The health effects of cannabis: key issues of policy relevance
Cannabis as the main illicit drug of choice
Problems of assessing the health effects of cannabis
Cannabis, the drug
Acute effects of cannabis
The health effects of chronic cannabis use
Therapeutic potential of cannabis
Biological basis for cannabis effects
Author: B. R. MARTIN, W. HALL
Creation Date: 1999/12/01
B. R. MARTIN
Department of Pharmacology and Toxicology, Virginia Commonwealth University,
Richmond, Virginia, USA
National Drug and Alcohol Research Centre, University of New South Wales,
Cannabis remains one of the most widely abused drugs worldwide, with a substantial number of users in many Western societies. Epidemiological studies reveal that most users are young individuals either in their teens or early twenties. The most prevalent pattern of use is intermittent. Traditional use of cannabis is also prevalent in many countries. The main acute adverse effects of cannabis are cognitive impairment, especially of attention and memory, psychomotor impairment, and a possible increased risk of traffic accidents. The main physical and psychological health effects of chronic, heavy cannabis use, especially daily use, over many years, are most commonly respiratory disease, dependence and subtle cognitive impairment. It is estimated that approximately 10 per cent of persons who try cannabis progress to daily use, with a further 20 to 30 per cent using it on a weekly basis. Cannabis use during pregnancy is likely to result in shortened gestation and low-birth-weight babies. Other potential dangers of chronic heavy use that remain to be confirmed include an increased risk of developing cancer, a decline in occupational performance, impaired educational attainment in adolescents and birth defects. While it is known that underachieving adolescents are more likely to smoke cannabis, a cause-effect relationship has not been established. There is considerable anecdotal information regarding the therapeutic usefulness of smoking cannabis. In recent times, the most intense interest has been directed towards the prevention of weight loss in patients with acquired immunodeficiency syndrome (AIDS), although management of pain, prevention of emesis and control of glaucoma and movement disorders still command attention. Of these potential uses, treatment of cachexia in AIDS patients and of chronic pain seems most worthy of scientific validation. Efforts to develop synthetic cannabinoid derivatives should remain a primary goal for treatment of most such disorders. The discovery of an endogenous cannabinoid system provides a means not only of developing new therapeutic agents but also of establishing the biological consequences of long-term cannabis exposure on the brain. The localization of cannabinoid receptors in brain areas associated with some of the most prominent pharmacological effects of cannabis, that is, cognition, pain perception and movement, provides an insight into the physiological importance of those receptors. The identification of anandamide, the endogenous ligand for the cannabinoid receptor, provided credence for a naturally occurring endogenous cannabinoid system in the brain. This endogenous system adapts to chronic exposure to tetrahydrocannabinol (THC) by a reduction in the number of receptors, the physiological consequence of which remains to be established.
Cannabis is the most widely used illicit drug in many Western societies. Surveys indicate that it has been tried by a third of adults in the United States of America  and other English-speaking countries, such as Australia , and that it has been tried by a substantial proportion of young adults in those countries [2-4]. In the majority of cases cannabis users use the drug on a small number of occasions and either discontinue their use or use it intermittently until discontinuing their use in their mid- to late twenties . Only a very small proportion of cannabis users use the drug on a daily basis over a period of years. United States and Australian survey data suggest that about 10 per cent of those who ever use cannabis become daily users and a further 20 per cent to 30 per cent use it on a weekly basis [2-4].
In contrast to the above description of cannabis as an illicit substance, cannabis use in several countries is interwoven into the social and religious fabric of some portions of the population and is therefore viewed as an acceptable practice or as traditional use. Despite the widespread use of cannabis in many of these countries, there have been no recently reported extensive epidemiological studies that carefully document the use patterns of cannabis and its probable impact on the health of that population. Consequently, the research community has not been able to incorporate traditional cannabis use into any assessment of health consequences.
Regardless of the using population, there are uncertainties about the dose of THC because of differences in smoking techniques as well as varying cannabis potencies. Hence, there is no reliable information on the amount of THC ingested by regular users. "Heavy" use is consequently defined according to 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 poses the greatest long-term physical and psychological health risks for users. Daily cannabis users are more likely to be male and less well educated; they are also more likely to use alcohol regularly and to have used amphetamines, hallucinogens, psychostimulants, sedatives and opioids [2, 5, 6].
Determining the adverse effects of a particular chemical in a large and diverse population is often difficult unless the effect is highly distinctive and of large magnitude. Oestrogen is a noteworthy example in that years of study and extremely large patient populations were required in order to establish the carcinogenic risks of oral contraceptives. Moreover, that evaluation occurred in a population where there was considerable precision regarding drug exposure. While nutritional supplements and herbal remedies have enjoyed considerable attention, there is little scientific documentation for either their beneficial or adverse effects. It is therefore not surprising that there has been and will doubtless continue to be controversy regarding the impact of cannabis use on health. There have been numerous reviews of cannabis [7, 8, 9]. Some reviewers conclude that cannabis is relatively harmless , while others have concluded that it causes considerable harm .
There are several factors that contribute to possible overestimation and underestimation of the adverse outcomes of cannabis use. As mentioned above, cannabis is frequently used by the younger generation, whose health status may be better than that of the general population. Moreover, most users partake of cannabis on an infrequent basis, thus probably mitigating the more serious health consequences. There is often a tendency to treat the cannabis-using population as homogenous, without reference to potential high-risk groups, such as adolescents, individuals with pre-existing psychological disorders and pregnant users. Predictions of outcome based primarily on the number of individuals who have ever tried cannabis irrespective of frequency of use or on high-risk groups have led to the erroneous conclusion that even the most modest adverse effects of cannabis should show up clearly given the large number of users. Of course, extrapolation of the adverse effects of chronic cannabis use in high-risk groups to the general population can lead to an overestimation of the health effects of cannabis use. Clearly, it is imperative, when drawing general conclusions regarding the effects of any substance, that due consideration be given to the health status of the user, frequency of use and associated risks.
In the present review, we have chosen to apply the rigorous standards essential for scientific review. The inference that cannabis use causes an adverse health outcome requires that (a) there is an association between cannabis use and the adverse health outcome; (b) chance is an unlikely explanation of the association; (c) the cannabis use preceded the health outcome; and (d) plausible alternative causal explanations of the association can be excluded. Reasonable evidence of an association between cannabis use and a health outcome is provided by the observation of a relationship between cannabis use and the outcome in a case-control, cross-sectional, cohort or experimental study. Evidence that chance is an unlikely explanation of any relationship observed between cannabis use and a health outcome may be provided when a statistical significance test or a confidence interval indicates that the observed association is unlikely to arise if there was no association in the population from which the sample was obtained. If cannabis use is the cause of an adverse health effect then there should be good evidence that cannabis use precedes the health effect. The strongest such evidence is provided by a cohort study or an experiment.
The alternative explanation most difficult to exclude is that any relationship between cannabis use and a health outcome is due to an unmeasured variable that causes both cannabis use and the adverse health effect. Experimental evidence provides the "gold standard" for ruling out such explanations of associations between drug use and health outcomes. The random assignment of persons to use cannabis or not, for example, would ensure that cannabis users and non-users were equivalent in all relevant respects prior to their cannabis use. When studying anything but acute and innocuous health effects, the assignment of individuals to long-term cannabis use is unacceptable for ethical reasons.
The acute health effects of a drug are easier to appraise than the chronic health effects: the temporal sequence of drug use and effect is clear; drug use and its effects typically occur close together in time; and provided the effects are not life-threatening or otherwise dangerous, they can be reliably reproduced in a substantial sample group by administering the drug under controlled conditions.
Causal inferences about the long-term effects of chronic cannabis use become more difficult the longer the interval between use and the occurrence of the alleged ill effects because lengthening this interval increases the number of alternative explanations of the association that need to be excluded. The most rigorous evidence of chronic health effects is provided by laboratory investigations using experimental animals in which well controlled drug doses are administered over a substantial period of their lives and correlated with precisely measured biological outcomes. However, the leap in reasoning from the health effects demonstrated in laboratory animals given large oral doses over short periods of time to the probable health effects of cannabis smoking over long periods of time involves a great many theoretical inferences.
Epidemiological evidence of a correlation between cannabis use and human disease is more relevant to human health, but reduced rigour in assessing exposure to cannabis and in excluding alternative explanations produces uncertainty about the interpretation of both associations between cannabis use and adverse health outcomes and failures to observe such associations. Heavy cannabis use, for example, is correlated with use of alcohol and tobacco, which are known to have an adverse effect on health in ways that may be difficult to distinguish from the effects of cannabis. A different problem arises when epidemiological studies fail to find associations between specific health outcomes and chronic cannabis use. Does this mean that cannabis use has no such effects or have we simply failed to detect them? The answer depends on the likely magnitude of the effects, their relationship to dose, frequency and duration of use, and the ability of studies with small sample sizes to detect them.
Cannabis is a generic name for a variety of preparations derived from the female plant of Cannabis sativa L., which contains more than 60 cannabinoid-type substances. Laboratory research on animals and human beings has demonstrated that the primary psychoactive constituent in cannabis is the cannabinoid (-)-trans-i9-tetrahydrocannabinol (THC) .
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 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 to 5 per cent, while the Sinsemilla variety with "heads" may have THC concentrations of 7 to 14 per cent. Hashish consists of dried cannabis resin and compressed flowers. The concentration of THC in hashish generally ranges from 2 to 8 per cent. Hash oil is a highly potent and viscous material obtained by extracting THC from hashish (or marijuana) by means of an organic solvent. The concentration of the THC in hash oil is generally between 15 and 50 per cent. There is also considerable commercial interest worldwide in the "fibre-type" cannabis, which is distinguished from the above "drug-type" cannabis by its low THC content (typically less than 0.5 per cent) coupled with high cannabidiol content.
The most common route of administration is smoking marijuana 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 or in 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 and less of the drug is lost through side-stream smoke. A few drops of hash oil may be applied to a cigarette, joint or the mixture in the pipe, or it may be heated and the vapours inhaled. Whatever the method used, smokers typically inhale deeply and hold their breath in order to maximize absorption of THC by the lungs.
Marijuana and hashish may also be eaten, in which case the onset of the psychoactive effects is delayed by approximately one hour. The "high" is of lesser intensity, but the duration of intoxication is prolonged by several hours. It is easier to titrate the dose and to achieve the desired level of intoxication by smoking than by 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 that little or no drug is actually present in these extracts.
A typical joint contains between 0.5 and 1.0 g of cannabis plant matter, which may vary in THC content between 5 and 150 mg (i.e. between 1 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 side-stream smoke. The bioavailability of THC (the fraction of THC in the cigarette that reaches the bloodstream) from marijuana cigarettes in human subjects has been reported to range from 5 to 24 per cent . Given all of these variables, the actual dose of THC absorbed when smoked is not easily quantified.
Only a small amount of cannabis (e.g. 2-3 mg 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. Generally, heavy smokers may consume five or more joints per day, while in Jamaica, for example, heavy users may consume up to 420 mg of THC per day. Clinical trials to assess the therapeutic potential of THC have employed single doses of up to 20 mg in capsule form. In human experimental research, THC doses of 10, 20 and 25 mg have been administered as low, medium and high doses .
There are several pharmacokinetic aspects of THC that have an impact on the effects of cannabis, but these are frequently misunderstood. THC is metabolized to the active metabolite 11-OH-THC, but this is unlikely to contribute to THC's pharmacological effects because it is converted to the corresponding active metabolite, which is inactive. It is this latter metabolite that serves as the primary urinary marker for detecting cannabis use. It has been shown that THC can be deposited in fatty tissues for long periods of time after use [16, 17]. However, there is no evidence that THC exerts a deleterious effect when deposited in tissue or during its slow egress from these sites. Although the primary psychoactive effects of cannabis are attributed to THC, there is no linear relationship between blood levels and pharmacological effects with respect to time, a situation that hampers the prediction of cannabis-induced impairment based on THC blood levels. Immediately following marijuana smoking, high concentrations of i9-THC are present in the blood and distributed to the tissues. The physiological and psychic effects of marijuana increase during this distribution phase, but may peak at times when blood concentrations of i9-THC are falling. Once equilibrium is established between brain and blood concentrations (approx. 45 minutes after use), a linear relationship between blood concentrations and pharmacological effects appears. Recently developed mathematical models are useful in interpreting the relationship of i9-THC and metabolite concentrations in blood to drug-induced effects and in estimating time elapsed since marijuana use .
The acute effects of cannabis use are an altered state of consciousness characterized by mild euphoria and relaxation, perceptual alterations, including time distortion, and the intensification of ordinary sensory experiences, such as those associated with eating, watching films and listening to music . When used in a social setting its effects may include infectious laughter and loquacity. There are also pronounced cognitive effects, such as impaired short-term memory and a loosening of associations, enabling the user to become lost in pleasant reverie and fantasy. Motor skills and reaction time are also impaired so that skilled activity of various kinds is frequently disrupted .
The most common unpleasant psychological effects are anxiety, panic reactions, a fear of losing one's mind and unpleasant depressive feelings [19, 20]. Less commonly, psychotic symptoms such as delusions and hallucinations may be 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 such effects after receiving a much larger dose of THC than intended. These effects can usually be prevented by adequate preparation of users about the type of effects they may experience; they can be readily managed by offering reassurance and support .
The inhalation of marijuana smoke or the ingestion of THC has a number of pharmacological effects. The most characteristic is an increase in heart rate of 20 to 50 per cent over baseline [21, 22]. This tachycardia occurs within a few minutes to a quarter of an hour and can last up to three hours. Changes in blood pressure also occur that depend upon posture: blood pressure increases while the person is sitting and decreases while he or she is 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 be only mildly stressed .
There are no confirmed cases of human deaths from cannabis poisoning in the world medical literature and animal studies indicate that the dose of THC required to produce 50 per cent mortality in rodents is extremely high compared 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 easily achieved by smoking or ingesting the drug . This feature distinguishes cannabis from other drugs of abuse in that almost all can produce lethality at high doses. Unfortunately, this fact is often used to portray cannabis as a safe drug, an implication that cannabis can be used without adverse effects. In actual fact, most problems stemming from cannabis abuse can be attributed to disruption of a normal productive life rather than death.
Psychomotor effects and driving
The main potential adverse acute effects of cannabis use arise from its effects on psychomotor performance. Intoxication produces dose-related impairments in a wide range of cognitive and behavioural functions that are relevant to a skilled performance such as driving an automobile or operating machinery . These include slowed reaction time and information processing, impaired perceptual-motor coordination and motor performance, impaired short-term memory, attention, signal detection and tracking behaviour, and slowed time perception .
The negative effects of cannabis on the performance of psychomotor tasks are almost always related to dose . The effects are generally greater, more consistent and more persistent in the case of difficult tasks requiring sustained attention. The acute effects of cannabis doses that are subjectively equivalent to or higher than the usual recreational doses on driving performance in laboratory simulators and over standardized driving courses resemble those of doses of alcohol that produce blood alcohol concentrations between 0.07 and 0.10 per cent [27-29].
While cannabis impairs performance in laboratory and simulated driving settings , there is no clear evidence that these impairments increase the risk of involvement in traffic accidents. Studies of the effects of cannabis on actual on-road driving performance have found slight impairments [31, 32]. It has been proposed that cannabis-intoxicated persons drive more slowly, perhaps because they are more aware of their level of psychomotor impairment than alcohol-intoxicated drinkers, who generally drive at faster speeds [29, 32].
This failure to prove a direct role for cannabis in traffic accidents does not exonerate it. Although no controlled epidemiological studies have established that cannabis users are at increased risk of traffic accidents, the role of cannabis in such accidents is likely to remain uncertain because the issue is difficult to research. Marijuana use has been detected in surveys of truck drivers , drivers in Tasmania, Australia , motor vehicle collision victims , homicide victims and vehicular fatalities [36, 37] and trauma patients . The frequency of detection of cannabinoids ranged from 6 to 34 per cent. Blood levels of cannabinoids do not indicate whether a driver or pedestrian was intoxicated with cannabis at the time of an accident, and many drivers with cannabinoids in their blood were found to be also intoxicated with alcohol at the time of the accident . Factors other than psychomotor performance also contribute to the danger of drug use when driving. Foremost among these is the user's readiness to take risks when intoxicated, which the available evidence suggests is reduced by cannabis intoxication by contrast with alcohol intoxication, which consistently increases risk-taking [29, 30, 32]. The fact that cannabis is rarely found on its own in fatalities is consistent with the epidemiological evidence that cannabis is most often used in combination with alcohol [38-40]. The separate effects of alcohol and cannabis on psychomotor impairment and driving performance are approximately additive [29, 30], a fact that should be emphasized in health education about cannabis use and driving.
Summary of acute effects
The major adverse acute effects 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; and an increased risk of experiencing psychotic symptoms among those who are vulnerable on account of a personal or family history of psychosis.
Cellular effects and the immune system
THC can produce alterations in cell metabolism and DNA synthesis in vitro  and cannabis smoke is mutagenic in vitro and in vivo, and is therefore potentially carcinogenic . These facts suggest that a likely health risk of smoking cannabis is the development of cancer after long-term exposure to cannabis smoke at the sites that receive maximum exposure, namely, the lung and upper aerodigestive tract.
There is also evidence that cannabinoids impair the cell-mediated and humoral immune systems in rodents , decreasing resistance to infection by bacteria and viruses. Further evidence indicates 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 relevance of these findings to human health is uncertain: high doses of THC have often been used in animal studies and the problem of extrapolating from the effects of such doses to those used by humans is complicated by the possibility that tolerance may develop to these effects .
The limited experimental and clinical evidence on immune effects in humans is mixed, the adverse effects suggested by a small number of early studies remaining unreplicated by later research [43, 44]. At present, there is no conclusive evidence that consumption of cannabinoids predisposes humans to immune dysfunction, as measured by reduced numbers or impaired functioning of T-lymphocytes, B-lymphocytes or macrophages, or reduced immunoglobulin levels. There is no epidemiological evidence of increased rates of infectious disease among chronic heavy cannabis users analogous to that seen among healthy young homosexual men in the early 1980s when AIDS was first recognized. Two prospective studies of human immunodeficiency virus (HIV)-positive homosexual men have found that cannabis use was not associated with an increased risk of progression to AIDS [45, 46]. Given the long history 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.
More difficult to exclude is the possibility that chronic heavy cannabis use produces minor impairments in immunity. Such effects would produce small increases in the incidence of common bacterial and viral illnesses among chronic cannabis users. A recent epidemiological study by Polen et al. , which compared health service utilization by "non-smokers" and "daily cannabis-only smokers", suggested a small increase among cannabis smokers in the rate of presentation of respiratory conditions. This finding remains suggestive, however, because infectious and non-infectious respiratory conditions were aggregated. The finding that cannabinoids produce minor impairments in immunity would cast doubt on the therapeutic value of cannabinoids in immunologically compromised patients, such as those undergoing cancer chemotherapy or those with AIDS.
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 [21, 48-50]. A series of controlled studies have been conducted by Tashkin and his colleagues , who found significant differences in the prevalence of symptoms of bronchitis (such as coughing, sputum production, wheezing and shortness of breath) between marijuana-only smokers, marijuana and tobacco smokers, tobacco-only smokers and controls. There were no differences between marijuana smokers and tobacco smokers in the prevalence of these symptoms. Lung function tests showed significantly poorer functioning and significantly greater abnormalities in small airways among tobacco smokers (regardless of concomitant marijuana use) while marijuana smokers showed poorer functioning of large airways than non-marijuana smokers (regardless of concomitant tobacco use). Follow-up studies of this cohort have broadly supported the results of the cross-sectional baseline study . In addition, there was evidence of an additive adverse effect of marijuana and cigarette smoking in that the marijuana and tobacco smokers group showed effects of both types of damage attributable to marijuana and tobacco smoking alone. All subjects who smoked (whether marijuana, tobacco or both) showed more severe histopathological abnormalities than non-smokers . Many of these abnormalities were more prevalent in marijuana smokers and were most marked in those who smoked both marijuana and tobacco.
Bloom et al.  studied the relationship between smoking "non-tobacco" cigarettes and respiratory symptoms and function in 990 individuals aged under 40 years. Subjects were asked about symptoms of coughing, phlegm production, wheezing and shortness of breath and had their respiratory function measured. Non-tobacco smoking was related to self-reported coughing, phlegm production and wheezing, regardless of whether the person smoked tobacco or not. There were also differences in forced respiratory function, those who had never smoked having the best functioning, followed in order of decreasing function by current cigarette smokers, current non-tobacco smokers and current smokers of both tobacco and non-tobacco cigarettes. Non-tobacco smoking alone had a larger effect on all respiratory function indices than tobacco smoking alone and the effect of both types of smoking was additive.
Most recently, Tashkin and colleagues  have reported data on rates of decline in respiratory function over eight years among marijuana and tobacco smokers in this cohort (65 per cent of whom were reassessed). They found that tobacco smokers showed the greatest rate of decline in respiratory function, but that the rate of decline in marijuana-only smokers did not differ from that in non-smokers. This contrasted with findings from a follow-up study , which found a greater rate of decline in respiratory function among marijuana-only smokers than tobacco smokers, and additive effects of tobacco and marijuana smoking. Although there were some inconsistencies, the evidence is consistent in showing that chronic cannabis smoking increases the prevalence of bronchitic symptoms. The impact on decline in respiratory function remains unclear.
Given the documented adverse effects of tobacco smoke and the qualitative similarity between tobacco and cannabis smoke , it is likely that chronic cannabis use predisposes individuals to developing respiratory cancer [56, 57]. There is as yet no controlled evidence showing a higher rate of respiratory cancers among cannabis smokers , but there is evidence that chronic cannabis smoking can produce histopathological changes in lung tissue of the type that precede the development of lung cancer in tobacco smokers .
More recently, concern about the possibility of cancers being caused by chronic cannabis smoking has been heightened by cases of cancers of the aerodigestive tract in young adults with a history of heavy cannabis use [58-61]. Although these reports fall short of providing convincing evidence because many of the cases involved concurrent use of alcohol and tobacco, they are clearly a cause for concern since such cancers are 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 research priority.
Reproductive and developmental effects
Chronic administration of high doses of THC disrupts male and female reproductive function in animals, reducing the secretion of testosterone and sperm production, motility and viability in males, and disrupting the ovulatory cycle in females . It is uncertain, however, whether marijuana smoking has these effects in human being, 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 healthy young adults.
Cannabis use during pregnancy probably impairs foetal development in animals, leading to a reduction in birthweight , possibly as a consequence of shorter gestation and probably by the same mechanism as cigarette smoking, namely, foetal hypoxia. The findings of epidemiological studies of the effects of cannabis use on human development have been more mixed for a number of reasons, firstly, because adverse reproductive outcomes and heavy cannabis use during pregnancy are both relatively rare, large sample sizes are required in order to detect adverse effects of cannabis use on foetal development and many of the studies undertaken have been too small.
Secondly, the stigma associated with illicit drug use, especially during pregnancy, may discourage honest reporting, compounding the usual problem of the stage at which women are asked about their drug use being disregarded, that is, whether it is during early pregnancy, late in their pregnancy or even after the birth . If a substantial proportion of cannabis users are misclassified as non-users, any relationship between cannabis use and adverse outcomes will be attenuated, requiring even larger samples for its detection .
Thirdly, even with large samples, difficulties arise in interpreting any associations found between adverse pregnancy outcomes and cannabis use because cannabis users are more likely to use tobacco, alcohol and other illicit drugs during their pregnancy. They also differ from non-users in other ways (e.g. social class, education, nutrition) that contribute to an increased risk of adverse outcome of pregnancy [66, 67].
Despite these difficulties, there is reasonable consistency in the findings that cannabis use in pregnancy is associated with reduced birthweight [65, 68, 69] and length at birth . This relationship has been found in the best controlled studies and has persisted after statistically controlling for potential confounding variables [65, 69]. The effect is small, however, and cannot be unequivocally attributed to cannabis as against tobacco smoking or alcohol use during pregnancy.
The findings on the relationship between cannabis use and birth abnormalities are more mixed. Four studies have reported no increased rate of major congenital abnormalities among children born to women who use cannabis [65, 67, 68, 70]. One study has reported a fivefold increased risk of children with features resembling those found in foetal alcohol syndrome being born to women who reported using cannabis , but the study also found no relationship between self-reported alcohol use and features of foetal alcohol syndrome. This is doubly surprising because of other evidence on the adverse effects of alcohol and because the epidemiological data indicates that cannabis and alcohol use are associated . Another study reported an increase in the rate of birth abnormalities among children born to women who reported using cannabis, but the association was no longer statistically significant after adjustment for confounders . The study by Zuckerman et al.  provides the most convincing failure to find an increased risk of birth defects among women who used cannabis during pregnancy. It included a large sample of women with a substantial prevalence of cannabis use verified by urinalysis. There was a low rate of birth abnormalities among the cannabis users and no suggestion of an increase by comparison with the controls. But given the uncertainty, it would be unwise to exonerate cannabis as a cause of birth defects until larger, better controlled studies have been conducted.
There is uncertainty about whether cannabis smoking during pregnancy produces a small increase in the risk of birth defects. There is some animal evidence of such effects although these studies have usually involved very high doses by the oral route . The limited studies in humans have generally but not consistently produced null results [65, 68-70].
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 [73, 74]. There are three studies that suggest an increased risk of certain types of childhood cancer (leukaemia, rhabdosarcoma and astrocytomas) in children born to women who reported using cannabis during their pregnancies . None of the studies was a planned investigation of the association between these cancers and cannabis use, which in each case was one of a large number of the possible confounding variables measured. Their urgent replication is a priority.
Behavioural effects in adolescence
A major concern about the psychological effects of chronic heavy cannabis use has been that it impairs adult motivation and adolescent development. The evidence for an "amotivational syndrome" among adults is at best equivocal, consisting largely of case histories and observational reports (e.g. [76, 77]). The small number of controlled field and laboratory studies have not found compelling evidence for such a syndrome [7, 78, 79]. The value of the negative field studies is limited by their small sample sizes and the limited socio-demographic characteristics of their samples, while the evidential value of the laboratory studies is limited by the short periods of drug use, the youth and good health of the volunteers and the minimal demands made on the motivation of volunteers in the laboratory .
There has been limited supportive evidence for the occurrence of an amotivational syndrome among adolescents. Cannabis use appears to increase the risk of discontinuing a high-school education and of experiencing job instability in young adulthood . The apparent strength of these relationships in cross-sectional studies  has been exaggerated because those adolescents who are most likely to use cannabis have lower academic aspirations and poorer high-school performance prior to using cannabis than their peers who do not .
There is suggestive evidence that heavy cannabis use has adverse effects upon family formation, mental health and involvement in drug-related crime . In each case, however, 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 pre-existing characteristics that independently predict these adverse outcomes.
Induction of other drug use
A consistent finding in research on patterns of drug use in adolescence and adulthood  has been the regular sequence of initiation into the use of illicit drugs among adolescents in the United States in the 1970s. In this sequence cannabis use has typically preceded involvement with "harder" drugs such as stimulants and opioids [82-85]. The causal significance of this sequence of drug initiation remains controversial. There is better support for two other hypotheses that are not mutually exclusive: (a) that there is a selective recruitment into cannabis use of non-conforming adolescents who have a propensity to use other illicit drugs; and (b) that, once recruited to cannabis use, the social interaction with other drug-using peers increases the opportunity to use other illicit drugs [6, 86, 87]. While it represents a scientific challenge, efforts should be made to determine whether there is a biological basis for the conclusion that cannabis use or cannabinoid administration enhances the likelihood of subsequent use of other drugs.
There is good experimental evidence that animals develop tolerance to the effects of THC on repeated exposure . There is also evidence that chronic heavy cannabis users develop tolerance to its subjective and cardiovascular effects and that some users experience withdrawal symptoms on the abrupt cessation of cannabis use [88-90]. There is clinical and epidemiological evidence that a cannabis dependence syndrome occurs in chronic heavy users of cannabis. Some of these users report problems in controlling their cannabis use and continue to use the drug despite experiencing adverse personal consequences [22, 91, 92]. There is a cannabis dependence syndrome that is analogous to the alcohol dependence syndrome [93-95]. The Epidemiologic Catchment Area (ECA) study found that cannabis dependence was the most common form of illicit dependence in the community .
The risk of becoming dependent on cannabis is probably more comparable to that for alcohol than that for nicotine or the opioids, with around 10 per cent of those who ever use cannabis meeting criteria for dependence . Persons who use cannabis on a daily basis over periods of weeks to months are at greatest risk of becoming dependent on it. The ECA data suggested that approximately half of those who used any illicit drug on a daily basis satisfied criteria for abuse or dependence as defined in the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) of the American Psychiatric Association . Kandel and Davis  estimated the risk of dependence among near-daily cannabis users (according to approximated DSM-III criteria) at one in three. Given the widespread use of cannabis and its continued reputation as a drug with a low risk of dependence, the clinical features of cannabis dependence need to be better defined. This would enable the prevalence of a dependence syndrome to be estimated more accurately and individuals who are dependent on cannabis to be recognized and treated.
Efforts to conduct abrupt withdrawal studies in animals with i9-THC have produced conflicting results. McMillan et al.  failed to detect withdrawal symptoms upon termination of chronic administration. A few reports have noted that abrupt cessation of i9-THC produces certain behavioural changes that include increased grooming and motor activity , aggression  and susceptibility to electroshock-induced convulsions . A second approach to assessing dependence is to precipitate an abstinence syndrome in chronically treated animals by administering an antagonist. The recent development of a specific cannabinoid antagonist  led to the demonstration that a withdrawal syndrome could be elicited in animals treated chronically with THC. In two studies rats were chronically injected or infused with i9-THC and then challenged with the antagonist SR 141716A. The behavioural signs included head shakes, facial tremors, tongue rolling, biting, wet-dog shakes, eyelid ptosis, facial rubbing, paw treading, retropulsion, immobility, ear twitch, chewing, licking, stretching and arched back [103, 104]. In a follow-up study, a precipitated withdrawal syndrome was characterized in mice . These studies provide convincing evidence that i9-THC can produce dependence. The challenge is to understand the relationship between these animal models and the abuse pattern of cannabis in humans. A high priority for future research is to identify the neuronal systems that subserve the cannabis withdrawal syndrome. Manipulation of those systems may provide a means for treating individuals who seek assistance in terminating their marijuana use.
The available evidence suggests that even long-term heavy use of cannabis produces no severe or grossly debilitating impairment of cognitive function [106-109]. There is no evidence, for example, that it produces anything comparable to the cognitive impairments found in chronic heavy alcohol drinkers; if it did, research to date should have detected it .
There is some 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 organization and the integration of complex information [110-113]. The evidence suggests that the longer the period of cannabis use, the more pronounced the cognitive impairment [112, 113]. It remains to be determined how significant these impairments are for everyday functioning and whether they are reversed after an extended period of abstinence from cannabis.
A suspicion that chronic heavy cannabis use may cause gross structural brain damage was raised 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 publicized in the popular media. Since then a number of better controlled studies using more sophisticated methods of investigation have consistently failed to provide evidence of structural change in the brains of heavy long-term cannabis users [8, 115, 116]. These negative results are consistent with the evidence that any cognitive effects of chronic cannabis use are subtle and hence unlikely to be manifested as gross structural changes in the brain.
There is suggestive evidence that large doses of THC can produce an acute psychosis in which confusion, amnesia, delusions, hallucinations, anxiety, agitation and hypomanic symptoms predominate. The main evidence comes from clinical observations of psychotic symptoms in heavy cannabis users that occur after unusually heavy cannabis use, appear to comprise a syndrome and remit rapidly after abstinence from cannabis [8, 117-119].
Epidemiological research has produced reasonably consistent evidence from case-control, cross-sectional and prospective studies that there is an association between cannabis use and schizophrenia. The prospective study of Andreasson et al.  showed a dose-response relationship between the frequency with which cannabis had been used by age 18 and the risks over the subsequent 15 years of being diagnosed as schizophrenic. This relationship has been interpreted by some as evidence that chronic cannabis use may precipitate schizophrenia in vulnerable individuals [120, 121]. Others are more sceptical. They note that in the only prospective 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 and other drug use, and there were doubts about whether the study could reliably distinguish between schizophrenia and acute psychoses induced by cannabis or other drugs [122, 123].
Even if this relationship is a causal one, its public health significance should not be overstated. The findings of Andreasson et al. indicate that fewer than 10 per cent of cases of schizophrenia are attributable to cannabis use . On the grounds of biological plausibility it is probable that cannabis use exacerbates the symptoms of schizophrenia and precipitates schizophrenic disorders . However, the declining incidence of treated cases makes it unlikely that cannabis use has caused schizophrenia that would not otherwise have occurred .
Summary of chronic effects
The main physiological and psychological effects of chronic heavy cannabis use, especially daily use over many years, remain uncertain. The main potential adverse effects are respiratory disease, cannabis dependence and subtle cognitive impairment. Respiratory diseases are those associated with smoking as the method of administration, such as chronic bronchitis. There is also some evidence that cannabis smokers show histopathological changes that may be precursors to the development of malignancy. The cannabis dependence syndrome is characterized by an inability to abstain from or to control cannabis use. The subtle forms of cognitive impairment affect attention and memory, persist while the user remains chronically intoxicated and may or may not be reversible after prolonged abstinence from cannabis.
In addition, there are a number of major possible adverse effects of chronic heavy cannabis use that remain to be confirmed by further research: an increased risk of developing cancers of the aerodigestive tract, that is, in the oral cavity, pharynx or oesophagus; an increased risk of leukaemia among offspring exposed while in utero; a decline in occupational performance marked by underachievement in adults in occupations requiring high-level cognitive skills; impaired educational attainment in adolescents; and birth defects occurring among the children of women who used cannabis during their pregnancies.
There are a number of groups who may be at higher risk of experiencing adverse effects of cannabis. These are adolescents, women of childbearing age and persons with pre-existing diseases. Adolescents who were at higher risk include those with a history of poor school performance, whose educational achievement may be further limited by the cognitive impairments produced by chronic intoxication with cannabis, and those who commence cannabis use in their early teens, who 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 who are at higher risk include pregnant women who continue to smoke cannabis, who are probably at increased risk of giving birth to low-birthweight babies and possibly of shortening their period of gestation, and women who smoke cannabis at the time of conception or while pregnant, because this may increase the risk of their children being born with birth defects. Persons with certain pre-existing diseases who smoke cannabis are probably at increased risk of precipitating or exacerbating the symptoms of their diseases. These include individuals with respiratory diseases, such as asthma, bronchitis and emphysema, individuals with schizophrenia, who may be at increased risk of precipitating or exacerbating schizophrenic symptoms, and individuals dependent on alcohol or other drugs, who are probably at increased risk of developing dependence on cannabis.
A rich and colourful history spans several thousand years of documented interest in the medical use of cannabis. References to the use of cannabis, as found in ancient Egyptian, Chinese (2700 B.C.) and Assyrian (800 B.C.) sources, indicate that it is one of the oldest drugs in history. The introduction of cannabis into Western medicine has been attributed to a British army physician serving in India who noted the anticonvulsive, analgesic, anti-anxiety and antitussive properties of the drug . Thus began the modern phase of therapeutic cannabis use. At about the same time, others reported on the use of cannabis for the treatment of psychiatric illnesses and on favourable results in inducing sleep and enhancing appetite without causing physical addiction. It was also tried as a treatment for opium addiction, chronic alcoholism, delirium tremens and a wide variety of painful disorders. Cannabis is but one of thousands of plants and animals that have attracted the attention of those attempting to relieve human pain and suffering through the decades. As with many herbal remedies, the putative therapeutic uses are so diverse that cannabis has defied simple drug classification. An example of this diversity can be found in the United States Pharmacopoeia in the late 1890s which claimed cannabis extracts to be useful as a remedy for neuralgia, gout, rheumatism, tetanus, hydrophobia, epidemic cholera, convulsions, chorea, hysteria, mental depression, delirium tremens, insanity and uterine haemorrhage. It is not surprising that a substance with such a wide pharmacological profile, and in particular psychoactive properties, should generate some degree of interest at a time when the development of therapeutic agents was in its infancy. Interest in cannabis as a medicinal agent waned in the United States with the passage in the 1930s of the Marijuana Tax Act, which made marijuana illegal. This action came after the introduction of aspirin, barbiturates and other synthetic analgesics and sedatives which further contributed to the demise of the medical use of extracted cannabis. However, the increasing prominence of the recreational use of cannabis in the 1960s led shortly thereafter to debate concerning the medical issues. Why does cannabis still attract so much interest? Why is there so much controversy surrounding the medical uses of cannabis rather than definitive conclusions? There are several possible explanations.
Clearly one of the difficulties in discussing almost any aspect of cannabis is that the debate has become so highly politicized by those who are strongly opposed to cannabis and also by those who passionately advocate its recreational, medicinal and commercial use. This is why the decision regarding the medical status of this plant material will not rest solely on basic pharmacological principles, even though it should. Nevertheless, the more rigorous the decision makers are in relying on scientific knowledge of the properties of cannabis as well as those of synthetic cannabinoids, the more likely a rational and just policy will emerge.
Cannabis versus tetrahydrocannabinol and its synthetic derivatives
As discussed above, there have been suggestions that cannabis may have beneficial effects in several disorders, including pain management and alleviation of intraocular pressure, nausea and vomiting, bronchodilation and the AIDS wasting syndrome. Despite the absence of carefully controlled studies demonstrating the efficacy of cannabis in those medical situations, medical uses of cannabis nonetheless attract some degree of interest, albeit confined almost entirely to reports by individuals who have self-medicated with cannabis . On the other hand, there have been numerous clinical trials involving THC and its synthetic derivatives, and it is often those data which are cited to justify the use of cannabis. However, it is inappropriate to justify the use of cannabis on the basis of controlled clinical trials conducted with THC because of the vast differences between the effects of smoking cannabis and ingesting pure synthetic compounds.
The answers supplied by the historical background do not, however, fully explain why no definitive evidence has emerged regarding the medical status of cannabis. Clearly, there has been scant enthusiasm among the medical profession for endorsing cannabis use for almost any disorder. The very idea of administering medicine in the form of smoked plant material to an ailing individual is the antithesis of modern therapeutics. There are even questions regarding which constituents in cannabis are responsible for its putative medicinal effects. Given the variability in i9-THC concentrations both in the plant and when absorbed by smoking, accurate dosing is problematic. A large population of patients either cannot or will not smoke because of the irritating effects of doing so. Cannabis smoke has the potential, moreover, for producing health hazards after chronic use, as discussed earlier. The justification for use of smoked cannabis for medicinal purposes should meet the same standards as are applied to all other therapeutic agents. Essentially, there should be reliable scientific evidence that the drug is efficacious, it should have an acceptable safety margin and it should be administered in a reliable fashion. Failure to meet these basic requirements obviously diminishes the therapeutic value of cannabis. Are there circumstances, however, that justify the use of cannabis? Certainly, an indication that cannabis is effective in patients who are refractory to all other medications would be a clear justification. The severity of the disorder and the status of the patient are also crucial factors.
Cannabis has been used most frequently for treating chemotherapy-induced nausea and vomiting. However, most of the clinical reports have been based on synthetic cannabinoids. The findings concerning THC can be best summarized by stating that THC has antiemetic effects superior to those of placebos in chemotherapy patients who are experiencing moderate emesis . Those findings are consistent with the observation that THC is approximately equivalent in potency to prochlorpromazine in most studies . On the other hand, Gralla et al.  found metoclopramide to be more efficacious than THC in controlling emesis in patients receiving cisplatin. Some of THC's synthetic analogues such as nabilone, levonantradol and nabitan have also been tested in mostly open clinical trials for antiemetic potency on cancer patients receiving chemotherapy and found to be effective in alleviating the inevitable side effects of nausea and vomiting . Side effects of THC and synthetic analogues can still be a problem, but evidence for THC's efficacy for this treatment led to its approval in the United States under the generic name dronabinol and the trade name Marinol. Dronabinol has been useful, although some patients dislike its psychotropic and soporific effects. Clinical trials have also been held to compare oral dronabinol and smoked cannabis. Levitt et al.  conducted a random-order crossover study in which 35 per cent of the patients preferred oral dronabinol, 20 per cent preferred smoked cannabis and the remainder had no preference. In an open study of patients who were refractory to antiemetic agents available at the time, Vinciguerra and colleagues  evaluated the effectiveness of smoked cannabis. Twenty-five per cent of the patients dropped out because of dissatisfaction, 24 per cent rated cannabis very effective, 35 per cent moderately effective and 16 per cent ineffective. Almost all patients reported adverse effects, including sedation, dry mouth and dizziness.
The introduction of serotonergic antagonists has dramatically improved treatment for chemotherapy-induced emesis, in particular when those agents are used in combination with dexamethasone , thereby reducing the likelihood of refractory patients requiring therapies such as cannabis and cannabinoids. Nevertheless, interest in smoked cannabis remains.
Appetite stimulation and cachexia
One of the most prominent effects of smoked cannabis is stimulation of appetite. Surveys typically find a positive correlation between cannabis smoking and increased eating, which has led to efforts to use cannabis for disorders involving loss of appetite and body weight, such as that associated with AIDS. Although there is considerable anecdotal information regarding increased weight gain in AIDS patients who smoke cannabis, no systematic studies have been carried out to confirm those reports. While there is intense pressure by the AIDS community to make cannabis available to those suffering from cachexia, the wasting of the body symptomatic, inter alia, of HIV infection, THC was approved in the early 1990s for that purpose. Results from clinical trials have suggested that it improves appetite, producing slight increases in caloric intake and weight gain [133-135]. Extensive animal studies indicate, however, that cannabinoids adversely affect the immune system. Should a drug with possible immunosuppressive properties be given to patients who already have a compromised immune system? Whitfield et al.  reported that Marinol/marijuana use was associated with declining health status in patients undergoing antiretroviral therapies. However, they found that all clinical indicators of pancreatitis improved in the patients who used Marinol/marijuana. In HIV-positive and AIDS patients with the lowest CD4+ counts, use of marinol/marijuana did not seem to have a deleterious impact. Beal and colleagues  reported the safe long-term use of THC for anorexia associated with weight loss in patients with AIDS.
In order to resolve the question of whether smoked cannabis represents a legitimate treatment for cachexia, several criteria should be fulfilled. Firstly, cannabis efficacy must be demonstrated in controlled clinical studies; secondly, if cannabis is proved to be efficacious, efforts should be made to determine whether it offers advantages over THC; and, thirdly, if cannabis smoking is more efficacious than oral THC, then the potential adverse effects of cannabis should be assessed carefully in this immunocompromised patient population. If cannabis is recommended for AIDS patients, guidelines should be formulated that could range from unrestricted use in all patients to limited use in the latter stages of the disease.
The therapeutic potential of cannabis as an anticonvulsant has sparked interest ever since a study in the 1940s showed that five retarded children, on conventional anticonvulsant medication but poorly controlled, improved after cannabis use . However, extensive animal studies have shown that THC is capable of producing both convulsant and anticonvulsant effects. The discovery that cannabidiol, a natural component of cannabis with practically no cannabis-like psychoactivity, produced anticonvulsant activity in animals generated considerable attention . However, interest waned when it failed to demonstrate sufficient efficacy for clinical use.
Neurological and motor disorders
There are numerous anecdotal reports that smoked cannabis is effective in relieving spasticity arising from multiple sclerosis or spinal cord injury. However, there have been no controlled studies comparing the effectiveness of either cannabis or THC with other therapies.
There has been little definitive evidence that cannabis is effective in controlling either acute or chronic pain, but there have been several controlled studies conducted with THC. One group of investigators reported that THC failed to alleviate pain in cancer patients and did not decrease their need for pain medication , whereas others demonstrated that orally administered THC was comparable to codeine in analgesic potency, although it produced considerable side effects in the effective dose range [141, 142]. Raft et al.  found that premedication with i9-THC (intravenous) was less effective than either diazepam or placebo in oral surgery.
Almost all animal analgesic assays involving THC show it to be highly effective, with a potency comparable to that of morphine . Furthermore, numerous analogues have been synthesized that are as much as several hundredfold more potent than THC . The endogenous cannabinoid ligand anandamide, described below, also has analgesic properties . However, the inability to develop a cannabinoid free from behavioural effects represents the primary limitation of cannabinoid analgesics. Cannabinoids are quite effective when administered intrathecally to laboratory animals, this being a possible means of producing analgesia with minimal behavioural effects . Additionally, cannabinoids have been shown to potentiate the analgesic effects of morphine when both are administered systemically  and intrathecally .
Drug development has also focused on the potent antinociceptive properties of cannabinoids. The synthesis of an analgesic agent free from the side effects and abuse liability of opioids would represent a great step forward. Unfortunately, cannabinoids produce antinociception at doses that also elicit other behavioural effects, such as sedation, hypothermia and catalepsy. Cannabinoids have a different pharmacological profile from the opioids and may act through a different mechanism for alleviating pain. Recent research demonstrated that a kappa receptor antagonist, nor-binaltorphimine (nor-BNI), blocked cannabinoid-induced antinociception but did not affect the other behaviours .
The ability of cannabis, THC and its synthetic derivatives to lower intraocular pressure in patients suffering from glaucoma has received a fair amount of attention . Although there is some variability among studies, most reveal that smoking cannabis lowers intraocular pressure to a significant degree. However, evidence is lacking that cannabis is capable of lowering intraocular pressure sufficiently to prevent damage to the optic nerve. The necessity of smoking cannabis or the systemic administration of synthetic cannabinoids for beneficial effects has tempered enthusiasm for their use in managing glaucoma. One major drawback of cannabis is that it has to be smoked at relatively short intervals in order to depress intraocular pressure. There is one report of a topical preparation of cannabis, marketed as Canasol in Jamaica, that is effective for glaucoma . However, there is no evidence at present that cannabis or THC is more effective than other agents in controlling glaucoma or that it is effective in patients refractory to current therapies. On the other hand, development of a cannabinoid derivative that is effective topically could be beneficial in that it would most probably exert its effects through a mechanism distinct from that of current medications.
Summary of therapeutic potential
There is considerable anecdotal information regarding the therapeutic value of smoked cannabis. In recent times, the most intense interest has been directed towards prevention of weight loss in AIDS patients, although management of pain, prevention of emesis and control of glaucoma and motor disorders still command attention. The use of smoked cannabis remains controversial because of its very nature, a psychoactive material that is inhaled along with particulate matter. The issue will certainly remain under debate until controlled clinical studies have been conducted with cannabis, and possibly even thereafter. Of course, there is the additional question of whether a different preparation of cannabis may be more acceptable for therapeutic uses. Researchers now have available standardized cigarettes, thus eliminating some of the uncertainties of drug delivery. More importantly, the availability of synthetic i9-THC in capsule form provides an alternative to the smoked plant material. There have been numerous efforts to use THC and synthetic derivatives in the treatment of a variety of disease states. However, those advocating the use of cannabis for medicinal purposes argue that THC is delivered more effectively in smoke, that cannabis is less expensive than THC and that cannabis produces few, if any, harmful effects.
Major challenges confront the clinician who attempts to evaluate the medicinal potential of a psychoactive substance that may also exhibit relatively weak efficacy and must be smoked. It seems only reasonable that the scientific community should choose the medicinal uses of cannabis that are most worthy of pursuit. Clearly, a scientific rationale for treating the AIDS wasting syndrome and chronic pain with smoked cannabis should be established prior to a legislative mandate. Such endeavours should not, however, be at the expense of elucidating the actions of cannabinoids on biological systems and developing synthetic derivatives for medicinal uses. Without this knowledge, no rational decision regarding the medical status of cannabis is likely to emerge.
Cannabis and its psychoactive synthetic derivatives produce a complex array of pharmacological and behavioural effects after acute and chronic administration, as discussed above. The subjective nature of many of the effects of cannabis, the influence of environmental factors and expectation, and the variability of human responsiveness all contribute to the difficulty of assessing the direct consequences of acute and chronic cannabis exposure or of drawing conclusions regarding potential medical uses of cannabis. Establishing the basis for the action of a drug in a biological system has proved to be crucial in disentangling the direct actions of that drug from those arising from other sources. Insufficient understanding of the direct biological actions of cannabis, which most probably involve numerous neurochemical mechanisms, has contributed to the controversy surrounding the substance. The failure to identify a specific mechanism of cannabinoid action has been due in part to the highly lipophilic nature of cannabinoids, which makes them particularly difficult to study, as well as the lack of specific antagonists. There is now definitive evidence that cannabinoids act on unique receptors in the brain to produce most of its effects. Evidence for a cannabinoid receptor has accumulated continually since THC was identified as the psychoactive constituent in cannabis . Structure-activity relationship studies have clearly demonstrated that subtle changes in the structure of THC have a profound influence on its pharmacological potency , the sine qua non for a receptor interaction.
Two significant accomplishments arising from the synthesis of novel cannabinoids were the development of highly potent agonists and structurally diverse analogues with THC-like properties. The first direct evidence for a cannabinoid receptor was made possible by the synthesis and radio-labelling of the potent bicyclic cannabinoid CP 55,940. In vitro binding studies with the compound led to identification of a receptor in rat brain membranes , which exhibits high selectivity for cannabinoids, as evidenced by the failure of a vast array of other centrally acting compounds to interact with this site. This receptor appears to be responsible for most of THC's effects on the brain. Compton et al.  demonstrated a high correlation between binding affinities for a large number of cannabinoids and potency in a variety of pharmacological assays, including production of antinociception, catalepsy, hypothermia and depression of spontaneous locomotor activity in mice, drug discrimination in rats and psychotomimetic activity in humans.
Another critical feature of a receptor is that it should be located in sites that are known to subserve physiological and pharmacological effects associated with the drug in question. According to autoradiographic studies, the cannabinoid receptor is distributed heterogeneously throughout neuronal tissue . The densest binding occurs in the basal ganglia (substantia nigra pars reticulata, globus pallidus, entropeduncular nucleus and lateral caudate putamen) and in the molecular layer of the cerebellum. Binding in those regions accounts for cannabinoid alteration in motor function. i9-THC disrupts short-term memory in human beings, which is consistent with intermediate levels of receptors in the hippocampus and selected areas of the cortex. The hippocampus stores memory and codes sensory information. The presence of cannabinoid receptors in regions associated with mediating brain reward (ventromeidal striatum and nucleus accumbens) suggests an association with dopamine neurons. Sparse concentrations were detected in the brainstem, hypothalamus, corpus callosum and the deep cerebellum nuclei. Low levels of receptors in brainstem areas controlling cardiovascular and respiratory functions are also consistent with the lack of lethality of cannabis.
While the binding studies described above provide compelling evidence for a receptor, unequivocal evidence was provided when the cannabinoid receptor was cloned . It was found to be a member of a large family of receptors that are coupled to G-proteins, which serve as common second messengers for most neurotransmitter receptors. Fortunately, the human cannabinoid receptor was subsequently cloned and found to be almost identical to the rat receptor . Most receptor systems in the brain consist of multiple receptor subtypes that subserve different physiological effects of a particular ligand. All the neurotransmitters act as multiple receptor subtypes. Cannabinoids appear to be distinct in that only one receptor subtype has been definitively characterized in the brain. On the other hand, a different cannabinoid receptor, designated CB2, has been identified in several immune cell types . This finding was particularly significant given the well known fact that cannabinoids have been demonstrated to have immunoinhibitory effects in several animal models. While the role of this receptor in the spleen remains unknown, it provides an opportunity for establishing whether either cannabis or the synthetic cannabinoids produce deleterious effects in immunocompromised individuals. In addition, the discovery of a second receptor raises the possibility that other receptors with unique functional roles may also exist.
If a receptor has physiological relevance, then it must have a naturally occurring substance that normally activates it. As with all other centrally located receptors, there is an endogenous ligand for the cannabinoid receptor. Professor Mechoulam's laboratory in Israel isolated a substance from porcine brain that reacts with the cannabinoid receptor . This substance, named anandamide, produces similar pharmacological effects to i9-THC, such as antinociception, catalepsy, hypomotility and hypothermia , and inhibits adenylyl cyclase  and N-type calcium channels . A comparison between anandamide and i9-THC revealed that anandamide is less potent and has a shorter duration of action than i9-THC . The discovery of an endogenous cannabinoid that is a derivative of arachidonic acid, the precursor to several classes of compounds bearing little pharmacological and no structural resemblance to cannabinoids, was quite unexpected. Considerable attention is now directed towards identifying the physiological stimuli that regulate the synthesis, storage and metabolism of anandamide. Neuronal tissue has the ability to both synthesize and degrade anandamide. Deutsch and Chin  showed that anandamide can be rapidly taken up by neuroblastoma and glioma cells and degraded by a cytosolic amidase. Degradation also occurs in tissues from the brain, heart, kidney and lungs. The most plausible metabolic pathway appears to occur through phosphodiesterase-mediated cleavage of a novel phospholipid precursor, N-arachidonoyl-phosphatidylethanolamine .
The recent discovery of the cannabinoid antagonist SR 141716A by Rinaldi-Carmona et al.  provides a means for delineating receptor- and non-receptor-mediated events. The investigators demonstrated that this antagonist has a high affinity for the CB1 receptor and antagonizes cannabinoid-induced inhibition of adenylyl cyclase and smooth muscle contractions. It effectively antagonizes the behavioural effects of THC in mice . Others have shown that it also antagonizes cannabinoid drug discrimination in rats  and the memory-disrupting effects of THC . The relevance of the findings lies in their implication of the cannabinoid receptor in these pharmacological effects of THC.
Physiological role of endogenous system
There has been considerable speculation regarding the role that the cannabinoid system plays in normal physiological processes. Extrapolation from the pharmacological effects of cannabinoids themselves would suggest a role in pain perception, cognition and motor coordination, to name but a few. Of course, exogenous administration of a plant-derived compound could very well produce an abnormal perturbation of endogenous systems not representative of the physiological role of endogenous ligands. A clearer understanding of the cannabinoid system should emerge as knowledge of the regulation of synthesis, metabolism and release of endogenous cannabinoids evolves. Moreover, development of "knock-out" mice, those genetically engineered with cannabinoid receptors, may provide some enlightenment. The ubiquitous nature of the receptor, coupled with its high density, in the central nervous system argues in favour of a prominent physiological role for cannabinoids. Furthermore, an aberration in this physiological system may well be corrected by the administration of cannabinoids.
The ability of an organism to adapt to chronic exposure to a chemical is generally considered to be a form of self-protection. While the physiological relevance of cannabinoid tolerance remains to be established, it is known that it occurs in a wide range of species and can be of considerable magnitude. Furthermore, the cannabinoid receptor and its transduction mechanisms are dramatically altered in the tolerant state [168-170]. The plasticity of the system provides an avenue for further exploration of the mechanism whereby cannabinoids produce their effects and for elucidation of the action of cannabis use on the central nervous system.
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