direct evidence of the adverse effects of cannabis on persons with heart disease (Jones, 1984). Among the few relevant pieces of research evidence are two laboratory studies of the acute cardiovascular effects of smoking marijuana cigarettes on patients with occlusive heart disease. Aronow and Cassidy (1974) conducted a double blind placebo control study comparing the effect on heart rate and the time required to induce chest pain during an exercise tolerance test, of smoking a single marijuana cigarette containing 20mg of THC, with the effect of a placebo marijuana cigarette. Heart rate increased by 43 per cent, and the time taken to produce chest pain was approximately halved, after smoking a marijuana cigarette. It appeared that cannabis increased the myocardial oxygen demand while reducing the amount of oxygen delivered to the heart (Aronow and Cassidy, 1974).

Aronow and Cassidy (1975) compared the effects of smoking a single marijuana cigarette and a high nicotine cigarette in 10 men with occlusive heart disease, all of whom were 20 a day cigarette smokers. A 42 per cent increase in heart rate was observed after smoking the marijuana cigarette compared with a 21 per cent increase after smoking the tobacco cigarette. Exercise tolerance time was halved (49 per cent) after smoking a marijuana cigarette by comparison with a 23 per cent decline after smoking a tobacco cigarette.

Apart from these studies, there is very little direct evidence on the risks of cannabis use by persons with cardiovascular disease. The reasons for the absence of adverse effects of chronic cannabis use on diseased cardiovascular systems are unclear. It should not be assumed in the absence of evidence, however, that such effects do not exist. The absence of evidence may simply reflect the lack of systematic study. It may be that the development of tolerance to the cardiovascular effects with chronic heavy dosing has protected the heaviest users from experiencing such effects: it may be that there has been an insufficient exposure to cannabis smoking of a sufficiently large number of vulnerable individuals (National Academy of Science, 1982); or it may be that cardiologists have missed any such evidence because they have not inquired about cannabis use among their patients.

On the face of it, the possibility of cannabis smokers developing heart disease may seem "theoretical". Most cannabis users are healthy young adults who smoke intermittently, most discontinue their use by their late 20s, and very few of the minority who become heavy cannabis users are likely to have clinical occlusive heart disease or other atherosclerotic disease. But the possibility of such adverse effects is not entirely theoretical.

First, any such effects would contraindicate the therapeutic uses of cannabinoids among older patients, such as those with cancer and glaucoma, who are at higher risk, because they are older, of having significant heart disease (Jones, 1984).

Second, the chronic heavy cannabis users who were inducted into cannabis use in the late 1960s and early 1970s are now entering the period in which that minority who have continued to smoke cannabis are at risk of experiencing symptoms of clinical heart disease. Among this group cannabis use may contribute to an earlier expression of heart disease, especially, if they have also been heavy cigarette smokers. Because of the high rates of cessation of cannabis use with age, however, this may be such a small number of persons that the effect is difficult to detect clinically, especially if cannabis use is not considered to be a risk factor about which cardiologists systematically inquire. It may be worth exploring this possibility by including questions on cannabis use in case-control studies of cardiovascular disease among middle-aged adults.

6.3.2 Conclusions

On the available evidence, it is still appropriate to endorse the conclusions reached by the expert committee appointed by the National Academy of Science in 1982 that, although the smoking of marijuana "causes changes to the heart and circulation that are characteristic of stress ... there is no evidence ... that it exerts a permanently deleterious effect on the normal cardiovascular system..." (p72). The situation may be less benign for those with "abnormal heart or circulation" since there is evidence that marijuana poses "a threat to patients with hypertension, cerebrovascular disease and coronary atherosclerosis" (p72) by increasing the work of the heart. The "magnitude and incidence" of the threat remains to be determined as the cohort of chronic cannabis users of the late 1960s enters the age of maximum risk for complications of atherosclerosis of the cardiac, brain and peripheral vessels. In the interim, because any such effects could be life threatening in patients with significant occlusion of the coronary arteries or other cerebrovascular disease, such persons should be advised not to smoke cannabis (Tennant, 1983).

6.4 Effects on the respiratory system

The most reliable acute effect of exposure to cannabis smoke is bronchodilation (National Academy of Science, 1982), which has principally been of interest because of its possible therapeutic effect upon asthma (see below pp193-194). Other than bronchodilation, it has proved difficult to demonstrate any effects of acute cannabis smoking on breathing "as measured by conventional pulmonary tests" (National Academy of Science, 1982, p58).

The major concerns about the respiratory effects of cannabis use have been the possible adverse effects of chronic, heavy cannabis smoking (Tashkin, 1993). The two largest issues of concern have been the production of chronic bronchitis as a precursor of irreversible obstructive lung disease, and the possible causation of cancers of the aerodigestive tract (including the lungs, mouth, pharynx, larynx, and trachea) after 20 to 30 years of regular cannabis smoking. These risks are the primary focus of this section of the review.

There is good reason to expect that chronic heavy cannabis smoking may have adverse effects upon the respiratory system (Tashkin, 1993). Cannabis smoke is similar in constitution to tobacco smoke, and contains a substantially higher proportion of particulate matter and of some carcinogens (e.g. benzpyrene) than does tobacco smoke (Leuchtenberger, 1983; National Academy of Science, 1982). Hence, the inhalation of cannabis smoke deposits irritating and potentially carcinogenic particulate matter onto lung surfaces. Cigarette smoking is known to cause diseases of the respiratory system, such as bronchitis, emphysema, and various forms of cancer affecting the lung, oral cavity, trachea, and oesophagus (Holman et al, 1988). Although tobacco smokers smoke many more cigarettes than cannabis smokers, cannabis smoke is typically inhaled more deeply, and the breath held for longer, than tobacco smoke, thereby permitting greater deposition of particulate matter on the lung surface (Hollister, 1986). It therefore seems a reasonable inference that chronic daily cannabis smoking may cause diseases of the respiratory system.

Despite the reasonableness of this hypothesis, it has nonetheless been difficult to investigate the contribution of chronic heavy cannabis smoking to diseases of the respiratory system (Huber et al, 1988; National Academy of Science, 1982). A major problem is that most marijuana smokers also smoke tobacco, which makes it difficult to disentangle the effects of cannabis from those of tobacco smoking. The problems in quantifying current and lifetime exposure to cannabis, because of variations in quality and potency, make it difficult to examine dose-response relationships between cannabis use and the risk of developing various respiratory diseases. There is also likely to be a long latency period between exposure and the development of these diseases, especially in the case of cancers of the aerodigestive tract. This period is approximately the length of time since cannabis smoking became widespread in Western societies. There are also technical difficulties in designing studies which are sufficiently sensitive to detect increased risks of diseases arising from relatively rare exposures, such as chronic daily cannabis use.

6.4.1 Bronchitis and airways obstruction

There is a small clinical literature containing case reports of acute lung diseases among heavy cannabis smokers in the US military stationed in West Germany during the early 1970s, when hashish was cheap and freely available (Henderson et al, 1972; Tennant et al, 1971). Tennant et al studied 31 soldiers who had smoked 100g or more of hashish monthly for six to 21 months, 21 of whom were also tobacco smokers. Nine complained of bronchitis which had its onset three to four months after they began to smoke hashish. Pulmonary function tests of five cases (two of whom did not smoke tobacco) revealed mild airflow obstruction that partially remitted after a reduction or cessation of hashish use. Tennant (1980) also reported histopathological studies of 23 of these patients in which all patients were found to have atypical cells of the type (squamous metaplasia in 21 cases) associated with chronic bronchitis and carcinoma of the lung.

Henderson et al (1972) reported on 200 servicemen who sought treatment for problems related to hashish use, 90 per cent of whom were also cigarette smokers. Twenty men who smoked large doses of hashish on a weekly basis presented with symptoms of chronic bronchitis, and on testing had vital capacity that was 15-40 per cent below normal. Six had a bronchoscopic examination which showed epithelial abnormalities. The interpretation of these findings was complicated by the fact that the majority of these hashish smokers were also tobacco smokers, as were Tennant et al's subjects, and there was no adequate comparison group.

The field studies of chronic cannabis smokers in Costa Rica (Carter et al, 1980) and Jamaica (Rubin and Comitas, 1975), which included comparison groups, have failed to support the clinical findings of Henderson et al, and Tennant et al. Neither of these studies found any statistically significant differences in lung function, or in the prevalence of respiratory symptoms, between chronic cannabis users and non-cannabis smoking controls. In both studies, however, the measures of respiratory function were relatively unsophisticated, the sample sizes were small, making it difficult to detect all but very large differences, and the comparisons were often confounded by a failure to control for tobacco smoking.

The most convincing evidence that chronic cannabis use may be a contributory cause of impaired lung function and symptoms of respiratory disease comes from a series of controlled studies which have been conducted by Tashkin and his colleagues since the mid-1970s. One of their early studies evaluated the subacute effects of heavy daily marijuana smoking on respiratory function. The subjects were young male marijuana smokers who were studied in a closed hospital ward where they were allowed ad libitum access to marijuana for 47 to 59 days. The results of lung function tests showed a statistically significant decrease in the function of large and medium-sized airways over the course of the study. The degree of impairment was positively correlated with the number of marijuana cigarettes smoked, suggesting that the quantity of inhaled irritants was the important factor, perhaps by producing an inflammatory reaction in the tracheobronchial epithelium. Although the impairment was apparently small and values were still within the normal range, these changes were of clinical significance. If continued over a year, for example, the rate of decline in lung function would be several times greater than the normal rate.

Tashkin and his colleagues (1987) subsequently recruited a volunteer sample of marijuana only smokers (MS, n=144), marijuana and tobacco smokers (MTS, n=135), tobacco only smokers (TS, n=70), and non-smoking controls (NS, n=97). A subset of these subjects were followed to examine changes in lung function, signs and symptoms of respiratory disease, and the occurrence of histopathological changes that may precede the development of carcinoma.

In the baseline observations of their cohort, Tashkin et al (1987) found significant differences in the prevalence of symptoms of bronchitis (such as cough, bronchitic sputum production, wheeze and shortness of breath) between all types of smokers (MS, MTS, TS) and controls. There were no differences between cannabis and tobacco smokers in the prevalence of these symptoms. Lung function tests showed significantly poorer functioning and significantly greater abnormalities in small airways among tobacco smokers (regardless of concomitant cannabis use) while marijuana smokers showed poorer large airways functioning than non-marijuana smokers (regardless of concomitant tobacco use). These findings suggest that "habitual smoking of marijuana or tobacco causes functional alterations at different sites in the respiratory tract, with marijuana affecting mainly the large airways and tobacco predominantly the peripheral airways and alveolated regions of the lung" (Tashkin et al, 1990, p67).

Follow-up studies of a subsample of this cohort have broadly supported the results of the cross-sectional baseline study, while providing more detail on some differences between marijuana and tobacco smoking in their effects on lung function (Tashkin et al, 1990). The first follow-up study was conducted two to three years after the baseline study. Approximately half of these subjects were retested and most remained in the same smoking categories as at baseline, namely, 40 of the 54 MTS, 60 of the 71 MS, 30 of the 32 TS, and 56 of 58 NS, respectively of those who were followed up.

The prevalence of bronchitic symptoms of cough, sputum, and wheeze was higher in all smoking groups than among non-smokers at both time one and time two, and there was no significant change in the respiratory status of any of the smoking groups from time one to time two when those individuals who ceased smoking were excluded. Substantially the same results were obtained when the subjects were followed up three to four years after initial assessment. In addition, there was evidence of an additive adverse effect of marijuana and cigarette smoking, in that the MTS group showed effects of both types of damage attributable to marijuana and tobacco smoking alone.

Tashkin and his colleagues (Fligiel et al, 1988; Gong et al, 1987) undertook histopathological studies of the lungs of a subsample of their cohort. Fligiel et al (1988) compared the bronchial morphology of males aged 25 to 49 years who were heavy smokers of marijuana only (n=30), marijuana and tobacco (n=17), tobacco only (n=15) and non-smoking controls (n=11). Bronchial biopsies were examined by pathologists who were "blind" as to their smoking status, and analyses were made of cellular inflammation. All subjects who smoked (whether cannabis, tobacco or both) showed more prevalent and severe histopathological abnormalities than non-smokers. Many of these abnormalities were more prevalent in marijuana smokers, and they were most marked in those who smoked both marijuana and tobacco.

These findings were especially striking because they were observed in young adults who did not have respiratory symptoms, and they occurred at a younger age on average in marijuana than tobacco smokers, despite the fact that the marijuana smokers smoked less than a quarter as many "joints" as the tobacco smokers smoked cigarettes. Fliegel et al concluded that "marijuana smoking may be as damaging or perhaps even more damaging to the respiratory epithelium than smoking of tobacco" (p46), and there was "a very good possibility ... that marijuana smoking combined with smoking of tobacco, leads to a more significant mucosal alteration than either of these substances smoked alone" (p47).

Evidence of inflammation was sought by examining the presence of alveolar macrophages, lymphocytes, neutrophils and eosinophils in the bronchial lavage of the same subjects. This examination revealed that marijuana and tobacco smoking induced an inflammatory cellular response in the alveoli, and that the combination of marijuana and tobacco smoking produced the largest inflammatory response, "implying an adverse effect of marijuana smoking on the lung that is independent of and additive to that of tobacco" (Tashkin et al, 1990, p74).

Additional research by Tashkin and his colleagues (Tashkin et al, 1988; Wu et al, 1988) suggests that the most likely explanations of the apparently greater toxicity of marijuana smoking are major differences in the topography of marijuana and tobacco smoking. Laboratory studies of the volume of inhaled smoke from tobacco and marijuana, and analyses of its particulate content, indicated that marijuana smokers inhaled a larger volume of smoke (40-54 per cent more), inhaled more deeply, took in more particulate matter per puff, and held their breath about four to five times longer, thereby retaining more particulate matter, and absorbing three times more carbon monoxide, than cigarette smokers (Wu et al, 1988).

Bloom et al (1987) have recently reported findings that broadly confirm those of Tashkin and his colleagues. Bloom et al conducted a cross-sectional study in a general population of the relationship between smoking "non-tobacco" cigarettes and respiratory symptoms and respiratory function. Their study sample was a community sample of 990 individuals aged under 40 years who were being followed as part of a prospective community study of obstructive airways disease. Subjects were asked about symptoms of cough, phlegm, wheeze and shortness of breath, and they were also measured on a number of indicators of respiratory function, including forced expiratory volume and forced vital capacity.

The prevalence of ever having smoked a "non-tobacco" cigarette was 14 per cent (the same as the prevalence of marijuana smoking in general population surveys), with 9 per cent being current smokers and 5 per cent ex-smokers. Non-tobacco smokers were younger and more likely to be male than non-smokers of non-tobacco. The mean frequency of current non-tobacco smoking was seven times per week, and the average duration of use was nine years. Non-tobacco smokers were more likely than non-tobacco non-smokers to have smoked tobacco, and more likely to inhale deeply than tobacco smokers.

Non-tobacco smoking was related to the prevalence of the self-reported respiratory symptoms of cough, phlegm, and wheeze, regardless of whether the person smoked tobacco or not. There were also mean differences in forced expiratory volume and forced vital capacity, with those who had never smoked having the best functioning, followed in decreasing order of function by current cigarette smokers, current non-tobacco smokers, and current smokers of both tobacco and non-tobacco cigarettes. Non-tobacco smoking alone had a larger effect on all flow indices than tobacco smoking alone, and the effect of both types of smoking was additive.

Although there were some inconsistencies between the studies of Tashkin and colleagues and those of Bloom and colleagues, there is reasonable coherence in the available evidence on the respiratory effects of cannabis use. Taken as a whole, it suggests that chronic cannabis smoking increases the prevalence of bronchitic symptoms, reduces respiratory function, and in very heavy smokers produces histopathological changes that may portend the subsequent development of bronchogenic carcinoma, a well known consequence of heavy tobacco smoking. Although, "there is still no conclusive evidence in man of clinically important pulmonary dysfunction produced by smoking marihuana" (Huber et al, 1988; p8), it is nonetheless a reasonable inference that chronic heavy cannabis smoking probably increases the risk of developing respiratory tract cancer, and possibly influences the development of irreversible obstructive pulmonary disease. Persons who wish to reduce their risks of developing these diseases would be wise to desist from cannabis smoking (Tashkin, 1993).

6.4.2 Cancers of the aerodigestive tract

Although "not a single case of bronchogenic carcinoma in man has been directly attributable to marijuana" (Tashkin, 1988), it would be unwise to infer from the absence of such cases that there is no such an effect (Huber et al, 1988; National Academy of Science, 1982). There is a 20 to 30-year latency period between the initiation of regular smoking and the development of cancer, and cannabis smoking only became widespread in Western societies in the early 1970s (National Academy of Science, 1982). There has also been a lack of clinical and epidemiological research on this question. Patients with lung or of other types of cancer, for example, have rarely been asked about their cannabis use as part of the clinical history-taking. No cohort or case-control studies of cancers among cannabis smokers have been reported, because the illegality of cannabis has made it difficult to obtain reliable information on habits of the large samples required, while the proportion of cannabis users who become long-term heavy users is likely to be small (Huber et al, 1988).

Despite the absence of such evidence, there are good reasons for suspecting that cannabis may contribute to the development of lung cancer and cancers of the aerodigestive tract (the oropharynx, nasal and sinus epithelium, and the larynx). A major reason is the similarity between the constituents of cannabis and tobacco smoke, an accepted cause of cancers in these organs (Doll and Peto, 1980; International Agency for Research on Cancer, 1990). The major qualitative differences between tobacco and cannabis smoke are the presence of cannabinoids in cannabis smoke and of nicotine in tobacco. There are also some quantitative differences in the amount of various carcinogens with cannabis smoke typically containing higher levels than tobacco smoke (Leuchtenberger, 1983; National Academy of Science, 1982).

The work of Fligiel et al (1988) has indicated that histopathological changes of the type that are believed to be precursors of carcinoma can be observed in the lung tissue of chronic marijuana smokers. These results confirmed the earlier finding of Tennant (1980), who performed bronchoscopies on 30 US servicemen stationed in Europe who had smoked large quantities of hashish and experienced symptoms of bronchitis. He found that 23 of these who also smoked tobacco had one or more pathological changes "identical to those associated with the later development of carcinoma of the lung when it occurs in tobacco smokers" (Tennant, 1983, p78).

The results of these clinical and laboratory studies have recently received suggestive support from case reports of cancers of the upper aerodigestive tract in young adults who have been chronic cannabis smokers. Donald (1991a, b) reported 13 cases of advanced head and neck cancer occurring in young adults under 40 years of age among 3,000 of his cancer patients. Their average age was 26 years (range 19-38 years), compared with an average age of 65 years among his other patients. Eleven of the 13 had been daily cannabis smokers. Interpretation is complicated by the fact that at least five of these patients also smoked tobacco, and at least three were heavy alcohol consumers, both known risk factors for cancers of the upper aerodigestive tract (Holman et al, 1988; Vokes et al, 1993). Donald acknowledged these facts, but emphasised that half of his cases neither smoked tobacco nor consumed alcohol. Moreover, he argued, the implication of marijuana as a cause of cancers of the upper aerodigestive tract was strengthened by the observation that such cancers are rare under the age of 40 years, even among tobacco smokers who consume alcohol.

Similar findings have been reported by Taylor (1988) in a retrospective analysis of cases of upper respiratory tract cancer occurring in adults under the age of 40 years over a four-year period. Because the medical records did not routinely report the patients' use of cannabis, Taylor asked the attending clinicians to make judgments about their patients' cannabis and other drug use. He found 10 cases among the 887 cases of cancer that were treated over the study period. They consisted of six males and four females with an average age of 33.5 years. Nine were cases of squamous cell carcinomas (of the tongue, the larynx, and the lung). Five cases had a documented history of heavy cannabis smoking, two patients were described as "regular" cannabis users, one was classified as a "possible" cannabis user because he was known to abuse other drugs, and two were judged not to be cannabis users. As with Donald's case series, interpretation was complicated by the fact that six out of 10 were heavy alcohol consumers, and six were cigarette smokers (four out of the five heavy cannabis users in each case).

Taylor argued "that the regular use of marijuana is a potent etiologic factor, particularly in the presence of other risk factors, in hastening the development of respiratory tract carcinomas" (p1216). While he allowed that alcohol and tobacco use may have contributed to the development of these cancer, he discounted their importance, arguing like Donald, that the patients were well under 40 years of age, while the peak incidence of such cancers in drinkers and smokers is in the seventh decade of life.

Other investigators (e.g. Caplan and Brigham, 1989; Endicott and Skipper, 1991, cited by Nahas and Latour, 1992) have also reported cases of upper respiratory tract cancers in young adults with histories of heavy cannabis use. Caplan and Brigham's (1989) report of two cases of squamous cell carcinoma of the tongue in men aged 37 and 52 years was especially noteworthy because neither of their cases smoked tobacco or consumed alcohol; a history of long-term daily cannabis use was their only shared risk factor.

These case reports provide limited support for the hypothesis that cannabis use is a cause of upper respiratory tract cancers. They did not compare the prevalence of cannabis use in cases with that in a control sample, and cannabis exposure was not assessed in a standardised way or in ignorance of the case or control status, all of which are standard controls to minimise bias in case-control studies of cancer aetiology. Nonetheless, there is a worrying consistency about the reports that should be addressed by case-control studies which compare the proportions of cannabis smokers among patients with cancers of the upper aerodigestive tract and appropriate controls (National Academy of Science, 1982). Now may be the time to conduct such studies, since chronic cannabis smokers who began their use in early 1970s are now entering the period of risk for such cancers. If carcinomatous changes occur earlier in heavy cannabis smokers, it may be better to restrict attention to early onset cases (e.g. cases occurring in individuals under 50 years of age). Information on cannabis use should also be obtained prospectively in newly diagnosed cases, because of the problems with retrospective assessment of cannabis and other drug use from either clinical records or the relatives of those who have died.

6.4.3 Conclusions

Chronic heavy cannabis smoking probably causes chronic bronchitis, and impairs functioning of the large airways. Given the documented adverse effects of cigarette smoking, it is likely that chronic cannabis use predisposes individuals to develop irreversible obstructive lung diseases. There is suggestive evidence that chronic cannabis smoking produces histopathogical changes in lung tissues that are precursors of lung cancer. Case studies raise a strong suspicion that cannabis may cause cancers of the aerodigestive tract. The conduct of case-control studies of these cancers is a high priority for research into the possible adverse health effects of chronic cannabis smoking.

6.5 Reproductive effects of cannabis

In the mid-1970s there seemed to be good reason to suspect that cannabis use had adverse effects on the human reproductive system. There was some animal experimentation which suggested that cannabis adversely affected the secretion of gonadal hormones in both sexes, and the foetal development of animals administered crude marijuana extract or THC during pregnancy (Bloch, 1983; Institute of Medicine, 1982; Nahas, 1984; Nahas and Frick, 1987; Wenger et al, 1992). Cannabis was being widely used by adolescents who were undergoing sexual maturation, and by young adults who were entering the peak age for reproduction (Linn et al, 1983). The suspicion that cannabinoids had adverse effects on the human reproductive system was first raised by case reports of breast development (gynecomastia) in young men aged 23 to 26 years of age, all of whom had a history of heavy cannabis use (Harman and Aliapoulios, 1972). The suspicion seemed confirmed by human observations published shortly after by Kolodny et al (1974), who reported that males who were chronic cannabis users had reduced plasma testosterone, reduced sperm count and motility, and an increased prevalence of abnormal sperm.

In the light of these observations, the widespread use of cannabis among young adults which began in the early 1970s and continued well into the mid-1980s raised understandable fears that fertility would be impaired in men, and the rates of unfavourable pregnancy outcomes would increase among women using cannabis during in their reproductive years. These outcomes could possibly include greater foetal loss, lower birth weight, and an increased risk of birth defects and perinatal deaths. Later, concerns were also raised about the possibility of adverse effects upon the subsequent behavioural development and health of children exposed to marijuana in utero. Evidence relevant to each of these concerns will be reviewed in this section.

6.5.1 Effects on the male reproductive system

In animals, marijuana, crude marijuana extracts, THC and certain other purified cannabinoids have been shown to "depress the functioning of the male reproductive endocrine system" (Bloch, 1983, p355). If used chronically, cannabis reduces plasma testosterone levels, retards sperm maturation, reducing the sperm count and sperm motility, and increasing the rate of abnormal sperm (Bloch, 1983, National Academy of Science, 1982; Wenger et al, 1992). Although the mechanisms by which cannabis produces these effects are uncertain, it is likely that they occur both directly as a result of action of THC on the testis, and indirectly via effects on the hypothalamic secretion of the hormones that stimulate the testis to produce testosterone (Wenger et al, 1992).

The small number of human studies on the effects of cannabis on male reproductive function have produced mixed results. The findings of the early study by Kolodny et al (1974) which reported reduced testosterone, sperm production, and sperm motility and increased abnormalities in sperm were contradicted shortly thereafter by the results of a larger, well controlled study of chronic heavy users, which failed to find any difference in plasma testosterone at study entry, or after three weeks of heavy daily cannabis use (Mendelson et al, 1974). Other studies have produced both positive and negative evidence of an effect of cannabinoids on testosterone, for reasons that are not well understood (Institute of Medicine, 1982). Hollister (1986) has conjectured that reductions in testosterone and spermatogenesis probably require long-term exposure. Even if there are such effects of cannabis on male reproductive functioning, their clinical significance in humans is uncertain (Institute of Medicine, 1982) since testosterone levels in the studies which have found effects have generally remained within the normal range (Hollister, 1986).

The putative relationship between cannabis use and gynecomastia now seems very doubtful. The magnitude of reductions observed in the positive studies are too small to explain the case reports of gynecomastia among heavy male cannabis smokers (Harman and Aliapoulios, 1972), and a small case-control study failed to find any relationship between cannabis use and gynecomastia in 11 cases and controls (Cates and Pope, 1977). Although the small sample size of this study did not exclude a four-fold higher risk of gynecomastia among cannabis smokers, studies in humans and animals have not shown any increased secretion of the hormone prolactin, the most likely mechanism of such effects in males. As Mendelson et al (1984) have argued, if chronic cannabis use caused gynecomastia, one would expect many more cases to have been reported in the clinical literature, given the widespread use of cannabis among young males during the past few decades.

Hollister has argued that the reductions in testosterone and spermatogenesis observed in the positive studies are probably of "little consequence in adults", although he conceded that they could be of "major importance in the prepubertal male who may use cannabis" (p10). He cited a case of growth arrest in a 16-year-old male who began heavy cannabis use at the age of 11, and who experienced a retardation of growth and the development of secondary sexual characteristics which partially remitted after three months abstinence from cannabis (Copeland, Underwood and Van Wyck, 1980). The possible effects of cannabis use on testosterone and spermatogenesis may therefore be most relevant to males whose fertility is already impaired for other reasons, e.g. a low sperm count.

6.5.2 Effects on the female reproductive system

The experimental animal studies suggests that cannabis use has similar effects on female reproductive system to those found in males. The acute effects of cannabis or THC exposure in the non-pregnant female animal is to transiently interfere with the hypothalamic-pituitary-gonadal axis (Bloch, 1983). Chronic cannabis exposure delays oestrous and ovulation by reducing leutinising hormone and increasing prolactin secretion.

There have been very few human studies of the effects of cannabis on the female reproductive system because of fears that cannabis use may produce teratogenic and genotoxic effects in women of childbearing age who would be the experimental subjects in such studies (Rosenkrantz, 1985). Two studies have been reported with conflicting results. In an unpublished study, Bauman (1980 cited by Nahas, 1984) compared the menstrual cycles of 26 cannabis smokers with those of 17 controls, and found a higher rate of anovulatory cycles among the cannabis users. Mendelson and Mello (1984) observed hormonal levels in a group of female cannabis users (all of whom had undergone a tubal ligation) under controlled laboratory conditions. They failed to find any evidence that sub-chronic cannabis use affected the cycling of the sex hormones, or the duration of the cycle. In the absence of any other human evidence, both Bloch (1983) and the Institute of Medicine (1982) argued on the basis of the animal literature that cannabis use probably had an inhibitory effect on human female reproductive function which was similar to that which occurs in males.

6.5.3 Foetal development and birth defects

Given evidence that THC affects female reproductive function, one might expect it to have a potentially adverse effect on the outcome of pregnancy. The possibility of adverse pregnancy outcomes is increased by evidence that THC crosses the placenta in animals (Bloch, 1983) and humans (Blackard and Tennes, 1984). This raises the possibility that THC, and possibly other cannabinoids, are teratogens, i.e. substances that may interfere with the normal development of the foetus in utero.

The animal evidence indicates that in sufficient dosage cannabis can "produce resorption, growth retardation, and malformations" in mice, rats, rabbits, and hamsters (Bloch, 1983, p406). Growth resorption and growth retardation have been more consistently reported than birth malformations (Abel, 1985). There are also several caveats on the evidence that cannabis increases rates of malformations. The doses required to reliably produce malformations have been very high (Abel, 1985), and such effects have been observed more often after the administration of crude marijuana extract than pure THC, suggesting that other cannabinoids may be involved in producing any teratogenic effects. There have also been doubts expressed about whether these teratogenic effects can be directly attributed to THC. Some have argued, for example, that the malformations may be a consequence of reduced nutrition caused by the aversive properties of the large doses of cannabis used in these studies (Abel, 1985; Bloch, 1983).  
Hollister (1986) has also discounted the animal research data, arguing that "virtually every drug that has ever been studied for dysmorphogenic effects has been found to have them if the doses are high enough, if enough species are tested, or if treatment is prolonged" (p4). Similar views have been expressed by Abel (1985) and by Bloch (1983), who concluded that THC was unlikely to be teratogenic in humans because "the few reports of teratogenicity in rodents and rabbits indicate that cannabinoids are, at most, weakly teratogenic in these species" (p416).

6.5.3.1 Human studies

The findings from the small number of epidemiological studies of the effects of cannabis use on human foetal development have been mixed for a number of reasons. First, both the adverse reproductive outcomes and the prevalence of heavy cannabis use during pregnancy are relatively rare events. Hence, unless cannabis use produces a large increase in the risk of abnormalities, very large sample sizes will be required to detect adverse effects of cannabis use on foetal development. Many of the studies that have been conducted to date have been too small to detect effects of this size (e.g. Greenland et al, 1982 a,b; Fried, 1980).

There are also likely to be difficulties in identifying cannabis users among pregnant women. The stigma associated with illicit drug use, especially during pregnancy, may discourage honest reporting, compounding the usual problem of women accurately recalling drug use in early pregnancy, when they are asked about it late in their pregnancy, or after the birth (Day et al, 1985). If, as seems likely, a substantial proportion of cannabis users are misclassified as non-users, any relationship between cannabis use and adverse outcomes will be attenuated, requiring even larger samples to detect it (Zuckerman, 1985).

Even when large sample sizes have been obtained, there are difficulties in interpreting any associations found between adverse pregnancy outcomes and cannabis use. Cannabis users are more likely to use tobacco, alcohol and other illicit drugs during their pregnancy. They also differ from non-users in social class, education, nutrition, and other factors which predict an increased risk of experiencing an adverse outcome of pregnancy (Fried, 1980, 1982; National Academy of Science, 1982; Tennes et al, 1985). These sources of confounding make it difficult to unequivocally attribute any relationship between reproductive outcomes and cannabis use to cannabis use per se, rather than to other drug use, or other variables correlated with cannabis use, such as poor maternal nutrition, and lack of prenatal care. Sophisticated forms of statistical control provide the only way of assessing to what degree this may be the case, but its application is limited by the small number of cannabis smokers identified in most studies.

Given these difficulties, and the marked variation between studies in the proportion of women who report cannabis use during pregnancy, the degree of agreement between the small number of studies is more impressive than the disagreement that seems at first sight to such be a feature of this literature. There is reasonable consistency (although not unanimity) in the finding that cannabis use in pregnancy is associated with foetal growth retardation, as shown by reduced birth weight (e.g. Gibson et al, 1983; Hatch and Bracken, 1986; Zuckerman et al, 1989), and length at birth (Tennes et al, 1985). This relationship has been found in the best controlled studies, and it has persisted after statistically controlling for potential confounding variables by sophisticated forms of statistical analysis (e.g. Hatch and Bracken, 1986; Zuckerman et al, 1989).

Uncertainty remains about the interpretation of this finding. Is it because the "marijuana products were toxic to foetal development", as argued by Nahas and Latour (1992)? Is it because THC interferes with the hormonal control of pregnancy shortening the gestation period, as has been reported by Gibson et al (1983) and Zuckerman et al (1989)? The fact that the lower birth weight among the children of women who used cannabis disappears after controlling for gestation length is supportive of the latter hypothesis. Is it because cannabis is primarily smoked, since tobacco smoking has been consistently shown to be associated with reduced birth weight (Fried, 1993)?

The findings on the relationship between cannabis use and birth abnormalities are more mixed, and conclusions accordingly less certain. Early case reports of children with features akin to the Foetal Alcohol Syndrome born to women who had smoked cannabis but not used alcohol during pregnancy (e.g. Milman, 1982, p42) suggested that cannabis may increase the risk of birth defects. Subsequent controlled studies have produced mixed results. Four studies have reported no increased rate of major congenital abnormalities among children born to women who use cannabis (Gibson et al, 1983; Hingson et al, 1982; Tennes et al, 1985; Zuckerman et al, 1989).

One study has reported a five-fold increased risk of children with foetal alcohol like features being born to women who reported using cannabis (Hingson et al, 1982). The significance of this finding is uncertain because the same study also found no relationship between self-reported alcohol use and "foetal alcohol syndrome" features. This is doubly surprising because of other evidence on the adverse effects of alcohol, and because the epidemiological data indicates that cannabis and alcohol use are associated (Norton and Colliver, 1988). An additional study reported an increase in the crude rate of birth abnormalities among children born to women who reported using cannabis. This result was no longer statistically significant after adjustment for confounders (Linn et al, 1983), although the confidence interval around this adjusted risk (OR=1.36) only narrowly included the null value (95 per cent CI: 0.97, 1.91).

The study by Zuckerman et al provides the most convincing failure to find an increased risk of birth defects among women who used cannabis during pregnancy. A large sample of women was obtained, among which there was a substantial prevalence of cannabis use that was verified by urinalysis. There was a low rate of birth abnormalities among the cannabis users, and no suggestion of an increase by comparison with the controls. On this finding, one might be tempted to attribute the small increased risk in the positive study (Linn et al, 1983) to recall bias, since the report of cannabis use during pregnancy was obtained retrospectively after birth, when women who had given birth to children with malformations may have been more likely to recall cannabis use than those who did not. However, given the uncertainty about the validity of self-reported cannabis use in many of the null studies, it would be unwise to exonerate cannabis as a cause of birth defects until larger, better controlled studies have been conducted.

6.5.4 Chromosomal abnormalities and genetic effects

Teratogenesis - interference with normal foetal development - is not the only way in which cannabis use might adversely affect human reproduction. Cannabis use could conceivably produce chromosomal abnormalities or genetic change in either parent which could be transmitted to their progeny. Although possible, there is no animal or human evidence that such events occur. The experimental evidence indicates that "in vivo and in vitro exposure to purified cannabinoids or cannabis resin failed to increase the frequency of chromosomal damage or mutagenesis" (Bloch, 1983, p412). Marijuana smoke exposure, by contrast, "has been ... associated with chromosomal aberrations ... [such as] hypoploidy, mutagenicity in the Ames test ... " (Bloch, 1983, p413). The latter fact is more relevant to an appraisal of the risk of cannabis users developing cancers from exposure to cannabis smoke rather than to the risks of transmissible genetic defects in their offspring.

Hollister (1986) discounted the evidence from cytogenetic studies that cannabinoids may be mutagenic, as did the Institute of Medicine (1982). He also argued that assessing chromosomal damage was "more of an art than a science", as indicated by poor inter-observer agreement, and that the clinical significance remained unclear because "similar types and degrees of chromosomal changes have been reported in association with other drugs commonly used in medical practice without any clinical evidence of harm ..." (p4). Hollister concluded that "even if a small increase in chromosomal abnormalities is produced by cannabis, the clinical significance is doubtful" (p4).

6.5.5 Post-natal development

A further possibility which needs to be considered is that cannabis use by the mother during pregnancy and breast feeding may affect the post-natal development of the child. This could occur either because of the enduring effects of developmental impairment arising from in utero exposure, or because the infant continued to be exposed to cannabinoids via breast milk. These are not well investigated possibilities, although there are a small number of animal studies which provide suggestive evidence of such effects (Nahas, 1984; Nahas and Frick, 1987).

The most extensive research evidence in humans comes from the Ottawa Prospective Prenatal Study (OPPS), which studied developmental and behavioural abnormalities in children born to women who reported using cannabis during pregnancy (Fried and colleagues, 1980, 1982, 1983, 1985, 1986, 1989, 1990, 1992). In this study, mothers were assessed about their drug use during pregnancy and their children were measured on the Brazelton scales after birth, neurologically assessed at one month, and assessed again by standardised scales of ability at six and 12 months. The results indicated that there was some developmental delay shortly after birth in the infants' visual system, and there was also an increased rate of tremors and startle among the children of cannabis users.

The behavioural effects discernible after birth had faded by one month, and no effects were detectable in performance on standardised ability tests at six and 12 months. Effects were subsequently reported at 36 and 48-month follow-ups (Fried and Watkinson, 1990) but these did not persist in a more recent follow-up at 60 and 72 months (Fried, O'Connell, and Watkinson, 1992). These results are suggestive of a transient developmental impairment occurring among children who had experienced a shorter gestation and prematurity. There is a possibility that the tests used in later follow-ups are insufficiently sensitive to the subtle effects of prenatal cannabis exposure, although they were able to detect effects of maternal tobacco smoking during pregnancy on behavioural development at 60 and 72 months (Fried and Watkins, 1990, 1992).

Attempts to replicate the OPPS findings have been mixed. Tennes et al (1985) conducted a prospective study of the relationship between cannabis use during pregnancy and postnatal development in 756 women, a third of whom reported using cannabis during pregnancy. The children were assessed shortly after birth using the same measurement instruments as Fried (1980), and a subset were followed up and assessed at one year of age. The findings failed to detect any differences in behavioural development between the children of users and non-users after birth; i.e. there was no evidence of impaired development of the visual system, and no increased risk of tremor or startle among the children of users. There was also no evidence of any differences at one year. More recently, Day et al (in press), have followed up children at age three born to 655 women who were questioned about their substance use during pregnancy. They found a relationship between the mothers' cannabis use during pregnancy and the children's performances on memory and verbal scales of the Stanford-Binet Intelligence Scale.

There is suggestive evidence that cannabis use during pregnancy may have a more serious and life threatening effect on post-natal development. This emerged from a case-control study of Acute Nonlymphoblastic Leukemia (ANLL), a rare form of childhood cancer (Neglia et al, 1991; Robinson et al, 1989). The study was not designed as a test of relationship between cannabis use and ANLL; it was designed to examine the possible aetiological role of maternal and paternal environmental exposures to petrochemicals, pesticides and radiation. Maternal drug use, including marijuana use before and during pregnancy, were assessed as possible covariates to be statistically controlled in any relationships observed between ANLL and environmental exposures.

An unexpected but strong association was observed between maternal cannabis use and ANLL. The mothers of cases were 11 times more likely to have used cannabis before and during their pregnancy than were the mothers of controls. The relationship persisted after statistical adjustment for many other risk factors. Comparisons of cases whose mothers did and did not use cannabis during their pregnancies showed that cases with cannabis exposure were younger, and had a higher frequency of ANLL with cell types of a specific pathological origin than did the cases without such exposure. The authors argued that these differences made it unlikely that the relationship was due to chance.

Reporting bias on the part of the mothers of cases is an alternative explanation of the finding that is harder to discount. The reports of cannabis use were obtained retrospectively after diagnosis of the ANLL, so it is possible that the mothers of children who developed ANLL were more likely to seek an explanation in something they did during their pregnancies, and hence, may have been more likely to report cannabis use than were mothers of controls. The authors investigated this possibility by comparing the rates of cannabis use reported in this study with the rates reported in several earlier case-control studies of other childhood cancers that they had conducted using the same methods. The rate was lower among controls in the ANLL study, but even when the rate of cannabis use among the controls in these other studies was used the odds ratio was still greater than three and statistically significant. Nonetheless, since this was an unexpected finding which emerged from a large number of exploratory analyses conducted in a single study, it should be replicated as a matter of some urgency.

6.5.6 Conclusions

On the balance of probabilities, high doses of THC probably disrupt the male and female reproductive systems in animals by interfering with hypothalamo-pituitary-gonadal system, reducing secretion of testosterone, and hence reducing sperm production, motility, and viability in males, and interfering with the ovulatory cycle in females. It is uncertain whether these effects also occur in humans, given the dose differences, the inconsistency in the literature on human males and the absence of research on human females. Even if cannabinoids have such effects in humans, their clinical significance in normal healthy young adults is unclear. They may be of greater concern among young adolescents who are now more likely to use, and among males with fertility impaired for other reasons.

Cannabis use during pregnancy probably impairs foetal development, leading to smaller birthweight, perhaps as a consequence of a shorter period of gestation. It is possible although far from certain that cannabis use during pregnancy produces a small increase in the risk of birth defects as a result of exposure of the foetus in utero. Prudence suggests that until this issue is resolved, we should err in the conservative direction by recommending that women not use cannabis during pregnancy, or when attempting to conceive (Hollister, 1986).

There is not a great deal of evidence that cannabis use can produce chromosomal or genetic abnormalities in either parent which could be transmitted to offspring. The available animal and in vitro evidence suggests that the mutagenic properties of cannabis smoke are greater than those of THC, and are probably of greater relevance to the risk of users developing cancer than to the transmission of genetic defects to children. There is suggestive evidence that infants exposed in utero to cannabis may experience transient behavioural and developmental effects during the first few months after birth. There is also a single study which raises concern about an increased risk of childhood leukemia occurring among the children born to women who used cannabis during their pregnancies.

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7. The psychological effects of chronic cannabis use

A major concern about the psychological consequences of cannabis use has been the possible effects of its chronic use on psychological adjustment in general, and its impact upon motivation and performance in occupational and social roles in particular. There have been two variations on this concern depending upon the age of the cannabis user. Among adults, an "amotivational syndrome" has been described, in which chronic cannabis users become apathetic, socially withdrawn, and perform at a level of everyday functioning well below their capacity prior to their cannabis use. Among adolescents, the concern has been about the effects of heavy cannabis use on motivation to undertake the educational and other psychological tasks that are an essential part of the transition from childhood to adulthood. The evidence for each of these adverse outcomes of heavy cannabis use will be considered separately, beginning with the effects on adolescent development, which have understandably provoked the greatest concern, and prompted the most research.

7.1 Effects on adolescent development

The effects of heavy cannabis use on adolescent development are of special concern for a number of reasons. First, adolescents are minors whose decisions about whether or not to use drugs are not conventionally regarded as free and informed in the way that adult choices are (Kleiman, 1989). Second, adolescence is an important period of transition from childhood to adulthood, in which regular cannabis intoxication may be expected to interfere with educational achievement, the process of disengagement from dependence upon parents, the development of relationships with peers, and making important life choices, such as whether, whom and when to marry, and what occupation to pursue (Baumrind and Moselle, 1985; Polich, Ellickson, Reuter and Kahan, 1984). Third, the age at which drug use begins has implications for subsequent drug use and health and well-being. Early initiation of cannabis use predicts an increased risk of escalation to heavier cannabis use, and to the use of other illicit drugs. It also means a longer period of heavy use, and hence, an increased risk of experiencing any adverse health effects that chronic cannabis use may have in later adult life (Kleiman, 1989; Polich, Ellickson, Reuter and Kahan, 1984). Fourth, since adolescence is a time of risk-taking, the use of any intoxicant, whether alcohol or cannabis while driving a car, increases the risks of accidental injury, and hence of premature death (Kleiman, 1989; Polich, Ellickson, Reuter and Kahan, 1984).

The type of evidence that initially excited concern about the effects of chronic cannabis use on adolescents came from clinical case studies in which bright adolescents' use of cannabis escalated to daily cannabis use, and the use of other illicit drugs, leading to declining social and educational performance, as evidenced by high school drop-out, and immersion in the illicit drug subculture (e.g. Kolansky and Moore, 1971; Lantner, 1982; Milman, 1982; Smith and Seymour, 1982). In some of these cases, the syndrome remitted after the adolescent had been abstinent from cannabis for some months (Meeks, 1982; Smith and Seymour, 1982). Nonetheless, the evidence was largely anecdotal and so of limited value in making causal inferences about the contribution that cannabis made to the development of these outcomes. It did not, that is, permit a decision to be made as to what extent cannabis use was a symptom rather than a cause of personality, or other psychiatric disorders, or a form of adolescent rebellion against parental values.

The concern about the adverse effects of cannabis use on adolescent development in the late 1970s prompted a number of large-scale prospective epidemiological studies of the antecedents, and to a limited degree, the consequences of adolescent drug use (e.g. Kandel, 1988; Kaplan, Martin and Robbins, 1982; Newcombe and Bentler, 1988). These studies have attempted to tease out the contributions of the users' pre-existing personal and social characteristics from the specific effects of drug use. Some of these studies have also attempted to examine the impact of illicit drug use in adolescence upon a number of social and personal outcomes in early adult life (e.g. Kandel, 1988; Newcombe and Bentler, 1988). The most important of these studies are reviewed below.

7.1.1 Is cannabis a gateway drug?

A major concern about cannabis has been that its use in adolescence may lead to, or increase the risk of using other more dangerous illicit drugs, such as cocaine and heroin (DuPont, 1984; Goode, 1974; Kleiman, 1992). The most popular evidence for this hypothesis is the fact that the majority of heroin and cocaine users used cannabis before heroin and cocaine. Such evidence is weak. In the absence of comparative data on the prevalence of cannabis use by non-heroin addicts we are unable to decide if there is an association between cannabis and heroin use. Even if there is an association, alternative explanations of its possible causal significance have to be evaluated and excluded (Goode, 1974).

There is now abundant evidence of an association between cannabis and heroin use from a series of cross-sectional studies of adolescent drug use in the United States and elsewhere, including Australia. In the late 1970s and into the 1990s in the United States there was a strong relationship between degree of current involvement with cannabis and the use of other illicit drugs such as heroin and cocaine users. Kandel (1984), for example, found that the prevalence of other illicit drug use increased with current degree of marijuana involvement: 7 per cent of those who had never used marijuana, 33 per cent of those who had used in the past, and 84 per cent of those who were currently daily cannabis users, had used other illicit drugs. Current cannabis users were also likely to have used a larger number of different types of illicit drugs.

Cross-sectional data on drug use among Australian adults in 1993 have also shown that those who have tried cannabis are more likely to have used heroin, and the greater the frequency of cannabis use, the higher the probability of their having tried heroin (see Donnelly and Hall, 1994). In the 1993 NCADA survey of drug use in Australia, for example, the crude risk of using heroin was approximately 30 times higher among those who have used cannabis than those who have not (even though 96 per cent of cannabis users had not used heroin) (see Donnelly and Hall, 1994).

The relationships between cannabis and heroin use observed in the cross-sectional studies have also been observed in the small number of longitudinal studies of drug use. In one of the first such studies Robins, Darvish and Murphy (1970) followed up a cohort of 222 African-American adolescents identified from school records at age 33, and interviewed them retrospectively about their drug use in adolescence and young adulthood, and their adult adjustment. They found a higher rate of progression to heroin use among the young men who had used cannabis before age 20.

These early results have been confirmed and elaborated upon in the extensive research on adolescent drug use by Kandel and her colleagues (e.g. Kandel et al, 1986). These investigators have identified a predictable sequence of involvement with licit and illicit drugs among American adolescents, in which progressively fewer adolescents tried each drug class, but in which almost all of those who tried drug types later in the sequence had used all drugs earlier in the sequence (Kandel and Faust, 1975). Typically, psychoactive drug use began with the use of the legal drugs alcohol and tobacco, which were almost universally used. A smaller group of the alcohol and tobacco users (although often the majority of adolescents) initiated cannabis use, and those whose progressed to regular cannabis use were more likely to use the hallucinogens and "pills" (amphetamines and tranquillisers). The heaviest users of "pills", in turn, were more likely to use cocaine and heroin. Generally, the earlier the initiation of any drug use, and the heavier the use of any particular drug in the sequence, the more likely the user was to use the next drug type in the sequence (Kandel, 1978; Kandel et al, 1984; Kandel, 1988).

This sequence of drug involvement has largely been confirmed by other researchers. Donovan and Jessor (1983), for example, found much the same sequence of initiation, with the variation that when problematic alcohol use was distinguished from non-problem alcohol use, then marijuana use preceded problem drinking in the sequence of progression. These sequences have also been observed in the small number of prospective studies which have followed a cohort of adolescents into early adulthood and examined the patterns of progression in drug use (e.g. Kaplan et al, 1982; Yamaguchi and Kandel, 1984a, b). For the majority (87 per cent) of men "the pattern of progression is one in which the use of alcohol precedes marijuana; alcohol and marijuana precede other illicit drugs; and alcohol, cigarettes and marijuana precede the use of prescribed psychoactive drugs" (Yamaguchi and Kandel, 1984a, p671). Among the majority of women (86 per cent) the sequence was such that "either alcohol or cigarettes precedes marijuana; alcohol, cigarettes and marijuana precede other illicit drugs; alcohol and either cigarettes or marijuana precede prescribed psychoactive drugs" (Yamaguchi and Kandel, 1984a, p671).

Yamaguchi and Kandel (1984b) also examined variables which predicted progression to illicit drug use beyond cannabis use. They were specifically interested in "whether the use of certain drugs lower in the sequence influences the initiation of higher drugs" (p673) and used sophisticated statistical methods to discover if the statistical relationship between cannabis use and subsequent illicit drug use persisted after controlling for temporally prior variables, such as pre-existing adolescent behaviours and attitudes, interpersonal factors, and age of initiation into drug use. If the relationship persisted after controlling for these variables, confidence was increased that the relationship was a causal one.

Yamaguchi and Kandel found that the relationship between marijuana use and progression to the use of other illicit drugs was not only explained by friends' marijuana use (which also predicted progression). Among men, the age of initiation of marijuana was an important modifier of this relationship: men who initiated marijuana use under the age of 16, were "even more likely to initiate other illicit drugs than is expected from the longer period of risk resulting from an early age of onset" (p677). Most importantly, "persons who have not used marijuana have very small probabilities of initiating other drugs, ranging from 0.01 to 0.03 (men) or 0.02 (women)" indicating that in their cohort, "marijuana appears to be a necessary condition for the initiation of other illicit drugs" (p677).

The work of Kandel and her colleagues and that of other researchers (e.g. O'Donnell and Clayton, 1982) has been interpreted by some as confirming the "gateway drug" hypothesis or "the stepping stone theory of drug use" (DuPont, 1984). Although it is not always clear what is being claimed by proponents of this hypothesis, it does not imply that a high proportion of those who experiment with marijuana will go on to use heroin. Indeed, the overwhelming majority of cannabis users do not use harder drugs like heroin. Kandel has explicitly disavowed this interpretation of her work:

The notion of stages in drug behavior does not imply that these stages are either obligatory or universal ... the model is not meant to be a variant of the controversial `stepping-stone' theory of drug addiction in which use of marijuana was assumed inexorably to lead to the use of other illicit 'hard' drugs, especially heroin (Kandel, 1988, pp58-61).

The view that cannabis use generally leads to the use of other illicit drugs is contradicted by the evidence from the studies of Kandel and her colleagues. Cannabis use is largely a behaviour of late adolescence and early adulthood. Kandel's research has shown that it has been initiated by the age of 19 in 90 per cent of those who ever used cannabis, and initiation is rare after 20 years. The frequency of its use peaks in the early 20s, when 50 per cent of males and 33 per cent of females reported using, and rapidly declines by age 23, with "the assumption of the roles of adulthood .. getting married, entering the labor force, or becoming a parent .. that may be incompatible with involvement in illicit drugs and deviant lifestyles" (Kandel and Logan, 1984, p665). Hence, although those who use cannabis are more likely to use other illicit drugs than those who do not, it is more usual for cannabis use to decline in early adult life, with only a minority continuing to use regularly, or progressing to the use of more dangerous illicit drugs. Even in the case of the minority (about one in four) who progress to daily cannabis use, the majority cease their use by the mid to late 20s (Kandel and Davies, 1992).

A better supported hypothesis is that cannabis use, especially heavy cannabis use, greatly increases the chances of progressing to the use of other illicit drugs. But even this type of relationship does not necessarily mean that cannabis use "causes" heroin use. As Kandel (1988) has stressed, the existence of sequential stages of progression does not "necessarily imply causal linkages among different drugs". The sequences "could simply reflect the association of each class of drugs with different ages of initiation or [with pre-existing] individual attributes, rather than the specific effects of the use of one class of drug on the use of another" (Kandel, 1988, p61).

A plausible alternative hypothesis is that of selective recruitment. That is, there is a selective recruitment to cannabis use of deviant and nonconformist persons with a predilection for the use of intoxicating substances. On this hypothesis, the sequence in which drugs are typically used reflects their differential availability and societal disapproval (e.g. Donovan and Jessor, 1983). Further, the sequence of initiation into drug use is held to be a consequence of the availability of different drugs at different ages, with the use of the least available, and most strongly socially disapproved "hard" drugs being last. This hypothesis exculpates cannabis use as a cause of progression to other illicit drug use, since cannabis use and other illicit drug use are the common consequences of adolescent deviance and nonconformity (Kaplan et al, 1982; Newcombe and Bentler, 1988).

The selective recruitment hypothesis has received support from a number of studies. There are substantial correlations between various forms of nonconforming adolescent behaviour, such as, high school drop-out, early premarital sexual experience and pregnancy, delinquency, and alcohol and illicit drug use (Jessor and Jessor, 1977; Osgood et al, 1988). All such behaviours are correlated with nonconformist and rebellious attitudes and anti-social conduct in childhood (Shedler and Block, 1990) and early adolescence (Jessor and Jessor, 1977; Newcombe and Bentler, 1988). Recent research indicates that those who are most likely to use other illicit drugs, namely, those who become regular cannabis users (Kandel and Davies, 1992), are more likely to have a history of anti-social behaviour (Brook et al, 1992; McGee and Feehan, 1993), nonconformity and alienation (Brook et al, 1992; Jessor and Jessor, 1978; Shedler and Block, 1990), perform more poorly at school (Bailey et al, 1992; Hawkins et al, 1992; Kandel and Davies, 1992), and use drugs to deal with personal distress and negative affect (Kaplan and Johnson, 1992; Shedler and Block, 1990). In general, the more of these risk factors that adolescents have, the more likely they are to progress to more intensive involvement with cannabis, and hence, to use other illicit drugs (Brook et al, 1992; Newcombe, 1992; Scheier and Newcombe, 1991).

One way of testing the selective recruitment hypothesis is to discover whether cannabis use continues to predict progression to "harder" illicit drugs after statistically controlling for pre-existing differences in personality and other characteristics (e.g. deviance) between cannabis users and non-users. In several such studies (e.g. Kandel et al, 1986; O'Donnell and Clayton, 1982; Robins et al, 1970) the relationship between cannabis and heroin use has been reduced when pre-existing differences have been controlled for, but in all cases the relationship has persisted, albeit in attenuated form. O'Donnell and Clayton (1982) have interpreted this type of finding as strong evidence in favour of a causal connection between cannabis and heroin use.

The credibility of such an argument for a causal interpretation of the relationship between cannabis and heroin use depends upon whether the most important prior characteristics have been adequately measured and statistically controlled for in these studies. It would be difficult to argue that this has been the case. Kandel et al (1986), for example, were unable to measure the users' attitudes and family characteristics at the time of drug initiation, or differential drug availability, either or both of which "may account for the observed relationships between the early and late stage drugs" (p679). In both the studies of O'Donnell and Clayton (1982) and Robins et al (1970) the measures of deviance "prior" to drug use were assessed retrospectively with unknown validity. Baumrind (1983) has contested the ability of these studies to exclude the alternative hypothesis that personality differences which preceded cannabis use were the causes of the progression to heroin use. She has argued that "it is safer in the absence of evidence of external validity" of these measures to assume that the relationship between marijuana use and heroin use is spurious.

Even if we assume for the purpose of argument that the association between cannabis and heroin use is not wholly explained by pre-existing differences in deviant behaviour between cannabis users and non-users, it remains to be explained how cannabis use "causes" heroin use. It may seem superficially plausible to suggest that there is something about the pharmacological effect of cannabis which predisposes heavy users to progress to the use of other intoxicants, but there is no obvious pharmacological mechanism for such progression. Is it the development of tolerance to the positive effects of cannabis, or to some form of experiential satiation with its effects? Does the euphoria of cannabis awaken appetite for intoxication by other drugs? These possibilities are difficult to test.

Any pharmacological explanation in which more potent illicit drugs serve as "substitutes" for less potent drugs like alcohol and cannabis has to contend with a number of facts. As already indicated, there are relatively low rates of progression from cannabis use to the sustained use of other illicit drugs; experimentation and abandonment is more the norm. Even those heavy cannabis users who use other illicit drugs continue to use cannabis as well as the new illicit drugs. As Donovan and Jessor (1983) have noted: "...`harder' drugs do not serve as substitutes for `softer' drugs. Rather, a deepening of regular substance use appears to go along with a widening of experience in the drug domain" (p548-549).

There is also good reason for believing that the pattern of progression observed among American adolescents in the 1970s was conditioned by historical differences in drug availability (Kandel, 1978). Historical evidence from among earlier cohorts of heroin users indicated that prior involvement with cannabis was confined to those geographic areas of the US in which it was readily available (Goode, 1974). Research on African-American adolescents also showed a variation in the sequence of drug use, with the use of more readily available cocaine and heroin preceding the use of the less readily available hallucinogens and "pills" (Kandel, 1978). Most dramatically, American soldiers in Vietnam were more likely to use heroin than alcohol because heroin was cheaper and more freely available than alcohol to most American troops who were younger than the minimum drinking age of 21 (Robins, 1993).

The historical and geographical variations in sequencing of illicit drug use suggest a sociological explanation of both the sequencing of illicit drug use and the higher rates of progression to heroin use among heavy cannabis users. One of the most popular sociological hypotheses is that cannabis use increases the chance of using other illicit drugs by increasing contact with other drug users as part of a drug using subculture. On this hypothesis, heavy cannabis use leads to greater involvement in a drug using subculture which, in turn, exposes cannabis users to the example of peers who have used other illicit drugs. Such exposure also increases opportunities to use other illicit drugs because of their increased availability within their social circle, and places the individual in a social context in which illicit drug use is encouraged and approved (e.g. Goode, 1974).

Although plausible, there is surprisingly little direct evidence on the drug subculture hypothesis. Goode (1974) presented data from the late 1960s indicating that the number of friends who used heroin was a stronger predictor of heroin use than was frequency of cannabis use, arguing that the "correlation between frequency of use and the use of dangerous drugs ... [is] the result of interaction and involvement with others who use" (p332). These observations have been supported by Kandel's (1984) finding that the strongest predictor of continued cannabis use in early adulthood was the number of friends who were cannabis users.

The hypotheses of selective recruitment and socialisation in a drug-using subculture are not mutually exclusive; both processes could independently contribute to the relationship between regular marijuana use and progression to heroin use (Goode, 1974). As already noted, the selective recruitment hypothesis is supported by the consistent finding of pre-existing differences between those who use marijuana and those who do not, which are most marked in those whose continued use of cannabis predicts their use of other illicit drugs. Once initiated into cannabis use, heavy users become further distinguished from non-users and those who have discontinued their use by the intensity of their social relations and activities which involve the use of marijuana, such as mixing with other drug users, and buying and selling illicit drugs. The illegality of these activities confers on the use, possession and sale of cannabis a socialising and subcultural influence not possessed by the possession and use of the legal drugs (Goode, 1974).

On the available evidence, the case for a pharmacological explanation of the role of cannabis use in progression to other illicit drug use is weak. A sociological explanation is more plausible than a pharmacological one. The predictive value of cannabis use is more likely to reflect a combination of: the selective recruitment to heavy cannabis use of persons with combination of pre-existing personality and attitudinal traits that predispose to the use of other intoxicants; and the effects of socialisation into an illicit drug subculture in which there is an increased availability of, and encouragement to use, other illicit drugs.

7.1.2 Educational performance

A major concern about the effects of adolescent cannabis use has been the possibility that its use impairs educational performance, and increases the chances of students discontinuing their education. Such a possibility is plausible: heavy cannabis use in the high school years would impair memory and attention, thereby interfering with learning in and out of the classroom (Baumrind and Moselle, 1985). If use became chronic, persistently impaired learning would produce poorer performance in high school and later in college, and increase the chance of a student dropping out of school. If the adolescent's school performance was marginal to begin with, as research reviewed above suggests it is more likely to be among marijuana users, then regular use could increase the pre-existing risk of high school failure. Because of the importance of high school education to occupational choice, this potential effect of adolescent cannabis use could have consequences which ramified throughout the affected individual's adult life.

Such a possibility has been supported by cross-sectional studies (e.g. Kandel, 1984; Robins et al, 1970). These and other studies (see Hawkins et al, 1992) have found a positive relationship between degree of involvement with cannabis as an adult and the risk of dropping out of high school. Studies of relationships between performance in college and marijuana smoking have produced more equivocal results (see below), usually failing to find consistent evidence that the performance of cannabis users was more impaired than would be predicted by their performance prior to cannabis use. These studies have been criticised (Baumrind and Moselle, 1985; Cohen, 1982), however. Baumrind and Moselle have argued that grade point average is an insensitive measure of adverse educational effects among bright high school and college students, while Cohen has argued that students whose learning has been most adversely affected by their chronic heavy cannabis use would not be found in college samples (Cohen, 1982).

Longitudinal studies of the effect of cannabis use on educational achievement have produced mixed support for the hypothesis (e.g. Kandel et al, 1986; Newcombe and Bentler, 1988). Kandel et al (1986), for example, analysed the follow-up data from the cohort on which their earlier cross-sectional finding of a relationship between cannabis use and high school drop-out had been reported. They reported a negative relationship between marijuana use in adolescence and years of education completed in early adulthood but this relationship disappeared once account was taken of the fact that those who used cannabis in adolescence had much lower educational aspirations than those who did not.

Newcombe and Bentler (1988) used a different approach to analysis in their study of the effects of adolescent drug use on educational pursuits in early adulthood. They used a composite measure of degree of drug involvement, which measured frequency of use of alcohol, cannabis and "hard drugs", and a measure of social conformity in adolescence as a control variable in the analyses, which examined the relationships between adolescent drug use and educational pursuits in early adulthood. They found negative correlations between adolescent drug use and high school completion, but after controlling for the higher nonconformity and lower academic potential among adolescent drug users, there was only a modest negative relationship between drug use and college involvement. The only specific effect of any particular type of drug use, over and above their measure of drug use involvement, was a negative relationship between hard drug use in adolescence and high school completion.

On the whole then, the available evidence from the longitudinal studies suggests that there may be a modest statistical relationship between cannabis and other illicit drug use in adolescence and poor educational performance. The apparently strong relationship between cannabis use and high school drop-out observed in cross-sectional studies exaggerates the adverse impact of cannabis use on school performance because adolescents who perform less well at school, and have lower academic aspirations, are more likely to use cannabis. But even if the relationship is statistically small, it may be substantively important, especially among those whose educational performance was marginal to begin with, because of the adverse effects that educational underachievement has on subsequent life choices, such as occupation, and the opportunities that they provide or exclude.

7.1.3 Occupational performance

Among those young adult cannabis users who enter the work-force, the continued use of cannabis and other illicit drugs in young adulthood might impair job performance for the same reasons that it has been suspected of impairing school performance, namely, that chronic intoxication impairs work performance. There is some suggestive support for this expectation, in that cannabis users report higher rates of unemployment than non-users (e.g. Kandel, 1984; Robins et al, 1970), but this comparison is likely to be confounded by the different educational qualifications of the two groups. Longitudinal studies have suggested that there is a relationship between adolescent marijuana use and job instability among young adults which is not explained by differences in education and other characteristics which precede cannabis use (e.g. Kandel et al, 1986). Newcombe and Bentler (1988) provided a more extensive analysis of the effects of adolescent drug use on occupational performance in young adulthood. They examined the relationships between adolescent drug use and income, job instability, job satisfaction, and resort to public assistance in young adulthood, while controlling for differences between users and non-users in social conformity, academic potential and income in adolescence. Their findings supported those of Kandel and colleagues in that adolescent drug users had a larger number of changes of job than non-drug users. Newcombe and Bentler conjectured that this reflects either impaired work performance, or a failure of illicit drug users to develop responsible employment behaviours such as conscientiousness, thoroughness, and reliability.

7.1.4 Interpersonal relationships

There are developmental and empirical reasons for suspecting that cannabis use may adversely affect interpersonal relationships. The developmental reason is that heavy adolescent drug use may produce a developmental lag, entrenching adolescent styles of thinking and coping which would impair the ability to form adult interpersonal relationships (Baumrind and Moselle, 1985). The empirical reason is the strong positive correlation between drug use, precocious sexual activity, and early marriage, which in turn predicts a high rate of relationship failure (Newcombe and Bentler, 1988).

Cross-sectional studies of drug use in young adults have indicated that a high degree of involvement with marijuana predicts a reduced probability of marriage, an increased rate of cohabiting, an increased risk of divorce or terminated de facto relationships, and a higher rate of unplanned parenthood and pregnancy termination (Kandel, 1984; Robins et al, 1970). Kandel (1984) also found that heavy cannabis users were more likely to have a social network in which friends and the spouse or partner were also cannabis users (Kandel, 1984). These findings have been largely confirmed in analyses of the longitudinal data from this cohort of young adults (Kandel et al, 1986).

Newcombe and Bentler (1988) found similar relationships between drug use and early marriage in their analysis of the cross-sectional data from their cohort of young adults in Los Angeles. Drug use in adolescence predicted an increased rate of early family formation in late adolescence and of divorce in early adulthood, which they interpreted as evidence that: "early drug involvement leads to early marriage and having children which then results in divorce" (p97). Newcombe and Bentler argued that this finding provided evidence for their theory of "precocious development", according to which drug use accelerates development and "... drug users tend to bypass or circumvent the typical maturational sequence of school, work and marriage and become engaged in adult roles of jobs and family prematurely without the necessary growth and development to enhance success with these roles ... [developing] a pseudomaturity that ill prepares them for the real difficulties of adult life" (pp35-36).

Less attention has been paid to the possibility that cannabis use has adverse effects on the development of social relationships outside marriage. Newcombe and Bentler (1988) have reported one of the few such studies. They investigated the relationship between adolescent drug use and degree of social support and the experience of loneliness reported in young adulthood. Cross-sectional analyses of data on drug use and degree of social support in adolescence showed that drug users reported having less social support than non-users (Newcombe and Bentler, 1988). But the effects of adolescent drug use on social support and loneliness in young adulthood were minor. Alcohol use in adolescence was associated with decreased loneliness in adulthood, while only hard drug use in adolescence was associated with decreased social support and increased loneliness in early adulthood.

7.1.5 Mental health

The impact of adolescent cannabis and other drug use on general health in early adult life has not been investigated, in large part because it will be difficult to detect any adverse effects of adolescent drug use on adult health in the longitudinal studies that have been conducted. In such cohorts, heavy cannabis use - the riskiest pattern of use from the perspective of health effects - has generally been observed to occur at low rates. In any case, young adulthood is too soon to expect any adverse health effects to be evident, because of the relatively short period of use by young adults.

For good reasons, the effects of cannabis use on mental health have been the health outcomes most studied. Cannabis is a psychoactive drug which effects the users' mood and feeling, so chronic heavy use could possibly adversely affect mental health, especially among those whose adjustment prior to their cannabis use was poor and who use cannabis to modulate and control their negative mood states and emotions. The relationships between cannabis use and the risks of developing dependence upon cannabis or major mental illnesses such as schizophrenia, are reviewed below (see pp110-122 and pp173-178 respectively). In this section attention is confined to non-psychotic symptoms of depression and distress.

A number of studies have suggested an association between cannabis use and poor mental health. Kandel's (1984) cross-sectional study found an inverse association between the intensity of marijuana involvement and degree of satisfaction with life, and a positive association between marijuana involvement and a greater likelihood of having consulted a mental health professional, and having been hospitalised for a psychiatric disorder (Kandel, 1984). Longitudinal analyses of this same cohort, however, found only weak associations between adolescent drug use and these adult outcomes; the strongest relationship between adolescent drug use and mental health, was a positive relationship between cigarette smoking in adolescence and increased symptoms of depression in adulthood (Kandel et al, 1986).

The cross sectional adult data in Newcombe and Bentler's (1988) study showed strong relationships between adolescent drug use and emotional distress, psychoticism and lack of a purpose in life. Emotional distress in adolescence predicted emotional distress in young adulthood, but there were no relationships between adolescent drug use and the experience of emotional distress, depression and lack of a sense of purpose in life in young adulthood. There were a number of small but substantively significant effects of adolescent drug use on mental health in young adulthood. Adolescent drug use predicted psychotic symptoms in young adulthood, and hard drug use in adolescence predicted increased suicidal ideation in young adulthood, after controlling for general drug use and earlier emotional distress. Newcombe and Bentler interpreted these findings as evidence that adolescent drug use "interferes with organised cognitive functioning and increases thought disorganisation into young adulthood" (p180).

7.1.6 Delinquency and crime

Since initiation into illicit drug use and the maintenance of regular illicit drug use are both strongly related to degree of social nonconformity or deviance (e.g. Donovan and Jessor, 1980; Newcombe and Bentler, 1988; Polich et al, 1984) it is reasonable to expect adolescent illicit drug use to predict social nonconformity and various forms of delinquency and crime in young adulthood. Cross-sectional studies of adult drug users seem to support this hypothesis: they indicate that there is a relationship between the extent of marijuana use as an adult and a history of lifetime delinquency (e.g. Kandel, 1984; Robins et al, 1970), having been convicted of an offence, and having had a motor vehicle accident while intoxicated (Kandel, 1984).

Johnston et al (1978) reported a detailed analysis of the relationship between intensity of drug use and delinquency across two waves of interviews of adolescent males undertaken as part of the "Youth in Transition" study. They found in their cross-sectional data that there was a strong relationship between involvement in delinquency and degree of involvement with illicit drugs, that is, self-reported rates of delinquent activity increased steadily with increasing degree of drug involvement. However, a series of analyses looking at changes in drug use and crime over time indicated that the groups defined on intensity of drug involvement differed strongly in their rate of delinquent acts before their drug use. Moreover, the onset of illicit drug use (including cannabis) had little effect on delinquent acts, except perhaps among those who used heroin, among whom there was a suggestion that the rates of delinquency increased. Finally, rates of delinquent acts declined over time in all drug use groups and at about the same rate. The findings were interpreted as delivering "a substantial, if not mortal, blow" to the hypothesis that "drug use somehow causes other kinds of delinquency" (p156).

Newcombe and Bentler (1988) reported a somewhat more complicated although no less plausible picture in their longitudinal study. They reported a positive relationship between drug use and criminal involvement in adolescence, but found more mixed results in the relationship between adolescent drug use and criminal activity in young adulthood. Adolescent drug use predicted drug crime involvement in young adulthood; but after controlling for other variables, it was negatively correlated with violent crime, and general criminal activities in young adulthood. Newcombe and Bentler argued that these negative correlations indicated that the correlation between different forms of delinquency in adolescence decreases with age, as criminal activities become differentiated into drug-related and non-drug-related offences. Hard drug use in adolescence also had a specific effect on young adult crime over and above that of drug use in general: it predicted an increased rate of criminal assaults in young adulthood.

7.1.7 Conclusions

There are a number of clear outcomes of research on adolescent cannabis and other illicit drug use. First, there is strong continuity of development from adolescence into early adult life in which many of the indicators of adverse development which have been attributed to cannabis use precede its first use (Kandel, 1978). These include minor delinquency, poor educational performance, nonconformity, and poor adjustment. Second, there was a predictable sequence of initiation into the use of illicit drugs among American adolescents in the 1970s in which the use of licit drugs preceded experimentation with cannabis, which preceded the use of hallucinogens and "pills", which in turn preceded the use of heroin and cocaine. Generally, the earlier the age of initiation into drug use, and the greater the involvement with any drug in the sequence, the greater the likelihood of progression to the next drug in sequence.

The causal significance of these findings, and especially the role of cannabis in the sequence of illicit drug use, remains controversial. The hypothesis that the sequence of use represents a direct pharmacological effect of cannabis use upon the use of later drugs in the sequence is the least compelling. A more plausible and better supported explanation is that it reflects a combination of the selective recruitment into cannabis use of nonconforming and deviant adolescents who have a propensity to use illicit drugs, and the socialisation of cannabis users within an illicit drug using subculture which increases the exposure, opportunity, and encouragement to use other illicit drugs.

There has been some support for the hypothesis that heavy adolescent use of cannabis impairs educational performance. Cannabis use appears to increase the risk of failing to complete a high school education, and of job instability in young adulthood. The apparent strength of these relationships in cross-sectional studies has been exaggerated because those who are most likely to use cannabis have lower pre-existing academic aspirations and high school performance than those who do not. Even though more modest than has sometimes been supposed, the apparently adverse effects of cannabis and other drug use upon educational performance may cascade throughout young adult life, affecting choice of occupation, level of income, choice of mate, and quality of life of the user and his or her children.

There is weaker but suggestive evidence that heavy cannabis use has adverse effects upon family formation, mental health, and involvement in drug-related (but not other types of) crime. In the case of each of these outcomes, the apparently strong associations revealed in cross-sectional data are much more modest in longitudinal studies after statistically controlling for associations between cannabis use and other variables which predict these adverse outcomes.

On balance, there are sufficient indications that cannabis use in adolescence adversely affects adolescent development to conclude that it is a socially desirable goal to discourage adolescent cannabis use, and especially regular cannabis use.

7.2 Psychological adjustment in adults

7.2.1 Is there an amotivational syndrome?

Anecdotal reports that chronic heavy cannabis use impairs motivation and social performance have been described in the older literature on cannabis use in societies with a long history of use, such as Egypt, the Carribean and elsewhere (e.g. Brill and Nahas, 1984). In these societies, heavy cannabis use is the prerogative of the poor, impoverished and unemployed. With the increase of cannabis use among young adults in the USA in the early 1970s, there were clinical reports of a similar syndrome occurring among heavy cannabis users (e.g. Kolansky and Moore, 1971; Millman and Sbriglio, 1986; Tennant and Groesbeck, 1972). These investigators have typically described a state among chronic, heavy cannabis users in which the users' focus of interest narrowed, they became apathetic, withdrawn, lethargic, unmotivated, and showed evidence of impaired memory, concentration and judgment (Brill and Nahas, 1984; McGlothin and West, 1968). This constellation of symptoms has been described as an "amotivational syndrome" (e.g. McGlothin and West, 1968; Smith, 1968), which some have claimed is an organic brain syndrome caused by the effects of chronic cannabis intoxication (Tennant and Groesbeck, 1972). All these reports have been uncontrolled, and often poorly documented, so that it has not been possible to disentangle the effects of chronic cannabis use from those of poverty and low socioeconomic status, or pre-existing personality and other psychiatric disorders (Edwards, 1976; Millman and Sbriglio, 1986; National Academy of Science, 1982; Negrete, 1983).

There is no research evidence which unequivocally demonstrates that cannabis does or does not adversely affect the motivation of chronic heavy adult cannabis users. It has proved singularly difficult to provide better controlled research evidence which has permitted a consensus to emerge upon the issue. Two types of investigation have been carried out in an attempt to assess the motivational effects of chronic heavy cannabis use: field studies of chronic heavy cannabis using adults in societies with a tradition of such use, e.g. Costa Rica (Carter et al, 1980) and Jamaica (Rubin and Comitas, 1975); and laboratory studies of the effects on the motivation and performance of volunteers who have been administered heavy doses of cannabis over periods of up to 21 days (e.g. Mendelson et al, 1974). There has also been some evidence on the prevalence of adverse psychological effects of cannabis from a small number of studies of chronic cannabis users (e.g. Halikas et al, 1982).

7.2.2 Field studies of motivation and performance

Rubin and Comitas (1975) examined the effects of ganja smoking on the performance of Jamaican farmers who regularly smoked cannabis in the belief that it enhanced their physical energy and work productivity. They used videotapes to measure movement and biochemical measures of exhaled breath to assess caloric expenditure before and after ganja smoking. Four case histories were reported which indicated that the level of physical activity increased immediately after smoking ganja, as did caloric expenditure, but not productivity. It seemed to be that after smoking ganja the workers engaged in more intense and concentrated labour, but this was done less efficiently, especially by heavy users. Contrary to the hypothesis that cannabis use produced an impairment in motivation, they concluded: "In all Jamaican settings observed, the workers are motivated to carry out difficult tasks with no decrease in heavy physical exertion, and their [mistaken] perception of increased output is a significant factor in bolstering their motivation to work." (p79).

A study of Costa Rican cannabis smokers produced mixed evidence on the impact of chronic cannabis use on job performance (Carter et al, 1980). A comparison was made of the employment histories of 41 pairs of heavy users (10 marijuana cigarettes per day for 10 or more years) and non-users who had been matched on age, marital status, education, occupation, and alcohol and tobacco consumption. The comparison indicated that non-users were more likely than users to have attained a stable employment history, to have received promotions and raises, and to be in full-time employment. Users were also more likely to spend all or more than their incomes, and to be in debt. Among users, however, the relationship between average daily marijuana consumption and employment was the obverse of what the amotivational hypothesis would predict, that is, those "who had steady jobs or who were self-employed were smoking more than twice as many marijuana cigarettes per day as those with more frequent job changes, or those who were chronically unemployed" (p153), indicating that "the level of consumption was related more to relative access than to individual preference" (p154).

Evidence from these field studies is usually interpreted as failing to demonstrate the existence of the amotivational syndrome (e.g. Dornbush, 1974; Hollister, 1986; Negrete, 1988). There are critics, however, who raise doubts about how convincing such apparently negative evidence is. Cohen (1982), for example, has argued that the chronic users in three field studies have come from socially marginal groups, so that the cognitive and motivational demands of their everyday lives were insufficient to detect any impairment caused by chronic cannabis use. Moreover, the sample sizes of these studies have been too small to exclude the possibility of an effect occurring among a minority of heavy users.

Other evidence suggests that an amotivational syndrome is likely to be a rare occurrence, if it exists. Halikas et al (1982), for example, followed up 100 regular cannabis users six to eight years after initially recruiting them and asked them about the experience of symptoms suggestive of an amotivational syndrome. They found only three individuals who had ever experienced such a cluster of symptoms in the absence of significant symptoms of depression. These individuals were not distinguished from the other smokers by their heaviness of use. Nor was their experience of these symptoms obviously related to changes in pattern of use; they seemed to come and go independently of continued heavy cannabis use.

7.2.3 Laboratory studies of motivation and performance

In the light of Halikas et al's low estimate of the prevalence of amotivational symptoms among chronic heavy cannabis users, it is perhaps not surprising that the small number of laboratory studies of long-term heavy cannabis use have failed to provide unequivocal evidence of impaired motivation (Edwards, 1976). The early studies conducted as part of the LaGuardia Commission inquiry (see Mendelson et al, 1974) reported deterioration in behaviour among prisoners given daily doses of cannabis over a period of some weeks, but these reports were based upon largely uncontrolled observation. So too was the more recent study of Georgotas and Zeidenberg (1979) in which it was reported that five healthy male marijuana users who were placed on a dose regimen of 210mg of THC per day for a month appeared "moderately depressed, apathetic, at times dull and alienated from their environment and with impaired concentration" (p430).

A study which used standardised measures of performance rather than relying on observational data failed to observe such effects (Mendelson et al, 1974). In this study 10 casual and 10 heavy cannabis smokers were observed over a 31 days study period in a research laboratory. For 21 of these days, subjects were given access to as many marijuana cigarettes as they earned by performing a simple operant task which involved pressing a button to move a counter. The points could be exchanged for money (60 points equal to a cent), packets of cigarettes (3,000 each), and marijuana cigarettes (6,000 each). Mendelson et al found that all subjects earned the maximum number of points allowed per day (60,000) throughout the study and that output was unaffected by marijuana smoking whereas ad libitum access to alcohol by heavy drinking subjects in the same setting profoundly disrupted performance of the same task. Mendelson et al concluded that: "our data disclosed no indication of a relationship between decrease in motivation to work at an operant task and acute or repeat dose effects of marihuana" (p176).

A number of criticisms can be made of this study. First, the period of heavy use was only 21 days by comparison with the life histories of 15 or more years daily use in heavy cannabis users in the field studies. Second, the subjects in the study were volunteers who were all healthy, young cannabis users with a mean IQ of 120 and nearly three years of college education, and some of whom reported during debriefing that they were motivated to perform well so as to demonstrate that their cannabis use did not have any adverse effect on their performance (Mendelson et al, 1974). Third, the tasks that users were asked to perform (button presses) were undemanding. Mendelson et al countered that these tasks had nonetheless been shown to detect the deleterious effects of heavy alcohol use. Moreover, they argued, there were other indicators that their subjects' performance and motivation was unimpaired while using cannabis, namely, all subjects completed the study, most undertook the daily assessments conducted throughout, all complied with a roster for cleaning and house-keeping duties, and all kept up their preferred recreational activities throughout the study period.

A similar study was completed at the Addiction Research Foundation, the results of which have not been fully published, although Campbell (1976) has provided a brief account of its findings. In this study, young cannabis users were studied in a residential token economy in which they could earn tokens that could be exchanged for money and other goods by manufacturing woven woollen belts. Unlike the Mendelson study, subjects' cannabis doses were under the experimenters' control and subjects were given mandatory high doses. The subjects showed no gross behavioural changes, no social deterioration, and no alterations in intellectual functioning, but the results suggested, contrary to those of Mendleson et al, that chronic heavy cannabis use reduced productivity, especially during the period of mandatory high dosing (30mg of THC per day) which many subjects found aversive. It remains unclear how applicable the results of performance with mandatory high dosing are to the situation where users have control over their own dose.

7.2.4 Discussion

The status of the amotivational syndrome remains contentious, in part because of differences in the appraisal of evidence from clinical observations and controlled studies. On the one hand, there are those who find the small number of cases of "amotivational syndrome" compelling clinical evidence of the marked deterioration in functioning that chronic heavy cannabis use can produce. On the other, there are those who are more impressed by the largely unsupportive findings of the small number of field and laboratory studies. Although the controlled studies have largely been interpreted as failing to substantiate the clinical observations (e.g. Millman and Sbriglio, 1986), the possibility has been kept alive by suggestive reports that regular cannabis users experience a loss of ambition and impaired school and occupational performance as adverse effects of their use (e.g. Hendin et al, 1987), and that some ex-cannabis users give impaired occupational performance as a reason for stopping (Jones, 1984). It seems reasonable to conclude that if there is an amotivational syndrome, it is a relatively rare consequence of prolonged heavy cannabis use. If this is the case, then studies of motivation and performance among dependent cannabis users may be the most promising place to look for examples of the syndrome.

Even if we assume that chronic heavy cannabis use impairs adult motivation and performance, there remains the question of mechanism (Baumrind, 1983). Is there a specific amotivational syndrome caused by the chronic intake of cannabinoids, or are we mistaking it for the impaired cognitive and psychomotor performance of chronically intoxicated dependent cannabis users (Edwards, 1976)? Are we perhaps mistaking a depressive syndrome among heavy cannabis users for the amotivational syndrome? (Cohen, 1982) Assuming that cases can be identified, how easy is it to reverse the syndrome or behaviour pattern after a period of abstinence from cannabis?

7.2.5 Conclusions

The evidence for an amotivational syndrome among adults is, at best, equivocal. The positive evidence largely consists of case histories, and observational reports. The small number of controlled field and laboratory studies have not found compelling evidence for such a syndrome, although their evidential value is limited by the small sample sizes and limited sociodemographic characteristics of the field studies, by the short periods of drug use, and the youthful good health and minimal demands made of the volunteers observed in the laboratory studies. It nonetheless is reasonable to conclude that if there is such a syndrome, it is a relatively rare occurrence, even among heavy, chronic cannabis users.

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7.3 Is there a cannabis dependence syndrome?

7.3.1 The significance of dependence

If there is a cannabis dependence syndrome, it has important implications for both cannabis users and public health (Edwards, 1982). First, people who currently use cannabis, and young adults who are considering whether to use it, should make decisions which are informed by an appraisal of the risk of their becoming dependent on the drug. If there is a risk of dependence, and cannabis continues to be regarded as a drug that does not produce dependence, such decisions cannot be informed.

Second, if there is a cannabis dependence syndrome, then persons who become dependent on cannabis place themselves at an increased risk of experiencing any adverse health effects attributable to cannabis use. Dependent cannabis users typically smoke two or more cannabis cigarettes daily over many years, putting themselves at risk of the pulmonary hazards of smoking. A chronic state of cannabis intoxication could place them at increased risk of accidents, and the THC they absorb may accumulate in their bodies, placing them at increased risk of experiencing any adverse health effects of THC (Edwards, 1982).

Third, although a dependent pattern of cannabis use may be rare in comparison with the more prevalent pattern of experimental and intermittent use, it may nonetheless have public health significance because of the widespread experimentation with cannabis in many Western societies. The public health significance of cannabis dependence would also increase if the prevalence of use substantially increased as a result of changes in the availability of the drug.

7.3.2 The nature of dependence

For much of the 1960s and 1970s the apparent absence of tolerance to the effects of cannabis, and of a withdrawal syndrome analogous to that seen in alcohol and opioid dependence, supported the consensus of informed opinion that cannabis was not a drug of dependence. Expert views on the nature of dependence changed during the late 1970s and early 1980s, when the more liberal definition of drug dependence embodied in Edwards and Gross's (1976) alcohol dependence syndrome was extended to all psychoactive drugs (Edwards et al, 1981). The drug dependence syndrome reduced the emphasis upon tolerance and withdrawal, and attached greater importance to symptoms of a compulsion to use, a narrowing of the drug using repertoire, rapid reinstatement of dependence after abstinence, and the high salience of drug use in the user's life. This new conception influenced the development of the Third Revised Edition of the Diagnostic and Statistical Manual of the American Psychiatric Association (1987) (DSM-III-R), which reduced the importance of tolerance and withdrawal symptoms in favour of a greater emphasis upon continued use of a drug in the face of its adverse effects.

7.3.2.1 Drug dependence in DSM-III-R

"Psychoactive substance use disorders" include all forms of drug and alcohol dependence in DSM-III-R (American Psychiatric Association, 1987; Kosten et al, 1987). "The essential feature of this disorder is a cluster of cognitive, behavioral and physiologic symptoms that indicate that the person has impaired control of psychoactive substance use and continues use of the substance despite adverse consequences" (p166). A diagnosis of psychoactive substance dependence is made if any three of the nine criteria listed below have been present for one month or longer:

1. the substance is often taken in larger amounts or over a longer period than the person intended;

2. there is a persistent desire or one or more unsuccessful efforts to cut down or control substance use;

3. a great deal of time is spent in activities necessary to get the substance (e.g., theft), taking the substance..., or recovering from its effects;

4. frequent intoxication or withdrawal symptoms when expected to fulfil major role obligations at work, school, or home..., or when substance use is physically hazardous...;

5. important social, occupational, or recreational activities given up or reduced because of substance use;

6. continued substance use despite knowledge of having a persistent or recurrent social, psychological, or physical problem that is caused or exacerbated by the use of the substance;

7. marked tolerance;

8. characteristic withdrawal symptoms;

9. substance often taken to relieve or avoid withdrawal symptoms" (American Psychiatric Association, 1987, pp167-8).

Criteria 8 and 9, are not required for the dependence syndromes of cannabis, hallucinogens and PCP to be diagnosed.

These criteria may seem to conflict with community conceptions of drug dependence, in that they explicitly include tobacco smoking as a form of drug dependence, and could conceivably include caffeine dependence (among heavy coffee drinkers). The fact that these forms of drug taking are not usually be regarded as producing drug dependence is less a reason for rejecting these diagnostic criteria than a signal of the need to persuade the community to adopt a broader conception of drug dependence, which reduces the emphasis upon "physical" dependence as evidenced by the occurrence of a marked withdrawal syndrome on abstinence.

7.3.2.2 Cannabis tolerance and withdrawal: experimental evidence

Although tolerance and withdrawal symptoms are not required within DSM-III-R, there is evidence that both can occur under certain conditions of dosing with cannabinoids. This should not be surprising since, as Hollister (1986) has observed, cannabis "would have been an exceptional centrally acting drug if tolerance/dependence were not one of its properties" (p9). Yet for many years it was believed that there was little tolerance to cannabis and no withdrawal syndrome. The predominant recreational pattern of intermittent use in the community, and the use of low doses of THC and short dosage schedules in laboratory studies, contributed to this belief (Hollister, 1986), as did the expectation that if there was a cannabis withdrawal syndrome, it would be as readily recognised as the opioid withdrawal syndrome (Edwards, 1982).

Since the middle 1970s evidence has emerged from human and animal studies that chronic administration of high doses of THC results in the development of marked tolerance to a wide variety of cannabinoid effects, such as cardiovascular effects, and to the subjective high in humans (Compton, Dewey, and Martin, 1990; Fehr and Kalant, 1983; Hollister, 1986; Jones, Benowitz, and Herning, 1981; National Academy of Science, 1982). Moreover, the abrupt cessation of chronic high doses of THC generally produces a mild withdrawal syndrome like that produced by other long-acting sedative drugs (Compton et al, 1990; Jones and Benowitz, 1976; Jones et al, 1981).

Jones and Benowitz (1976) provided convincing evidence in humans of the development of tolerance to the cardiovascular and subjective effects of THC. They conducted human laboratory studies of the effects of high doses of THC (210 mg per day) administered orally over a period of 30 days on a fixed dosing schedule to healthy male volunteers who had an extensive history of cannabis use. Clinical observations of the subjects showed that as the duration of the high dose regimen increased, there was a decline in the positive effects of intoxication, and in the subjects' ratings of the "high". There was a marked deterioration in the subjects' social functioning according to nurses' ratings during the early days of the high dose regimen, but there was almost complete recovery to baseline levels by the end of the dosing period. There was similar evidence of recovery in cognitive and psychomotor performance in the course of the high dose regimen.

The most convincing evidence of tolerance came from observations of the cardiovascular and subjective effects of smoking a marijuana cigarette at various points during the study. The magnitude of both the cardiovascular and subjective responses to smoking a single "joint" decreased with the length of time subjects had received a high dose of THC. After a few days of high doses of THC, the increased heart rate was replaced by a normal, and in some cases a slowed, heart rate. Similarly, self-ratings indicated that the "high" produced by the cigarette all but disappeared in the course of the high dose regimen.

Similar observations of tolerance to the subjective effects of cannabis have been made by Georgotas and Zeidenberg (1979). They studied five healthy male marijuana smokers over a four-week period, in which they smoked an average of 10 joints per day, providing an average daily dose of 210mg of THC. In the course of this experiment, subjects rapidly developed tolerance to the drug's effects:

Although initially they found the marijuana to be of good quality, they now found it much weaker and inferior to what they were getting outside. They felt it did not make them as high as often as they were accustomed (p429).

An abstinence syndrome has been observed in monkeys maintained on a schedule of chronic high doses of THC. Its symptoms consisted of: "yawning, anorexia, piloerection, irritability, tremors and photophobia" (Jones and Benowtiz, 1976). Similar symptoms were observed by Jones and Benowitz (1976) after their subjects were abruptly withdrawn from high doses of THC. Within six hours of withdrawal subjects complained of "inner unrest", and by 12 hours, "increased activity, irritability, insomnia, and restlessness were reported by the subjects and obvious to staff" (p632). Common symptoms reported were " `hot flashes', sweating, rhinorrhea, loose stools, hiccups and anorexia" (p632) which many subjects compared to a bout of influenza. These symptoms were reduced by the resumption of marijuana use (Jones et al, 1981).

Georgotas and Zeidenberg (1979) reported similar withdrawal phenomena in their long-term dosing study. During the first week of a four-week wash-out period after four weeks of receiving 210mg of cannabis a day, the subjects "became very irritable, uncooperative, resistant, and at times hostile ... their desire for food decreased dramatically and they had serious sleeping difficulties" (p430). These effects disappeared during the final three weeks of the wash out. These studies suggest that tolerance can develop to cannabis's effects and that a withdrawal syndrome can occur on abstinence under certain conditions, namely, chronic administration of doses as low as 10 mg per day for 10 days (Jones et al, 1981).

The results of laboratory studies have received suggestive support from a small number of studies of heavy cannabis users. Weller and Halikas (1982), for example, found that the self-reported positive effects of cannabis use diminished over a five to six-year period in regular users of cannabis. The average reduction in the frequency of experiencing the positive effects was small, perhaps because only 27 per cent were daily users, but they were consistent and included some of the symptoms reported in laboratory studies.

The laboratory and observational studies raise the following questions: How relevant are these observations to contemporary cannabis users? How often does sufficient tolerance to cannabis develop for users to experience a withdrawal syndrome? How often is cannabis used to relieve or avoid withdrawal symptoms, and if so, does such behaviour play any role in maintaining use and producing dependence? These questions remain unanswered (Edwards, 1982; Jones, 1984), although (as will be seen below) there is clinical and observational evidence that some heavy chronic users experience tolerance and withdrawal symptoms, and that some use cannabis to control these symptoms.

7.3.3 Clinical and observational evidence on dependence

There has not been an organised program of research on the cannabis dependence syndrome comparable to that undertaken on the alcohol and the opiate dependence syndromes. Instead, its existence and characteristics have had to be inferred from a diverse body of research studies. This comprises: limited data on the prevalence and characteristics of persons seeking professional help in dealing with their cannabis use and associated problems; a small number of observational studies of problems reported by non-treatment samples of long-term cannabis users; and a very small and recent literature examining the validity of the cannabis dependence syndrome, usually as part of larger investigations of the validity of the substance dependence syndromes embodied in DSM-III-R and other classification systems.

During the 1980s evidence began to emerge that there had been an increase in the number of persons seeking help with cannabis as their major drug problem. Jones (1984), for example, reported that 35,000 patients sought treatment in the United States in 1981 for drug problems in which "cannabis was their primary drug" (p703), an increase of 50 per cent over three years. Many of these patients behaved "as if they were addicted to cannabis" and they presented "some of the same problems as do compulsive users of other drugs" (p711). More recently, Roffman and colleagues (1988) have reported a strong response to a series of community advertisements offering help to people who wanted to stop using marijuana.

Sweden, which has had a long history of hashish use, has also experienced an increase in numbers of heavy hashish users presenting to treatment services for assistance with problems caused by its use (Engstrom et al, 1985). Tunving et al (1988) have described their experience treating approximately 100 individuals per year who presented to Swedish treatment services requesting help in controlling their cannabis use. Although no data were reported on the proportion of these individuals who satisfied the DSM-III-R criteria for cannabis dependence, these patients typically complained of symptoms which arguably would meet some of its criteria. They reported, for example, that they had been unable to stop using cannabis after having made several unsuccessful attempts to stop or cut down, that they were frequently intoxicated, often every day, and that they continued to use despite suffering adverse effects which they recognised were connected with their cannabis use, such as sleeplessness, depression, diminished ability to concentrate and memorise, and blunting of emotions. Hannifin (1988) and Miller and Gold (1989) have reported similar behaviour patterns among cannabis users who have sought assistance.

In Australia, there are indications that some heavy cannabis users request help in controlling their use. Didcott et al (1988), for example, reported on the characteristics of 3,462 clients seen in 12 residential treatment services in New South Wales in 1985 and 1986. They found that cannabis was identified as the "primary drug problem" by 25 per cent of clients seen, second only to the opioid drugs, which were so identified by 73 per cent of clients. Just over half of all clients (52 per cent), the majority of whom were polydrug users, identified their cannabis use as "a problem". The prevalence of cannabis use as a principal drug problem was lower in a 1992 National Census of Clients of Australian Treatment Service Agencies (Chen, Mattick and Bailey, 1993). In this census cannabis use was the main drug problem for 6 per cent of the 5,259 clients, fifth in order of importance behind alcohol (52 per cent), opiates (26 per cent), tobacco (9 per cent) and opiate/polydrug problems (7 per cent).

Suggestive evidence of cannabis dependence has emerged from a small number of observational studies of regular cannabis users. Weller, Halikas and Morse (1984), for example, followed up a cohort of 100 regular marijuana users who were first identified in 1970-1971, and assessed them for alcohol and marijuana abuse using Feighner's criteria for alcoholism and an analogous set of criteria for marijuana (see Weller and Halikas, 1980). Their concept of abuse would arguably have included most cases of dependence. They were able to interview 97 of their subjects about the amount and frequency of alcohol and marijuana use, and their experience of problems related to the use of both drugs. According to Feighner's criteria, 9 per cent of subjects were alcoholic and 9 per cent were "abusers" of marijuana, with 2 per cent qualifying for both diagnoses. The most common symptoms reported among those classified as marijuana abusers were feeling "addicted", a history of failed attempts to limit use, early morning use, and traffic arrests related to marijuana use.

Hendin et al (1987) reported on the experiences of 150 long-term daily cannabis users who had been recruited through newspaper advertisements. Although they did not explicitly inquire about the symptoms of a cannabis dependence syndrome, substantial proportions of their sample reported experiencing various adverse effects of long-term use, despite which they continued to use cannabis. These included: impaired memory (67 per cent); an impaired ability to concentrate on complex tasks (49 per cent); difficulty getting things done (48 per cent); or thinking clearly (43 per cent); reduced energy (43 per cent); ill health (36 per cent); and accidents (23 per cent). Substantial minorities reported that it had impeded their educational (31 per cent), and career achievements (28 per cent), and half of the sample reported that they would like to cut down or stop their use.

These findings have been broadly supported by Kandel and Davies (1992) and by Stephens and Roffman (1993). Kandel and Davies reported on the characteristic problems reported by near daily cannabis users (aged 28-29 years) who were identified in a prospective study of the consequences of adolescent drug use. The major adverse consequences of use were: subjectively experienced cognitive deficits; reduced energy; depression; and problems with spouse. Stephens and Roffman's sample of users answering an advertisement offering assistance in quitting cannabis complained of: "feeling bad about using"; procrastinating because of their use; memory impairment; loss of self-esteem; withdrawal symptoms; and spouse complaints about their use. In the absence of control groups, however, it is impossible to be certain that the prevalence of these symptoms is higher than in the community, and that they were not present prior to cannabis use, as has been reported in some longitudinal studies (e.g. Shedler and Block, 1990).

The most direct support for the validity of the cannabis abuse dependence syndrome comes from a series of studies of the validity of diagnostic criteria for substance dependence. Kosten et al (1987) tested the extent to which the DSM-III-R psychoactive substance dependence disorders for alcohol, cannabis, cocaine, hallucinogens, opioids, sedatives and stimulants constituted syndromes. A sample of 83 persons (41 from an inpatient psychiatric unit and 42 from an outpatient substance abuse treatment unit) was interviewed using a standardised psychiatric interview schedule to elicit the symptoms of drug dependence as defined in DSM-III-R for each of the drug classes. Multiple diagnoses were allowed, so many individuals qualified for more than one type of drug dependence.

There was consistent support for a unidimensional dependence syndrome for alcohol, cocaine and opiates. The results were more equivocal in the case of the cannabis dependence syndrome. All the items were moderately positively correlated, had good internal consistency, and seemed to comprise a Guttman scale, but a Principal Components Analysis of the cannabis items suggested that (unlike alcohol, cocaine and heroin, all of which had a single underlying factor) there seemed to be three independent dimensions of dependence: compulsion indicated by impaired social activity attributable to drug use, preoccupation with drug use, giving up other interests, and using more than intended; inability to stop use, indicated by not being able to cut down the amount used, rapid reinstatement after abstinence, and tolerance to drug effects; and withdrawal identified by withdrawal symptoms, use of cannabis to relieve withdrawal symptoms, and continued use despite problems.

Two more recent studies on much larger samples have provided stronger support for the concept of a cannabis dependence syndrome. Newcombe (1992) reported factor analyses of 29 questionnaire items designed to measure DSM-III-R abuse and dependence for a community sample of 614 young adults reporting on their use of alcohol, cocaine, and cannabis. He reported a strong common factor for all three drug types which accounted for 36 per cent to 40 per cent of the item variance. Rounsaville, Bryant, Babor, Kranzler and Kadden (1993) report the results of factor analyses of items designed to assess dependence in each of three diagnostic systems (DSM-III-R. DSM-IV and ICD-10) for each of six drug classes (alcohol, cocaine, marijuana, opiates, sedatives and stimulants). Their sample comprised 521 persons recruited from inpatient and outpatient drug treatment, psychiatric treatment services, and the general community. They found that a single common factor explained the variation between diagnostic criteria for all diagnostic systems, and for all drug types.

7.3.4 Epidemiological evidence on cannabis abuse and dependence

The best evidence on the prevalence of cannabis abuse and dependence in the community comes from the Epidemiological Catchment Area (ECA) study (Robins and Regier, 1991) which involved face-to-face interviews with 20,000 Americans in five catchment areas: Baltimore, Maryland; Los Angeles, California; New Haven, Connecticut; Durham, North Carolina; and St Louis, Missouri. A standardised and validated clinical interview schedule was used to elicit a history of psychiatric symptoms found in 40 major psychiatric diagnoses, including drug abuse and dependence. This information was used to diagnose the presence or absence of a DSM-III diagnosis of drug dependence (Anthony and Helzer, 1991). Although not a true random sample of the American population, it is the best available data on the prevalence of different types of drug dependence and their correlates in a non-treatment population.

Illicit drug use was defined as "any non-prescription psychoactive agents other than tobacco, alcohol and caffeine, or inappropriate use of prescription drugs" (Anthony and Helzer, 1991, p116). To exclude individuals who had only briefly experimented with illicit drugs, individuals had to have used an illicit drug on more than five occasions before they were asked about any symptoms of drug dependence. The focus of the interview schedule was on the "consequent psychiatric symptoms and behavioral changes that constitute the syndromes of drug abuse and dependence" (p117).

The criteria used to define drug abuse and dependence were derived from the DSM-III, which divided symptoms of abuse and dependence into four main groups: (1) tolerance to drug effects; (2) withdrawal symptoms; (3) pathological patterns of use; and (4) impairments in social and occupational functioning due to drug use. Drug abuse required a pattern of pathological use and impaired functioning. In the case of cannabis, a diagnosis of dependence required pathological use, or impaired social functioning, in addition to either signs of tolerance or withdrawal. The problem had to have been present for at least one month, although there was no requirement that all criteria had to be met within the same period of time. In reporting the results Anthony and Helzer report the prevalence of abuse and/or dependence combined for all drug types.

Illicit drug use was relatively common in the sample, with 36 per cent of persons having used at least one illicit drug. Cannabis was the most commonly used illicit drug, having been used by 76 per cent of those who had used any illicit drug more than five times. Drug abuse and dependence were relatively common, with 6.2 per cent of the population qualifying for such a diagnosis. Cannabis abuse and/or dependence was the most common form of abuse and/or dependence, with 4.4 per cent of the population being so diagnosed compared with 1.7 per cent for stimulants, 1.2 per cent for sedatives, and 0.7 per cent for opioid drugs. Two-thirds of cases of cannabis abuse and/or dependence had used cannabis within the past year, and half had used within the past month. "Almost two-fifths (38 per cent) of those with a lifetime history of cannabis abuse and/or dependence reported active problems in the prior year" (Anthony and Helzer, 1991, p123)

When DSM-III-R diagnoses of dependence and abuse were approximated, three fifths of those with a diagnosis of dependence and/or abuse met the criteria for dependence. The proportion of current users who were dependent increased with age, from 57 per cent in the 18-29 year age group to 82 per cent in the 45-64 year age group, reflecting the remission of less severe drug abuse problems with age. Only a minority of those who had a diagnosis of abuse and/or dependence (20 per cent of men and 28 per cent of women) had mentioned their drug problem to a health professional, even though 60-70 per cent had sought medical treatment in the previous month. There were predictable age and gender differentials in prevalence of drug abuse and/or dependence. Men had higher prevalence than women (7.7 per cent versus 4.8 per cent). This was largely due to differences in exposure to illicit drugs, since the prevalence of a diagnosis of abuse and/or dependence among persons who had used an illicit drug more than five times was the about the same for men and women (21 per cent and 19 per cent). The highest prevalence of abuse and/or dependence (13.5 per cent) was in the 18-29 year age group (16.0 per cent among men and 10.9 per cent among women), declining steeply thereafter in both sexes.

It is difficult to make clear inferences about the prevalence of cannabis dependence in the community from the ECA study, because DSM-III rather than DSM-III-R criteria were used, and the data on the prevalence of drug abuse and/or dependence have not been broken down either by abuse and dependence or by drug class. The first of these problems may not be too serious, since studies comparing DSM-III and DSM-III-R criteria (e.g. Rounsaville et al, 1987) suggest that there is reasonable agreement between a DSM-III diagnosis of abuse or dependence and DSM-III-R dependence, in the case of cannabis dependence. Any disagreements in diagnosis seem to be in the direction of DSM-III-R identifying more cases as dependent than DSM-III, suggesting that any errors in the prevalence of drug abuse in the ECA study will be in the direction of underestimation.

The absence of detailed ECA reports on the separate prevalence of drug abuse and dependence is more difficult to circumvent. If we assume that any differences between drug types in the proportion of users who became dependent would have been reported (and hence that the ratio of cases of dependence to abuse for cannabis is 3:2), then the prevalence of cannabis dependence in the USA in 1982-1983 would have been 2.6 per cent of the population. If we also assume that the ratio of cases of cannabis dependence to cases of cannabis abuse was the same for men and women, then 3.2 per cent of men and 2.0 per cent of women would have been diagnosed as cannabis dependent.

Similar estimates of the population prevalence of cannabis dependence were produced by a community survey of psychiatric disorder conducted in Christchurch, New Zealand, in 1986, using the same sampling strategy and diagnostic interview as the ECA study (Wells et al, 1992). This survey used the DIS to diagnose a restricted range of DSM-III diagnoses in a community sample of 1,498 adults aged 18-64 years of age. The prevalence of having used cannabis on five or more occasions was 15.5 per cent, remarkably close to that of the ECA estimate, as was the proportion who met DSM-III criteria for marijuana abuse or dependence, namely 4.7 per cent. The fact that this survey largely replicated the ECA findings for most other diagnoses, including alcohol abuse and dependence, enhances confidence in the validity of the ECA study findings.

7.3.5 The risk of cannabis dependence

It is important to put the existence of a cannabis dependence syndrome into perspective to avoid a falsely alarmist impression that all cannabis users run a high risk of becoming dependent upon cannabis. A variety of estimates suggest that the crude risk is small, and probably more like that for alcohol rather than nicotine or the opioids. Other data suggests that certain characteristics of users increase the risk of dependence developing, although in most cases it is impossible to place quantitative estimates on the latter risks.

As with all drugs of dependence, persons who use cannabis on a daily basis over periods of weeks to months are at greatest risk of becoming dependent upon it. The ECA data suggested that approximately half of those who used any illicit drug on a daily basis satisfied DSM-III criteria for abuse or dependence (Anthony and Helzer, 1991). Since this estimate was based upon drug abuse and dependence for all drug types, including opioids, it probably overestimates the risks of dependence among daily cannabis users. Kandel and Davis (1992) estimated the risk of dependence among near daily cannabis (according to approximated DSM-III criteria) at one in three.

The risk of developing dependence among less frequent users of cannabis, including experimental and occasional users, would be substantially less than that for daily users. A number of reasonably consistent estimates of the risks of a broader spectrum of users becoming dependent on cannabis can be obtained from recent studies. A crude estimate from the ECA study was that approximately 20 per cent of persons who used any illicit drug more than five times met DSM-III criteria for drug abuse and dependence at some time. The specific rate of abuse and dependence for cannabis (calculated by dividing the proportion who met criteria for abuse and dependence by the proportion who had used the drug more than five times) was 29 per cent. A more conservative estimate which removed cases of abuse (40 per cent) from the overall estimate of cannabis abuse and dependence would be that 17 per cent of those who used cannabis more than five times would meet DSM-III criteria for dependence.

Estimates derived from a number of other studies suggest that the ECA estimates of the risk of dependence are reasonable. The crude percentage of cases of dependence and abuse among persons who had used cannabis five or more times in the Christchurch epidemiology study (Wells et al, 1992) was 30 per cent, while an estimate derived from Newcombe's community survey of young adults was 25 per cent of those who had ever used cannabis. A comparable estimate can be derived from Kandel and Davies' (1992) study of near daily cannabis users. [This was done by multiplying the ECA estimate of the proportion of daily users who met criteria for abuse and dependence (50 per cent) by the proportion of near daily users in Kandel and Davis sample (44 per cent), and adding this to the ECA estimate of the proportion of non-daily illicit drug users who met the criteria (30 per cent) multiplied by their proportion in the Kandel and Davies sample (55 per cent)]. On Kandel and Davies data the estimated rate of abuse and dependence among those who had used cannabis 10 or more times was 39 per cent, the higher rate reflecting the higher number of times of use required to be counted as a cannabis user in Kandel and Davies study (10 times versus five times in ECA). A lower estimate of 12 per cent for DSM-III-R cannabis dependence was obtained by McGee and colleagues (1993) in a prospective study of 18-year-old youth in Dunedin, New Zealand. A lower estimate was to be expected given the youth of the sample, and the fact that the estimate is the proportion of dependent users among those who had ever used cannabis.

Although one would not want to claim a great deal of precision for any of these individual estimates of the risk of cannabis dependence, it is reassuring that they are within a range of 12-37 per cent, and that the estimates vary in predictable ways with the ages of the samples and the stringency of the criteria used in defining cannabis use. The reasonable consistency of the estimates suggests the following rules of thumb about the risks of cannabis dependence. For those who have ever used cannabis, the risks of developing dependence is probably of the order of one chance in 10. The risk of dependence rises with the frequency of cannabis use, as it does with all drugs, so that among those who use the drug more than a few times the risk of developing dependence is in the range of from one in five to one in three. The range of the estimates reflects variations in the number of occasions of use that is taken to reflect more than simple experimentation, with the general rule being that the more often the drug has been used, and the longer the period of use, the higher is the risk of becoming dependent. Although there have been few formal comparisons of the dependence potential of cannabis with that of other drugs, these risks are probably more like those associated with alcohol than those associated with tobacco and opiates (Woody, Cottler and Cacciola, 1993).

Apart from frequency of use, other risk factors have been identified in the series of prospective studies of adolescent illicit drug use reviewed above. These include the following factors which have been shown to predict continued use and more intensive involvement with illicit drugs: poor academic achievement; deviant behaviour in childhood and adolescence; nonconformity and rebelliousness; personal distress and maladjustment; poor parental relationships; earlier use; and a parental history of drug and alcohol problems (Brook et al, 1992; Kandel and Davies, 1992; Newcombe, 1992; Shedler and Block, 1990). For most of these variables it is difficult to attach any quantitative estimates to the increased risk of dependence, because they have been measured in different ways in different studies.

These overall statements of the risks of cannabis dependence ignore the fact that the risk of dependence is not equally distributed in the population. The ECA study suggested that men have a higher risk of developing dependence than women, and that the risk was highest among the younger 18-29 year old cohort. In both cases, however, the most likely explanation was the different rates of exposure to cannabis among men and women, and among younger and older persons (Anthony and Helzer, 1991). When this was controlled by looking at the rates of dependence among daily users of the drug among men and women and younger and older persons, the differences in the risk of dependence largely disappeared (Anthony and Helzer, 1991).

7.3.6 The consequences of cannabis dependence

Another important issue that needs to be considered when placing the risks of cannabis dependence into perspective is that of the consequences of developing dependence. How easy or difficult is it for those who decide to stop using cannabis to achieve and maintain abstinence? This question is difficult to answer in the absence of systematic research on the natural history of cannabis dependence. The following are reasonable inferences about what the rate of remission might be. First, cannabis dependence resembles alcohol dependence in the risk of dependence, and the similarity in the age and gender distributions of heaviest use, and abuse, and dependence. It seems reasonable then to suppose that there is likely to be a high rate of remission without treatment in cannabis dependence, as there is in as in alcohol dependence in the community (Helzer, Burnham and McEvoy, 1991). The large discrepancy between the ECA estimates of cannabis abuse and dependence in the community, and the proportions of cannabis users among drug users seeking treatment provides indirect support for this inference. Kandel and Davies' (1992) findings provide more direct support. They found that 44 per cent of those who had used cannabis more than 10 times became near daily users for an average period of three years. Yet by age 28-29, less than 15 per cent of those who had ever been daily users were still daily users, indicating a very high rate of remission during the 20s.

Among those who develop cannabis dependence, how disruptive to everyday life and functioning is it? This is even more difficult to answer. All that can be said with confidence is that there are some cannabis users who are sufficiently troubled by the consequences of their dependence to seek assistance. The experience of Roffman and colleagues suggests that this number may be increased if more effort was made to attract dependent cannabis users into treatment. Among the population of cannabis dependent persons seeking treatment, the major complaints have been the loss of control over their drug use, cognitive and motivational impairments which interfere with occupational performance, lowered self-esteem and depression, and the complaints of spouses and partners (see above). There is no doubt that some dependent cannabis users report impaired performance and a reduced enjoyment of everyday life, but more detailed research is necessary to make a better judgment about how common this is, and how severe the impairment typically produced by cannabis dependence is.

7.3.7 The treatment of cannabis dependence

Given the widespread scepticism about the existence of a cannabis dependence syndrome, the question of what should be done to assist those who present for help with their cannabis use has largely been ignored (see Kleber, 1989). Indeed, Stephens and Roffman (1993) have suggested that there is a widespread view among drug and alcohol treatment practitioners that cannabis dependence does not require treatment because the withdrawal syndrome is so mild that most users can quit without assistance. Although, as argued above, it is likely that rates of remission without treatment are substantial, the fact that many users succeed without professional assistance does not mean we should ignore requests for assistance from those who are unable to stop on their own. As with persons who are nicotine dependent, those dependent cannabis users who have repeatedly failed in attempts to stop their cannabis use need professional assistance to do so. But what types of treatment should be offered?

There is not a lot of information on which to base useful recommendations. The available literature largely consists of treatment suggestions based upon personal experience, or upon clinical wisdom derived from opinions about the best forms of treatment for other related forms of dependence, such as alcohol and tobacco (e.g. de Silva, DuPont, and Russell, 1981). Jones (1984), for example, suggested that because cannabis was usually smoked in social settings, the treatment for cannabis dependence should be based upon principles derived from successful forms of treatment for nicotine dependence. Such treatment would include: assisted cessation of cannabis use accompanied by education about the acute and chronic effects of the drug; social skills training in resisting the social cues for cannabis use; and the mobilisation of peer support to maintain abstinence through self-help groups.

Others have preferred to adopt approaches adapted from those developed to treat alcohol dependence. Hannifin (1988), in arguing for the concept of "cannabism" by analogy to "alcoholism", implied that it be managed in much the same way. Miller and his colleagues (Miller and Gold, 1989; Miller, Gold and Pottash, 1989) have recommended a treatment model based upon the preferred form of treatment for alcohol dependence in the United States, namely, detoxification, a 12-step program delivered during an extended inpatient stay, and enrolment in Alcoholics Anonymous or Narcotics Anonymous after discharge. Stephens and Roffman (1993) and Zweben and O'Connell (1992) have suggested eclectic approaches combining management of withdrawal, relapse prevention methods, and enrolment in 12-step programs. Tunving et al (1988) have described their experience with a similar eclectic outpatient program for cannabis users in Sweden. De Silva et al (1981) provide short accounts of a variety of treatment approaches for marijuana dependent adolescents.

There have been very few controlled evaluations of the effectiveness of these recommendations. Smith et al (1988) reported a simple pre-treatment and post-treatment comparison of cannabis use among patients who received outpatient aversion therapy and group self-management counselling. They found good self-reported rates of abstinence, but these were obtained from telephone interviews conducted by the therapists who delivered the treatment. Roffman et al (1988) have reported a randomised controlled trial comparing group based relapse prevention or social support. Subjects were 120 men and women (average age 32 years with an average history of 16 years marijuana use) who had answered advertisements publicising a treatment program for adults seeking help to stop using marijuana. Their results at one month follow-up were much less positive than those of Smith et al: only 30 per cent of their patients were still abstinent, although 75 per cent had set abstinence as a treatment goal. By the end of a year the abstinence rate had dropped to 17 per cent. Results were a little more positive when evaluated in terms of average number of days of use, and in problems experienced, suggesting that the outcome of cannabis cessation treatment is much like that for alcohol and tobacco (Heather and Tebbutt, 1989).

Much more research is clearly required before sensible advice can be given about the best ways to achieve abstinence from cannabis. In the absence of better evidence of treatment effectiveness, those who offer treatment for cannabis dependence should avoid replicating experience in the alcohol field, where intensive and expensive forms of inpatient treatment have been widely adopted in the absence of any good evidence that they are more effective than less intensive outpatient forms of treatment (Heather and Tebbut, 1989; Miller and Hester, 1986).

7.3.8 Conclusions

In 1982 Edwards reviewed the available evidence on the question of whether there was a cannabis dependence syndrome as defined by the 1981 World Health Organisation criteria. Although he argued that there was good evidence of tolerance and a withdrawal syndrome, there was insufficient evidence bearing on the criteria of compulsion, narrowing of repertoire, reinstatement after abstinence, use to relieve or prevent withdrawal symptoms and salience of cannabis use. He added that although tolerance and withdrawal were insufficient to prove the existence of a dependence syndrome, they nonetheless constituted "grounds for believing that such a syndrome may exist" (p38). Until these issues were resolved, he concluded, the question remained "very open".

On the basis of evidence gathered since Edwards wrote, we conclude that there probably is a cannabis dependence syndrome like that defined in DSM-III-R which occurs in heavy chronic users of cannabis. There is good experimental evidence that chronic heavy cannabis use can produce tolerance and withdrawal symptoms, and some clinical and epidemiological evidence that some heavy cannabis users experience problems controlling their cannabis use, and continue to use despite the experience of adverse personal consequences of use. There is reasonable observational evidence that there is a cannabis dependence syndrome like that for alcohol, cocaine and opioid dependence. If the estimates of drug dependence from the ECA study are approximately correct, cannabis dependence is the most common form of dependence on illicit drugs, reflecting its high prevalence of use in the community. The risk of developing the syndrome is probably of the order of: one chance in ten among those who ever use the drug; between one in five and one in three among those who use more than a few times; and around one in two among those who become daily users of the drug.

Recognition of the cannabis dependence syndrome has been delayed because of its apparent rarity in Western societies, which reflects a number of factors. First, heavy daily cannabis use has been relatively uncommon by comparison with the intermittent use of small quantities of cannabis. Second, until recently there have been few individuals who have presented requesting assistance for cannabis related problems. This may have been because it is easier to stop using cannabis than opioids or alcohol without specialist assistance, or it may be that the impact of cannabis dependence on the user is not as transparently adverse as that of alcohol or opioid problems to users and their families. Third, an overemphasis on the occurrence of tolerance and a withdrawal syndrome in the past has hindered its recognition in those individuals who have presented for treatment. Fourth, cannabis dependence (which is widespread among opioid dependent persons) has been perceived to be a less serious problem than dependence on alcohol, opioids and stimulants, which have accordingly been given priority in treatment (Hannifin, 1988).

Given the widespread use of cannabis, and its continued reputation as a drug which is free of the risk of dependence, the clinical features of cannabis dependence deserve to be better delineated and studied. This would enable its prevalence to be better estimated, and individuals with this dependence to be better recognised and treated. Treatment should probably be on the same principles as what is effective for other forms of dependence. Treatment for tobacco dependence may provide a better model than treatment for alcohol dependence, although this area is in need of research.

Although cannabis dependence is likely to be a larger problem than previously thought, we should be wary of over-estimating its social and public health importance. It will be most common in the minority of heavy chronic cannabis users. Even in this group, the prevalence of drug-related problems may be relatively low by comparison with those of alcohol dependence, and the rate of remission without formal treatment is likely to be high. While acknowledging the existence of the syndrome, we should avoid exaggerating its prevalence and the severity of its adverse effects on individuals. Better research on the experiences of long-term cannabis users should provide more precise estimates of the risk.

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7.4 Effects of chronic cannabis use on cognitive functioning

Because cannabis use acutely impairs cognitive processes, a concern has arisen that chronic cannabis use may cause chronic cognitive impairment. Such a chronic effect need not necessarily be permanent, but it would persist beyond the elimination of cannabinoids from the body, and hence would be the result of secondary changes induced by cumulative exposure to cannabinoids. Such chronic effects could produce relatively enduring behavioural deficits which presumably reflect changes in brain function.

This chapter deals with the evidence from a variety of different types of study about the cognitive effects of chronic cannabis use. The caveats mentioned in the introduction must be born in mind whilst critically assessing this evidence: many other factors must be controlled in order to confidently attribute any cognitive effects to cannabis use. Among these, the most important are ensuring that the cognitive impairment did not precede cannabis use, and ensuring that the cognitive effects are not the result of the multiple drug use that is especially common among heavy cannabis users (Carlin, 1986).

7.4.1 Clinical observations

Concerns about the cognitive effects of chronic cannabis use during the early 1970s were first prompted by clinical reports of mental deterioration in persons who had used cannabis heavily (at least daily) for more than one year (Fehr and Kalant, 1983). Kolansky and Moore (1971, 1972), for example, reported cases of psychiatric disorder in adolescents and young adults (38 cases) and among adults (13 cases) who had used marijuana at least twice per week. The clinical picture was one of "very poor social judgment, poor attention span, poor concentration, confusion, anxiety, depression, apathy, passivity, indifference and often slowed and slurred speech" (Kolansky and Moore, 1971). Cognitive symptoms included: apathetic and sluggish mental and physical responses; mental confusion; difficulties with recent memory; and incapability of completing thoughts during verbal communication. These symptoms typically began after cannabis use and disappeared within three to 24 months of abstinence. The course and remission of symptoms also appeared to be correlated with past frequency and duration of cannabis smoking. Those with a history of less intensive use showed complete remission of symptoms within six months; those with more intensive use took between six and nine months to recover; while those with chronic intensive use were still symptomatic nine months after discontinuation of drug use.

These clinical reports, similar observations by Tennant and Groesbeck (1972) among hashish smoking US soldiers in West Germany, and a report of cerebral atrophy in young cannabis users (Campbell et al, 1971) excited substantial controversy about the cognitive effects of chronic cannabis use. Critics were quick to object to the lack of objective measures of impairment and the biased sampling from psychiatric patient populations. It was also difficult to rule out alternative explanations of the apparent association between cannabis use and cognitive impairment, namely, that many of these effects either preceded cannabis use, or were the result of other drug use. Whatever their limitations, these clinical reports alerted the community to the possible risks of using cannabis when it was becoming popular among the young in Western countries; they also prompted better controlled empirical research on the issue.

7.4.2 Cross-cultural studies

In response to public anxiety about the increase in marijuana use in the late 1960s, the National Institute on Drug Abuse (NIDA) in the United States commissioned three cross-cultural studies in Jamaica, Greece and Costa Rica to assess the effects of chronic cannabis use on cognitive functioning (among other things). The rationale for these studies was that any cognitive effects of chronic daily cannabis use would be most apparent in cultures with a long-standing tradition of heavy cannabis use.

7.4.2.1 Jamaica

Bowman and Pihl (1973) conducted two field studies of chronic cannabis use in Jamaica, one with a small sample of 16 users and 10 controls from rural and semi-rural areas, and the other with a small urban slum sample of 14 users and controls. Users had consumed cannabis daily for a minimum of 10 years (current use of about 23 high potency joints/day), while controls had no previous experience with cannabis. Tests were selected on the basis of having previously been shown to be sensitive to impairment following chronic heavy alcohol use (Bowman and Pihl, 1973). The groups were matched for age, sex, social class, alcohol use, education and "intelligence", but most subjects were illiterate or semi-literate, with an average age of 30. No differences were found between the users and non-users in either study, even when the rural and urban samples were combined.

Soueif (1976b) argued that a null result would be expected according to his hypothesis that cannabis-induced impairments require a minimum level of literacy to be detected. Bowman and Pihl replied that the controls were sufficiently literate to enable any impairment in the users to manifest. Moreover, their study required only a minimum of four hours abstinence prior to testing, which meant that some subjects were still intoxicated at the time of testing. This possibility would have biased the test results in favour of finding poorer performance among the users.

A more extensive study of 60 working class males in Jamaica (Rubin and Comitas, 1975) compared 30 users and 30 non-users matched on age, socioeconomic status and residence. The users who were aged between 23 and 53 years with a mean age of 34 years, had used cannabis for an average of 17.5 years (range seven to 37 years) at around seven joints per day (range one to 24) containing an estimated 60mg of THC. They had not used any other substances other than alcohol and tobacco. While no control subject had used cannabis heavily in recent years, nine were current "occasional" users of cannabis and all but 12 of the controls had some experience with cannabis.

A battery of 19 psychological tests were administered after three days of abstinence, as part of a six-day inpatient stay. The psychological tests included three tests of intellectual and verbal abilities, and 15 neuropsychological tests measuring abilities previously shown to be affected by acute cannabis intoxication. Comparisons of the users and non-users on 47 test scores failed to reveal any consistent significant differences. There were three statistically significant results which were not easily interpreted and were considered chance findings. There was no strong suggestion of differences that failed to be detected because of a small sample size, since the user group scored better than the non-user group on 29 variables, albeit non-significantly.

The interpretation of these null results must be qualified because several factors may have attenuated differences between users and non-users. First, the tests used were not standardised for use in Jamaica. The authors' argued that any cultural bias would be the same for both users and controls and therefore would not obscure any group differences (Rubin and Comitas, 1975, p111). Second, the Weschler Adult Intelligence Scale (WAIS) subtests may have been too easy or too difficult to allow detection of group differences. Third, the inclusion of cannabis users in the control group may have further reduced the chance of detecting group differences. Fourth, the Jamaican sample were primarily farmers, fishermen and artisans from rural areas, or casual urban labourers. The failure of cannabis to impair their cognitive performance does not exclude the possibility that the long-term use of cannabis may impair the performance of persons required to perform at a cognitively more demanding level.

7.4.2.2 Greece

The Greek NIDA study (Stefanis et al 1976, 1977) compared the cognitive performance of a sample of 47 chronic hashish users and 40 controls matched for age, sex, education, demographic region, socioeconomic status and alcohol consumption. The subjects were mostly refugees from Asia Minor, residing in a low income, working class area of Athens. The average duration of hashish use was 23 years of 200mg per day. Most users had smoked hashish on the day before testing, and some had smoked several hours before the test session. Controls were slightly better educated than users.

These researchers administered the Weschler Adult Intelligence Scale (WAIS) and Raven's Progressive Matrices to assess general intelligence and mental functioning (Kokkevi and Dornbush, 1977). Subtests of the WAIS were used to evaluate impairment in specific cognitive and perceptual functions. The Raven's test was considered to be a more culture-free assessment of intelligence and was used for reliability and validity purposes. The groups did not differ in global IQ score on either the WAIS or Raven's Progressive Matrices, but non-users obtained a higher verbal IQ score than users. The users' performance was worse than controls on all but one of the subtests of the WAIS, even if not significantly so. Significant differences in performance between the two groups were obtained in three subtests of the WAIS, indicating possible defects in verbal comprehension and expression, verbal memory, abstraction and associative thinking, visual-motor coordination and memorising capacity, and logical sequential thought.

The interpretation of these results was complicated by the lack of a requirement that subjects abstain from hashish prior to testing. Consequently, it was not clear whether the impairments found on these subtests were related to long-term use of hashish, or were due to the persistence of an acute drug effect at the time of testing. Because the differences between verbal and performance IQ were similar in both groups, the authors argued that there was no evidence of deterioration in mental abilities in the hashish users.

7.4.2.3 Costa Rica

The NIDA study of chronic heavy cannabis users in Costa Rica was modelled upon the Jamaican project, but with greater sensitivity to cross-cultural issues. It involved an intensive physiological, psychological, sociological and anthropological study of matched pairs of users and non-users (Carter, 1980). Satz, Fletcher and Sutker (1976) compared 41 male long-term heavy cannabis users (9.6 joints per day for 17 years) with matched controls on an extensive test battery designed to assess the impact of chronic cannabis use on neuropsychological, intellectual and personality variables. The educational level of the Costa Rican sample was slightly higher than that of either the Greek or the Jamaican samples, although more than half of the user group had not completed primary school, and both users and non-users had left school at 12 years of age. The users were working class, mostly tradesmen with lower than average income, who reported that they often used cannabis to improve their work performance.

Despite their long duration and heavy use, the Costa Rican users did not differ significantly from controls on any test. Users scored consistently lower, if not significantly so, than non-users on 11 of 16 neuropsychological tests. Although users' performance was poorer, particularly in the mean number of errors made, learning curves were similar for both groups. The authors concluded that there was insufficient evidence for significant impairment of memory function in the chronic cannabis users. Users performed slightly better on six of the 11 WAIS subtests and had a slightly higher verbal and full-scale IQ. There were no correlations between test results and the level of marijuana use.

A 10-year follow-up of the Costa Rican sample was conducted by Page, Fletcher and True (1988). By the time of follow-up, the users had an average 30 years experience with cannabis, but the sample size had dropped to 27 of the 41 original users and 30 of the 41 controls. The test protocol included some of the original tests, as well as additional tests which measured short-term memory and attention, and which had been selected for their sensitivity in detecting subtle changes in cognitive functioning.

No differences were detected on any of the original tests, but three tests from the new battery yielded significant differences between users and controls. In Buschke's Selective Reminding Test, the user group retrieved significantly fewer words from long-term storage than the non-user group, although the groups did not differ on a measure of storage. Users performed more slowly than non-users in the Underlining Test, with particularly poor performance in the most complex subtest. The Continuous Performance Test also revealed users to be slower than controls on measures requiring sustained attention and effortful processing, although there were no differences in performance.

Page et al (1988) interpreted their results as evidence that long-term consumption of cannabis was associated with difficulties in sustained attention and short-term memory. They hypothesised that such tests require more mental effort than the tests used in the original study, and, as such, that long-term users of cannabis experience greater difficulties with effortful processing. This study differs from previous cross-cultural investigations in that it found differences between users and non-users in tests of information processing, sustained attention and short-term memory. Nevertheless, Page et al (1988) emphasised that the differences they found were "quite subtle" and "subclinical", with only a small number of subjects being clinically impaired. Because the differences are so small and subtle, it was difficult to exclude the alternative explanation that the differences were due to acute intoxication or recent use, since 24-hour abstinence was requested but not verified.

7.4.2.4 Egypt

Soueif (1971) studied 850 Egyptian hashish smokers and 839 controls obtained from a male prison population which was poorly educated, largely illiterate and of low socioeconomic status. Significant differences were found between users and controls on 10 out of 16 measures of perceptual speed and accuracy, distance and time estimation, immediate memory, reaction time and visual-motor abilities (Soueif, 1971; 1975; 1976a; 1976b). These differences were more marked in those under 25 years and among the best educated urban users.

Soueif's study was subsequently criticised for methodological reasons (Fletcher and Satz, 1977). A major criticism was that the groups differed on a number of variables that were relevant to cognitive performance, including education (with literate non-users being better educated than illiterate users). There were also higher rates of opiate and alcohol use among the cannabis users. Soueif (1977) later reported that in his sample, differences between users and non-users were not explained by education or polydrug use (Soueif, 1977). The validity of these findings remain under doubt, however, because some of the tests used did not have established neuropsychological validity (Carlin, 1986).

7.4.2.5 India

Agarwal et al (1975) studied 40 subjects who had used bhang (a tea-like infusion of cannabis leaves and stems) daily for about five years. These users were less than 45 years of age, and reasonably well educated: none were illiterate and 65 per cent had completed high school. There was no control group, so scores were compared to normative data on the tests used. By comparison with these norms, 18 per cent of the bhang users had memory impairment, 28 per cent showed mild intellectual impairment on an intelligence test (IQs less than 90) and 20 per cent showed substantial cognitive disturbances on the Bender-Gestalt Visuo-Motor Test. Wig and Varma (1977) substantially replicated these results.

Mendhiratta, Wig and Verma (1978) compared 50 heavy cannabis users (half bhang drinkers, half charas smokers of at least 25 days per month for a mean of 10 years) with matched controls. The entire sample was of low socioeconomic status. Tests were administered after 12 hours abstinence which was verified by overnight admission to a hospital ward. The cannabis users reacted more slowly, and performed more poorly in concentration and time estimation. The charas smokers were the poorest performers, showing impaired memory function, lowered psychomotor activity and poor size estimation. A follow-up of 11 of the original bhang drinkers, 19 charas smokers and 15 controls nine to 10 years later (Mendhiratta et al, 1988) showed significant deterioration on several of the tests.

Ray et al (1978) assessed the cognitive functioning of 30 chronic cannabis users (aged 25-46) who had used bhang, ganja or charas for a minimum of 11 times/month for at least five years. They compared their performance to 50 randomly selected non-user controls of similar age, occupation, socioeconomic status and educational background. Few differences were found on tests of attention, visuomotor coordination, or memory. Cannabis users' performance was impaired on one of the subtests of the memory scale. However, the matching of subjects was not rigorous, and the fact that all subjects were illiterate may have produced a floor effect masking differences between groups.

Varma et al (1988) administered 13 psychological tests selected to assess intelligence, memory and other cognitive functions, to 26 heavy marijuana smokers and 26 controls matched on age, education and occupation. The average daily intake of the cannabis users was estimated as 150mg THC, with a frequency of at least 20 times per month, and a mean duration of use 6.8 years (minimum five years). Twelve hours abstinence was ensured by overnight hospitalisation. Cannabis users were found to react more slowly on perceptuomotor tasks, but did not differ from controls on the tests of intelligence. When the scores of all the memory tests were combined, there was no difference between the total scores of cannabis users and controls, although cannabis users scored significantly more poorly on a subtest of recent memory. There were trends toward poorer performance on subtests of remote memory, immediate and delayed recall, retention and recognition.

7.4.2.6 Summary

The results of the cross-cultural studies of long-term heavy cannabis users provided at most equivocal evidence of an association between cannabis use and more subtle long-term cognitive impairments. Given that cognitive impairments are most likely to be found in subjects with a long history of heavy use, it is reassuring that most such studies have found few and typically small differences. It is unlikely that the negative results of these studies can be attributed to an insufficient duration or intensity of cannabis use within the samples studied, since the duration of cannabis use ranged between 16.9-23 years, and the estimated amount of THC consumed daily ranged from 20-90mg daily in Rubin and Comitas's Jamaican study to 120-200mg daily in the Greek sample.

The absence of differences is all the more surprising, since a number of factors may have biased these studies toward finding poorer performance among cannabis users. These include: higher rates of polydrug use, poor nutrition, poor medical care, and illiteracy among users; and the failure in many studies to ensure that subjects were not intoxicated at the time of testing. Given the generally positive biases in these studies, it has been argued that if cannabis use did produce cognitive impairment, then these studies should have shown positive results (Wert and Raulin, 1986b).

The force of this argument is weakened by the fact that most of these studies also suffered from methodological difficulties which may have operated against finding a difference. First, the instruments used have been developed and standardised on Western populations. Second, many of these studies were based on small samples of questionable representativeness. Third, a number of studies failed to include a control group, while others used inappropriate controls. Fourth, generalisation of the results of these studies to users in the West or other cultures is difficult, given the predominance of illiterate, rural, older and less intelligent or less educated subjects in these studies. Fifth, the studies were only capable of detecting gross deficits. Sixth, few attempts were made to examine relationships between neuropsychological test performance and frequency and duration of cannabis use.

Despite all these problems, there was nonetheless suggestive evidence of more subtle cognitive deficits. Slower psychomotor performance, poorer perceptual motor coordination, and memory dysfunction were the most consistently reported deficits. In terms of memory function, four studies detected persistent short-term memory and attentional deficits (Page et al, 1988; Soueif, 1976a; Varma et al, 1988; Wig and Varma, 1977), while three failed to detect such deficits (Bowman et al, 1973; Satz et al, 1976; Mendhiratta et al, 1978). The measures of short-term memory were often inadequate, failing to determine which processes may be impaired (e.g. acquisition, storage, encoding, retrieval) and often excluded higher mental loads and conditions of distraction. A proper evaluation of the complexity of effects of long-term cannabis use on higher cognitive functions requires greater specificity in the selection of assessment methods, as well as the use of more sensitive tests.

7.4.3 Studies of young Western users

A number of studies have been conducted on the cognitive performance of American or Canadian cannabis users. These samples have generally been young and well educated college students with relatively short-term exposure to cannabis, by comparison with the long history of use among chronic users in the cross-cultural studies.

In one of the earliest studies, Hochman and Brill (1973) surveyed 1,400 college students and compared the performance of non-users (66 per cent), occasional users (26 per cent) and chronic users (9 per cent: defined as having used three times/week for three years or, had used daily for two years). They found no relationship between either frequency or duration of use and academic achievement. In about 1 per cent of marijuana users there was impaired ability to function. In a follow-up of the original sample over two consecutive years (1971: N=1,133; 1972: N=901), Brill and Christie (1974) compared non-users, occasional users (2 times per week), frequent (2-4/week), and regular users (ò5/week) by a self-report questionnaire. The majority of users reported no effect of cannabis use on psychosocial adjustment. A small proportion (12 per cent) who reported that their academic performance had declined were likely to have either reduced their frequency of use or quit. There were no significant differences between users, non-users or former users in grade point average.

A series of studies conducted since then has largely confirmed the results of Hochman and Brill's studies. Grant et al (1973), for example, studied the effects of cannabis use on psychological test performance on eight measures from the Halstead-Reitan Battery among medical students. They found no differences between 29 cannabis users (of median duration, four years and median frequency of use, three times per month) and 29 age and intelligence matched non-users on seven of the eight measures. The failure to find any difference in sensory-motor integration or immediate sensory memory was later replicated by Rochford, Grant and LaVigne (1977) in a comparison of 25 users (of at least 50 times over a mean 3.7 years) and 26 controls matched on sex, age and scholastic aptitude scores.

Weckowicz and Janssen (1973) compared eleven male college students who smoked cannabis three to five times per week for at least three years with non-users who were matched on age, education and socioeconomic and cultural backgrounds. They were assessed on a variety of tests of cognitive function. Users performed better than controls on eight of the 11 cognitive tests but performed more poorly on one which suggested that chronic use may affect sequential information processing. Otherwise, there was no evidence of gross impairment of cognitive functioning. Weckowicz, Collier and Spreng (1977) largely replicated these findings in a comparison of 24 heavy smokers (at least daily for three years) belonging to the "hippie subculture" with non-user controls matched for age, education, and social background. Similar results were reported by Culver and King (1974) in a comparison of the neuropsychological performance of three groups of undergraduates (N=14) from classes in two successive years: marijuana users (at least twice/month for 12 months); marijuana plus LSD users (LSD use at least once/month for 12 months); and non-drug users. There were no consistent differences between the groups across the different years.

In 1981, Schaeffer et al (1981) reported no impairment of cognitive function in one of the first studies of a prolonged heavy cannabis using population in the United States, who used the drug for religious reasons. They assessed 10 long-term heavy users of ganja, aged between 25 and 36 years, all of whom were Caucasian, and had been born, raised and educated in the USA. All had smoked between 30gm and 60gm of marijuana (>8 per cent THC) per day for a mean of 7.4 years. They had not consumed alcohol or other psychoactive substances. This study was also used a laboratory test to detect recent ingestion of cannabis. Schaeffer et al reported that at the time of testing, all subjects had at least 50ng/ml cannabinoids in their urines. Performance on a series of tests of cognitive ability was compared with the standardised-normative information available for each test. Overall, WAIS IQ scores were in the superior to very superior range, and the scores of all other tests were within normal limits. Despite the heavy and prolonged use of cannabis, there was no evidence of impairment in the cognitive functions assessed, namely, language function, non-language function, auditory and visual memory, remote, recent and immediate memory, or complex multimodal learning.

Carlin and Trupin (1977) assessed 10 normal subjects (mean age 24 years) who smoked marijuana daily for at least two years (mean five years) and who denied other drug use. They administered the Halstead Neuropsychological Test Battery after 24 hours abstinence. No significant impairment was found by comparison with non-smoking subjects matched for age, education and full-scale IQ. Cannabis users performed better on a test sensitive to cerebral impairment than non-users.

Not all studies have produced null results, however. Gianutsos and Litwack (1976), for example, compared the verbal memory performance of 25 cannabis smokers who had used for two to six years and at least twice/week for the last three months, with 25 non-smokers who had never smoked cannabis. Subjects were drawn from an undergraduate university student population and were matched on age, sex, year at university, major and grade point average. Cannabis users reported that they had not smoked prior to testing, although the length of abstinence was not reported. Cannabis users recalled significantly fewer words overall than non-users, and the difference in performance increased as a function of the number of words they were required to learn.

Entin and Goldzung (1973) also found evidence of impairment in two studies of the residual impact of cannabis use on memory processes. In the first study, verbal memory was assessed by the use of paired-associate nonsense syllable learning lists. Twenty-six cannabis users (defined as daily for at least six months) were compared to 37 non-users drawn from a student population. Cannabis users scored significantly more poorly on both free recall (the number of words recalled after a delay) and on acquisition, measured as improvement in recall over repeated trials. In the second study, verbal and numerical memory were tested by the pre

7.4.3.1 Summary

The results of these empirical studies served to allay fears that cannabis smoking caused gross impairment of cognition and cerebral function in young adults. The lack of consistent findings failed to support Kolansky and Moore's (1971, 1972) clinical reports of an organic impairment, although some critics (e.g. Cohen, 1982) argued that the value of these studies was weakened by their small sample sizes and the fact that by studying college students, they had sampled from a population unlikely to contain many impaired persons. On Cohen's hypothesis, the younger, brighter college cannabis users may reflect the survivors, whereas Kolansky and Moore sampled the casualties. Such an hypothesis conflicts with the explanations provided for the failure to find impairment in the cross cultural studies. Soueif's hypothesis, for example, was that the lower the non-drug level of proficiency, the smaller the size of functional deficit associated with drug usage. This would imply maximal differences at the high end of cognitive ability.

A more pertinent explanation for the lack of impairment is that the duration of cannabis use in these samples was quite brief, generally less than five years. It has been argued that cannabis has not been smoked long enough in Western countries for impairments to emerge. Further, when psychometric testing was used as a metric of cognitive function as opposed to self-report questionnaires, sample sizes were often too small to permit the detection of all but very large differences between groups.

Not all studies found negative results. A small number of studies did find significant impairments in their cannabis users. It is noteworthy that these studies selected tests to assess a specific cognitive function (memory), and attempted to determine the specific stages of processing where dysfunction occurred. Entin and Goldzung (1973), for example, found that users were impaired on both verbal recall and acquisition of long-term storage memory tasks, but not on arithmetic manipulations which require short-term storage of information.

7.4.4 Controlled laboratory studies

Dornbush et al (1972) administered 1g of marijuana containing 14mg THC to five regular smokers (all healthy young students) for 21 consecutive days. The subjects were tested immediately before and 60 minutes after drug administration. Data were collected on short-term memory and digit symbol substitution tests. Performance on the short-term memory test decreased on the first day of drug administration but gradually improved until by the last day of the study, performance had returned to baseline levels. On the post-experimental day baseline performance was surpassed. Performance on the digit symbol substitution test was unaffected by drug administration and also improved with time, suggesting a practice effect.

Mendelson, Rossi and Meyer (1974) reported a 31-day cannabis administration study in which 20 healthy, young male subjects (10 casual and 10 heavy users, mean age 23) were confined in a research ward and allowed 21 days of ad libitum marijuana smoking. Psychological tests were administered during a five-day drug-free baseline phase, the 21 day smoking period and a five-day drug-free recovery phase. Acute and repeat dose effects of marijuana on cognitive function were studied with a battery of psychological tests known to be sensitive to organic brain dysfunction. There was no overt impairment of performance prior to or following cannabis smoking, nor was there any difference between the performance of the heavy and the casual users. Short-term memory function, as assessed by digit span forwards and backwards, was impaired while intoxicated, and there was a relationship between performance and time elapsed since smoking.

Similar failures to detect cognitive effects have been reported by three other groups of investigators. Frank et al (1976) assessed short-term memory and goal directed serial alternation and computation in healthy young males over 28 days of cannabis administration. Harshman et al (1976) and Cohen (1976) conducted a 94-day cannabis study in which 30 healthy moderate to heavy male cannabis users, aged 21-35, were administered on average 5.2 joints per day (mean 103mg THC, range 35-198mg) for 64 days, and were assessed on brain hemisphere dominance before, during and after cannabis administration. Psychometric testing was not employed, but subjects were given two work assignments with financial incentive: a "psychomotor" task involving the addition of two columns of figures on a calculator, and a "cognitive task" of learning a foreign language. No long-term impairments were detected with these somewhat inadequate assessment methods.

7.4.4.1 Summary

The experimental studies of daily cannabis usage for periods of up to three months in young adult male volunteers have consistently failed to demonstrate a relationship between marijuana use and neuropsychological dysfunction. This is not surprising given the short periods of exposure to the drug in these studies. Furthermore, since subjects served as their own controls, and had all used cannabis for at least one year prior to the study, it would be surprising if a few additional weeks of cannabis use produced any significant decrements in performance.

7.4.5 Recent research

The equivocal results of the early investigations into long-term effects of cannabis on cognitive function led to something of a hiatus in research on the cognitive effects of cannabis in the 1980s. Although the accumulated evidence indicated that cannabis did not severely affect intellectual functioning, uncertainty remained about more subtle impairments. Their study required advances in methodology and assessment techniques which were made in the field of cognitive psychology and neuropsychology in the 1980s. Modern theories of cognition, memory function and information processing were developed, as were more sensitive measures of cognitive processes. By the late 1980s, interest in the cognitive effects of cannabis revived at a time when cannabis had been widely used for more than 15 years, its use was widespread and initiated at a progressively younger age among young Americans.

Research from the late 1980s through the 1990s improved upon the design and methodology of previous studies by using adequate control groups, verifying abstinence from cannabis prior to testing, and precisely measuring the quantity, frequency and duration of cannabis use. In addition, greater attention was paid to investigating specific cognitive processes and relating impairments in them to the quantity, frequency and duration of cannabis use.

The greater specificity in study focus was made possible by accumulating evidence that cannabis primarily exerts its effect upon those areas of the brain responsible for attention and memory. Miller and Branconnier (1983), for example, reviewed the literature and concluded that impaired memory was the single most consistently reported psychological deficit produced by cannabinoids acutely, and the most consistently detected impairment in long-term cannabis use. Intrusion errors were one of the most robust type of cannabis-induced memory deficits in both recall and recognition (Miller and Branconnier, 1983). Such errors involve the introduction of extraneous items, word associations or new material during free recall of words, or the false identification of previously unseen items in recognition tasks. Miller and Branconnier conjectured that these intrusion errors occurred because cannabis users were unable to exclude irrelevant associations or extraneous stimuli during concentration of attention, a process in which the hippocampus plays a major role. The finding of high densities of the cannabinoid receptor in the cerebral cortex and hippocampus (Herkenham et al, 1990) supports the hypothesis that cannabinoids are involved in attentional and memory processes.

7.4.5.1 Studies of long-term adult users

Solowij et al (1991; 1992; 1993) conducted a series of studies of the effects of long-term cannabis use on specific stages of information processing. In keeping with Miller and Branconnier's hypothesis, Solowij et al assessed the integrity of attentional processes in long-term cannabis users using a combination of performance and brain event-related potential measures. Event-related potential (ERP) measures are sensitive markers of covert cognitive processes underlying overt behaviour; the amplitude and latency of various ERP components have been shown to reflect various stages of information processing.

Solowij et al, (1991) studied a small and heterogeneous group of long-term cannabis users (N=9), aged 19-40, who had used cannabis for a mean of 11.2 years at the level of 4.8 days per week. The cannabis users were matched on age, sex, years of education and alcohol consumption with nine non-user controls who had either never used or had limited experience with cannabis (maximum use 15 times). Strict exclusion criteria were applied to any subjects with a history of head injury, neurological or psychiatric illness, significant use of other drugs, or high levels of alcohol consumption. The groups did not differ in premorbid IQ, as estimated by the NART score (Nelson, 1984).

Subjects were instructed to abstain from cannabis and alcohol for 24 hours prior to testing and two urine samples were analysed to ensure that subjects were not acutely intoxicated at the time of testing. Subjects completed a multidimensional auditory selective attention task in which random sequences of tones varying in location, pitch and duration were delivered through headphones while brain electrical activity (EEG) was recorded. They were instructed to attend to a particular ear and a particular pitch, and to respond to the long duration tones with a button press. This procedure enabled an examination of the brain's response to attended and unattended tones.

Cannabis users performed significantly more poorly than controls, with fewer correct detections, more errors and slightly longer reaction times. Analysis of the ERP measures showed that cannabis users had reduced P300 amplitudes compared to controls, reflecting dysfunction in the allocation of attentional resources and stimulus evaluation strategies. Further, cannabis users showed an inability to filter out irrelevant information, while controls were able to reject this irrelevant information from further processing at an early stage. These results suggested that long-term cannabis use impairs the ability to efficiently process complex information.

Solowij et al (1992; 1993) conducted a second study with a larger sample to examine the relationships between degree of impairment and the frequency and duration of use. Thirty-two cannabis users recruited from the general community were split into four groups of equal size (N=8) defined by frequency (light: ó twice/week vs heavy: ò three times/week) and duration (short: 3-4 years vs long: ò five years) of cannabis use. The mean number of years of use for the long duration users was 10.1, and 3.3 for short duration users (range three to 28 years). The mean frequency of use was 18 days per month for the heavy group and six for the light group (range: once/month to daily use). Subjects were matched to a group of non-user controls (N=16) as in the first study, and a similar methodology was employed.

Once again cannabis users performed worse than the controls, with the greatest impairment observed in the heavy user group, thereby replicating the earlier ERP findings. In addition, different cognitive processes were differentially affected by frequency and duration of cannabis use. The long duration user group showed significantly larger processing negativity to irrelevant stimuli than did short duration users and controls, who did not differ from each other. There were no differences between groups defined on frequency of use. A significant correlation between the ERP measure and duration of cannabis use indicated that the ability to focus attention and filter out irrelevant information was progressively impaired with the number of years of use, but was unrelated to frequency of use. Frequency of use affected the speed of information processing, as reflected in a delayed P300 latency in the heavy user group compared to light users and controls. There was a significant correlation between P300 latency and increasing frequency of use, while this measure was unrelated to duration of use.

These results suggest that different mechanisms underlie the short-term and long-lasting actions of cannabinoids. The slowing of information processing suggests a chronic build up of cannabinoids, and reflected a residual effect which could be eliminated by reducing the frequency of use. The inability to focus attention and reject irrelevant information possibly reflected long-term changes at the cannabinoid receptor site. The consequences of these impairments may be apparent in high levels of distractability when driving, operating complex machinery, and learning in the classroom situation, and interference with efficient memory and general cognitive functions.

Solowij et al also conducted specific analyses to disentangle the relationship between duration of cannabis use and age. The results of these analyses indicated that impairment was greatest in younger subjects. Further, the studies demonstrated the insensitivity of performance measures to cannabinoid effects, emphasising the need to use more sensitive measures to examine otherwise inaccessible, covert cognitive processes.

Supportive evidence has emerged from a project funded by the National Institute on Drug Abuse (NIDA) in the U.S. (principal investigator F. Struve) that investigated persistent central nervous system sequelae of chronic cannabis exposure. This research, which has focused upon quantitative EEG, has found evidence of larger changes in EEG frequency, primarily in frontal-central cortex, in daily cannabis users of up to 30 years duration compared to short-term users and non-users (e.g. Struve et al, 1993). The results also suggest a dose-response relationship between EEG changes and the total cumulative exposure (duration in years) of daily cannabis use which may indicate organic changes. The major limitation of this research is that changes in frequency of EEG spectra have not been shown to be related to cognitive events.

One study from this research group has used cognitive event-related potential measures. It found smaller P2 and N2 amplitudes in long-term cannabis users (>15 years) compared to moderate users (of three to six years). Cannabis users overall showed significantly smaller auditory and visual P300 amplitudes than controls, but no significant latency differences (Straumanis et al, 1992). Unfortunately, this study has only been reported in abstract form, and results have not been examined as a function of frequency of cannabis use.

This research group has also assessed cognitive functioning by neuropsychological tests (e.g. Leavitt et al, 1991; 1992; 1993). These investigations have been well controlled. Subjects were extensively screened for current or past psychiatric or medical disease or CNS injury, and underwent extensive drug history assessments, with eight weeks of twice weekly drug screens. Groups were matched for age and sex. Daily cannabis users who had at least three years to six years of use were compared to a group who had used for six to 14 years, a group who had used on a daily basis for 15 years or more, and a non-user control group. Sample sizes varied from study to study, but averaged 15 per group.

An extensive battery of psychological tests included measures of simple and complex reaction time, attention and memory span, language and comprehension tasks, construction, verbal and visual learning and memory, and mental abilities such as concept formation and logical reasoning. The effects of age and education have been statistically controlled for by multiple regression. Preliminary analyses have shown a dose-response relationship between test performance and intensity of cannabis use, with the best performance characterising controls, followed by the daily cannabis users, and the worst mean scores occurring in the very long-term group (Leavitt et al, 1991; 1992; 1993; Leavitt, personal communication). Tests sensitive to mild cortical dysfunction were those most affected in the long-term user groups.

The authors acknowledge that small sample sizes dictate caution, and that there were no data available to assess premorbid cognitive capacity of these subjects. Nevertheless, the results suggested that long duration users seem to process some kinds of information more slowly than non-users, and that the effects of long-term cannabis use are most likely to surface under conditions of moderately heavy cognitive load.

One crucial requirement for evaluating the performance of chronic marijuana users is comparison with an appropriately matched group of non-using subjects. Although the studies described have made substantial progress in this regard, one concern remains that some of these impairments may have been present in the cannabis users prior to their cannabis use. Block et al (1990) used scores on the Iowa Tests of Basic Skills collected in the fourth grade of grammar school as a measure of premorbid cognitive ability. Block et al matched their user and non-user samples on this test to ensure that they were comparable in intellectual functioning before they began using marijuana. The study aim was to determine whether chronic marijuana use produced specific cognitive impairments, and if so, whether these impairments depend on the frequency of use. Block and colleagues assessed: 144 cannabis users, 64 of whom were light users (one to four/week for 5.5 years) and 80 heavy users (òfive/week for 6.0 years), and compared them with 72 controls. Subjects were aged 18-42. Twenty-four hours of abstinence were required prior to testing.

Subjects participated in two sessions. In the first session they completed the 12th grade version of the Iowa Tests of Educational Development, which emphasise basic, general intellectual abilities and academic skills and effective utilisation of previously acquired information in verbal and mathematical areas. In the second session, subjects were administered computerised tests that emphasise learning and remembering new information, associative processes and semantic memory retrieval, concept formation and psychomotor performance. These tasks had been previously shown to be sensitive to the acute and chronic effects of cannabis, and to relevant skills required in school and work performance. The results showed that heavy users who were matched to controls on fourth-grade Iowa scores, showed impairment on two tests of verbal expression and mathematical skills when tested on the 12th-grade Iowa test. No results have been reported to date from the computerised tests.

7.4.5.2 Studies in children and adolescents

A very different approach to assessing the long-term consequences of exposure to cannabis has been taken in a well controlled longitudinal study of children who were exposed to cannabis in utero (Fried, 1993). The levels of exposure to cannabis in the sample were approximately as follows: 60 per cent of the mothers used cannabis irregularly, 10 per cent reported smoking two to five joints per week, and 30 per cent smoked a greater amount during each trimester of pregnancy. Prenatal exposure to cannabis was associated with high pitched cries, disturbed sleep cycles, increased tremors and exaggerated startles in response to minimal stimulation in newborn to 30-day-old babies. The babies showed poorer habituation to visual stimuli, consistent with the sensitivity of the visual system to the teratogenic effects of cannabis demonstrated in rhesus monkeys and rats. Fried hypothesised that exposure to cannabis may affect the rate of development of the central nervous system, slowing the maturation of the visual system. This hypothesis was supported by visual evoked potential studies of the children at four years of age, when children who had been exposed to cannabis in utero showed greater variability and longer latency of the evoked potential components, indicating immaturity in the system.

From one to three years of age, no adverse effects of prenatal exposure were found. At two years it appeared that the children were impaired on tests of language comprehension, but this effect did not persist after controlling for other factors such as ratings of home environment. At four years of age, however, the children of cannabis using mothers were significantly inferior to controls on tests of verbal ability and memory. The explanation for the failure to detect impairments in the preceding age group was that the degree and types of deficits observed may only be identifiable when cognitive development has proceeded to a certain level of maturity.

At five and six years of age, the children were not impaired on global tests of cognition and language. By age six, however, there was a deficit in sustained attention on a task that differentiated between impulsivity and vigilance. Fried proposed that "instruments that provide a general description of cognitive abilities may be incapable of identifying nuances in neurobehavior that may discriminate between the marijuana-exposed and non-marijuana exposed children" (p332). He suggested the need for tests which examine specific cognitive characteristics and strategies, such as the test of sustained attention. Fried concluded that cannabis "may affect a number of neonatal behaviours and facets of cognitive behavior under conditions in which complex demands are placed on nervous system functions".

The effects of long-term cannabis use on adolescents have not been adequately addressed. This issue is of greater relevance with an increase in the prevalence of cannabis use among adolescents and young adults in Western society. In the first study of its kind with adolescents, Schwartz et al (1989) reported the results of a small controlled pilot study of persistent short-term memory impairment in 10 cannabis-dependent adolescents (aged 14-16 years). Schwartz's clinical observations of adolescents in a drug-abuse treatment program suggested that memory deficits were a major problem, which according to the adolescents persisted for at least three to four weeks after cessation of cannabis use. His sample was middle-class, North American, matched for age, IQ and history of learning disabilities with 17 controls, eight of whom were drug abusers who had not been long-term users of cannabis, and another nine whom had never abused any drug. The cannabis users consumed approximately 18g per week, smoking at a frequency of at least four days per week (mean 5.9) for at least four consecutive months (mean 7.6 months). Subjects with a history of excessive alcohol or phencyclidine use were excluded from the study. Cannabinoids were detected in the urines of eight of the 10 users over two to nine days.

Users were initially tested between two and five days after entry to the treatment program, this length of time allowing for dissipation of any short-term effects of cannabis intoxication on cognition and memory. Subjects were assessed by a neuropsychological battery which included the Wechsler Intelligence Scale for Children, and six tests "to measure auditory/verbal and visual/spatial immediate and short-term (delayed) memory and praxis (construction ability)" (p1215). After six weeks of supervised abstinence with bi-weekly urine screens for drugs of abuse, they were administered a parallel test battery.

On the initial testing, there were statistically significant differences between groups on two tests: cannabis users were selectively impaired on the Benton Visual Retention Test and the Wechsler Memory Scale Prose Passages. The differences were smaller but were still detectable six weeks later. Cannabis users committed significantly more errors than controls initially on the Benton Visual Retention Test for both immediate and delayed conditions, but differences in the six-week post-test were not significant. Users scored lower than controls on both immediate and delayed recall in the Wechsler Memory Prose Passages Test in both test sessions. The fact that there was a trend toward improvement in the scores of cannabis users suggests that the deficits observed were related to their past cannabis use and that functioning may return to normal following a longer period of abstinence.

Schwartz's study was the first controlled study to demonstrate cognitive dysfunction in cannabis-using adolescents with a relatively brief duration of use. The implications of these results are that young people may be more vulnerable to any impairments resulting from cannabis use. Unfortunately, like many of its predecessors, Schwartz's team made little effort to interpret the significance of the selectivity of their results. There was nothing to indicate which specific elements of memory formation or retrieval were disrupted.

7.4.6 Discussion

Previous reviewers have generally concluded that there is insufficient evidence that cannabis produces long-term cognitive deficits (e.g. Wert and Raulin, 1986a; 1986b). This is a reasonable conclusion when gross deficits are considered. However, the findings from recent, more methodologically rigorous studies provide evidence of subtle cognitive impairments which appear to increase with duration of cannabis use. The evidence suggests that impairment on some neuropsychological tests may become apparent only after 10-15 years of use, but very sensitive measures of brain function are capable of detecting specific impairments after five years of use.
Impairments appear to be specific to the organisation and integration of complex information, involving various mechanisms of attention and memory processes. The similarity between the kinds of subtle impairments associated with long-term cannabis use and frontal lobe dysfunction is becoming more apparent (e.g. short-term memory deficits, increased susceptibility to interference, lack of impairment on general tests of intelligence or IQ). Frontal lobe function is difficult to measure, as indicated by the fact that patients with known frontal lobe lesions do not differ from controls on a variety of neuropsychological tests (Stuss, 1991), so the difficulty of assessing frontal lobe functions is not unique to research into the long-term effects of cannabis.

One of the functions of the frontal lobes is the temporal organisation of behaviour, a key process in efficient memory function, self-awareness and planning. The frontal lobe hypothesis of impairments due to long-term use of cannabis is consistent with the altered perception of time demonstrated in cannabis users and with cerebral blood flow studies which demonstrate greatest alterations in the region of the frontal lobes (see Section 7.5 brain damage).
The equivocal results of previous studies may be due primarily to poor methodology and insensitive test measures. Wert and Raulin (1986b) had rejected the possibility that tests used previously were not sensitive enough to detect impairments, on the grounds that the same tests have demonstrated impairment in alcoholics and heavy social drinkers. However, the cognitive deficits produced by chronic alcohol consumption may be very different to those produced by cannabis. The mechanisms of action of the two substances are different, with cannabis acting on its own specific receptor, and Solowij et al (1993) showed that the attentional impairments detected in their long-term cannabis users were not related to their alcohol consumption. Furthermore, tests may have been selected inappropriately because they were previously shown to be affected by acute intoxication, when the consequences of chronic use may be very different. A priority for future research is the identification of specific mechanisms of impairment by making direct comparisons with the effects of a variety of other substances.

Recent research has aimed at identifying specific cannabis effects by using strict exclusion criteria, and carefully matching control groups to ensure that any deficits observed are attributable to cannabis. However, interactions between the effects of long-term cannabis use concurrent with use of other substances need to be further explored. Subjects have also been excluded if they have had a history of childhood illness, learning disabilities, brain trauma or other neurological or psychiatric illness. The effects of long-term cannabis use on such individuals may be worthy of further investigation.
Cognitive deficits may not be an inevitable consequence of cannabis use. The long-term effects of cannabis on healthy individuals may differ from those in individuals with co-existing mental illness or pre-existing cognitive impairments. On the other hand, some individuals appear to function well even in cognitively demanding occupations despite long-term cannabis use. Wert and Raulin (1986b) suggested that some individuals may adapt and overcome some forms of cognitive impairment by a process of relearning.
When users and non-users are compared, differences may not always reach statistical significance due to large individual variability, particularly when small sample sizes are used. Carlin (1986) proposed that "studies that rely upon analysis of central tendency are likely to overlook impairment by averaging away the differences among subjects who have very different patterns of disability". Individual differences in vulnerability to the acute effects of cannabis are well recognised and are likely to be a factor in determining susceptibility to a variety of cognitive dysfunctions associated with prolonged use of cannabis.

There has been no research designed to identify individual differences in susceptibility to the adverse effects of cannabis. A susceptibility may be due to structural, biochemical or psychological factors, or as Wert and Raulin suggested, to lack of the "cerebral reserve that most of us call on when we experience mild cerebral damage", for example, after a night of heavy drinking. Wert and Raulin suggested that prospective studies are the ideal way to identify those subjects who show real impairment in functioning by comparing pre- and post- cannabis performance scores. However, even in a retrospective design it is possible to compare the characteristics of subjects who show impairment with those who do not, thereby identifying possible risk factors. Insufficient consideration has been given to gender, age, IQ and personality differences in the long-term consequences of cannabis use.
Almost all of the studies reviewed have been retrospective studies of naturally occurring groups (users vs. non-users). Although the matching of control groups has become more stringent, and attempts to obtain estimates of premorbid functioning have increased, prospective studies where each subject is used as his/her own control would eliminate the possibility of cannabis users having demonstrated poorer performance before commencing their use of cannabis. A longitudinal study in which several cohorts at risk for drug abuse are followed over time would be the best way to assess the detrimental effects of long-term cannabis use on cognition and behaviour.

Given the growing prevalence of cannabis use, and proposals to reduce legal restrictions on cannabis use, it is essential that research into cognitive effects of long-term cannabis use continues. According to US survey data (Deahl, 1991), more than 29 million people in the United States may be using cannabis, and more than seven million of these use on a daily basis. While there is some controversy surrounding the issue, it seems likely that the potency of cannabis has increased over the years, as more potent strains have been developed for the black market. Increased THC potency combined with decreased age of first use may result in the more marked cognitive impairments in larger numbers of individuals in the future.
Future research should adhere to rigorous methodology. This should include the use of the best available techniques for detecting cannabinoids in the body to provide greater precision in the investigation of the effects of abstinence on performance. This would permit a distinction to be made between those impairments which are residual, and likely to resolve with abstinence over time, from those of a more enduring or chronic nature, which would be associated with cumulative exposure.

Given that recent research has identified cognitive impairments that are associated with cumulative exposure, it is a priority to investigate the extent and rate of recovery of function following cessation of cannabis use. Furthermore, the parameters of drug use require careful scrutiny in terms of evaluating how much cannabis must be smoked and for how long, before impairments are manifest in different kinds of individuals. One of the problems in assessing the cannabis literature is the arbitrariness with which various groups of users have been described as "heavy", "moderate" or "light", "long-term", "moderate" or "short-term".

The use of very sensitive measures of cognitive function is important for the detection of early signs of impairment, which may permit a harm minimisation approach to be applied to cannabis use. With further research, it may be possible to specify levels of cannabis use that are "safe", "hazardous" and "harmful" in terms of the risk of cognitive impairment. Further research examining the consequences of cannabis use in comparison to other substances could provide users with the ability to make an informed decision about whether or not to use the drug, and if they use, how much and how often to use.

7.4.7 Conclusion

The weight of evidence suggests that the long-term use of cannabis does not result in any severe or grossly debilitating impairment of cognitive function. However, there is clinical and experimental evidence which suggests that long-term use of cannabis produces more subtle cognitive impairments in specific aspects of memory, attention and the organisation and integration of complex information. While these impairments may be subtle, they could potentially affect functioning in daily life. The evidence suggests that increasing duration of use leads to progressively greater impairment. It is not known to what extent such impairment may recover with prolonged abstinence.

It is apparent that not all individuals are affected equally by prolonged exposure to cannabis. Individual differences in susceptibility need to be identified and examined. For those who are dysfunctional, there is a need to develop appropriate treatment programs which address the subtle impairments in cognition and work toward their resolution. There has been insufficient research on the impact of long-term cannabis use on cognitive functioning in adolescents and young adults, or on the effects of chronic use on the cognitive decline that occurs with normal aging. Gender differences have not been examined to date and may be important, given that such differences have become apparent in differential responses to alcohol.

Future research should aim to identify with greater specificity those aspects of cognitive functioning which are affected by long-term use of cannabis, and to examine the degree to which they are reversible. There is converging evidence that dysfunction due to chronic cannabis use lies in the higher cognitive functions that are subserved by the frontal lobes and which are important in organising, manipulating and integrating a variety of information, and in structuring and segregating events in memory.

Until better measures have been developed to investigate the subtleties of dysfunction produced by chronic cannabis use, cannabis may be viewed as posing a lesser threat to cognitive function than other psychoactive substances such as alcohol. Nevertheless, the fact remains that in spite of its illegal status, cannabis use is widespread. We therefore have a continuing responsibility to minimise drug-related harm by identifying potential risks, subtle though they may be, and communicating the necessary information to the community.

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7.5 Chronic cannabis use and brain damage

A major concern about the recreational use of cannabis has been whether it may lead to functional or structural neurotoxicity, or "brain damage" in ordinary language. Fehr and Kalant (1983) defined neurotoxicity as "functional aberrations qualitatively distinct from the characteristic usual pattern of reversible acute and chronic effects, and that may be caused by identified or identifiable neuronal damage" (p27). On this definition, an enduring impairment of cognitive functioning may be interpreted as a manifestation of neurotoxicity. Since such impairments are discussed in the previous chapter on chronic effects on cognitive functioning, this chapter will concentrate on direct investigations of neurological function and structural brain damage arising from exposure to cannabinoids. The review begins with an examination of the evidence for behavioural neurotoxicity from animal studies. Neurochemical, electrophysiological and brain substrate investigations of functionality follow, and the chapter concludes with the findings of more invasive examinations of brain structure and morphology in animals, and of less invasive techniques for imaging the human brain.

7.5.1 Behavioural neurotoxicity in animals

Animal research provides the ultimate degree of control over extraneous variables; it is possible to eliminate factors known to influence research findings in humans, e.g. nutritional status, age, sex, previous drug history, and concurrent drug use. The results, however, are often difficult to extrapolate to humans because of between-species differences in brain and behaviour and in drug dose, patterns of use, routes of administration and methods of assessment.

Animal research on the effects of cannabis on brain function has typically administered known quantities of cannabinoids to animals for an extended period of time and then examined performance on various tasks assessing brain function, before using histological and morphometric methods to study the brains of the exposed animals. In general, the results of studies with primates produce results that most closely resemble the likely effects in humans; the monkey is physiologically similar to humans, while rats, for example, metabolise drugs in a different way; and monkeys are able to perform complex behavioural tasks. Nevertheless, every animal species examined to date has been found to have cannabinoid receptors in the brain. In animal models, non-targeted staring into space following administration of cannabinoids is suggestive of psychoactivity comparable to that in humans. The most characteristic responses to cannabinoids in animals are mild behavioural aberrations following small doses, and signs of gross neurotoxicity manifested by tremors and convulsions following excessively large doses. Where small doses are given for a prolonged period of time, evidence of behavioural neurotoxicity has emerged (see Rosenkrantz, 1983). Chronic exposure produces lethargy, sedation and depression in many species, and/or aggressive irritability in monkeys.

A clear manifestation of neurotoxicity in rats is what has been called the "popcorn reaction" (Luthra, Rosenkrantz and Braude, 1976), characterised by a pattern of sudden vertical jumping in rats exposed to cannabinoids for five weeks or longer. It is also seen in young animals exposed to cannabinoids in utero and then given a small dose challenge at 30 days of age. Several studies of prenatal exposure indicate that the offspring of cannabis treated animals show small delays in various stages of post-natal development, such as eye opening, various reflexes and open field exploration, although after several weeks or months their development is indistinguishable from normal (e.g. Fried and Charlebois, 1979). This means that either the developmental delay was not chronic, the remaining damage is too subtle to be detected by available measures, or the "plasticity of nervous system organisation in the newborn permitted adequate compensation for the loss of function of any damaged cells" (Fehr and Kalant, 1983, p29).

Behavioural tests in rodents have included conventional and radial arm maze learning, operant behaviour involving time discriminations, open field exploration and two-way shuttle box avoidance learning. Correct performance on these tests is dependent on spatial orientation or on response inhibition, both of which are believed to depend heavily on intact hippocampal functioning. Some studies have found decreased learning ability on such tasks several months after long-term treatment with cannabinoids (see Fehr and Kalant, 1983). For example, Stiglick and Kalant (1982a, 1982b) reported altered learning behaviour in rats one to six months after a three-month oral dosing regimen of marijuana extract or THC. They claimed that the deficits were reminiscent of behavioural changes seen after damage to the hippocampus. Long lasting impairment of learning ability and hippocampal dysfunction suggests that long-lasting damage may result from exposure to cannabis. However, some studies have been carried out too soon after last drug administration to exclude the possibility that the observed effects are residual effects, that is, due to the continued action of accumulated cannabinoids.

Memory function in monkeys has often been assessed by delayed matching-to-sample tasks. In a recent study (Slikker et al, 1992), rhesus monkeys were trained for one year to perform five operant tasks before one year of chronic administration of cannabis commenced. One group was exposed daily to the smoke of one standard joint, another on weekends only, and control groups received sham smoke exposure (N=15 or 16 per group). Performance on the tasks indicated the induction of an "amotivational syndrome" during chronic exposure to cannabis, as manifested in a decrease in motivation to respond, regardless of whether the monkeys were exposed daily or only on weekends. This led the authors to suggest that motivational problems can occur at relatively low or recreational levels of use (in fact the effect was maximal with intermittent exposure). Task performance was grossly impaired for more than a week following last exposure, although performance returned to baseline levels two to three months after cessation of use. Thus, the effects of chronic exposure were slowly reversible with no long-term behavioural effects, and the authors concluded that persistent exposure to compounds that are very slowly cleared from the brain could account for their results. This hypothesis is consistent with the long half life of THC in the body (see Section 4.7 on metabolism).

One of the problems with these studies is that animals are often only exposed for a relatively short period of time, for example, one year or less. Slikker and colleagues acknowledge that it remains to be determined whether longer or greater exposures would cause more severe or additional behavioural effects. It may be that chronic dysfunction becomes manifest only after many years of exposure. Nevertheless, it is of concern that behavioural impairments have been shown to last for several months after exposure, but reassuring that they have generally resolved over time.

A further difficulty with animal studies is a consequence of differences between animals and humans in route of cannabinoid administration. In humans, the most common route of exposure to THC is via the inhalation of marijuana smoke, whereas most animals studies have relied upon the oral administration or injection of THC because of the difficulty in efficiently delivering smoke to animals and the concern about the complications introduced by carbon monoxide toxicity. While it may well be impossible to evaluate the pharmacological and toxicological consequences of exposure to the hundreds of compounds in cannabis simultaneously, it is arguably inappropriate to assess the long-term consequences of human cannabis smoking by administering THC alone. Hundreds of additional compounds are produced by pyrolysis when marijuana is smoked, which may contribute either to acute effects or to long-term toxicity. Future studies need to address these issues for comparability to human usage. Appropriate controls, including those which mimic the carbon monoxide exposure experienced during the smoking of marijuana may be necessary.

7.5.2 Neurochemistry

The discovery of the cannabinoid receptor and its endogenous ligand anandamide revolutionised previous conceptions of the mode of action of the cannabinoids. However, much further research is required before the interactions between ingested cannabis, anandamide and the cannabinoid receptor are fully understood. Nor should the anandamide pathways be seen as responsible for all of the central effects of the psychoactive cannabinoids. There is good evidence that cannabinoids affect the concentration, turnover, or release of endogenous substances (see Pertwee, 1988). Much research has been devoted to examining the interactions between cannabinoids and several neurotransmitter receptor systems (e.g. norepinephrine, dopamine, 5-hydroxytryptamine, acetylcholine, gamma-aminobutyric acid (GABA), histamine, opioid peptides, and prostaglandins). The results suggest that all these substances have some role in the neuropharmacology of cannabinoids, although little is known about the precise nature of this involvement. Cannabinoids may alter the activities of neurochemical systems in the central nervous system by altering the synaptic concentrations of these mediators through an effect on their synthesis, release, or metabolism, and/or by modulating mediator-receptor interactions. There have been numerous reports of neurotransmitter perturbations in vitro and after short-term administration (see Martin, 1986; Pertwee, 1988).

Domino (1981) demonstrated in cats that large doses of THC elevate brain acetylcholine and reduce its turnover by producing a decrease in acetylcholine release from the neocortex. At large doses, THC may depress the brain stem activating system. With lower doses, brain acetylcholine utilisation was reduced primarily only in the hippocampus. Some of the potential undesirable side effects of cannabinoids may be related to a decrease in acetylcholine release and turnover. Domino also reported that THC decreased EEG activation and induced slow wave activity: high voltage slow waves in neocortical EEG were produced in frontal regions and tended to be exaggerated by small doses but reduced by larger doses. These findings support the general observation made in a variety of studies, that low doses of THC stimulate, while high doses depress the noradrenergic and dopaminergic system.

Bloom (1984) reported that cannabinoids increase the synthesis and turnover of dopamine and norepinephrine in rat and mouse brain, while producing little or no change in endogenous levels of catecholamines. However, THC and other cannabinoids were reported to alter functional aspects of catecholaminergic neurotransmission. THC was found to increase the utilisation of the catecholamine neurotransmitters, to alter the active uptake of biogenic amine neurotransmitters and their precursors into synaptosomes, and to alter transmitter release from synaptosomes. Further, THC was reported to alter the activity of enzymes involved in the synthesis and degradation of the catecholamines. THC and other cannabinoids can selectively alter the binding of ligands to several different membrane-bound neurotransmitter receptors.

Relatively few studies have examined whether long-term exposure to cannabinoids results in lasting changes in brain neurotransmitter and neuromodulator levels. An early study examined cerebral and cerebellar neurochemical changes accompanying behavioural manifestations of neurotoxicity (involuntary vertical jumping) in rats exposed to marijuana smoke for up to 87 days (Luthra, Rosenkrantz and Braude, 1976). Sex differences emerged in the neurochemical consequences of chronic exposure: in females, AChE showed a cyclic increase and cerebellar enzyme activity declined. For both sexes cerebellar RNA increased, but at different times for each sex, and at 87 days remained elevated only in females. Some of these neurochemical changes persisted during a 20-day recovery period, but the authors predicted the return to normality after a much longer recovery period. Cannabinoids administered prenatally not only impaired developmental processes in rats, but produced significant decrements in RNA, DNA and protein concentrations and reductions in amine concentrations (dopamine, norepinephrine) in mice, which could be important in the role of protein and nucleic acids in learning and memory (see Fehr and Kalant, 1983). Bloom (1984) reported that chronic exposure to cannabinoids has been shown to lead to increased activity of tyrosine in rat brain.

However, recent evidence suggests that there are few, if any, irreversible effects of THC on known brain chemistry. Ali and colleagues (1989) administered various doses of THC to rats for 90 days and then assessed several brain neurotransmitter systems 24 hours or two months after the last drug dose. Examination of dopamine, serotonin, acetylcholine, GABA, benzodiazepine and opioid neurotransmitter systems revealed that no significant changes occurred. A larger study with both rats and monkeys examined receptor binding of the above neurotransmitters and the tissue levels of monoamines and their metabolites (Ali et al, 1991). No significant irreversible changes were demonstrated in the rats chronically treated with THC. Monkeys exposed to a chronic treatment of marijuana smoke for one year and then sacrificed after a seven-month recovery period were found to have no changes in neurotransmitter concentration in caudate, frontal cortex, hypothalamus, or brainstem regions. The authors concluded that there are no significant irreversible alterations in major neuromodulator pathways in the rat and monkey brain following long-term exposure to the active compounds in marijuana.

Slikker et al (1992), reporting on the same series of studies, noted that there were virtually no differences between placebo, low dose or high dose groups of monkeys in blood chemistry values. The general health of the monkeys was unaffected, but the exposure served as a chronic physiological stressor, evidenced by increases in urinary cortisol levels which were not subject to tolerance (although plasma cortisol levels did not differ). Urinary cortisol elevation has not been demonstrated in other studies with monkeys. Slikker et al reported a 50 per cent reduction in circulating testosterone levels in the high dosed group, with a dramatic (albeit non-significant) rebound one to four weeks after cessation of treatment. It is worth noting that these monkeys were three years of age at the commencement of the study and would have experienced hormonal changes over the course of entering adolescence during the study.

A recent pilot study compared monoamine levels in cerebrospinal fluid (CSF) in a small sample of human cannabis users and age and sex-matched normal controls (Musselman et al, 1993). The justification for the study was that THC administered to animals has been shown to produce increases in serotonin and decreases in dopamine activity. No differences were found between the user and non-user groups in the CSF concentration of HVA, 5HIAA, MHPG, ACTH and CRH. The authors proposed a number of explanations for these results: (1) cannabis use has no chronic effect on levels of brain monoamines; (2) those who use cannabis have abnormal levels of brain monoamines which are normalised over long periods of time by cannabis use; or (3) those who use cannabis have normal levels of brain monoamines which are transiently altered with cannabis use and then return to normal. However, there is insufficient data from this study to permit a choice between these hypotheses to be made. The frequency and duration of cannabis use, and the time since last use in the user group could not be determined. All users had denied using cannabis, having been drawn from a larger normative sample and identified as cannabis users by the detection of substantial levels of cannabinoids in urine screens. Furthermore, the "normal" controls were assumed to be non-users on the basis of their drug free urines, a far from adequate source of evidence for or against cannabis use. Thus, the small sample size and faulty methodology preclude any conclusions to be drawn from this study about possible alterations in monoamine levels in cannabis users.

7.5.3 Electrophysiological effects

Cannabis is clearly capable of causing marked changes in brain electrophysiology as determined by electroencephalographic (EEG) recordings. Long-term residual abnormalities in EEG tracings from cortex and hippocampus have been shown in cats (Barratt & Adams, 1972; Domino, 1981; Hockman et al, 1971), rats (see Fehr and Kalant, 1983) and monkeys (Heath et al, 1980) exposed to cannabinoids. Withdrawal effects are also apparent in the EEG (see Fehr and Kalant, 1983), with epileptiform and spike-like activity most often seen.

Shannon and Fried (1972) related EEG changes in rat to the distribution of bound and unbound radioactive THC. Disposition of the tracer was primarily in the extra-pyramidal motor system and some limbic structures, and 0.8 per cent of the total injected drug which was weakly bound in the brain accounted for the EEG changes. In monkeys, serious subcortical EEG anomalies were observed in those exposed to marijuana smoke for six months (Heath et al, 1980). The septal region, hippocampus and amygdala were most profoundly affected, showing bursts of high amplitude spindles and slow wave activity. Such early studies often lacked critical quantitative analysis. The definition of abnormal spike-like waveforms in EEG were not made to rigorous criteria,and EEG frequency was not assessed quantitatively.

More recent studies have examined the effects of THC on extracellular action potentials recorded from the dentate gyrus of the rat hippocampus (Campbell et al, 1986a; 1986b). THC produced a suppression of cell firing patterns and a decrease in the amplitude of sensory-evoked potentials, also impairing performance on a tone discrimination task. The evoked-potential changes recovered rapidly (within four hours), but the spontaneous and tone-evoked cellular activity remained significantly depressed, indicating an abnormal state of hippocampal/limbic system operation. The authors proposed that such changes accounted for decreased learning, memory function and general cognitive performance following exposure to cannabis. The long-lasting effects of prolonged cannabis administration on animal electrophysiology has not been investigated to any degree of specificity.

The waking or sleep EEG is increasingly recognised as a particularly sensitive tool for evaluating the effects of drugs, especially drugs that affect the CNS, since EEG signals are sensitive to variables affecting the brain's neurophysiological substrate. The recording of the EEG is one of the few reasonably direct, non-intrusive methods of monitoring CNS activity in man. However, alterations in EEG activity are difficult to interpret in a functional sense. Struve and Straumanis (1990) provide a review of the human research dating from 1945 on the EEG and evoked potential studies of acute and chronic effects of cannabis use. While the data have often been contradictory, the most typical human alterations in EEG patterns include an increase in alpha activity and a slowing of alpha waves with decreased peak frequency of the alpha rhythm, and a decrease in beta activity (Fink, 1976; Fink et al, 1976). In general, this is consistent with a state of drowsiness. Desynchronisation, variable changes in theta activity, abnormal sleep EEG profiles and abnormal evoked responses have also been reported (see Fehr and Kalant, 1983). Clinical reports have associated cannabis with triggering seizures in epileptics (Feeney, 1979) and experimental studies have shown THC to trigger abnormal spike waveforms in the hippocampus, whereas cannabidiol has an opposite effect. Yet there is suggestive evidence that cannabis may be useful in the treatment of convulsions. Feeney (1979) discusses these paradoxical effects.

A number of studies have investigated EEG in chronic cannabis users. The early cross-cultural studies were flawed in many respects (see Section 7.4 on cognitive functioning) and also failed to used quantitative techniques in analysing EEG spectra. No EEG abnormalities were found in the resting EEG of chronic users from Greek, Jamaican or Costa Rican populations compared to controls (Karacan et al, 1976; Rubin and Comitas, 1975; Stefanis, 1976). In all of these studies, only subjects who were in good health and who were functioning adequately in the community, were selected, thereby systematically eliminating subjects who may have been adversely affected by cannabis use and who may therefore have shown residual EEG changes. The evidence from many studies has been contradictory: users have been found to show either higher or lower percentages of alpha-components than non-users, and to have higher or lower visual evoked response amplitudes (Richmon et al, 1974). Subjects in a 94-day cannabis administration study (Cohen, 1976) showed lasting EEG changes. The abnormalities were more marked in subjects who had taken heavier doses, but it was observed that even in abstinence, cannabis users had more EEG irregularities than non-using controls. It was not determined for how long after cessation of use the EEG changes persisted. It has also been reported that chronic users develop tolerance to some of the acute EEG changes caused by cannabis (Feinberg et al, 1976). The question as to why chronic cannabis users can continue to display changes in EEG when tolerance is known to develop to such alterations remains unanswered.

In a series of well controlled ongoing studies, Struve and colleagues (1991, 1993) have been using quantitative techniques to investigate persistent EEG changes in long-term cannabis users, characterised by a "hyperfrontality of alpha". Significant increases in absolute power, relative power and interhemispheric coherence of EEG alpha activity over the bilateral frontal-central cortex in daily THC users compared to non-users were demonstrated and replicated several times. The quantitative EEGs of subjects with excessively long cumulative THC exposures (>15 years) appear to be characterised by increases in frontal-central theta activity in addition to the hyperfrontality of alpha found in THC users in general (or those with much shorter durations of use). Ultra-long-term users have shown significant elevations of theta absolute power over frontal-central cortex compared to short-term users and controls, and significant elevations in relative power of frontal-central theta in comparison to short-term users. Over most cortical regions, ultra-long-term users had significantly higher levels of theta interhemispheric coherence than short-term users or controls. Thus, excessively long duration of THC exposure (15-30 years) appears to be associated with additional topographic quantitative EEG features not seen with subjects using THC for short to moderately long time periods.

These findings have led to the suspicion that there may be a gradient of quantitative EEG change associated with progressive increases in the total cumulative exposure (duration in years) of daily THC use. Infrequent, sporadic or occasional THC use does not seem to be associated with persistent quantitative EEG change. As daily THC use begins and continues, the topographic quantitative EEG becomes characterised by the hyperfrontality of alpha. While it is not known at what point during cumulative exposure it occurs, at some stage substantial durations of daily THC use become associated with a downward shift in maximal EEG spectral power from the mid alpha range to the upper theta/low alpha range. Excessively long duration cumulative exposure of 15-30 years may be associated with increases of absolute power, relative power and coherence of theta activity over frontal-central cortex. One conjecture is that the EEG shift toward theta frequencies, if confirmed, may suggest organic change. These data are supplemented by neuropsychological test performance features separating long-term users from moderate users and non-users, however the relationship between neuropsychological test performance and EEG changes has not been investigated.

While the EEG provides little interpretable information about brain function, brain event-related potential measures are direct electrophysiological markers of cognitive processes. Studies by Herning et al (1979) demonstrated that THC administered orally to volunteers alters event-related potentials according to dose, duration of administration, and complexity of the task. Event-related potential studies of chronic cannabis users in the unintoxicated state have provided evidence for long-lasting functional brain impairment and subtle cognitive deficits (see Section 7.4 on cognitive functioning).

7.5.4 Cerebral blood flow studies

Brain cerebral blood flow (CBF) is closely related to brain function. The use of CBF may help to identify brain regions responsible for the behavioural changes associated with drug intoxication. Since, however, psychoactive drugs may induce CBF changes through mechanisms other than alteration in brain function (e.g. by increasing carbon monoxide levels, changing blood gases or vasoactive properties, affecting blood viscosity, autonomic activation or inhibition of intraparenchymal innervation, acting on vasoactive neuropeptides), any conclusions drawn from drug-induced CBF changes must be treated with caution.

Mathew and Wilson (1992) report several studies of cannabis effects on cerebral blood flow. Acutely, cannabis administration to inexperienced users produced global CBF decreases, while acute intoxication increased CBF in both hemispheres, at frontal and the left temporal regions, in experienced users. There was an inverse relationship between anxiety and CBF. The authors attributed the decrease in CBF in naive subjects to their increased anxiety after cannabis administration, while the increased CBF in experienced users was attributed to the behavioural effects of cannabis. A further study showed that the largest increases in CBF occurred 30 minutes after smoking. The authors concluded that cannabis causes a dose related increase in global CBF, but also appears to have regional effects, with a greater increase in the frontal region and in particular in the right hemisphere. CBF increases were correlated with the "high", plasma THC levels and pulse rate, loss of time sense, depersonalisation, anxiety and somatisation scores (positively with frontal flow and inversely with parietal flow).

The authors claimed their results suggested that altered brain function was mainly, if not exclusively, responsible for the CBF changes. Carbon monoxide increased after both cannabis and placebo but did not correlate with CBF. Cannabis induced "red eye" lasted for several hours, but the CBF increases declined significantly within two hours of smoking. Nevertheless, the possibility remains that the CBF changes reflected drug-induced vascular (cerebral) change. Continued reduction in cerebral blood velocity was demonstrated following cannabis administration, and reports of dizziness but with normal blood pressure suggested that cannabis may impair cerebral autoregulation.

The time course of CBF changes resembled that of mood changes more closely than plasma THC levels. Global CBF was closely related to levels of arousal mediated by the reticular activating system. High arousal states generally show CBF increases while low arousal states show CBF decreases. Of all cortical regions, the frontal lobe has the most intimate connections with the thalamus which mediates arousal, and CBF increases after cannabis use were most pronounced in frontal lobe regions. The right hemisphere is known to mediate emotions, and the most marked changes after cannabis were seen there. Time sense and depersonalisation, which are associated with the temporal lobe, were severely affected, but there were no significant correlations between these scores and temporal flow. Perhaps CBF techniques are not sensitive enough in terms of spatial resolution to detect such effects. The parietal lobes are associated with perception and cognition. Cannabis reduces perceptual acuity, but during intoxication subjects report increased awareness of tactile, visual and auditory stimuli. Maybe their altered time sense and depersonalisation are related to such altered awareness.

There have been a few investigations of chronic effects of cannabis on CBF. Tunving et al, (1986) demonstrated globally reduced resting levels of CBF in chronic heavy users of 10 years compared to non-user controls, but no regional flow differences were observed. CBF increased by 12 per cent between nine and 60 days later, indicating reduced CBF in heavy users immediately after cessation of cannabis use, with a return to normal levels with abstinence. This study was flawed in that some subjects were given benzodiazepines (which are known to lower CBF) prior to the first measurement. Mathew and colleagues (1986) assessed chronic users of at least six months (mean 83 months) after two weeks of abstinence. No differences in CBF levels were found between users and non-user controls. The number of studies available on the effects of cannabis on CBF are relatively small. Use of techniques with better spatial resolution and the ability to quantify subcortical flow, such as positron emission tomography (PET), would yield more useful findings.

7.5.5 Positron emission tomography (PET) studies

Positron emission tomography (PET) is a nuclear imaging technique which allows the concentration of a positron-labelled tracer to be imaged in the human brain. PET can measure the time course and regional distribution of positron-labelled compounds in the living human brain. Most PET studies have utilised an analog of glucose to measure regional brain glucose metabolism, since nervous tissue uses glucose as its main source of energy. Measurement of glucose metabolism reflects brain function, since activation of a given brain area is indicated by an increase in glucose consumption. PET may be used to assess the effects of acute drug administration by using regional brain glucose metabolism to determine the areas of the brain which are activated by a given drug. Assessment of brain glucose metabolism has been useful in identifying patterns of brain dysfunction in patients with psychiatric and neurological diseases. It is a direct and sensitive technique for identifying brain pathology, since it can detect abnormalities in the functioning of brain regions in the absence of structural changes, such as is likely to occur with the neurotoxic effects of chronic drug use. It is accordingly more sensitive than either computer-assisted tomography (CAT) scans or magnetic resonance imaging (MRI) in detecting early pathological changes in the brain.

Only one study to date has used the PET technique to investigate the effects of cannabis use. Volkow et al (1991) reported preliminary data from an investigation comparing the acute effects of cannabis in three normal subjects (who had used cannabis no more than once or twice per year) and in three chronic users (who had used at least twice a week for at least 10 years). The regions of interest were the prefrontal cortex, the left and right dorsolateral, temporal, and somatosensory parietal cortices, the occipital cortex, basal ganglia, thalamus and cerebellum. A measure of global brain metabolism was obtained using the average for the five central brain slices, and relative measures for each region were obtained using the ratios of region/global brain metabolism. Due to the small number of subjects, descriptive rather than inferential statistical procedures were used for comparison. The relation between changes in metabolism due to cannabis and the subjective sense of intoxication was tested with a regression analysis.

In the normal subjects, administration of cannabis led to an increase in metabolic activity in the prefrontal cortex and cerebellum; the largest relative increase was in the cerebellum and the largest relative decrease was in the occipital cortex. The degree of increase in metabolism in the cerebellar cortex was highly correlated with the subjective sense of intoxication. The cannabis users reported less subjective effects than the normal controls and showed less changes in regional brain metabolism, reflecting tolerance to the actions of cannabis. However, the authors did not report comparisons of baseline levels of activity in the users and controls, perhaps due to the limitations of the small sample size. Such a comparison would have enabled some evaluation of the consequences of long-term cannabis use on resting levels of glucose metabolism. The increases in regional metabolism are in accord with the increases in cerebral blood flow reported by Mathew and Wilson (1992). The regional pattern of response to cannabis in this study is consistent with the localisation of cannabinoid receptors in brain. A further application of PET would be to label cannabinoids themselves: labelling of cannabis with a positron emitter has been achieved and preliminary biodistribution studies have been carried out in mice and in the baboon (Charalambous et al, 1991; Marciniak et al, 1991). The use of PET in future human studies is promising.

7.5.6 Brain morphology

7.5.6.1 Animal studies

Early attempts to investigate the effects of chronic cannabinoid exposure on brain morphology in animals failed to demonstrate any effect on brain weight or histology under the light microscope. Electron microscopic examination, however, has revealed alterations in septal, hippocampal and amygdaloid morphology in monkeys after chronic treatment with THC or cannabis. A series of studies from the same laboratory (Harper et al, 1977; Myers and Heath, 1979; Heath et al, 1980 discussed below) reported widening of the synaptic cleft, clumping of synaptic vesicles in axon terminals, and an increase in intranuclear inclusions in the septum, hippocampus and amygdala. These findings incited a great deal of controversy, and the studies were criticised for possible technical flaws (Institute of Medicine, 1982), with claims that such alterations are not easily quantifiable.

Harper et al (1977) examined the brains of three rhesus monkeys six months after exposure to marijuana, THC or placebo, and two non-exposed control monkeys. In the treated group, one monkey was exposed to marijuana smoke three times each day, five days per week; another was injected with THC once each day and the third was exposed to placebo smoke conditions. The latter two had electrode implants for EEG recording and had shown persistent EEG abnormalities following their exposure to cannabis. Morphological differences were not observed by light microscopy, but electron microscopy revealed a widening of the synaptic cleft in the marijuana and THC treated animals, with no abnormalities detected in the placebo or control monkeys. Further, "clumping" of synaptic vesicles was observed in pre- and post-synaptic regions in the cannabinoid treated monkeys, and opaque granular material was present within the synaptic cleft. The authors concluded that chronic heavy use of cannabis alters the ultrastructure of the synapse, and proposed that the observed EEG abnormalities may have been related to these changes.

Myers and Heath (1979) examined the septal region of the same two cannabinoid treated monkeys, and found the volume density of the organised rough endoplasmic reticulum to be significantly lower than that of the controls, and fragmentation and disorganisation of the rough endoplasmic reticulum patterns, free ribosomal clusters in the cytoplasm, and swelling of the cisternal membranes was observed. The authors noted that similar lesions have been observed following administration of various toxins or after axonal damage, reflecting disruptions in protein synthesis.
Heath et al (1980) extended the above findings by examining a larger sample of rhesus monkeys (N=21) to determine the effects of marijuana on brain function and ultrastructure. Some animals were exposed to smoke of active marijuana, some were injected with THC and some were exposed to inactive marijuana smoke. After two to three months of exposure, those monkeys that were given moderate or heavy exposure to marijuana smoke developed chronic EEG changes at deep brain sites, which were most marked in the septal, hippocampal and amygdaloid regions. These changes persisted throughout the six to eight month exposure period, as well as the postexposure observation period of between one and eight months. Brain ultrastructural alterations were characterised by changes at the synapse, destruction of rough endoplasmic reticulum and development of nuclear inclusion bodies. The brains of the placebo and control monkeys showed no ultrastructural changes. The authors claimed that at the doses used, which were comparable to human usage, permanent alterations in brain function and ultrastructure were observed in these monkeys.

Brain atrophy is a major non-specific organic alteration which must be preceded by more subtle cellular and molecular changes. Rumbaugh et al (1980) observed six human cases of cerebral atrophy in young male substance abusers of primarily alcohol and amphetamines. They then conducted an experimental study of six rhesus monkeys treated chronically with various doses of cannabis extracts orally for eight months and compared them to groups that were treated with barbiturates or amphetamines, or untreated. No signs of cerebral atrophy were demonstrated in the cannabis exposed group, and light microscopy revealed no histological abnormalities in four of the animals, but "equivocal" results for the other two. Brains were not examined under the electron microscope. The amphetamine treated group showed the greatest histological, cerebrovascular and atrophic changes.

More recently, McGahan et al (1984) used high resolution computerised tomography scans in three groups of four rhesus monkeys. One was a control group, a second was given 2.4mg/kg of oral THC per day for two to 10 months, and a third group received a similar daily dose over a five-year period. The dosage was considered the equivalent of smoking one joint a day. The groups receiving THC were studied one year after discontinuing the drug. There was a statistically significant enlargement of the frontal horns and the bicaudate distance in the brains of the five-year treated monkeys as compared to the control and short-term THC groups. This finding suggests that the head of the caudate nucleus and the frontal areas of the brain can atrophy after long-term administration of THC in doses relevant to human exposure.

A number of rat studies have found similar results to those in rhesus monkeys described above. Investigators have reported that after high dose cannabinoid administration, there is a decrease in the mean volume of rat hippocampal neurons and their nuclei, and that after low dose administration, there is a shortening of hippocampal dendritic spines. Scallet and coworkers (1987) used quantitative neuropathological techniques to examine the brains of rats seven to eight months after 90-day oral administration of THC. The anatomical integrity of the CA3 area of rat hippocampus was examined using light and electron microscopy. High doses of THC resulted in striking ultrastructural alterations, with a significant reduction in hippocampal neuronal and cytoplasmic volume, detached axodendritic elements, disrupted membranes, increased extracellular space and a reduction in the number of synapses per unit volume (i.e. decreased synaptic density). These structural changes were present up to seven months following treatment. Lower doses of THC produced a reduction in the dendritic length of hippocampal pyramidal neurons two months after the last dose, and a reduction in GABA receptor binding in the hippocampus, although the ultrastructural appearance and synaptic density appeared normal. The authors suggested that such hippocampal changes may constitute a morphological basis for the persistent behavioural effects demonstrated following chronic exposure to THC in rats, effects which resemble those of hippocampal brain lesions. These findings are in accord with those of Heath et al (1980) with rhesus monkeys, and the doses administered correspond to daily use of approximately six joints in humans.

A study by Landfield et al (1988) showed that chronic exposure to THC reduced the number of nucleoli per unit length of the CA1 pyramidal cell somal layer in the rat hippocampus. The brains of rats treated five times per week for four or eight months with 4-10mg/kg injected subcutaneously were examined by light and electron microscopy. Significant THC-induced changes were found in hippocampal structure; pyramidal neuronal cell density decreased and there was an increase in glial reactivity, reflected by cytoplasmic inclusions similar to that seen during normal aging or following experimentally induced brain lesions. However, no effects were observed on ultrastructural variables such as synaptic density. Adrenal-pituitary activity increased, resulting in elevated ACTH and corticosterone elevations during acute stress. The authors claimed that the observed hippocampal morphometric changes produced by THC exposure were similar to glucocorticoid-dependent changes that develop in rat hippocampus during normal aging. They proposed that, given the chemical structural similarity between cannabinoids and steroids, chronic exposure to THC may alter hippocampal anatomical structure by interacting with adrenal steroid activity. More recently, Eldridge et al (1992) reported that delta-8-THC bound with the glucocorticoid receptors in the rat hippocampus, and was displaced by corticosterone or delta-9-THC. A glucocorticoid agonist action of delta-9-THC injections was demonstrated. Injection of corticosterone increased hippocampal cannabinoid receptor binding. These interactions suggest that cannabinoids may accelerate brain aging.

It should be noted that where THC has been administered to monkeys for six months, this represents only 2 per cent of their life span and may not have been long enough to detect the gradual effects that could arise from interactions with steroid systems (and affect the aging process). In contrast, eight months administration to rats represents approximately 30 per cent of their life span. The differences in the ultrastructural findings of Landfield's and Scallet's studies may be due to the largely different doses administered; the 8mg/kg of Landfield's study was not sufficient to produce any marked behavioural effects. Further, the two studies examined slightly different hippocampal areas (CA1 or CA3).

Most recently, Slikker and colleagues (1992) reported the results of their neurohistochemical and electronmicroscopic evaluation of the rhesus monkeys whose dosing regime, behavioural and histochemical data were reported above. They failed to replicate earlier findings: no effects of drug exposure were found on the total area of hippocampus, or any of its subfields; there were no differences in hippocampal volume, neuronal size, number, length or degree of branching of CA3 pyramidal cell dendrites. Nor were there effects on synaptic length or width, but there were trends toward increased synaptic density (the number of synapses per cubic mm), increased soma size, and decreased basilar dendrite number in the CA3 region with marijuana treatment. Slikker et al (1992) were able to demonstrate an effect of enriched environments upon neuroanatomy: daily performance of operant tasks increased the total area of hippocampus and particularly the CA3 stratum oriens, producing longer, more highly branched dendrites and less synaptic density, while the reverse occurred in the animals deprived of the daily operant tasks. The extent of drug interaction with these changes was not clear and may explain some of the inconsistencies between this study and those described above. Clearly, the question of whether prolonged exposure to cannabis results in structural brain damage has not been fully resolved.

The development of tolerance following chronic administration of psychoactive compounds is often mediated by a down-regulation of receptors. Thus, chronic exposure to THC could result in a decreased number of cannabinoid receptors in the brain. Such receptor down-regulation and reduced binding has recently been demonstrated in rats (Oviedo, Glowa and Herkenham, 1993). However, previously Westlake et al (1991) found that cannabinoid receptor properties were not irreversibly altered in rat brain 60 days following 90-day administration of THC, nor in monkey brain seven months after one year of exposure to marijuana smoke. It was argued that these recovery periods were sufficient to allow the full recovery of any receptors that would have been lost during treatment. Nevertheless, studies have not yet confirmed the parameters of any alterations in cannabinoid receptor number and function that may result from chronic exposure to cannabinoids, and the extent of reversibility following longer exposures has not been determined.

7.5.6.2 Human studies

There is very little evidence from human studies of structural brain damage. In their controversial paper, Campbell et al (1971) were the first to present evidence suggesting that structural/morphological brain damage was associated with cannabis use. They used air encephalography to measure cerebral ventricular size, and claimed to have demonstrated evidence of cerebral atrophy in ten young males who had used cannabis for three to 11 years, and who complained of neurological symptoms, including headaches, memory dysfunction and other cognitive impairment. Compared to controls, the cannabis users showed significantly enlarged lateral and third ventricular areas. Although this study was widely publicised in the media because of its serious implications, it was heavily criticised on methodological grounds. Most subjects had also used significant quantities of LSD and amphetamines, and the measurement technique was claimed to be inaccurate, particularly since there were great difficulties in assessing ventricular size and volume to any degree of accuracy (e.g. Bull, 1971; Susser, 1972; Brewer, 1972). Moreover, the findings could not be replicated. Stefanis (1976) reported that echoencephalographic measurements of the third ventricle in 14 chronic hashish users and 21 non-users did not support Campbell et al's pneumoencephalographic findings of ventricular dilation.

The introduction of more accurate and non-invasive techniques, in the form of computerised tomographic (CT) scans, (also known as computer-assisted tomographic (CAT) scans), permitted better studies of possible cerebral atrophy in chronic cannabis users (Co et al, 1977; Kuehnle et al, 1977). Co et al (1977), for example, compared 12 cannabis users recruited from the general community, with 34 non-drug using controls, all within the ages of 20-30. The cannabis users had used cannabis for at least five years at the level of at least five joints per day, and most had also consumed significant quantities of a variety of other drugs, particularly LSD. Kuehnle et al's (1977) subjects were 19 heavy users aged 21-27 years, also recruited from the general community who had used on average between 25 and 62 joints per month in the preceding year, although their duration of use was not reported. CT scans were obtained presumably at the end of a 31-day study, which included 21 days of ad libitum smoking of marijuana (generally five joints per day), and were compared against a separate normative sample. No evidence for cerebral atrophy in terms of ventricular size and subarachnoid space was found in either study. Although these studies could also be criticised for their research design (e.g. inappropriate control groups, and the fact that cannabis users had used other drugs), these flaws would only have biased the studies in the direction of detecting significant differences between groups, yet none were found. The results were interpreted as a refutation of Campbell's findings, and supporting the absence of cortical atrophy demonstrated by Rumbaugh et al's (1980) CAT scans of monkeys. A further study (Hannerz and Hindmarsh, 1983) investigated 12 subjects who had smoked on average 1g of cannabis daily for between six and 20 years, by thorough clinical neurological examination and CT scans. As in the studies above, no cannabis related abnormalities were found on any assessment measure.

7.5.7 Discussion

Surprisingly few studies of neurotoxicity have been published, and the results have been equivocal. There is convincing evidence that chronic administration of large doses of THC leads to residual changes in rodent behaviours which are believed to depend upon hippocampal function. There is evidence for long-term changes in hippocampal ultrastructure and morphology in rodents and monkeys. Animal neurobehavioural toxicity is characterised by residual impairment in learning, EEG and biochemical alterations, impaired motivation and impaired ability to exhibit appropriate adaptive behaviour. Although extrapolation to man is not possible, the results of these experimental studies have demonstrated cannabinoid toxicity at doses comparable to those consumed by humans using cannabis several times a day. There is sufficient evidence from human research to suggest that the cannabinoids act on the hippocampal region, producing behavioural changes similar to those caused by traumatic injury to that region.

The cognitive, behavioural and functional responses to long-term cannabis consumption in animals and man appear to be the most consistent manifestation of its potential neurotoxicity. The extent of damage appears to be more pronounced at two critical stages of central nervous system development: in neonates when exposed to cannabis during intrauterine life; and in adolescence, during puberty when neuroendocrine, cognitive and affective functions and structures of the brain are in the process of integration. As discussed in Section 7.4 on cognitive functioning, research needs to investigate the possibility that more severe consequences may occur in adolescents exposed to cannabinoids. Human research has defined a pattern of acute CNS changes following cannabis administration; there is convincing evidence for long-lasting changes in brain function after long-term heavy use; whether or not these changes are permanent has not been established.

Human studies of brain morphology have yielded generally negative results, failing to find gross signs of "brain damage" after chronic exposure to cannabis. Nevertheless, the results of many human studies are indicative of more subtle brain dysfunction. It may be that existing methods of brain imaging are not sensitive enough to establish subcellular alterations produced in the CNS. Many psychoactive substances exert their action through molecular biochemical mechanisms which do not distort gross cell architecture. The most convincing evidence on brain damage would come from postmortem studies, but this type of information has not been available.

In 1983, Fehr and Kalant concluded that "The state of the evidence at the present time does not permit one either to conclude that cannabis produces structural brain damage or to rule it out" (p602). Nahas (1984) wrote "The brain is the organ of the mind. Can one repetitively disturb the mental function without impairing brain mechanisms? The brain, like all other organs of the human body, has very large functional reserves which allow it to resist and adapt to stressful abnormal demands. It seems that chronic use of cannabis derivatives slowly erodes these reserves" (p299). In 1986, Wert and Raulin (1986) proposed, that on the available evidence "there are no gross structural or neurological deficits in marijuana-using subjects, although subtle neurological features may be present. However, the type of deficit most likely to occur would be a subtle, functional deficit which could be assessed more easily with either psychological or neuropsychological assessment techniques." (p624). In 1993, little further evidence has emerged to challenge or refute these earlier conclusions.

This conclusion was anticipated by the Parisian physician Moreau as early as 1845 when he observed:

...unquestionably there are modifications (I do not dare use the word "lesion") in the organ which is in charge of mental functions. But these modifications are not those one would generally expect. They will always escape the investigations of the researchers seeking alleged or imagined structural changes. One must not look for particular, abnormal changes in either the gross anatomical or the fine histological structure of the brain; but one must look for any alterations of its sensibility, that is to say, for an irregular, enhanced, diminished or distorted activity of the specific mechanisms upon which depends the performance of mental functions. (Moreau (de Tours), 1845).

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7.6 Does cannabis use cause psychotic disorders?

There is a prima facie case for believing that cannabis use may in certain circumstances be a contributory cause of major psychological disorders such as psychotic disorders, i.e. illnesses in which symptoms of hallucinations, delusions and impaired reality testing are predominant features. First, THC is a psychoactive substance which produces some of the symptoms found in psychotic disorders, namely, euphoria, distorted time perception, cognitive and memory impairments (Brill and Nahas, 1984; Halikas et al, 1971; Thornicroft, 1990). Second, under controlled laboratory conditions with normal volunteers, THC has been shown at high doses to produce psychotic symptoms which include visual and auditory hallucinations, delusional ideas, thought disorder, and symptoms of hypomania (Georgotas and Zeidenberg, 1979; National Academy of Science, 1982). Third, a putative "cannabis psychosis" has been identified by clinical observers in regions of the world with a long history of chronic, heavy cannabis use, e.g. India, Egypt, and the Carribean (Brill and Nahas, 1984; Ghodse, 1986).

7.6.1 The nature of the relationship

How might cannabis use causally contribute to the development of psychosis? The following are the major mechanisms that have been suggested by proponents of a relationship between cannabis use and severe psychological disorder (Thornicroft, 1990).

7.6.1.1 Is there a 'cannabis psychosis'?

The first possibility is that acute or chronic cannabis use may produce a "cannabis psychosis". Four possible variants of this hypothesis can be distinguished. The first hypothesis is that the acute use of large doses of cannabis may induce a "toxic" or organic psychosis with prominent symptoms of confusion and hallucination, which remit with abstinence from cannabis. The second hypothesis is that cannabis use may produce an acute functional psychosis, similar in its clinical presentation to paranoid schizophrenia, and lacking the organic features of a toxic psychosis which remits after abstinence from cannabis. A third hypothesis is that chronic cannabis use may produce a chronic psychosis, i.e. a psychotic disorder which persists beyond the period of intoxication. The fourth hypothesis (a variant of the third) is that chronic cannabis use may induce an organic psychosis which only partially remits with abstinence, leaving in its train a residual deficit state with symptoms that are analogous to the negative symptoms of schizophrenia, or a mild chronic brain syndrome. This has also been described as "an amotivational syndrome" which is characterised by withdrawal, lack of interest in others, impaired performance and lack of motivation to perform one's social responsibilities.

7.6.1.2 Does cannabis use precipitate a latent psychosis?

Cannabis use could conceivably precipitate a latent psychosis, i.e. bring forward an episode of schizophrenia or manic depressive psychosis in a vulnerable or predisposed individual. This could occur either as a result of a specific pharmacological effect of THC (or other constituents of cannabis preparations), or as the result of stressful experiences while intoxicated, such as a panic attack or a paranoid reaction to the acute effects of cannabis (Edwards, 1976). Schizophrenia is the disorder about which concern has been most often expressed in the case of cannabis use.

A related hypothesis would be that cannabis use exacerbates the symptoms of a functional psychosis such as schizophrenia or manic depressive psychosis. This could occur if cannabis use precipitated a relapse in the same way that it has been hypothesised to precipitate the onset of a latent psychosis. Alternatively, the pharmacological effects of cannabis might impair the effectiveness of the neuroleptic drugs used to treat major psychoses.

7.6.2 Methodological issues

Until recently, our ability to test these hypotheses has been hampered by a lack of sophistication in research design (Mueser et al, 1990; Thornicroft, 1990; Turner and Tsuang, 1990). First, the possible mechanisms for a causal relationship between cannabis use and psychosis have not always been clearly distinguished, and so have not often informed the design of research studies purporting to test them. Second, studies of the relationships between cannabis use and psychological disorder have often been uncontrolled. Only rarely have they compared cannabis use in psychotic patients and controls, or compared the clinical characteristics and course of psychotic patients who have and have not used cannabis. Third, the extent of cannabis and other drug use, and its relationship to the onset of psychotic symptoms, has often been poorly documented. There has been a heavy reliance upon self-reported use, and few attempts have been made to distinguish between use, abuse and dependence (Mueser et al, 1990). Fourth, the diagnosis of a psychotic disorder, or of psychotic symptoms, has only rarely used standardised diagnostic criteria such DSM-III-R or ICD-9. Fifth, many studies have used small samples, reducing the chances of detecting any association between cannabis use and psychotic disorder. As a consequence of these deficiencies, many studies have failed to provide convincing evidence of even an association between cannabis use and psychotic symptoms or psychotic syndromes.

Even when an association between cannabis use and psychosis has been demonstrated, it has proved difficult to distinguish between alternative explanations of it. There has been a readiness to assume that the data supports the hypothesis that cannabis use is a contributory cause of psychosis (whether that is a specific "cannabis psychosis" or a functional psychosis such as schizophrenia). Only recently have other hypotheses been acknowledged, and attempts made to test them (e.g. Dixon et al, 1990, 1991; Turner and Tsuang, 1990).

There are a number of ways in which cannabis use could be associated with psychotic disorders without being a contributory cause of such disorders. One possibility is that the psychosis is a contributory cause of cannabis use, and that cannabis is used to self-medicate depression, anxiety, negative psychotic symptoms, or the side effects of neuroleptic drugs. Another possibility is that drug use among schizophrenic individuals is a consequence of pre-existing personality characteristics which predispose them to use illicit drugs and to develop schizophrenia. A third possibility is that heavy cannabis use may be a marker of the use of amphetamine and cocaine for which there is strong evidence for causing acute paranoid psychoses (Angrist, 1983; Bell, 1973; Connell, 1959).

In the review that follows, the best available clinical and epidemiological studies bearing on these issues is reviewed. Although we have preferred to cite controlled studies, we have not excluded all the early uncontrolled studies which have been most often cited. Attempts will also be made to distinguish the very different non-causal explanations of the apparent association between cannabis use and psychosis.

7.6.3 'Cannabis psychoses'

7.6.3.1 Toxic psychosis

Much of the literature on cannabis psychoses consists of case studies (e.g. Carney, Bacelle and Robinson, 1984; Drummond, 1986; Edwards, 1983; Weil, 1970), case series (e.g. Bernardson and Gunne, 1972; Cohen and Johnson, 1988; Kolansky and Moore, 1971; Onyango, 1986) and reviews of such reports (e.g. Tunving, 1985) which often suffer from a circularity in their argument (Thornicroft, 1990). Typically a group of patients have been identified as having a toxic "cannabis psychosis" (with little information given on how they came to be so identified) and their behaviour and clinical history are then presented as evidence for the existence of the diagnostic entity they were meant to be testing. The better examples of these reports have attempted to justify their inclusion of cases within this diagnosis, and have attempted to assess the contribution of predisposition and drug use to the development of the psychosis.

Chopra and Smith (1974) have presented one of the largest case series of a toxic "cannabis psychosis". They described the characteristics of 200 East Indian patients who were admitted to a psychiatric hospital in Calcutta between 1963 and 1968 with "psychotic symptoms following the use of cannabis preparations" (p24). Their cases resembled cases of acute organic brain disorder in that their major symptoms included confusion and amnesia. The most common symptoms "were sudden onset of confusion, generally associated with delusions, hallucinations (usually visual) and emotional lability ... amnesia, disorientation, depersonalisation and paranoid symptoms" (p24). Most psychoses were preceded by the ingestion of a large dose of cannabis which produced intoxication and amnesia for the period between ingestion and hospitalisation.

Patients were classified into three groups on the basis of their history of previous psychiatric disorder. The first consisted of a third of patients who had no previous personality problems or psychiatric disorder, whose only constant feature was "recent use of cannabis preparations as the apparent precipitant of the psychotic episode" (p25). They exhibited symptoms of excitement, confusion, disorientation, delusions, visual hallucinations, depersonalisation, emotional instability and delirium. These symptoms were usually of short duration, varying between a few hours and several days, and all these patients returned to their normal state after remission.

The second group consisted of 61 per cent of patients who did not have a prior history of psychosis but had a history of schizoid, sociopathic, and unstable personalities. Their clinical picture was much like that of the first group, and they also had a high probability of remission within a few days of admission. The third group consisted of 10 patients with a prior history of psychosis (most often schizophrenia) who rarely experienced a short remission and usually required continued hospitalisation and treatment.

Chopra and Smith argued that their case series provided evidence for the existence of the clinical entity of "cannabis psychosis". Although they conceded that excessive drug use could be a sign of pre-existing psychopathology, they argued that this was an unlikely explanation of their findings, because at least a third of their cases had no prior psychiatric history, the symptoms reported were remarkably uniform regardless of prior psychiatric history, and there was evidence of a dose-time relationship in that those who used the most potent cannabis preparations experienced psychotic reactions after the shortest period of use.

The findings of Chopra and Smith have received some support from case series published in other countries (e.g. Bernardson and Gunne, 1972; Onyango, 1986; Tennant and Groesbeck, 1972). Bernardson and Gunne (1972) reported on 46 cases of putative cannabis psychosis admitted to Swedish psychiatric hospitals between 1966 and 1970. These were primary cannabis users who had no history of psychosis prior to their cannabis use, and who presented with a clinical picture of paranoid delusions, motor restlessness, auditory and visual hallucinations, hypomania, aggression, anxiety and clouded consciousness. Their symptoms usually remitted within five weeks of admission, and those who returned to cannabis use after discharge were most likely to relapse.

Tennant and Groesbeck (1972) report on psychoses they had treated among US servicemen stationed in Germany between 1968 and 1971. During this period, potent hashish was cheap and readily available and widely used, with 46 per cent of servicemen reporting that they had used hashish, and 16 per cent reporting using it three or more times per week. They reported 18 cases of a short-term panic reaction or toxic psychosis developing after a single high dose of hashish, and 85 cases of toxic psychoses developing after the simultaneous consumption of cannabis and other drugs. The toxic psychoses usually resolved within three days on neuroleptic medication.

Onyango (1986) reported one of the few case series which used biochemical measures of recent cannabis use to identify possible cases of toxic cannabis psychosis among young adults who presented to a London psychiatric hospital with psychotic symptoms. He screened the urines of 25 such admissions and found that, although half reported having used cannabis at some time, only four had cannabinoid metabolites in their urines at the time of presentation. In three cases the patients had a prior history of psychosis, their phenomenology was unremarkable, and they did not respond rapidly to treatment. Only one case seemed to fit the picture of a cannabis psychosis. He had no prior history of psychosis, and a history of chronic, heavy cannabis use prior to admission. He presented with hallucinations, delusions, and labile, elated mood which responded rapidly to haloperidol, and he had no further episodes during a two-year follow-up.

All considered, there is a reasonable case for believing that large doses of potent cannabis products can produce a toxic psychotic illness in persons who do not have a personal history of psychotic illness (Edwards, 1976; Negrete, 1983; Thomas, 1993). Such psychoses are characterised by symptoms of confusion and amnesia, paranoid delusions, and auditory and visual hallucinations, and they have a relatively benign course in that they typically remit within a week of abstinence (Chaudry et al, 1991; Thomas, 1993). They seem most likely to occur in populations which use high doses of THC, and probably occur rarely otherwise (Smith, 1968). Given the poor standards of research design and lack of adequate controls in all but a few of these studies, and the failure to use standardised diagnostic criteria, it would be premature to claim that the existence of a toxic "cannabis psychosis" has been established beyond reasonable doubt.

7.6.3.2 An acute functional psychosis

Other investigators have argued that heavy cannabis use may produce an acute functional psychosis. That is, it produces an illness which does not reflect an organic state produced by drug intoxication, but rather a psychotic illness that resembles schizophrenia. Thacore and Shukla (1976), for example, reported a case control study comparing cases with a putatively functional cannabis psychosis with controls diagnosed as having paranoid schizophrenia. Their 25 cases of cannabis psychosis had a paranoid psychosis resembling schizophrenia, in which "a clear temporal relationship between the prolonged use of cannabis [longer than five years in all but one case] and the development of psychosis has been observed on more than two occasions" (p384). Their 25 age and sex-matched controls were individuals with paranoid schizophrenia who had no history of cannabis use.

The comparison revealed that the patients with a cannabis psychosis displayed more odd and bizarre behaviour, violence, panic affect, and insight and less evidence of thought disorder. They also responded swiftly to neuroleptic drugs and recovered completely. According to Thacore and Shukla, this functional psychotic disorder could be distinguished from the toxic "cannabis psychosis" reported by Chopra and Smith (1974), because there was no evidence of confusion and amnesia, and the major presenting symptoms were delusions of persecution, and auditory and visual hallucinations occurring in a state of clear consciousness.

Rottanburg et al (1982) provide one of the most convincing research studies in favour of the hypothesis that cannabis can produce an acute functional psychosis. They conducted a case-control study in which psychotic patients with cannabinoids in their urines were compared with psychotic patients who did not have cannabinoids in their urines. Both groups were assessed shortly after admission, and seven days later, by psychiatrists who used a standardised psychiatric interview schedule (PSE) and who were blind as to presence or absence of cannabinoids in the patients' urine.

Every third admission of a Cape coloured man during a period of a year (n=117) were screened for cannabinoids, alcohol and other toxins. Sixty per cent (N=70) had urines that were positive for cannabinoids, and 36 cases had levels which suggested heavy cannabis use prior to admission. Sixteen patients left hospital before the study was completed, leaving a group of 20 cases with psychoses and cannabinoids only in their urines. They were compared with 20 psychotic controls, matched for age and clinical diagnosis, whose urines were negative for cannabinoids and other drugs and toxins.

The results showed that psychotic patients with cannabinoids in their urine had more symptoms of hypomania and agitation, and less auditory hallucinations, flattening of affect, incoherent speech and hysteria than controls. They also showed strong improvements in symptoms by the end of a week, as against no change in the controls despite receiving comparable amounts of anti-psychotic drugs. They concluded that "heavy cannabis intake is associated with a rapidly resolving psychotic illness characterised by marked hypomanic features" (p1366).

Imade and Ebie (1991) conducted a retrospective comparison of the symptoms reported by 70 patients with putatively cannabis-induced psychosis, 163 patients with schizophrenia, and 39 patients with mania. No details were provided on how these diagnoses were made, and the ratings of symptoms were made retrospectively from case records by psychiatrists who were not blind as to the patients' diagnoses. A large number of statistical comparisons produced a number of statistically significant differences in individual symptoms between the three patient groups, although they did not differ in symptoms of violence, panic and bizarre behaviour. Imade and Ebie argued that there were no symptoms that were unique to cannabis psychosis, and that there was no consistency of clinical picture that enabled them to distinguish a "cannabis psychosis" from schizophrenia. This negative study is unconvincing. The symptom ratings were made retrospectively from clinical records of unknown quality, and the patients' diagnoses were not made using standardised diagnostic criteria. There was no information on how "cannabis psychosis" was diagnosed, or on the clinical course of the psychoses. The authors also failed to use appropriate statistical methods to test the claim that cannabis psychosis can be distinguished from schizophrenia.

A number of cohort studies have been conducted on the prevalence of psychotic symptoms in chronic cannabis users and controls. Beaubruhn and Knight (1973) conducted a small study comparing the psychiatric history and symptoms of 30 chronic daily Jamaican cannabis users (with a history of at least seven years use) with that of 30 non-cannabis using controls matched on social class, income, age and sex. Both cases and controls were assessed by personal psychiatric interview and personality questionnaires during a six day hospitalisation. There were few statistically significant differences between the two groups, only a higher rate of family history of psychiatric disorder and of hallucinatory experiences in the cannabis users. Only one user and one non-user reported a personal history of psychiatric disorder.

Similar results have been reported by Stefanis et al (1976) in a study of 47 chronic cannabis users in Greece and 40 controls matched for age, family origin, residence at birth and upbringing. They found a higher incidence of personality disorders among their cannabis users, but no statistically significant difference in the rates of psychiatric disorder diagnosed by a personal interview with a psychiatrist. Three cases of schizophrenia were diagnosed in the cannabis using group, but a connection with cannabis use was discounted on the ground that two of the three had a family history of schizophrenia.

The small number of cases and the relative rarity of psychosis makes these studies unconvincing. The authors interpreted their results far too strongly, by inferring that a failure to find a difference in rates of psychiatric disorder in sample sizes of 30 and 47 indicated that there was no difference in prevalence between chronic cannabis users and controls. In Beaubruhn and Knight's study (1973), for example, the failure to detect a difference in the rate of psychosis between 30 cannabis users and 30 controls does not rule out a 17 fold higher rate of psychiatric disorder among cannabis users (as shown by the upper limit of a 95 per cent confidence interval around the odds ratio).

All considered, the case for believing that cannabis use can produce a functional paranoid illness is much less compelling than that for a toxic psychosis (Thomas, 1993; Thornicroft, 1990). The research designs for studies of this diagnosis have more often included control groups, but proponents of this hypothesis have not presented evidence that satisfactorily distinguishes it from other functional psychoses (Thornicroft, 1990).

If there is a toxic cannabis psychosis, then a strong case has not been made for distinguishing it from the putatively functional cannabis psychosis. Thacore and Shukla (1976) emphasised the history of chronic heavy cannabis use among their cases of functional cannabis psychoses, and the absence of the confusion and amnesia reported in persons with the toxic psychosis.

The differentiation in terms of chronicity of drug use is unconvincing. Some of the cases of the toxic cannabis psychosis described by Chopra and Smith (1974), for example, had a long history of heavy cannabis use. The hypothesised difference in symptoms is more difficult to evaluate. Because few of the studies used standardised assessments of symptoms, the absence of reports of confusion and amnesia in the functional cases may indicate differences in diagnostic practice. There are also strong similarities between the putatively toxic and functional psychoses, namely, the occurrence of delusions, and auditory and visual hallucinations, and a relatively benign course, typically remitting within a week.

There is some recent support for the distinction between toxic and functional cannabis-induced psychoses. Tsuang et al, (1982) compared the demographic and clinical characteristics, and family histories of four groups of patients: those with drug abuse who had experienced a psychotic illness (DAP), those with diagnoses of drug abuse alone (DA), those with schizophrenia (SC), and those with diagnoses of atypical schizophrenia (AS). They subdivided the patients with drug abuse and psychosis into those with shorter and longer duration of symptoms. They found that the DAP patients were more likely to have abused hallucinogens and cannabis, and less likely to have abused sedative-hypnotics and opiates, than DA patients. The DAP patients also had an earlier onset of illness, and better premorbid personalities than the SC patients.

Comparisons of the DAP patients with short and long duration of illness produced some interesting results. The patients with short duration disorders had better premorbid personalties, fewer psychotic symptoms, and fewer core schizophrenic symptoms, such as poor insight, shallow and inappropriate affect, thought disorder, delusions and Schneiderian "first rank symptoms". They were more likely to have presented with "organic" symptoms such as confusion, disorientation, visual hallucinations, and amnesia than the patients with long duration disorders. By definition, the shorter duration patients had shorter periods of admission; they also had shorter duration of drug treatment, and more were discharged without being referred for further treatment. The prevalence of family histories of schizophrenia among the longer duration DAP patients was similar to that of the SC, while the shorter duration DAP patients had no such family history.

On the basis of their comparisons, Tsuang et al argued that the short duration disorders were drug-induced toxic psychoses, while the longer duration disorders reflected functional psychoses precipitated by drug use in predisposed individuals. If these findings are accepted, the simplest explanation of the allegedly functional "cannabis psychoses" is that they are functional psychoses occurring in heavy cannabis users.

7.6.3.3 Chronic psychoses

If cannabis can produce an acute organic psychosis, the possibility must be considered that chronic cannabis use may produce a chronic psychosis in much the same way as chronic alcohol heavy use can produce a chronic organic brain syndrome. As Ghodse (1986) has suggested, it is "theoretically possible in a situation of easy availability of cannabis, that regular, heavy users may suffer repeated, short episodes of psychosis and effectively `maintain' themselves in a chronic, psychotic state" (p477).

Although this is a possibility, there is no good evidence that chronic cannabis use causes a psychotic illness which persists after abstinence from cannabis (Thomas, 1993). This possibility is difficult to study because of the near impossibility of distinguishing a chronic cannabis psychosis from a functional psychosis such as schizophrenia in which there is concurrent cannabis use (Negrete, 1983). Certainly the findings of Tsuang et al (1982) suggest that the strong presumption must be that individuals with a history of drug abuse and a psychotic illness have a functional psychosis which has been precipitated or exacerbated by drug use. Follow-up studies of patients with acute cannabis psychoses, if they could be reliably identified, would be the best way of throwing some light on this issue.

7.6.3.4 A residual state

A number of investigators have described a state among chronic, heavy cannabis users in which the users' focus of interest narrows, they become apathetic, withdrawn, lethargic, and unmotivated, and they have impaired memory, concentration and judgment (Brill and Nahas, 1984; McGlothin and West, 1968). This has been described as an "amotivational state", which some have attributed to an organic syndrome caused by the effects of chronic cannabis intoxication, from which there is incomplete recovery after prolonged abstinence (Tennant and Groesbeck, 1972).

The major clinical evidence in favour of such a hypothesis consists of case series among contemporary chronic cannabis users (e.g. Kolansky and Moore, 1971; Millman and Sbriglio, 1986), and historical reports of the syndrome among chronic, heavy users in countries such as Egypt, Greece, and the Carribean, where there has been a tradition of chronic heavy cannabis use among the lower socioeconomic groups (Brill and Nahas, 1984). These reports are often poorly documented and uncontrolled, and do not permit the effects of chronic drug use to be easily disentangled from those of poverty and low socioeconomic status, or pre-existing personality disorders (Edwards, 1976; Millman and Sbriglio, 1986; Negrete, 1983).

A small number of controlled studies of heavy chronic users in other cultures have largely failed to substantiate the clinical observations (Millman and Sbriglio, 1986), although there are enough reports of regular users complaining of loss of ambition and impaired school and occupational performance (e.g. Hendin et al, 1987), and of ex-users giving this as a reason for stopping (Jones, 1984), to keep the possibility alive. The small number of laboratory studies of long-term heavy use have produced mixed evidence (Edwards, 1976). Georgotas and Zeidenberg (1979), for example, reported that five healthy male marijuana users on a dose regimen of 210mg of THC per day for a month appeared "moderately depressed, apathetic, at times dull and alienated from their environment and with impaired concentration" (p430). Others have failed to observe such effects (e.g. Mendelson et al, 1974). The status of the amotivational syndrome consequently remains uncertain (see pp102-105).

7.6.4 Cannabis and schizophrenia

7.6.4.1 Precipitation

The possibility that heavy, chronic cannabis use may precipitate schizophrenia was raised by Tennant and Groesbeck (1972) in their study of the consequences of chronic heavy hashish use among American servicemen in Germany between 1968 and 1971. They reported 112 cases of "persistent schizophrenic reactions following prolonged hashish use" (p134), and they presented evidence that there had been a four fold increase in the incidence of schizophrenia among American servicemen during the period in which hashish use became endemic. As with all ecological evidence, a causal relationship is only one of the possible explanations of the apparently concurrent increase in the prevalence of hashish use and schizophrenia among American servicemen in Germany. The attribution of the increase to hashish use alone was also complicated by fact that many of their cases of schizophrenia also used hallucinogens, amphetamines, and alcohol.

The precipitation hypothesis has received some support from a series of case-control studies of cannabis and other psychoactive drug use among schizophrenic patients (Schneier and Siris, 1987). The usual finding has been that schizophrenic patients have higher rates of use of psychomimetic drugs such as amphetamines, cocaine, and hallucinogens than other patients (Dixon et al, 1990; Schneier and Siris, 1987; Weller et al, 1988) or normal controls (Breakey et al, 1974; Rolfe et al, 1993). The results for cannabis use have been more mixed, with some finding a higher prevalence of use or abuse (e.g. Mathers et al, 1991) and others not having done so (Dixon et al, 1990; Mueser et al, 1990; Schneier and Siris, 1987).

There is also good epidemiological evidence for an association between schizophrenia and drug abuse and dependence in the Epidemiological Catchment Area (ECA) study. In this study (Anthony and Helzer, 1991) there was an increased risk of schizophrenia among men and women with a diagnosis of any form of drug abuse and dependence: the excess risk of schizophrenia was 6.2 for men and 6.4 for women. Although separate estimates were not provided for cannabis abuse and dependence, it seems reasonable to assume that the same sort of relationship applied. Bland, Norman and Orn, (1987) have obtained a similar finding in a population survey of the prevalence of psychiatric disorder in Edmonton Alberta, using the same ECA interview schedule and diagnostic criteria. They found that the odds of receiving a diagnosis of drug abuse and dependence were 11.9 times higher among persons with schizophrenia.

Many researchers have favoured a causal interpretation of the increased prevalence of psychoactive drug use among schizophrenics, that is, they have concluded that cannabis and other drug use precipitates schizophrenic disorders in persons who may not otherwise have experienced them. In support of this hypothesis are the common findings that drug abusing schizophrenic patients have an earlier age of onset of psychotic symptoms (with their drug use typically preceding the onset of symptoms), a better premorbid adjustment, fewer negative symptoms (e.g. withdrawal, anhedonia, lethargy), and a better response to treatment and outcome than schizophrenic patients who do not use drugs (Allebeck et al, 1993; Dixon et al, 1990; Schneier and Siris, 1987).

There are other interpretations of these findings, however. Arndt et al (1992), for example, have suggested that the association between cannabis use and an early onset of schizophrenia in persons with a good premorbid personality and outcome is spurious. According to Arndt et al, schizophrenics with a better premorbid personality were simply more likely to be exposed to illicit drug use among peers than those with a withdrawn and socially inept premorbid personality, and because of this prior exposure to drugs, they were also more likely to use drugs to cope with the symptoms of an emerging psychosis. On this account, cannabis and other illicit drug use is a correlate of a good prognosis in schizophrenia, and pathological drug use is a response to the unrelated emergence of psychotic symptoms.

A further possibility is that cannabis and other illicit drug use is a consequence of schizophrenia. That is, such illicit drug use is a form of self-medication to deal with some of the unpleasant symptoms of schizophrenia, such as depression, anxiety, lethargy, and anhedonia, and the side effects of the neuroleptic drugs used to treat it (Dixon et al, 1990). There is some support for this hypothesis in the work of Dixon et al (1990), who surveyed 83 patients with schizophrenia or schizophreniform psychoses about the effects of various illicit drugs on their mood and symptoms. Their patients reported that cannabis reduced anxiety and depression, and increased a sense of calm, at the cost of some increase in suspiciousness, and with mixed effects on hallucinations and energy.

Prospective evidence. The most convincing evidence of an association between cannabis use and the precipitation of schizophrenia has been provided by a prospective study of cannabis use and schizophrenia in Swedish conscripts undertaken by Andreasson et al (1987). These investigators used data from a 15-year prospective study of 50,465 Swedish conscripts to investigate the relationship between self-reported cannabis use at age 18 and the risk of receiving a diagnosis of schizophrenia in the subsequent 15 years, as indicated by inclusion in the Swedish psychiatric case register. Substantial data were collected on the conscripts (such as family circumstances, personal psychiatric disorder and other drug use) and statistical methods were used to examine the effect of these potentially confounding variables on the association between cannabis and schizophrenia.

Their results showed that the relative risk of receiving a diagnosis of schizophrenia was 2.4 times higher [95 per cent confidence interval 1.8, 3.3] for those who had ever tried cannabis compared to those who had not. There was also a dose-response relationship between the risk of a diagnosis of schizophrenia and the number of times that the conscript had tried cannabis by age 18. The crude relative risk of developing schizophrenia was 1.3 times higher [95 per cent confidence interval 0.8, 2.3] for those who had used cannabis one to ten times, 3.0 times higher [95 per cent confidence interval 1.6, 5.5] for those who had used cannabis between one and 50 times, and 6.0 times higher [95 per cent confidence interval 4.0, 8.9] for those who had used cannabis more than fifty times (compared in each case to those who had not used cannabis).

The size of the risk was substantially reduced by statistical adjustment for variables that were independently related to the risk of developing schizophrenia (namely, having a psychiatric diagnosis at conscription, and having parents who had divorced). Nevertheless, the relationship between cannabis use and schizophrenia remained statistically significant and still showed a dose response relationship. The risk of a diagnosis of schizophrenia for those who had smoked cannabis from one to ten times was 1.5 times that of those who had never used, and the relative risk for those who had used 10 or more times was 2.3 times that for those who had never used [95 per cent confidence interval 1.0, 5.3].

Andreasson et al (1987) carefully scrutinised the validity of their data on cannabis use and the diagnosis of schizophrenia. They acknowledged that cannabis use was likely to have been under-reported because the information was not confidential, but they argued this was most likely to have under-estimated the relative risk of developing schizophrenia among users and non-users. Self-reported cannabis use at age 18 showed a strong dose-response relationship to the risk of receiving a diagnosis of drug abuse in the subsequent 15 years. Data from a small validity study indicated that 80 per cent of those diagnosed as schizophrenic in the case register met the DSM-III criteria for schizophrenia (which include a minimum duration of six months).

Andreasson et al (1987) and Allebeck (1991) argued for a causal interpretation of the association, conjecturing that cannabis use precipitated schizophrenia in vulnerable individuals. They rejected as implausible the hypothesis that cannabis consumption was a consequence of emerging schizophrenia. The cannabis users who developed schizophrenia had better premorbid personalities, a more abrupt onset, and more positive symptoms than the non-users who developed schizophrenia (Andreasson et al, 1989). Although over half of the heavy cannabis users (58 per cent) had a psychiatric diagnosis at the time of conscription, there was still a dose-response relationship between cannabis use and schizophrenia among those conscripts who did not have such a history. They stressed that cannabis use "only accounts for a minority of all cases" (p1485) since most of the 274 conscripts who developed schizophrenia had not used cannabis, and only 21 of them were heavy cannabis users.

No single study ever settles an issue. Even a prospective study as well designed, and as carefully interpreted as that of Andreasson et al has been criticised (Johnson, Smith and Taylor, 1988; Negrete, 1989). Among these criticisms are the following, which raise a number of alternative explanations to the causal one proposed by Andreasson and his colleagues.

First, there was a large temporal gap between self-reported cannabis use at age 18-20 and the development of schizophrenia over the next 15 years or so (Johnson, Smith and Taylor, 1988; Negrete, 1989). Because the diagnosis was based upon a case register, there was no information on whether the individuals continued to use cannabis up until the time that their schizophrenia was diagnosed. Andreasson et al (1987) anticipated and dealt with this criticism by showing that self-reported cannabis use at age 18 was strongly related to the risk of subsequently attracting a diagnosis of drug abuse. This suggests that cannabis use at age 18 was predictive of continued drug use, and the more so the more frequently it had been used by age 18.

A second possibility is that the excess rate of "schizophrenia" among the heavy cannabis users was due to acute cannabis-induced toxic psychoses which were mistakenly diagnosed as schizophrenia (Johnson et al, 1988; Negrete, 1989). Andreasson et al (1989) attempted to address this criticism by a study of the validity of the schizophrenia diagnoses in 21 conscripts in the case register (8 of whom had used cannabis and 13 of whom had not). This study indicated that 80 per cent of these cases met the DSM-III requirement that the symptoms had been present for at least six months, to exclude transient psychotic symptoms. This sample size (21 case) was small, however, and the confidence interval around a 20 per cent rate of misdiagnosis of schizophrenia is between 3 per cent and 37 per cent. Even if the rate of misdiagnosis was only 20 per cent, this could, if it varied between cannabis and non-cannabis users, be large enough to explain the relationship they observed.

A third, more serious concern about the causal interpretation of the relationship between cannabis use and schizophrenia is that the relationship may be a consequence of the use of other illicit psychoactive drugs. Longitudinal studies of illicit drug use indicate that intensity of cannabis use in late adolescence predicts the later use of other illicit drugs. These drugs include amphetamine and cocaine (Johnson, 1988; Kandel and Faust, 1975) which can produce an acute paranoid psychosis (Angrist, 1983; Bell, 1973; Connell, 1959; Gawin and Ellinwood, 1988; Grinspoon and Hedblom, 1975). There is also good evidence that amphetamine was the major illicit drug of abuse in Sweden during the study period (Inghe, 1969; Goldberg, 1968 a, b), which suggests that intervening amphetamine use may have produced the correlation between cannabis use and schizophrenia. Andreasson et al's (1989) study reported that only two of their eight schizophrenic cannabis users had also been abusers of amphetamines prior to the diagnosis of their schizophrenia, but with a sample size as small as this, the true rate (indicated by a 95 per cent confidence interval) could be anywhere between 0 per cent and 55 per cent.

A fourth concern is that Andreasson et al (1987) have not ruled out the possibility that cannabis use at age 18 was a symptom of emerging schizophrenia. Statistical adjustment for a psychiatric diagnosis at conscription did not eliminate the relationship between cannabis use and schizophrenia, but it substantially reduced the size of the relative risk, because over half of the heavy users of cannabis had received a psychiatric diagnosis by age 18. Andreasson et al argued that this hypothesis was implausible because the dose response relationship between cannabis use and the risk of a schizophrenia diagnosis held up among those who did not have a psychiatric history. The persuasiveness of this argument depends upon how credible the screening for psychiatric diagnosis was at the time of conscription, and in particular, how confident we can be that a failure to identify a psychiatric disorder at conscription means that no disorder was present. This is difficult to evaluate.

The fifth and final criticism relates to the validity of self-reported cannabis use at conscription. Andreasson et al (1987) acknowledged that there was likely to be under-reporting of cannabis use because this information was not collected anonymously, but they argued that this was most likely to lead to an under-estimation of the relationship between cannabis use and the risk of schizophrenia. This will only be true, however, if the schizophrenic and non-schizophrenics conscripts were equally likely to under-report. If, however, pre-schizophrenic subjects were more candid about their drug use, the apparent relationship between cannabis use and schizophrenia would be due to response bias (Negrete, 1989). Although a possibility, this seems unlikely in view of the strong dose-response relationship with frequency of cannabis use, and the large size of the unadjusted relative risk of schizophrenia among heavy users.

When all these criticisms are considered, the Andreasson et al (1987) study still provides strong evidence of an association between cannabis use and schizophrenia which is not completely explained by prior psychiatric history. Uncertainty remains about the causal significance of the association because it is unclear to what extent the relationship is a result of drug-induced psychoses being mistaken for schizophrenia, and to what extent it is attributable to amphetamine rather than cannabis use.

Even if the relationship is causal, its public health significance needs to be kept in perspective. Although they did not report calculations of attributable risk, an estimate based upon the relative risk adjusted for psychiatric disorder (Feinstein, 1985) indicates that even if their association is causal, at most 7 per cent of cases of schizophrenia would be attributable to cannabis use. That is, on the prevalence rate of cannabis use reported by Andreasson et al, cannabis use would have explained 7 per cent (at most) of cases of schizophrenia occurring in Sweden during the period of study. Even this small potential contribution to an increased incidence of schizophrenia seems difficult to accept, since there is good independent evidence that the incidence of schizophrenia, and particularly of early onset, acute cases, declined during the 1970s, the period when the prevalence of cannabis use increased among young adults in Western Europe and North America (Der et al, 1990).

7.6.4.2 Exacerbation of schizophrenia

There is reason to be concerned about the effects of cannabis on psychotic symptoms among individuals with schizophrenia. Cannabis is psychoactive drug that is probably psychotomimetic in high doses, and its use seems to be relatively common among schizophrenic patients, as indicated above. There is also anecdotal clinical evidence that schizophrenic patients who use cannabis and other drugs experience exacerbations of symptoms (Weil, 1970), and have a worse clinical course, with more frequent psychotic episodes, than those who do not (Knudsen and Vilmar, 1984; Perkins et al, 1986; Turner and Tsuang, 1990).

However, there have been very few controlled studies of the relationship between cannabis use and the clinical outcome of schizophrenia. Negrete et al (1986) conducted a retrospective study using clinical records of symptoms and treatment seeking among 137 schizophrenic patients with a disorder of at least six months duration, and three visits to their psychiatric service during the previous six months. The proportion of cannabis users among their patients was the same as in the Canadian population, but heavy users were over-represented, and the proportion of former users who had stopped using was higher than in the general population. Negrete et al (1986) compared the prevalence of hallucinations, delusions and hospitalisations among the active users (N=25), the past users (n=51), and those who had never used cannabis (N=61). The crude comparison showed higher rates of continuous hallucinations and delusions, and of hospitalisations among active users. This pattern of results persisted after statistical control for differences in age and sex between the three user groups.

Negrete et al argued that cannabis use exacerbated schizophrenic symptoms. They rejected the alternative hypothesis that patients with a poorer prognosis were more likely to use cannabis, because they found that past cannabis users experienced fewer symptoms, and reported a high rate of adverse effects when using (91 per cent). They also discounted the possibility that these were toxic psychoses, because in all cases the minimum duration of symptoms had been six months. They left open the mechanism by which cannabis use exacerbated schizophrenic symptoms, suggesting three possibilities: that cannabis disorganises psychological functioning; that it causes a toxic psychosis that accentuates schizophrenic symptomatology; or that it interferes with the therapeutic action of anti-psychotic medication.

More recently, Cleghorn et al (1991) have provided supportive evidence. They compared the symptom profiles of schizophrenic patients with histories of substance abuse of varying severity (none, moderate, and severe), among whom cannabis was the most heavily used drug. Comparisons with a subset of the patients who were maintained on neuroleptic drugs revealed that the drug abusers had a higher prevalence of hallucinations, delusions and positive symptoms.

These studies provide a slender basis upon which to draw conclusions about the effects of cannabis use on schizophrenic symptoms. One can only agree with the conclusion of Turner and Tsuang (1990) that "the impact of substance abuse on the course and outcome of schizophrenia remains largely undefined" (p93), and that it will remain so until large prospective studies in general population and clinical samples recommended by Turner and Tsuang (1990) have been conducted. Until such research has been undertaken, prudence would demand that schizophrenic patients, and others at risk of schizophrenia by virtue of family history, personality, or marginal social functioning, should be strongly discouraged from using cannabis and other psychoactive drugs, especially the psychostimulants amphetamine and cocaine.

7.6.5 Conclusions

There is reasonable evidence that heavy cannabis use, and perhaps acute use in susceptible individuals, can produce an acute psychosis in which confusion, amnesia, delusions, hallucinations, anxiety, agitation and hypomanic symptoms predominate. The evidence for a toxic cannabis psychosis comes from laboratory studies of the effects of THC on normal volunteers and clinical observations of psychotic symptoms in heavy cannabis users, which seem to comprise a toxic psychotic syndrome and which remit rapidly following abstinence from cannabis. There is also an argument by analogy with the fact that heavy chronic amphetamine use has been shown to induce a paranoid psychosis (Angrist, 1983).

There is little support for the hypothesis that cannabis use can cause a chronic psychosis which persists beyond the period of intoxication. Such a possibility is difficult to study because of the likely rarity of such psychoses, and the near impossibility of distinguishing them from individuals with schizophrenia and manic depressive psychoses who also abuse cannabis (Negrete, 1983).

The occurrence of a chronic residual state, or "amotivational syndrome", in chronic heavy cannabis users is not well supported by research evidence. At best, a prima facie case has been made by clinical observations, that withdrawal, lethargy, and apathy occur among a minority of chronic, heavy users. This syndrome has proved difficult to study in the laboratory, difficult to distinguish from the effects of chronic intoxication (Negrete, 1988), and it so far been impossible to rule out confounding effects of pre-existing disease, malnutrition, personality disorder, and lifestyle.

There is strongly suggestive evidence that chronic cannabis use may precipitate a latent psychosis in vulnerable individuals. This is still strongly suggestive rather than established beyond reasonable doubt, because in the best study conducted to date (Andreasson et al, 1987) the use of cannabis was not documented at the time of diagnosis, there was a possibility that cannabis use was confounded by amphetamine use, and there remains a question about the ability of the study to reliably distinguish between schizophrenia and acute cannabis or other drug-induced psychoses.

Even if the relationship between cannabis use and schizophrenia is a causal one, its public health significance should not be overstated. It is most likely to indicate that cannabis use can precipitate schizophrenia in vulnerable individuals, since the estimated attributable risk of cannabis use is small, and the incidence of schizophrenia has declined during the period in which cannabis use has increased among young adults.

The substantial prevalence of cannabis use among young adults in Western societies makes the relationships between cannabis use and psychosis deserving of further research. What are required are case-control studies of people with schizophrenia and normals, and case-control studies of psychotic individuals who do and do not have a documented history of recent heavy cannabis use. Mueser et al (1990) provide detailed suggestions for the types of controls that ought to be incorporated in such studies. If the results of the case control studies warrant it, prospective studies should be done. Longitudinal studies like that undertaken by Andreason et al (1987) would be most desirable, but can probably only be undertaken in exceptional circumstances. Turner and Tsuang (1990) provide detailed suggestions for prospective studies which would clarify the contribution of cannabis and other drug use to the precipitation and exacerbation of schizophrenia and other psychoses.

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8. The therapeutic effects of cannabinoids

8.1 Historical background

Cannabis has had a long history of medical and therapeutic use in India and the Middle East (Grinspoon and Bakalar, 1993; Mechoulam, 1986; Nahas, 1984) where it has been variously used as an analgesic, anti-convulsant, anti-spasmodic, anti-emetic, and hypnotic. Cannabis was introduced to British medicine in the mid-nineteenth century by O'Shaugnessy (1842) who had gained clinical experience with the drug while an Army surgeon in India (Mechoulam, 1986; Nahas, 1984). He recommended its use for the relief of pain, muscle spasms, and convulsions occurring in tetanus, rabies, rheumatism and epilepsy (Nahas, 1984). Partly as the result of his advocacy, cannabis came to be widely used as an analgesic, anti-convulsant and anti-spasmodic throughout the middle part of the 19th century in Britain and the USA.

The medical use of cannabis declined around the turn of the present century. Because the active constituents of cannabis were not isolated until the second half of the twentieth century, cannabis continued to be used in the form of natural preparations which varied in purity and, hence in effectiveness. The use of cannabis was largely supplanted by other pharmaceutically purer drugs, which could be given in standardised doses to produce more dependable effects. These included the opiates, aspirin, chloral hydrate, and the barbiturates (Mechoulam, 1986; Nahas, 1984). In the early part of the century, the medical use of such crude cannabis preparations was further discouraged by laws which treated cannabis as a "narcotic" drug and severely restricted its availability. It finally disappeared from the American pharmacopoeia in the early 1940s after the passage of the Marijuana Tax Act (Grinspoon and Bakalar, 1993), although it continued to be used in Australia into the 1960s (Casswell, 1992).

THC, the major psychoactive ingredient of cannabis, was not isolated until 1964 (Goani and Mechoulam, 1964), shortly before cannabis achieved widespread popularity as a recreational drug among American youth. Its widespread recreational use, and its symbolic association with a rejection of traditional social values, undoubtedly hindered pharmaceutical research into its therapeutic uses. Consequently, the rediscovery of some of its traditional therapeutic uses was largely serendipitous, as was the discovery of some newer uses. For example, its value as an anti-emetic agent in the treatment of nausea caused by cancer chemotherapy seems to have been rediscovered by young adults who had used cannabis recreationally prior to undergoing chemotherapy for leukemia (Grinspoon, 1990).

From the mid-1970s some clinical research on the therapeutic value of cannabis and cannabinoids was undertaken. On the whole, however, this research has been very thin and uneven, and, consequently, many of the claims for the therapeutic efficacy of cannabinoids rely heavily, and, in the case of rare medical conditions, solely upon anecdotal evidence, that is, the testimonies of individuals who claim to have derived medical benefit from its use (e.g. Grinspoon and Bakalar, 1993; Randall, 1990), and small numbers of cases reported by physicians (e.g. Consroe et al, 1975; Meinck et al, 1989).

Evidence will be reviewed for the best-supported therapeutic uses of cannabinoids. The review begins with the evidence on the effectiveness of cannabinoids as anti-emetic drugs for nausea caused by cancer chemotherapy, and as agents to control intra-ocular pressure in glaucoma. Briefer reviews are provided of the evidence in favour of other putative therapeutic uses of cannabinoids which are less well supported by clinical evidence, chief among which are its uses as an anti-convulsant, an anti-spasmodic, and an analgesic agent. The value and limitations of the largely anecdotal evidence of efficacy in these latter conditions will also be briefly considered. The review will include a discussion of the controversy in the United States about "marijuana rescheduling" which has coloured much recent discussion of the issue. This controversy concerns the vexatious issue of whether smoked cannabis should be available for medical use in addition to synthetic cannabinoids such as THC.

8.2 Cannabinoids as anti-emetic agents

Profound nausea and vomiting can be such serious complications of chemotherapy and radiotherapy for cancer that patients may discontinue potentially life-saving treatment (Institute of Medicine, 1982). Although various types of drugs (e.g. the phenothiazines) have been shown to be effective in controlling nausea and vomiting in cancer patients, substantial minorities of patients do not benefit from these drugs. The seriousness of the problem of chemotherapy-induced nausea, and the incomplete success of existing treatments, prompted oncologists in the late 1970s and early 1980s to take a particular interest in the anti-emetic properties of cannabinoids (Institute of Medicine, 1982).

8.2.1 Clinical trials

One of the earliest trials of the effectiveness of THC as an anti-emetic was prompted by patient reports that smoking marijuana relieved nausea and vomiting (Sallan et al, 1975). In this study, 22 patients (10 males and 12 females, average age 30 years) with a variety of neoplasms were studied. In 20 patients, the nausea and vomiting had proven resistant to existing anti-emetic drugs. A randomised placebo-controlled trial with crossover was used, in which patients were randomly assigned to receive oral THC (10mg per m2) and placebo in one of four different orders (THC-placebo-THC; THC- placebo-placebo; placebo-THC-placebo; placebo-THC-THC). Outcome was assessed by grading patients' self-reports of nausea and vomiting after THC and placebo into three categories: complete response if there was vomiting after placebo but not after THC; partial response if there was a greater than 50 per cent reduction in nausea and vomiting after THC compared to placebo; and no response if there was a less than 50 per cent reduction in nausea and vomiting.

Ten patients completed all three courses of THC and placebo and vomited on at least one trial. After excluding one trial because of a variation in the chemotherapy dose, there were 29 trails available for analysis, 14 of placebo and 15 of THC. All 14 placebo trials resulted in no response, while in the 15 THC trials there were five complete responses, seven partial responses, and three no responses. This difference was statistically significant when full and partial responses were combined. Most patients (13/16) reported a "high" after receiving THC, an experience which was correlated with the anti-emetic effect. The most common side-effect was somnolence which curtailed activities for two to six hours in a third of patients. Only two patients experienced any symptoms of toxicity, (both after receiving 20mg doses of THC), namely, visual distortions and hallucinations and depression lasting several hours. Sallan et al reported "preliminary" observations from several patients that smoking marijuana produced an equivalent anti-emetic effect to oral THC.

A trial by Chang et al (1979) largely supported the findings of Sallan et al. In this study 15 patients with osteogenic sarcoma (10 males and five females, average age 24 years) served as their own controls in the course of monthly high dose methotrexate therapy. They were assigned to receive three THC and three placebo trials in randomised order during six treatment sessions. THC (10mg per m2 of body area) and placebo were administered orally five times at three hourly intervals, beginning two hours before chemotherapy. If the patients vomited, the remaining doses of either THC or placebo were administered by smoking a cigarette using a standardised smoking technique. The effect of THC and placebo were assessed by nursing staff who rated various endpoints (e.g. number of vomiting and retching episodes, volume of emesis, degree and duration of nausea) without being aware of which treatment patients had received. Patient response was graded into three categories: excellent (greater then 80 per cent reduction after THC by comparison with placebo in each of these endpoints); fair (greater than 30 per cent and less than 80 per cent reduction), and no response (less than 30 per cent reduction).

The results showed that eight patients had an excellent response, six a fair response, and one had no response. On all endpoints THC produced a statistically significant reduction in nausea and vomiting by comparison with placebo. There was also a dose-response relationship between blood levels of THC and the incidence of nausea and patient reports of feeling "high". Generally, higher THC blood levels were achieved when marijuana was smoked than when THC was taken orally. There were few side effects reported, with sedation being the most common (12/15 patients). Four patients experienced five dysphoric reactions in the course of 281 THC drug doses (2 per cent), none of which lasted more than 30 minutes, and all of which were successfully managed with simple reassurance.

In a second phase of the study, four patients who had an excellent response to THC in the first phase were retested under double-blind conditions using two placebo trials in the next 10 treatments. A small number of patients who had a fair response were also studied using an increased dose of THC. All patients showed a reduction in the average anti-emetic benefit of THC, decreasing from excellent to fair in the case of previous excellent responders, and from fair to no response in the case of the fair responders. Chang et al hypothesised that the decline in effect reflected either the development of tolerance to the effects of THC, or the development of conditioned nausea and vomiting that was resistant to the anti-emetic effects of THC.

Since these early studies, a large number of controlled clinical studies have been conducted which compared the effectiveness of THC with either a placebo or with other anti-emetic drugs (see Carey et al, 1983; Poster et al, 1981; Levitt, 1986 for reviews). The results of this literature have sometimes been unfairly described as "confused" (e.g. Carey et al, 1983; Nahas, 1984). This description betrays an unreasonably high expectation of the consistency of results from studies which have generally used small samples of heterogenous patients who have received various forms of chemotherapy. It also ignores the fact that the cross-over studies comparing the anti-emetic effects of THC with placebo have generally reported greater anti-emetic effects for THC than placebo (Poster et al, 1981); the single exception to this finding was a study which had a sample size of only eight patients.

Comparisons of the effectiveness of oral THC with that of existing anti-emetic agents have been less consistent than the results of comparisons with placebo. Nonetheless, the results have generally indicated that THC is at least equivalent in effectiveness to the widely used anti-emetic drug prochlorperazine (Carey et al, 1983; Levitt, 1986). The inconsistencies in this case arise because some studies have shown THC to be superior, probably because of the practice in some trials of enlisting patients whose nausea had previously proven resistant to prochlorperazine (Carey et al, 1983).

The equivalence of THC and prochlorperazine has been supported by the results of one of the largest and best conducted studies (Ungerleider et al, 1982). In this study 214 patients with a variety of forms of cancer (carcinomas, sarcomas, lymphomas and leukemias) were recruited if they had already undergone chemotherapy and experienced nausea and vomiting, or they were to receive a form of chemotherapy which had a high emetic potential. Patients were randomly assigned to receive a paired trial of either oral THC followed by prochlorperazine or vice versa. The dose of THC was dependent on body surface area (7.5mg if less than 1.4m2, 10mg for 1.4 to 1.8m2, and 12.5mg for greater than 1.8m2). Separate analyses were conducted on three groups of patients: patients who received their cancer chemotherapy on a single day some weeks apart (N=98); patients who received their chemotherapy on a daily basis over several successive days (N=41); and patients who discontinued the trial after a single episode of either THC or prochlorperazine. Outcomes were patient self-ratings of nausea and vomiting, and a variety of mood states and behaviours.

The results showed that there "were no statistically significant differences in the anti-nausea/anti-emetic effect of THC and prochlorperazine" (p640) in any of the three patient groups, even though there were differences between patients in the single- and multiple-day chemotherapy regimens in the time course of the nausea. There were differences in mood and behaviour between the THC and prochlorperazine trials, with patients reporting greater impairment of concentration and less social interaction after receiving THC. There were also more side effects from THC than prochlorperazine, with sedation, sleepiness and mental clouding being the most common. There was no difference in the frequency of panic attacks between the two drugs. Despite these differences in side effects there was a small patient preference in favour of THC as an anti-emetic, with 41 per cent experiencing less nausea on THC, 31 per cent experiencing less nausea on prochlorperazine, and 29 per cent reporting no difference in effectiveness. The effectiveness of THC was not related to age or prior experience with marijuana, but it was related to the experience of side effects, with patients experiencing them reporting less nausea.

Given the wide variety of patients who have been studied in terms of age and type of cancer, the wide variety of chemotherapeutic agents that have been used to treat their cancers, and the variety of different anti-emetics with which THC has been compared, the fact that findings of these studies are generally positive for THC is more impressive than the apparent differences in outcome. The positive results from the controlled trials also seem to be borne out by clinical experience with cannabinoids in managing cancer patients. A recent survey of a large sample of American oncologists, for example, found that 44 per cent of oncologists had recommended marijuana to at least one cancer patient, and 64 per cent of these physicians reported that it was successful controlling nausea in at least half of their patients. Overall, just under half of the oncologists in the sample (44 per cent) believed that cannabinoids could be safely used in the treatment of nausea caused by chemotherapy and radiotherapy (Dobin and Kleiman, 1991). A similar proportion (48 per cent) reported that they would prescribe marijuana for their patients if it was legal.

The general conclusion on the available literature is that THC is superior to placebo, and equivalent in effectiveness to other widely-used anti-emetic drugs, in its capacity to reduce the nausea and vomiting caused by some chemotherapy regimens in some cancer patients. There are a number of issues that remain to be resolved in deciding upon the clinical role of cannabinoids as anti-emetic agents in cancer chemotherapy. These issues include: the types of nausea against which it may be most effective, and hence the types of patients for which they are most appropriately prescribed; the degree of patient tolerance of the psychotropic side effects of THC and other cannabinoids; the potential seriousness of possible THC induced immunosuppression in patients who are already immunologically compromised; the most effective dosing schedules for THC as an anti-emetic; the potential use of THC in combination with other anti-emetic drugs; and the extent to which the motivation for the use of THC may have been reduced by the availability of newer anti-emetic drugs that are more effective than prochlorperazine (the main anti-emetic drug in the 1980s).

8.2.2 Which patients?

Which patients with what types of nausea are the most suitable for treatment with cannabinoids as anti-emetics? Patients with various forms of cancer have been the most extensively investigated patient group, but the numbers of different types of cancer have been too small to allow convincing analyses of differences in patient response. The same point can be made about types of chemotherapy regimens; they have varied widely in these studies, and have often not been reported, but there has been no systematic analysis of the effectiveness of cannabinoids in controlling emesis produced by different agents. It is uncertain to what extent the cannabinoids may be effective against nausea from other causes. The mechanisms that produce nausea are not well understood but there are believed to be one or more protective mechanisms located in the brain stem that can be triggered by a variety of emetic agents. This raises the possibility that cannabinoids may be therapeutically useful against nausea from a variety of causes.

8.2.3 Side effects

The psychoactive effects of cannabis which are prized by recreational users - euphoria, relaxation, drowsiness - are not always welcomed by older patients, most of whom are cannabis-naive. In some studies a substantial minority of such patients have discontinued the use of THC because of the unwelcome dysphoria and somnolence (Levitt et al, 1986). This has not been a universal experience, so further research is required to discover to what extent this has been the result of unnecessarily large doses, or poor patient preparation for these effects, and failure to adequately manage them by reassurance. What does seem to be the case is that the experience of some psychological effects of THC, including the "high", is necessary for the occurrence of a clinically significant anti-emetic effect. This fact has led to the search, so far unsuccessful, for cannabinoid derivatives of THC which possess its anti-emetic properties but not its psychoactive ones. The recent discovery of the cannabinoid ligand and receptor, and receptor subtypes (see pp7-8) has encouraged researchers to believe that this may be an achievable goal (Iversen, 1993).

A potentially more serious side effect of therapeutic THC is its possible immunosuppressive effect. Any such effect would limit its use as an anti-emetic in the treatment of cancer, since cancer patients experience immune suppression as a side effect of their treatment. There are several reasons why this may be less serious an issue that it seems at first glance. First, there are doubts about the existence of any immunosuppressive effect of cannabinoids (see Section 6.2 on the immune system, pp62-68), and the effect is small in those studies which report one. Second, the clinical significance of any such effects is doubtful in the use of THC in cancer chemotherapy. Such use would be intermittent, and relatively short-term, and the possible gain in increased life expectancy from being able to complete a course of cancer chemotherapy is such that most patients would be prepared to take the risk, in the same way that they chose to undergo the highly toxic chemotherapy in the first place.

8.2.4 Unresolved clinical issues

If THC has a place in the management of nausea from cancer treatment (Poster et al, 1981), and perhaps other causes, a number of clinical issues remain to be resolved (Levitt, 1986). Foremost among these is the best way in which to administer the drug. Should it be given well in advance of treatment at low doses to ensure a stable blood level, or should it be given in larger doses shortly before chemotherapy or radiotherapy? This issue has not been systematically studied (Levitt, 1986).

An additional question is whether there is any clinical benefit to be derived from combining THC with existing anti-emetic agents. There is suggestive evidence that there might be, since the mechanisms of action, while not well understood, appear to be different, raising the possibility that there may be positive synergistic effects from the combination of THC and other anti-emetics. One single-blind study of the combination of dronabinol and prochlorperazine, for example, suggested that the combination of these drugs may have a superior anti-nausea effect to either drug used alone (Plasse et al, 1991). Clearly, more research is warranted on this issue, especially as it may enable cannabinoids to be used as anti-emetics at lower doses with fewer unwanted psychotropic effects.

It seems surprising that the desirability of undertaking research on dosing and combined use of cannabinoids was highlighted by Poster et al in 1981 and by the Institute of Medicine in 1982. Yet very little research has been done, and THC has not been routinely incorporated into the management of nausea caused by cancer chemotherapy. One of the likely reasons has been the American controversy about the rescheduling of marijuana under the Controlled Substances Act, which some argue has discouraged clinical research on cannabinoids (see below). Another reason has been that the motivation for further research on the anti-emetic properties of THC has been removed by the recent development of newer anti-emetic drugs which are superior to prochlorperazine (Iversen, 1993), the "gold standard" drug when the major controlled trials were conducted on cannabis in the 1970s and 1980s. In the absence of trials comparing THC with these newer drugs, its comparative efficacy is unknown, although given its approximate equivalence to prochlorperazine it is likely to be inferior to the newer drugs.

8.3 Cannabinoids as anti-glaucoma agents

Glaucoma is the leading cause of blindness in the United States, affecting two million people and producing 300,000 new cases each year (Adler and Geller, 1986). It is a condition "which is generally characterised by an increase in intraocular pressure ... that progressively impairs vision and may lead to absolute blindness" (Adler and Geller, 1986, p54). Although its causes are not understood, it is believed to involve an obstruction to the outflow of the aqueous humour in the eye leading to a gradual increase in intraocular pressure (IOP) which, if untreated, may damage the optic nerve, resulting in blindness. Its incidence increases over the age of 35, especially among individuals who are myopic (i.e. short-sighted). Although various drugs are available which reduce IOP, all possess unwanted side-effects and patients may become tolerant to their therapeutic effects.

The effects of cannabis in reducing IOP were discovered serendipitously by researchers and patients in the early and middle 1970s. Hepler and his colleagues (1971, 1976) observed a substantial decrease in IOP while researching the effects of cannabis intoxication on pupil dilation. They demonstrated that both cannabis and oral THC produced substantial reductions in IOP in both normal volunteers and patients with glaucoma (Hepler and Petrus, 1976; Hepler et al, 1976). Subsequent research identified THC as the agent responsible for producing this effect (Adler and Geller, 1986).

Around the same time, patients with glaucoma who had used cannabis recreationally also discovered its therapeutic effects. One such patient, Robert Randall, used cannabis daily to control his glaucoma. When arrested for possession and cultivation of cannabis, he successfully used the defence of "medical necessity" arguing, with the support of his physicians, that he would go blind if he stopped his cannabis use. He subsequently was given legal access to cannabis for medical purposes (Randall Affidavit, in Randall, 1988).

Although there have been a number of case reports of the successful use of cannabis in the management of glaucoma (e.g. Grinspoon and Bakalar, 1993; Randall, 1990), there have not been any controlled clinical studies of its effectiveness and safety in the long-term management of glaucoma. Informed clinical opinion has been that THC is an effective anti-glaucoma agent when used acutely, but there are doubts about its effectiveness with chronic use because of the development of tolerance to its effects on IOP (Jones et al, 1981). Ophthalmologists who are opposed to the clinical use of THC point to a number of major disadvantages. First, because THC is not water-soluble, it cannot, unlike other anti-glaucoma agents, be applied topically to the eye to ensure that enough is absorbed to produce a clinically significant reduction in IOP. Second, as a consequence, THC must be absorbed systemically in order to produce a therapeutic effect on IOP, which means that patients must experience the psychoactive effects of THC in order to derive its therapeutic benefits against glaucoma. Third, because glaucoma is a chronic condition, THC or cannabis would need to be taken in substantial doses on a daily basis over long periods of time, if not for the remainder of adult life. There has been an understandable concern about the health risks of chronic daily cannabis use (e.g. Hepler, 1990; American Academy of Ophthalmology, 1990).

The position adopted by the American Academy of Ophthalmology has been to insist that cannabis has no accepted medical use in the management of glaucoma, and cannot have such medical use until a large controlled trial has been conducted into its safety and effectiveness in daily chronic use. There has been no evidence that the Academy has any interest in, or has given any encouragement to, the conduct of such a trial. Consequently, its position is that THC and other cannabinoids should not be used be in the management of glaucoma.

A contrary position has been taken by Randall, who has argued that patients should be allowed to make the choice between the uncertain health risks of chronic cannabis use and the more certain risks to sight of poorly controlled glaucoma:

"People with life- and sense-threatening diseases are routinely confronted by stark choices ... [between] the devastating consequences of a debilitating, progressive disease ... [and] often highly damaging biological and mental consequences of the toxic chemicals required to check the progression of disease. .. Viewed in this medical context, marihuana is more benign and far less damaging that the synthetic toxins routinely prescribed by physicians" (cited in Grinspoon and Bakalar, 1993, p153)

8.4 Cannabinoids and neurological disorders

8.4.1 Anti-convulsant

Historically one of the commonest medical uses of cannabis preparations has been as an anti-convulsant. O'Shaughnessy (1842), for example, recommended the use of cannabis to control seizures in epilepsy, tetanus and rabies (Nahas, 1984). Animal studies have provided some support for this use in showing that THC has dual effects on convulsions, i.e. they can produce convulsions in susceptible animals, and suppress the maximum severity of convulsions from a variety of causes, while cannabidiol (CBD) appears to be a potent anti-convulsant (Chesher and Jackson, 1974; Consroe and Snider, 1986; Institute of Medicine, 1982).

Despite this animal evidence, there is very limited evidence on the therapeutic effects of cannabinoids in humans with epilepsy. There are a small number of case studies of individuals with epilepsy in which the recreational use of cannabis appeared to enhance the anti-convulsant effects of more traditional anti-convulsant medication (e.g. Consroe et al, 1975; Grinspoon and Bakalar, 1993). There is a single randomised placebo controlled study of the administration of CBD in 15 patients with epilepsy that was not well controlled by conventional anti-convulsants. Four of the eight patients who received CBD in addition to their usual anti-convulsant drugs were free of seizures throughout the study period, and three were improved. By contrast, only one out of seven patients in the placebo condition showed any clinical improvement (Cunha et al, 1980). Despite this suggestive evidence of efficacy in epilepsy, CBD has not been widely used in clinical management. Perhaps this is not surprising given the absence of evidence of its efficacy, the existence of other effective anti-convulsant drugs, and concerns about the safety of chronic use in the management of a chronic disease. It is perhaps more surprising that there has been no further research on the anti-convulsant properties of CBD, especially as it has no psychoactive side effects (Nahas, 1984).

8.4.2 Anti-spasmodic

Cannabinoids have been used in an empirical way in the management of some patients with movement disorders, a variety of syndromes that have in common a deficit in non-pyramidal motor control function, which is expressed in usually one or more of the non-epileptic, abnormal involuntary movements, such as those found in Parkinson's disease, Huntington's disease, multiple sclerosis, and spasticity. Although a number of drugs may be of benefit in the management of these conditions, they are not always effective, and may produce troublesome side-effects (Consroe and Snider, 1986).

There has been some animal evidence which indicates that THC and its analogues produce a broad spectrum of neurological effects, which include alterations in motor function, and changes in muscle tone and reflexes. The acute motor effects in normal humans - ataxia, tremulousness and subjective weakness - also suggest a potential for therapeutic effects in some movement disorders (Consroe and Snider, 1986).

The evidence that cannabinoids have therapeutic effects in patients with movement disorders is largely anecdotal. Grinspoon and Bakalar (1993), for example, present four case histories of individuals with multiple sclerosis whose condition improved while they smoked marijuana, and deteriorated after they stopped smoking. Meinck et al (1989) report a case history of a young man with multiple sclerosis with severe limb and gait ataxia who complained of erectile impotence. After smoking marijuana his gait improved sufficiently to be able to walk unaided, and he was able to achieve and sustain an erection. When cannabis was withdrawn under medical supervision, the patient's motor function deteriorated to the point where he was unable to walk without assistance.

There has been one controlled study by Clifford (1983) who examined the effects of THC on tremor in eight patients (four male and four female) with advanced multiple sclerosis who had ataxia and tremor. Five patients reported subjective benefit from THC and there was objective evidence of benefit in two of these cases. Single-blind placebo challenge in these cases produced evidence that their clinical condition deteriorated when given placebo and improved with the reinstatement of THC.

Grinspoon and Bakalar (1993) described several case histories of individuals with paraplegia and quadriplegia who reported that cannabis use helped to reduce muscle spasm. The experiences of these individuals were supported by similar reports obtained from a survey of 43 individuals with spinal cord injuries, 22 of whom reported that they used cannabis to control their muscle spasm.

The only controlled trial of a cannabinoid in a movement disorder has been an evaluation of the effects of CBD on severity of chorea in patients with advanced Huntington's disease (Consroe et al, 1991). This study was prompted by the authors' observation that CBD had improved the condition of an individual with Huntington's disease (Sandyck et al, 1988). In this study 19 Huntington's patients were enrolled in a double-blind controlled trial in which they received six weeks administration of CBD or placebo in a cross-over design. The outcome was the severity of chorea, as assessed by blind clinical ratings, patient self-report, and a variety of measures of motor function. Although the study had sufficient statistical power to detect a relatively small clinical benefit, there was no evidence of improvement in chorea on any of the clinical, self-report or motor measures. In the light of Consroe et al's failure to replicate the earlier favourable single case, further controlled trials are warranted before any of the cannabinoids can be routinely used in treating movement disorders.

8.5 Cannabinoids as anti-asthmatic agents

Smoked cannabis, and to a lesser extent oral THC, have an acute bronchodilatory effect in both normal persons and persons with asthma (Tashkin et al, 1975; Tashkin et al, 1976). Tashkin et al (1975), for example, compared the bronchodilator effect of smoked cannabis with that of a standard clinical dose of the bronchodilator isoproterenol in relieving experimentally induced asthma in asthmatic patients. They found that smoking a 2 per cent-THC cannabis cigarette produced a bronchodilator nearly equivalent to that of a clinical dose of isoproterenol.

Despite this early suggestion of a therapeutic effect in asthma, cannabinoids have not been used therapeutically, nor have they been extensively investigated as anti-asthmatic agents other than by Tashkin and his colleagues (Tashkin, 1993). A major obstacle to therapeutic use has been the route of administration. Oral THC produces a smaller bronchodilator effect after a substantial delay, and when used as an inhalant produces irritation and reflex bronchoconstriction. Hence, smoking marijuana has been the most dependable way of delivering a clinically effective dose of THC. There is an understandable concern among clinical researchers that smoking is an unsuitable mode of administering any drug, and an especially inappropriate way to administer a drug to patients with asthma, because it would inevitably involve the delivery of other noxious chemicals that would nullify its therapeutic value in the short term, and carry an increased risk of other respiratory disease and possibly cancer in the long term (Tashkin, 1993). The unwanted psychotropic effects from marijuana smoking have also been a barrier to its use as an anti-asthmatic drug. Some investigators (e.g. Graham, 1986) have nonetheless argued that the suitability of THC as a spray should be further investigated because of the possible hazards of the chronic use of the more widely-used beta-blocker antagonists. The recent discovery of the cannabinoid receptor and ligand may prompt a re-examination of this question.

8.6 Cannabinoids as analgesics

There is some animal evidence that THC has an analgesic effect which operates via a different mechanism from that of the opioid drugs (Segal, 1986). There is a small amount of human experimental studies which have reported mixed evidence of an analgesic effect (Nahas, 1984). There has been little clinical evidence beyond historical use for various forms of chronic pain, including migraine, dysmenorrhoea, and neuralgia, and the small number of case histories of its use in chronic pain, dysmenorrhoea, labour pain, and migraine reported by Grinspoon and Bakalar (1993).

Only one double-blind controlled cross-over study has been reported. This study compared the analgesic effect of THC and codeine in patients with cancer pain (Noyes et al, 1975). The findings suggested that 20mg of THC was of equivalent analgesic effect to 120mg of codeine. However, neither drug produced substantial analgesia in these patients, and the majority of patients found the psychotropic effects of 20mg of THC sufficiently aversive that they discontinued its use. Clearly, much more basic pharmacological and animal investigation is required before cannabinoids or their derivatives have any clinical use as analgesics. Nevertheless, such investigations may be worth pursuing because of the dependence potential of the more potent opioid analgesics, and the likelihood that any cannabinoid mediated analgesic effect operates by a different mechanism to that of the opioids.

8.7 Other possible therapeutic uses

A variety of other therapeutic uses have been suggested, although few have been investigated in any depth. In the late 1940s, for example, there were some investigations of the therapeutic uses of the euphoriant properties of cannabis, as a possible anti-depressant agent in the form of synhexil, a synthetic cannabis analogue. The results in one uncontrolled study were positive, but these were not replicated in later studies using lower doses (Nahas, 1984; Grinspoon and Bakalar, 1993). None of these suggestions have been further investigated, probably because of the potential for THC to produce dysphoric and other unwanted psychotropic side effects.

8.8 Cannabis and AIDS

One of the areas of greatest contemporary interest in the therapeutic uses of cannabinoids and cannabis has been their possible roles as an anti-nausea agent, an appetite stimulant and an analgesic in patients with AIDS (Randall, 1989). The development of this interest seems to have replicated the earlier discovery of the anti-emetic effects of cannabis in young cancer patients in the 1970s. AIDS patients often experience nausea and weight loss, either while receiving cytotoxic drugs to suppress HIV, or as a direct effect of the AIDS spectrum diseases. Many patients have been recreational cannabis users, and so have reported that the smoking of marijuana produces a diminution in their nausea, an increased appetite, reduced pain, and general improvements in well being. AIDS advocacy groups have accordingly argued that marijuana should be made legally available to AIDS patients (e.g. Randall, 1991).

So far the bulk of evidence for these therapeutic claims has been provided by case reports (see Randall, 1989). There has been one small uncontrolled study of 10 symptomatic AIDS patients which suggested that dronabinol (synthetic THC) may be effective in reducing nausea and stimulating appetite (Plasse et al, 1991). The evidence of its anti-emetic properties in cancer patients seems to support its potential application in AIDS treatment, and is deserving of further investigation.

A potential concern with the use of cannabinoids in HIV positive individuals and AIDS patients is the possible immunosuppressive effects of cannabinoids. Although, as argued above, this effect is likely to be small and of limited concern when used intermittently in cancer patients, it is of potentially greater significance in AIDS patients, since cannabis would be used regularly by patients with a major immune system disorder. Even a small impairment in immunity may have major consequences for HIV and AIDS affected individuals. Recent epidemiological evidence does something to allay this concern. A large prospective cohort study of HIV/AIDS in homosexual and bisexual men recently failed to find any relationship between cannabis use, or any other psychoactive drug use, and the rate at which HIV positive men developed clinical AIDS (Kaslow et al, 1989). Nonetheless, the issue of immunosuppression needs to be explicitly investigated in any research which is undertaken into the therapeutic uses of cannabinoids in the treatment of AIDS.

8.9 The limitations of anecdotal evidence

Much of the case for the therapeutic uses of cannabinoids as other than anti-emetic agents depends upon anecdotal evidence from case histories. Such evidence has justifiably come to be distrusted as evidence of therapeutic effectiveness in clinical medicine, especially in the case of chronic conditions which have a fluctuating course of remission and exacerbation. In such diseases, it is difficult to exclude alternative explanations of any apparent relationship between the use of a drug (e.g. THC) and an improvement in a patient's condition. Among the alternative explanations that are most difficult to exclude in a single case or even a succession of single cases is simple coincidence: that is, there may be no relationship between the use of the drug and improvement; the apparent relationship between the two may have arisen because the use of the drug preceded an improvement in the patient's condition that would have occurred in its absence. This is especially likely to occur in a chronic condition with a fluctuating course. In addition, the well-known placebo effect which is observed in many conditions may explain the apparent benefits of a drug or other treatment. It is for these reasons that this review has relied upon evidence from controlled clinical trials in appraising the therapeutic uses of cannabinoids.

Grinspoon and Bakalar (1993) have attempted to defend anecdotal evidence of therapeutic efficacy of cannabinoids. They argue that a double standard has been used in the appraisal of the safety and efficacy of cannabinoids: anecdotal evidence of harm has been readily accepted while anecdotal evidence of benefit has been discounted. Although at first glance "double standards" may seem to describe the behaviour of the regulatory authorities, it is defensible to use different standards of proof when evaluating the benefits and the costs of therapeutic drugs. It is reasonable to err on the side of caution by requiring stronger evidence of benefit from putatively therapeutic drugs in order to ensure that the possible risks incurred by their therapeutic use do not outweigh their benefits. Moreover, this behaviour is not peculiar to the therapeutic appraisal of cannabinoids; it is standard practice in the therapeutic appraisal of all drugs. Medical practitioners are encouraged to report cases histories of possible adverse effects of prescribed drugs. Such reports are treated as a noisy but necessary way of detecting rare but serious side effects of drugs that have not been detected in clinical trials or animal studies.

8.10 The politics of therapeutic cannabinoid use

A puzzle in the field of cannabinoid therapeutics is that despite the positive appraisal of the therapeutic potential of cannabinoids as anti-emetics and anti-glaucoma agents, they have not been widely used. Nor has the detailed type of clinical pharmacological research been undertaken on optimal methods of clinical use in those areas where the cannabinoids do have therapeutic potential (e.g. as anti-emetics). Part of the reason for this is that research on the therapeutic use of these compounds has become a casualty of the debate in the United States about the legal status of cannabis. This emerges from an inspection of the arguments recently advanced for and against an application to the United States Drug Enforcement Agency to change the status of marijuana under the Controlled Substances Act, 1970 from a schedule I drug which has no accepted medical use to a schedule II drug which has an accepted medical use (see Randall, 1988, 1989, 1990).

The proponents of rescheduling (National Organisation for the Reform of Marijuana Laws, Alliance for Cannabis Therapeutics, and Cannabis Corporation of America) have argued that marijuana should be available for medical use, as smoking is the most effective mode of delivering THC for some therapeutic purposes. The opponents of rescheduling (Drug Enforcement Agency, International Chiefs of Police, The National Federation of Parents for a Drug Free Youth) have countered that marijuana has no therapeutic use, since its few uses are better met, either by other more effective drugs which do not have the psychoactive effects of THC, or by the oral delivery of synthetic cannabinoids. They have been supported by medical researchers and practitioners who argue for the therapeutic superiority of pharmaceutically pure drugs which can be given in defined doses (e.g. Levitt, 1986; Mechoulam, 1988; Nahas, 1984).

Medical researchers who have supported the rescheduling of marijuana (e.g. Grinspoon and Bakalar, 1993; Merritt, 1988; Mikuriya, 1990; Morgan, 1990; Weil, 1988) have argued that smoked cannabis is superior to oral synthetic cannabinoids in effectiveness and has a lower risk of producing unwanted psychoactive side-effects. Apart from the unsuitability of oral medication for patients who are vomiting, their main arguments in favour of smoking as a route of THC administration are similar to the reasons recreational users often give for preferring smoking to the oral use of cannabis. The greater bioavailability of THC via smoking produces a more dependable therapeutic effect, which is more easily controlled because users have a greater ability to titrate their dose, and hence, to maximise the desired effects while minimising the unpleasant effects. An additional argument sometimes used is that there may be other cannabinoids present in the crude plant product which modulate the undesired side effects, including the unpleasant dysphoric effects of THC (Grinspoon and Bakalar, 1993). There is also suggestive evidence that smoked cannabis is as effective as oral THC, and may be preferred by patients because of the greater control they have over dose (Chang et al, 1979).

Opponents of marijuana rescheduling argue that the undesirable psychoactive side effects of THC disqualify it from widespread medical use, whatever the route of administration. Most also believe that smoking is a medically unacceptable route of administration of THC because it is unsuitable for very young and very old patients, there is a risk of infection with micro-organisms which may contaminate the plant material, and there is the danger that chronic smoke inhalation may produce or exacerbate bronchitis, and expose the user to carcinogens (e.g. Levitt, 1986; Mechoulam, 1988; Nahas, 1984).

The proponents of rescheduling respond that none of these are compelling reasons for rejecting smoked marijuana for therapeutic purposes until more potent and specific therapeutic cannabinoids have been identified and synthesised. Smoking, they point out, would not be a compulsory method of administration; only an option for those patients who preferred it, as would the use of cannabinoids if patients did not like their psychoactive effects. The contamination of micro-organisms reported with blackmarket cannabis can be overcome, they argue, by standardising dose and using an anti-microbial treatment, as has been done by National Institute on Drug Abuse (NIDA) in preparing cannabis cigarettes for research (Randall, 1988). The risks of bronchitis and respiratory tract cancers, it is argued, are small with the intermittent and time-limited smoking of cannabis that would occur in the course of cancer chemotherapy. In any case, proponents of rescheduling argue, it is probably a risk that many patients with a life-threatening illness may be prepared to run, as shown by their preparedness to take highly toxic and carcinogenic anti-cancer agents.

Weil (1988) has argued that some opponents have used double standards in appraising the risks of marijuana smoking. According to Weil, the most common psychoactive effects of marijuana (euphoria, somnolence and dysphoria) are minor, non-life-threatening and self-limiting effects that can be easily managed, and are of much less severity than the side effects of many other widely-used therapeutic drugs. Medical witnesses for the government, he claims, "do not contrast marijuana's supposed adverse effects with the known adverse effects of drugs routinely prescribed for the treatment of conditions like cancer, glaucoma and multiple sclerosis. Instead, ... [they] compare marijuana to some abstract, unobtainable standard of perfection" (p437).

Merritt (1988) has made a similar point in criticising the arguments raised against the therapeutic use of marijuana to manage glaucoma: " ... each drug family used in glaucoma therapy is capable of producing a lethal response, even when properly prescribed and used .. [p470] [but] these drugs are all deemed "safe" for use in glaucoma therapy .. because their adverse consequences are considered less threatening to the patient than blindness" (p472). Yet marijuana is excluded from therapeutic use because of a possible risk of cancer from long-term daily smoking. "I cannot see", observes Merritt, "how an alleged case of marijuana-induced lung cancer which results in death is significantly different in result from an acute adverse reaction to a myotic drug which results in respiratory failure, except, of course, that the patient with cancer is likely to outlive the patient who is unable to draw in a breath of air" (p474).

Although the debate about the rescheduling of marijuana has been ostensibly about the safety and efficacy of marijuana use, it has been driven by the debate about the legal status of recreational marijuana use. For example, some of the groups advocating the therapeutic use of cannabis have also been proponents of cannabis legalisation (e.g. NORML), thereby fuelling the fears of opponents of cannabis use that success in the campaign for marihuana rescheduling will be the thin edge of a wedge to legalise cannabis. Other proponents of legalisation (e.g. Grinspoon and Bakalar, 1993) have turned this reasoning around, by arguing for the legalisation of cannabis as a way of making cannabis available for therapeutic purposes.

On the other side of the argument are those opponents of marijuana use who fear that the admission that marijuana, or any of its constituents, may have a therapeutic use will send the "wrong message" to youth. This has led to the denial that cannabinoids have any therapeutic effects, and to attempts to stifle all scientific inquiry into any such effects. For example, Mr Bernstein representing the National Federation of Parents for a Drug Free Youth had the following to say in his summing up against Rescheduling marijuana before Judge Young (1989):

"If marijuana were to be rescheduled to Schedule II, what kind of message are we sending to a nation that is engaged in a battle for it's very survival because of epidemic drug abuse? ... will not the message be that marijuana is good for cancer, good for glaucoma, good for spasticity and a host of other illnesses? Now to all of this who are the most vulnerable? The answer is, of course, our young people. Their reaction will be that if it is good for all of these things, it can't be bad for me. We then have another youngster trying marijuana, the gateway drug and probably starting down the road that leads to nowhere but destruction" (in Randall, 1989, p395).

It is unfortunate that a connection has been forged between the debates about the legal status of cannabis as a recreational drug and the use of cannabinoids for therapeutic use. Any such connection is spurious, since there is a world of difference between the use of controlled doses of a purified drug under medical supervision and the recreational use of crude preparations of a drug. In a rational world, clinical decisions about whether to use pure cannabinoid drugs should not be abrogated because crude forms of the drug may be abused by those who use it recreationally. As a community we do not allow this type of thinking to deny us the use of opiates for analgesia. Nor should it be used to deny access to any therapeutic uses of cannabinoids derivatives that may be revealed by pharmacological research.

8.11 Conclusions

The following provisional conclusions can be drawn on the available evidence. First, there is good evidence for the therapeutic potential of THC as an anti-emetic agent. Although uncertainty exists about the most optimal method of dosing and the advantages and disadvantages of different routes of administration, there is sufficient evidence to justify it being made available in pure synthetic form to cancer patients. In the light of the recent development of more effective anti-emetic agents, it remains to be seen how widely used the cannabinoids will be. Second, there is reasonable evidence for the potential efficacy of THC in the treatment of glaucoma, especially in cases which have proved resistant to existing anti-glaucoma agents. Further research is clearly required, but this should not prevent its use under medical supervision in poorly controlled cases, provided patients make informed decisions about its use in the light of information about the possible health risks of long-term use. Third, there is sufficient suggestive evidence of the potential usefulness of various cannabinoids as analgesic, anti-asthmatic, anti-spasmodic, and anti-convulsant agents to warrant further basic pharmacological and experimental investigation, and perhaps clinical research into their effectiveness.

Despite the basic and clinical research work which was undertaken in late 1970s and early 1980s, the cannabinoids have not been widely used therapeutically, nor have further investigations been conducted along the lines suggested in the positive evaluations made by the Institute of Medicine (1982). This seems largely attributable to the fact that clinical research on the therapeutic use of cannabinoids has been discouraged by regulation and a lack of funding in the United States, where most cannabis research has been conducted. The discouragement of therapeutic research, in turn, derives from the fact that THC, the most therapeutically effective cannabinoid, has the psychoactive effects sought by recreational users. In opposing the therapeutic uses of cannabinoids, some researchers have used double standards in appraising efficacy and safety, setting unreasonably high standards in assessing the evidence on the comparative therapeutic safety and efficacy of cannabinoids and existing agents. The application of the same demanding standards to existing agents for the candidate diseases, and more generally, to existing psychoactive drugs that are widely used in medical practice, would denude the pharmacopoeia. The recent discovery of the cannabinoid receptor may help to overcome some of the resistance to research into the therapeutic uses of cannabinoids, by holding out the prospect that the psychoactive effects of the cannabinoids can be disengaged from their other therapeutically desirable effects.

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9. An overall appraisal of the health and psychological effects of cannabis

9.1 Summary

The following is a summary of the major adverse health and psychological effects of acute and chronic cannabis use, grouped according to the degree of confidence in the view that the relationship between cannabis use and the adverse effect is a causal one.

9.1.1 Acute effects

The major acute psychological and health effects of cannabis intoxication are:

• anxiety, dysphoria, panic and paranoia, especially in naive users;

• cognitive impairment, especially of attention and memory for the duration of intoxication;

• psychomotor impairment, and probably an increased risk of accidental injury or death if an intoxicated person attempts to drive a motor vehicle or operate machinery;

• an increased risk of experiencing psychotic symptoms among those who are vulnerable because of a personal or family history of psychosis; and

• an increased risk of low birth weight babies if cannabis is used

during pregnancy. 9.1.2 Chronic effects

The major health and psychological effects of chronic cannabis use, especially daily use over many years, remain uncertain. On the available evidence, the major probable adverse effects appear to be:

• respiratory diseases associated with smoking as the method of administration, such as chronic bronchitis, and the occurrence of histopathological changes that are precursors to the development of malignancy;

• development of a cannabis dependence syndrome, characterised by an inability to abstain from or to control cannabis use; and

• subtle forms of cognitive impairment, most particularly of attention and memory, which persist while the user remains chronically intoxicated, and may or may not be reversible after prolonged abstinence from cannabis.

The following are the major possible adverse effects of chronic, heavy cannabis use which remain to be confirmed by controlled research:

• an increased risk of developing cancers of the aerodigestive tract, i.e. oral cavity, pharynx, and oesophagus;

• an increased risk of leukemia among offspring exposed in utero; and

• a decline in occupational performance marked by underachievement in adults in occupations requiring high level cognitive skills, and impaired educational attainment in adolescents.

• birth defects occurring among children of women who used cannabis during their pregnancies.

9.1.3 High risk groups

A number of groups can be identified as being at increased risk of experiencing some of these adverse effects.

Adolescents

• Adolescents with a history of poor school performance may have their educational achievement further limited by the cognitive impairments produced by chronic intoxication with cannabis.

• Adolescents who initiate cannabis use in the early teens are at higher risk of progressing to heavy cannabis use and other illicit drug use, and to the development of dependence on cannabis.

Women of childbearing age

• Pregnant women who continue to smoke cannabis are probably at increased risk of giving birth to low birth weight babies, and perhaps of shortening their period of gestation.

• Women of childbearing age who continue to smoke cannabis at the time of conception or while pregnant possibly increase the risk of their children being born with birth defects.

Persons with pre-existing diseases

Persons with a number of pre-existing diseases who smoke cannabis are probably at an increased risk of precipitating or exacerbating symptoms of their diseases. These include:

• individuals with cardiovascular diseases, such as coronary artery disease, cerebrovascular disease and hypertension;

• individuals with respiratory diseases, such as asthma, bronchitis, and emphysema;

• individuals with schizophrenia, who are at increased risk of precipitating or of exacerbating schizophrenic symptoms; and

• individuals who are or have been dependent upon alcohol and other drugs, who are probably at an increased risk of developing dependence on cannabis.

9.1.4 A caveat

As has been stressed throughout this document, there is uncertainty surrounding many of these summary statements about the adverse health effects of acute, and especially chronic, cannabis use. To varying degrees, these statements depend upon inferences from animal research, laboratory studies, and clinical observations about the probable ill effects. In some cases, the inferences depend upon arguments from what is known about the adverse health effects of other drugs, such as tobacco and alcohol. In very few cases are there sufficient studies which provide the detailed evidence that epidemiologists would require to make informed judgments about the health effects of cannabis; the interpretation of what epidemiological evidence is available is complicated by difficulties in quantifying degree of exposure to cannabis, and in excluding alternative explanations (including other drug use) of associations observed between cannabis use and adverse health outcomes. These interpretative problems are especially obvious in the case of many of the alleged psychological outcomes of cannabis use in adolescence, since many of these putative "consequences" (e.g. poor school performance, deviant behaviour) also antedate the use of cannabis. Nevertheless, these statements provide the best available basis for making societal decisions about what policies ought to be adopted towards cannabis use.

9.2 Two special concerns

Two issues which have hitherto been ignored require brief discussion. These are the possible health implications of: the storage of THC in body tissue; and any increases in the average potency of cannabis products (as indexed by THC content) that may have occurred in recent decades.

9.2.1 Storage of THC

There is good evidence that with repeated dosing of cannabis at frequent intervals, THC can accumulate in fatty tissues in the human body where it may remain for considerable periods of time (see above pp34-35). Attitudes towards this fact are strongly coloured by the perceiver's views about cannabis use: those who are opposed to its use usually regard this as a cause for major concern; proponents of cannabis use largely ignore it. There is no evidence to make a confident judgment one way or the other. The storage of cannabinoids would be serious cause for concern if THC were a highly toxic substance which remained physiologically active while stored in body fat. The evidence that THC is a highly toxic substance is weak, although it does have a bewildering variety of biological effects (Martin, 1986). Its degree of activity while stored has not been investigated. One potential health implication of THC storage is that the release of stored cannabinoids into blood may produce unexpected symptoms of cannabis intoxication. The release of stored THC has been suggested as an explanation of "flashback experiences" (e.g. Negrete, 1988; Thomas, 1993). Such experiences have been rarely reported by cannabis users (e.g. Edwards, 1983), and even in these cases interpretation of their significance is complicated by the fact that those who have reported such experiences have typically used other hallucinogenic drugs. Whatever the uncertainties about health implications of THC storage, all potential users of cannabis should be aware that it occurs.

9.2.2 Increases in the potency of cannabis

Cohen (1986) has been credited (Mikuriya and Aldrich, 1988) with initiating the recent claim that the existing medical literature on the health effects of cannabis underestimates its adverse effects because it was based upon research conducted on less potent forms of marijuana (O.5 per cent to 1.0 per cent THC) than those that became available in the USA in the past decade (3.5 per cent THC in 1985-1986). This claim has been repeated often in the popular and scientific media, and supported by anecdotal evidence that samples containing up to 40 per cent THC have been seized by the police. An alleged "ten-fold" increase in potency has contributed to recent concerns about the health effects of cannabis, because of the assumption that increases in average potency necessarily mean substantial increases in the health risks of cannabis use. In Australia this concern has been recently raised by the discovery of hydroponically cultivated clones of cannabis plants that produce high levels of THC, and by reports of the importation of high THC producing strains of cannabis from New Guinea.

There are a number of points to be made about this issue. First, the evidence for an increase in potency is not as clear as Cohen (1986) claimed, or as it seems from the data reported by ElSohy and ElSohy (1989). The inference that these data demonstrate that potency has increased depends upon the assumption that the samples analysed are representative of cannabis consumed. Mikuriya and Aldrich (1988), for example, have contested this assumption. They cite the results of chemical analyses conducted on cannabis samples in California during the middle 1970s in which the average potency was well within the ranges reported in samples seized by the US Drug Enforcement Agency in the middle 1980s. They also argue that the analyses of the DEA samples from the middle 1970s underestimated THC potency because the samples were not properly stored, allowing their average THC content to be degraded.

Second, even if we allow that there probably has been a small increase in the THC potency of cannabis products in the USA, there is at present no evidence of a similar increase in Australia. There is good evidence from police samples analysed in New Zealand over the past decade that average potency has not increased there (Bedford, 1993). Press reports of increased potency have often been misleading in that they have been based upon individual samples of highly concentrated cannabis extracts, such as hash oil, which have never had a major share of the cannabis market.

Third, the use of average potency can be also be potentially misleading, since the average ignores differences between cannabis users in preferences for cannabis products of varying potency. There probably has always been a market for more potent products among the heavier, and hence, more THC-tolerant, cannabis users. Marijuana probably remains the majority preference of cannabis users, although this is an issue worthy of investigation.

Fourth, it is not obvious that more potent forms of cannabis inevitably have more adverse effects on users' health than less potent forms. Indeed, it is conceivable that increased potency may have little or no adverse effect if users are able to titrate their dose to achieve the desired state of intoxication, as some have argued they do (e.g. Kleiman, 1992; Mikuyira and Aldrich, 1988). If users were able to titrate their dose, the use of more potent cannabis products would reduce the amount of cannabis material that was smoked, which would marginally reduce the risks of developing respiratory diseases.

Fifth, even if users do not titrate their dose of THC, (or if they do so inefficiently), any increase in the average dose received would not inevitably have an adverse impact on users' health. The effect would depend upon the type of health effect in question, and the relative experience of users. Higher average doses may produce an increase in the risk of minor adverse psychological effects of acute use, especially among naive users. This could be a desirable outcome if it discouraged further experimentation with the drug. Among experienced cannabis users, an increased average dose may increase the risks of accidents among those who drive while intoxicated, especially if combined with alcohol. Higher average doses may also increase the risk of regular users developing dependence.

All considered then, it is far from established that the average THC potency of cannabis products has substantially increased over recent decades. If potency has increased, it is even less certain that the average health risks of cannabis use have materially changed as a consequence, since users may titrate their dose to achieve the desired effects. Even if the users are inefficient in titrating their dose of THC, it is far from certain that the probability of adverse health effects will be thereby increased. Nevertheless, given these concerns about THC potency, it would be preferable to conduct research on the issue rather than to rely upon inferences about the likely effects of increased cannabis potency. Studies of the ability of experienced users to titrate their dose of THC would contribute to an evaluation of this issue, as would the inclusion in sample surveys of questions about the form and perceived potency of cannabis products used.

9.3 A comparative appraisal of health risks: alcohol, tobacco and cannabis use

The probable and possible adverse health and psychological effects of cannabis need to be placed in comparative perspective to be fully appreciated. A useful standard for such a comparison is what is known about the health effects of alcohol and tobacco, two other widely used psychoactive drugs. Cannabis shares with tobacco, smoking as the usual route of administration, and resembles alcohol in being used for its intoxicating and euphoriant effects.

Considerable care must be exercised in making such comparisons. Firstly, the quantitative risks of tobacco and alcohol use are much better known than the health risks of cannabis, since alcohol and tobacco have been consumed by substantial proportions of the population, and there have been 40 years of scientific studies of the health consequences of their use. Cannabis, by contrast, has been much less widely used, and for a shorter period, in Western society; it has been primarily used by healthy young adults, and there have been few studies of its adverse health effects.

Secondly, the prevalence of use of alcohol and tobacco is much higher than that of cannabis. For example, the proportions of the Australian population who are at least weekly users of alcohol, tobacco and cannabis are: 61 per cent, 29 per cent, (Department of Health, Housing and Community Services, 1992), and 11 per cent (Donnelly and Hall, 1994) respectively. Any overall comparison of the health consequences of the three drug types that was based upon existing patterns of use would unfairly disadvantage alcohol and tobacco. Any attempt to adjust for the differences in prevalence (e.g. by estimating the health effects if the prevalence of cannabis use was the same as those for alcohol and tobacco) would involve making controversial assumptions, so no such attempt has been made.

The very different prevalence of use of alcohol, tobacco and cannabis, and the fact that we know a great deal more about the adverse effects of alcohol and tobacco use, precludes any quantitative comparison of the current health consequences of these drugs. Nevertheless, a qualitative comparison of the probable health risks of cannabis with the known health risks of alcohol and tobacco serves the useful purpose of reminding us of the risks we currently tolerate with our favourite psychoactive drugs.

In undertaking this qualitative comparison, we have avoided the necessity to comprehensively review the vast literatures on the health effects of alcohol and tobacco by using the following authorities as the principal sources of evidence for our assertions about their health risks: Anderson et al (1993); Holman et al's (1988) compendium of the health effects of alcohol and tobacco; the Institute of Medicine (1987); the International Agency for Research into Cancer (1990); Roselle et al (1993); and the Royal College of Physicians (1987).

9.3.1 Acute effects

Alcohol. The major risks of acute cannabis use are similar to the acute risks of alcohol intoxication in a number of respects. First, both drugs produce psychomotor and cognitive impairment, especially of memory and planning. The impairment produced by alcohol increases risks of various kinds of accident, and the likelihood of engaging in risky behaviour, such as dangerous driving, and unsafe sexual practices. It remains to be determined whether cannabis intoxication produces similar increases in accidental injury and death, although on balance it probably does.

Second, there is good evidence that substantial doses of alcohol taken during the first trimester of pregnancy can produce a foetal alcohol syndrome. There is suggestive but far from conclusive evidence that cannabis used during pregnancy may have similar adverse effects.

Third, there is a major health risk of acute alcohol use that is not shared with cannabis. In large doses alcohol can cause death by asphyxiation, alcohol poisoning, cardiomyopathy and cardiac infarct. There are no recorded cases of fatalities attributable to cannabis, and the extrapolated lethal dose from animal studies cannot be achieved by recreational users.

Tobacco. The major acute health risks that cannabis shares with tobacco are the irritant effects of smoke upon the respiratory system, and the stimulating effects of both THC and nicotine on the cardiovascular system, both of which can be detrimental to persons with cardiovascular disease.

9.3.2 Chronic effects

Alcohol. There are a number of risks of heavy chronic alcohol use, some of which may be shared by chronic cannabis use. First, heavy use of either drug increases the risk of developing a dependence syndrome in which users experience difficulty in stopping or controlling their use. There is strong evidence of such a syndrome in the case of alcohol and reasonable evidence in the case of cannabis. A major difference between the two is that it is uncertain whether a withdrawal syndrome reliably occurs after dependent cannabis users abruptly stop their cannabis use, whereas the abrupt cessation of alcohol use in severely dependent drinkers produces a well defined withdrawal syndrome which can be potentially fatal.

Second, there is reasonable clinical evidence that the chronic heavy use of alcohol can produce psychotic symptoms and psychoses in some individuals. There is suggestive evidence that chronic heavy cannabis use may produce a toxic psychosis, precipitate psychotic illnesses in predisposed individuals, and exacerbate psychotic symptoms in individuals with schizophrenia.

Third, there is good evidence that chronic heavy alcohol use can indirectly cause brain injury - the Wernicke-Korsakov syndrome - with symptoms of severe memory defect and an impaired ability to plan and organise. With continued heavy drinking, and in the absence of vitamin supplementation, this injury may produce severe irreversible cognitive impairment. There is good reason for concluding that chronic cannabis use does not produce cognitive impairment of comparable severity. There is suggestive evidence that chronic cannabis use may produce subtle defects in cognitive functioning, that may or may not be reversible after abstinence.

Fourth, there is reasonable evidence that chronic heavy alcohol use produces impaired occupational performance in adults, and lowered educational achievements in adolescents. There is suggestive evidence that chronic heavy cannabis use produces similar, albeit more subtle impairments in occupational and educational performance of adults.

Fifth, there is good evidence that chronic, heavy alcohol use increases the risk of premature mortality from accidents, suicide and violence. There is no comparable evidence for chronic cannabis use, although it is likely that dependent cannabis users who frequently drive while intoxicated with cannabis increase their risk of accidental injury or death.

Sixth, alcohol use has been accepted as a contributory cause of cancer of the oropharangeal organs in men and women. There is suggestive evidence that chronic cannabis smoking may also be a contributory cause of cancers of the aerodigestive tract.

Tobacco. The major adverse health effects shared by chronic cannabis and tobacco smokers are chronic respiratory diseases, such as chronic bronchitis, and probably, cancers of the aerodigestive tract (i.e. the mouth, tongue, throat, oesophagus, lungs). The increased risk of cancer in the aerodigestive tract is a consequence of the shared route of administration by smoking. It is possible that chronic cannabis smoking also shares the cardiotoxic properties of tobacco smoking, although this possibility remains to be investigated.

It should be stressed that this section only describes the adverse health effects of alcohol and tobacco for which there is some evidence that chronic heavy cannabis use may also cause. It does not, therefore, provide an exhaustive inventory of all the adverse health effects of either chronic alcohol or tobacco use. Among the major additional adverse health effects of chronic heavy alcohol use which are not shared by cannabis are: liver cirrhosis, peripheral neuropathy, and gastritis.

9.4 Implications for harm reduction

The simplest health advice to anyone who wishes to avoid the probable acute and chronic adverse health effects of cannabis is to abstain from using the drug. This advice is especially apt for persons with any of the diseases (e.g. cardiovascular) or conditions (e.g. pregnancy) which would make them more vulnerable to the adverse effects of cannabis.

Current cannabis users should be aware of the following risks of using the drug. First, the risk of being involved in a motor vehicle accident is likely to be increased when cannabis users drive while intoxicated by cannabis. The combination of alcohol and cannabis intoxication will substantially increase this risk. Second, the chronic smoking of cannabis poses significant risks to the respiratory system, apart from any specific effects of THC. Third, the respiratory risks of cannabis smoking are amplified if deep inhalation and breath-holding are used to maximise the absorption of THC in the lungs. This technique greatly increases the delivery and retention of particulate matter and tar. Fourth, daily or near daily use of cannabis is to be avoided, as it has a high risk of producing dependence.

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