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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