he health and psychological consequences of cannabis use chapter 5
5. The acute effects of cannabis intoxication 5.1 Psychological and physical effects Any attempt to summarise the acute effects of cannabis, or of any psychoactive drug, is necessarily an oversimplification. The effects experienced by the user will depend upon: the dose, the mode of administration, the user's prior experience with the drug, any concurrent drug use, and the "set" - the user's expectations, mood state and attitudes towards drug effects - and "setting" - the social environment in which the drug is used (Jaffe, 1985). The following descriptions of the typical effects of cannabis are made with this qualification in mind. The major motive for the widespread recreational use of cannabis is the experience of a subjective "high", an altered state of consciousness which is characterised by: emotional changes, such as mild euphoria and relaxation; perceptual alterations, such as time distortion, and; intensification of ordinary sensory experiences, such as eating, watching films, listening to music, and engaging in sex (Jaffe, 1985; Tart, 1970). When used in a social setting, the "high" is often accompanied by infectious laughter, talkativeness, and increased sociability. Cognitive changes are usually marked during a "high". These include an impaired short-term memory, and a loosening of associations, which make it possible for the user to become lost in pleasant reverie and fantasy, while making it difficult for the user to sustain goal-directed mental activity. Motor skills, reaction time and motor coordination are also affected, so many forms of skilled psychomotor activity are impaired while the user is intoxicated (Jaffe, 1985). Not all the effects of cannabis intoxication are welcomed by users. Some users report unpleasant psychological reactions, ranging from a feeling of anxiety to frank panic reactions, and a fear of going mad to depressed mood (Smith, 1968; Weil, 1970; Thomas, 1993). These effects are most often reported by naive users who are unfamiliar with the effects of cannabis, and by some patients given THC for therapeutic purposes. More experienced users may also report these effects on occasion, especially after the oral ingestion of cannabis when the effects may be more pronounced and of longer duration than those usually experienced after smoking cannabis. These effects can usually be successfully prevented by adequate preparation of users about the type of effects they may experience. If these effects develop they can be managed by reassurance and support (Smith, 1968; Weil, 1970). Psychotic symptoms, such as delusions and hallucinations, are very rare experiences that occur at very high doses of THC, and perhaps in susceptible individuals at lower doses (Smith, 1968; Thomas, 1993; Weil, 1970). The inhalation of marijuana smoke, or the ingestion of THC, the psychoactive derivative of cannabis, has a number of bodily effects. Among these the most dependable are the effects on the heart and vascular system. The most immediate effect of cannabis use by all routes of administration is an increase in heart rate of 20-50 per cent over baseline which occurs within a few minutes to a quarter of an hour and lasts for up to three hours (Huber et al, 1988; Jones, 1984). Changes in blood pressure also occur which depend upon posture: blood pressure is increased while the person is sitting, and decreases while standing. A sudden change from a recumbent posture may produce postural hypotension and fainting, an effect which may explain the feeling of "light-headedness" and faintness that is often the earliest indication of intoxication in naive users (Maykut, 1984). Increases are also observed in the production of the catecholamine norepinephrine, although these lag behind the cardiovascular changes, and their mechanisms are not well understood (Hardman and Hosko, 1976). In healthy young users these cardiovascular effects are unlikely to be of any clinical significance. They may, however, magnify anxiety in naive users. The cannabis-induced tachycardia and postural hypotension may contribute to the panic attacks sometimes experienced by naive users (Weil, 1970) who may mistakenly interpret the palpitations, and the feeling of faintness, as symptoms of serious misadventure, magnifying pre-existing anxiety in a positive feedback cycle that leads to a panic attack. 5.2 Toxic dose levels THC appears to be the component of cannabis which has the highest direct toxicity in all animals so far tested. The toxic effects of cannabis are mediated through its effects on neural systems. The cause of death in experimental animals is almost invariably apnoea or cardiac arrest, if apnoea is prevented (Rosencrantz, 1983). Due to the development of tolerance, toxic doses depend upon the amount by which they exceed the customary dose. In contrast to the increase in toxic dose typical of many drugs when moving from primates to lower animals, it appears that phylogenetically higher animals are less susceptible to the acute toxicity of THC. Thus, the dose of THC which kills 50 per cent of animals (LD50) when administered intravenously is 40mg/kg in the rat but 130mg/kg in the dog and monkey (Rosencrantz, 1983). For obvious ethical reasons there is no experimental evidence to determine a lethal dose in humans. Nor is there any clinical evidence, since there have been no reported cases of death attributable to cannabis in the world medical literature (Blum, 1984; Nahas, 1984). Extrapolation from the animal evidence suggests that the lethal human dose of THC is at least as high as, and probably higher than, that observed in the monkey. If this is so, then the toxic dose of THC in a 65kg adult would be 8.45kg. A number of non-fatal toxic reactions occur in humans with higher than normal doses. The tachycardia almost invariably produced in acute intoxication, combined with the sensory alterations and increased tremor commonly reported, probably contribute to the affective components of these reactions. CNS and respiratory depression are noted with high doses, which in severe overdose may be life-threatening (Rosencrantz, 1983). These effects are, of course, more dangerous to those with pre-existing cardiac irregularities. Because of the large effective to lethal dose ratio in humans (probably in excess of 1:1000 in non-tolerant users) the risk of experiencing severe toxic effects of cannabis is limited by the aversive psychotropic effects of high doses, which usually lead to cessation of use before the onset of dangerous physical consequences. 5.3 Tolerance to acute effects In animals, tolerance develops to the lethal, hypothermic and some of the behavioural effects of cannabinoids. This has been attributed to functional or pharmacodynamic adaptations of the CNS rather than to a more rapid metabolic disposition (Jaffe, 1985). Laboratory studies in humans involving daily dosing at high levels over periods of weeks have demonstrated tolerance to mood effects, tachycardia, decrease in skin temperature, increased body temperature, and impaired performance on psychomotor tests. Abrupt discontinuation in these studies usually produces a mild withdrawal syndrome (see below pp111-113). 5.4 Psychomotor effects A major societal concern about cannabis intoxication is its potential to impair psychomotor performance in ways which may directly affect the well-being of non-users of cannabis. The prototype outcome is an automobile accident caused by a cannabis user driving while intoxicated. It is well known that individuals who drive while intoxicated with alcohol are dangerous to others in proportion to their level of intoxication. Is there evidence that intoxication with cannabis produces impaired psychomotor performance of a nature and degree sufficient to warrant restrictions upon its use by automobile drivers? To what extent has cannabis intoxication contributed to road accidents? Psychoactive substances typically have both acute and chronic effects on performance of a variety of tasks. Given the fact that most tasks of interest to researchers require effort and concentration, only those substances which enhance these very general abilities typically improve performance. Recreational drugs are usually valued for effects which remove the user from mundane concerns, produce relaxation, and enhance experiences which would normally interfere with concentration on a skilled task. Consequently, many societies enact restrictions on the use of such drugs, either during specific tasks such as motor vehicle driving, or at any time, as is the case with cannabis in most Western societies, and with alcohol in many Islamic societies. The subjective effects of cannabis include feelings of well-being and relaxation, and sensory and temporal distortions which might be expected to decrease performance in situations where perceptual accuracy and attention are important. In deciding whether the recreational use of cannabis presents a danger to the user and others we need to consider two things: (1) the extent to which its use disrupts the performance of potentially dangerous tasks such as motor vehicle driving or the operation of machinery, and (2) the effect that the drug has on the user's compliance with restrictions upon its use. The second point refers to any disinhibitory effects of the drug which might predispose users to ignore prohibitions on driving, or may increase their willingness to take risks while intoxicated. The risks of cannabis intoxication and driving will be assessed in the following way. First, laboratory evidence on the effects of cannabis on various psychomotor tasks will be reviewed. In the following review of this evidence, when a number of studies have produced similar results, only the most typical studies will be cited. (For a more complete review of such studies see Chait and Pierri, 1992). Second, the possible mechanisms of the psychomotor effects of cannabis will be briefly discussed. Third, the literature on the effects of cannabis on performance in driving and flying simulators will be briefly reviewed. Fourth, the experimental literature on the effects of cannabis intoxication on on-road driving will be reviewed. Finally, the limited epidemiological evidence on the contribution of cannabis to motor vehicle accidents will be considered. 5.4.1 Effects of cannabis on psychomotor tasks Muscle control. Standing steadiness (Kiplinger et al, 1971) and hand steadiness (Klonoff et al, 1973) are both adversely affected by cannabis. Finger or toe tapping speed does not appear to be reliably affected (Weckowicz et al, 1975; Evans et al, 1976; Milstein et al, 1975; Dalton et al, 1975), as only one study (Klonoff et al, 1973) found a decrement in finger tapping. Reaction time. Simple reaction time does not appear to be reliably affected by cannabis. Some studies have reported decrements in mean reaction time (Borg et al, 1975; Dornbush et al, 1971), or the variability of reaction time (Braden et al, 1974), while others have found no difference (Evans et al, 1973). Choice reaction time tasks, in which the response is conditional not only upon the occurrence of a stimulus, but also the presence of some other discriminant (such as the pitch of a tone or the colour of a visual stimulus), have been administered to determine the effect of cannabis. In a number of these studies, reaction time was indeed slower after cannabis use (Borg et al, 1975; Block & Wittenborn, 1984; 1986), although there were some studies which found no change (Peeke et al, 1976; Block & Wittenborn, 1984). With only one exception (Low et al, 1973), errors in choice reaction time were not increased by cannabis. Single tasks of manual dexterity. Pursuit rotor tasks, in which the subject attempts to follow a rotating target with a pointer, are generally performed worse after cannabis use (Manno et al, 1971; Manno et al, 1970), although studies employing regular users (Salvendy & McCabe, 1975; Carlin et al, 1972) have found no effect, suggesting that the regular users developed tolerance to the effects of cannabis. Other tracking tasks are generally not affected (Zacny & Chait, 1991; Heishman et al, 1989). Tests in which the subject must manipulate and accurately place small items (Dalton et al, 1975; 1976; Evans et al, 1973) are usually affected, while sorting tasks may (Chait et al, 1985) or may not (Kelly et al, 1990) be performed less well. Concurrent tasks. Most concurrent task studies use one task which requires almost continuous attention, typically tracking, and one in which significant stimuli occur sporadically, often within a larger number of non-significant stimuli. The tasks are often referred to as the central and peripheral tasks respectively. The performance of concurrent tasks is almost always affected negatively by cannabis, although the effects on the component tasks are not consistent. Number or proportion of peripheral targets missed (MacAvoy & Marks, 1975; Marks & MacAvoy, 1989; Casswell & Marks, 1973; Moskowitz et al, 1972), proportion of hits (Moskowitz, Sharma & McGlothlin, 1972), false alarms (Chait et al, 1988, MacAvoy & Marks, 1975; Moskowitz & McGlothlin, 1974) or reaction time to peripheral targets (Perez-Reyes et al, 1988; Evans et al, 1976; Moskowitz et al, 1976) may suffer, but no interpretable pattern of decrements has emerged. It may be the case that while overall performance on concurrent tasks is decreased during cannabis intoxication, differences in the tasks used produce various patterns of effect. While there has been some speculation as to whether the effects of cannabis in concurrent tasks might be concentrated on the central or peripheral tasks (Moskowitz, 1985), no observed pattern has emerged to clearly support these conjectures. 5.4.2 Possible mechanisms of psychomotor effects Sensory disturbances. Reports of the subjective experience of cannabis intoxication include altered experience in all sensory modalities, as well as in the perception of space and time (Tart, 1970). Since almost all tasks of psychomotor performance include important visual and auditory components, sensory disturbances might well affect the ability to perform such tasks. Studies of the ability to discover embedded figures within complex designs have shown that this is impaired by cannabis (Carlin et al, 1972; Carlin et al, 1974; Pearl et al, 1973). Performance decrements due to cannabis in the Stroop colour naming test have been reported (Carlin et al, 1972; 1974), although it is not clear whether disturbed perception has any significant effect upon this task. Central Nervous System depression. Both the toxic and behavioural effects of cannabis indicate that it acts as a CNS depressant, at least in moderate to high doses. It might seem reasonable to hypothesise that this general effect might contribute to slowed reaction times, inability to maintain concentration, and lapses in attention. This is certainly the case with alcohol and other CNS depressants. When compared to the relatively large and reliable depressant effects of moderate doses of alcohol, it is clear that this effect of cannabis is not the primary mediator of performance changes. It must be stressed, however, that high doses of cannabis would make this aspect of its action on psychomotor skills more important. Motivational changes. A great deal has been written about the supposed effects of cannabis on human motivation. Hypotheses concerning the motivational effects of chronic cannabis use have been reviewed separately (see chapter 7.2). Cannabis users routinely report reduced desire for physical activity and increased difficulty of concentrating on intellectually demanding tasks such as reading for study (Tart, 1970). Studies designed to test the effect of cannabis on the willingness to perform laboratory "work" have found no striking decrements (Mendelson, 1983). This is consistent with comparisons of manual workers who used cannabis with those who did not (Rubin & Comitas, 1975; Stefanis et al, 1977). Indeed, the counter-argument that cannabis users can voluntarily compensate for some of the impairing effects of the drug has received experimental support (Cappell & Pliner, 1973; Robbe & O'Hanlon, 1993). As discussed below, motivational changes are surely important in decisions made outside the laboratory, but there appears to be no reliable evidence that motivational changes are responsible for any major proportion of the psychomotor effects of cannabis. 5.4.3 Effects of cannabis on simulated driving and flying Simulated driving tasks. As the previous sections have shown, there is considerable evidence that cannabis intoxication has some negative effects upon performance which become more pronounced with increasing task difficulty. Motor vehicle driving is a complex task, especially in conditions of heavy traffic or poor road or weather conditions, and as such, it might be expected to be adversely affected by cannabis. Simulated driving tasks require skills which are similar to those involved in driving, which can be performed under controlled laboratory conditions. When special efforts are made to simulate the performance characteristics of a car, simulations have two major advantages (Smiley, 1986). First, cannabis users an be tested after taking doses of cannabis which it would be unethical to use on the road. Second, they can be placed in simulated emergency situations which test their level of impairment in ways that would be impermissible on the road. The disadvantage of simulator studies derives from the difficulty of achieving sufficient fidelity to on-road driving tasks. One of the earliest studies by Crancer et al, (1969) found only that "speedometer errors" increased in simulated driving after cannabis use. In one of the more influential studies, Dott (1972) reported an apparent decrease in the willingness to take risks in simulated passing of another vehicle after cannabis use, while alcohol had the opposite effect. Alcohol also tended to hamper the subjects' response to stimuli signalling an emergency condition, while cannabis had little effect on this response. Both, however, increased reaction time to a more routine signal. A similar dissociation of the effects of alcohol and cannabis was reported by Ellingstad, et al, (1973) who found that cannabis did not appear to increase risk-taking, whereas alcohol did. Cannabis affected the ability to judge the time taken to pass another vehicle, while alcohol did not. Moskowitz et al (1976) found that alcohol altered the visual search patterns of subjects performing a simulated driving task, while cannabis did not. The alterations found with alcohol were, in theory, consistent with a reduced ability to scan for hazardous events, but no reliable difference in task performance was found with either drug. Smiley (1986) critically reviewed the research on the effects of cannabis intoxication on simulated driving. She argued that the earlier studies which showed fewer effects on car control than later studies suffered because of their unrealistic car dynamics. Later studies which used driving simulators with more realistic car dynamics have shown impairments of lane control after cannabis use. Some of the studies have also shown reductions in risk-taking as manifested in slower speeds, and maintenance of a larger distance from the car in front in following tasks (Smiley, 1986). Simulated flying. Janowsky et al (1976) found substantial increases in the number and magnitude of errors during a simulated flight after taking cannabis. These were principally in keeping the plane at the proper altitude and heading. Yesavage et al (1985) originally reported negative effects of cannabis on some components of a simulated flying task up to 24 hours after smoking, but this study did not include a control group. A later study (Leirer et al, 1989) which attempted to replicate this result with a control group found only an effect one to four hours after smoking. A third study which also included a control group (Leirer et al, 1991) again demonstrated decrements in the composite performance score up to 24 hours after smoking cannabis. Much has been made of these findings by critics of cannabis use, but the effects are very small and of uncertain significance for flying safety. Jones (1987) has argued that the use of cannabis by pilots in the 24 hours preceding flying may be more an indicator of poor judgment, rather than a cause for concern about the residual psychomotor effects of cannabis. 5.4.4 Effects of cannabis on on-road driving It is often remarked that the activity most often cited as dangerous when performed under the influence of recreational drugs - motor vehicle driving - is one of the least studied. Given the concern about the safety of the experimental subject in drug and driving experimentation, it is understandable that such studies have been relatively uncommon. A review by Nichols (1971) found that there were no well controlled observations of the effects of cannabis on driving performance. This situation changed with research commissioned by the Canadian Commission of Inquiry into the Non-Medical use of Drugs. A comprehensive report published by Hansteen et al (1976) showed that a moderate dose of alcohol (approximately 0.07 BAC) or THC (5.9mg) impaired driving on a traffic-free course (as measured by the number of times the lane-defining cones ("witch's hats") were struck). Driving speed was decreased after cannabis but not after alcohol use. Smiley et al (1975), using a different type of course, found that reaction time to signal stimuli was increased with the combination of cannabis and alcohol. Klonoff (1974) studied driving on a closed course, and in city traffic, after a placebo and two doses of smoked cannabis (4.9mg and 8.4mg THC). Closed course driving was scored by the number of cones hit on a precisely laid out path. Driving in traffic was scored by observation of eleven categories of driving skill, similar to those used in some driving tests. Driving on the closed course was impaired by both doses, as indicated by a higher proportion of subjects whose performance declined after cannabis use. Driving in traffic, however, while showing a trend toward poorer performance, was not significantly affected, and the effects of cannabis were much more variable. Sutton (1983) also found that cannabis had little effect on actual driving performance. Peck et al (1986) recorded performance on a range of driving tasks on a closed circuit on four occasions after the administration of placebo, up to 19mg of smoked THC, 0.84g/kg of alcohol, and the combination of both drugs. On most individual and derived composite measures, cannabis impaired performance. This study is important in that there was a high degree of concordance between objective performance measures (e.g. number of traffic markers hit during manoeuvres), subjective estimates of performance by the drivers, and ratings by police observers. However, the conclusion reached was that the effects of cannabis on driving performance were somewhat less than those of alcohol. Robbe and O'Hanlon (1993), have reported the methodology, but not the detailed results, of a study of driving in traffic. Their brief report suggests that their results also indicated little impairment of actual driving skills after cannabis. They speculated that since drivers were aware of their intoxication, they had successfully attempted to counter the impairment. Overall, the effects of cannabis use on on-road driving have been smaller than the comparable effects of intoxicating doses of alcohol in the same settings (Smiley, 1986). The most consistent cannabis effect has been that drivers reduce their risk by slowing down; a finding that contrasts with the consistent finding that subjects typically increase their speed when intoxicated with alcohol. It is probably this compensatory behaviour by cannabis users that explains the comparatively small effects of cannabis intoxication in on road studies. For ethical reasons such studies have not been able to adequately test the response of cannabis intoxicated drivers to situations that require emergency decision, in which there is less opportunity to compensate for impairment. The few studies which have attempted to simulate this situation (e.g. by using subsidiary reaction tasks in addition to driving) have shown that cannabis intoxication impairs emergency decision-making (Smiley, 1986). The small effects of cannabis on driving performance seem at odds with its effects on laboratory tasks requiring divided attention. Peck et al (1986) have pointed out, however, that the subtle performance effects of drugs in laboratory divided attention tasks may be poor predictors of driving performance. While the combination of performance abilities which is tapped by the typical divided attention task, such as concurrent pursuit tracking and visual discrimination, is plausibly related to driving, the tracking task is usually a much more difficult task than driving under normal conditions. Much more attention must be allocated to the central task in most divided attention tests, for example, leading to a substantial decrease in performance when drugs such as cannabis are taken. In addition, in the laboratory the subject is unable to vary a key task parameter, such as driving speed, in order to compensate for any perceived impairment. Hence, while laboratory divided attention tasks may be ideal for detecting small drug effects, they may over-estimate the effects of drugs on actual driving. It is not surprising then that many studies which have used both types of test have reported less effect on actual driving than on laboratory tasks or simulated driving. 5.4.5 Studies of cannabis use and accident risk While cannabis produces decrements in psychomotor performance in laboratory and controlled settings, it does not necessarily follow that these decrements will increase the risk of being involved in accidents. It may be, for example, that cannabis users are less likely to drive than drinkers because they are more aware of their intoxication. The survey evidence suggests that this is not the case. Several surveys (e.g. Dalton et al, 1975; Thompson, 1975; Klonoff, 1974; Robbe & O'Hanlon, 1993) have found that cannabis users are generally aware that their driving is impaired after using cannabis but the majority had driven, or would drive, after using cannabis, despite this recognition of impairment (Klonoff, 1974). This finding is consistent with observations on the recreational use of alcohol when driving (Smart, 1974). Even if cannabis users drive when intoxicated it does not necessarily follow that they will be over-represented among drivers involved in accidents. It could be, for example, that cannabis users take special care and avoid risk-taking when driving while intoxicated. This possibility is difficult to investigate because there have been no controlled epidemiological studies conducted to establish whether cannabis users are at increased risk of being involved in motor vehicle or other accidents. This is in contrast to the instance of alcohol use and accidents, where case-control studies have shown that persons with blood alcohol levels indicative of intoxication are over-represented among accident victims (Holman et al, 1988). In the case of cannabis, all that is available are studies of the prevalence of cannabinoids in the blood of motor vehicle and other accident victims (see McBay, 1986 for a review). Most often these have been retrospective studies of the prevalence of cannabinoids in blood tested post-mortem, which have found that between 4 per cent and 37 per cent of blood samples have contained cannabinoids, typically in association with blood alcohol levels indicative of intoxication (e.g. Cimbura et al, 1982; Mason and McBay, 1984; Williams et al, 1985). Zimmerman et al (1983) have reported similar prevalence data on blood cannabinoid levels among Californian motorists tested because of suspicion of impairment by the Highway patrol. Soderstrom et al (1988) have conducted one of the few prospective studies among trauma patients rather than accident fatalities, which showed a high prevalence of bloods positive for cannabinoids (35 per cent). These studies are difficult to evaluate for a number of reasons. First, in the absence of information on the prevalence of cannabinoids in the blood of non-accident victims, we do not know whether persons with cannabinoids are over-represented among accident victims (Terhune, 1986). Although a prevalence of 35 per cent may seem high, this is of the order of the prevalence of cannabis use among young males who are at highest risk of involvement in motor vehicle and other accidents (Soderstrom et al, 1988). Second, there are major problems in using cannabinoid blood levels to determine whether a driver or pedestrian was intoxicated with cannabis at the time of an accident (Consensus Development Panel, 1985). The simple presence of cannabinoids indicates only recent use, not necessarily intoxication at the time of the accident (see above pp35-36). Third, there are also serious problems of causal attribution, since more than 75 per cent of drivers with cannabinoids in their blood also have blood levels indicative of alcohol intoxication (McBay, 1986). On the basis of the available evidence, it is accordingly difficult to draw any conclusions about the contribution that cannabis intoxication may make to the occurrence of motor vehicle accidents (Terhune, 1986). One approach that has been used in an attempt to get around the absence of data on the prevalence of cannabis use among drivers not involved in accidents has been to perform "culpability analyses" (Terhune, 1986). In such analyses, decisions are made as to which drivers killed in fatal accidents are culpable (i.e. responsible for the accident). Drivers with no alcohol or other drugs in their blood are then used as the control group in analyses of the relationship between the presence of drugs in blood and degree of culpability. These studies have their problems: the culpability of the drug-free drivers is usually high thereby reducing the ability to detect an increase in culpability among drivers with alcohol and cannabis; different studies use different criteria for deciding that when a driver was intoxicated with cannabis; and as a consequence, different studies have produced very different estimates of the relationship between cannabinoids in blood and driver culpability (although most have shown an increased culpability for drivers with intoxicating levels of alcohol in their blood). As Simpson (1986) concluded after reviewing the culpability literature: "the results are mixed and inconclusive" (p28). Gieringer (1988) used a different approach to circumvent the absence of data on the prevalence of cannabinoids in drivers not involved in accidents. He used data from a National Institute of Drug Abuse (NIDA) household survey of drug abuse in the United States to estimate the proportion of all drivers who might be expected to have blood and urine samples positive for cannabinoids. On the basis of these data, he estimated that cannabis users are two to four times more likely to be represented among accident victims than non-cannabis users, and that cannabis users who also used alcohol were even more likely to be over-represented among the victims of motor vehicle accidents. Gieringer's inference about the risks of combining alcohol and cannabis when driving receive some support from the studies of Mason and McBay (1984) and Williams et al (1985). Mason and McBay estimated that at most one driver in their series of 600 drivers killed in single-vehicle accidents was significantly impaired by cannabis use alone, compared with between nine and 28 drivers who were impaired by marijuana and alcohol, and 476 drivers who had blood alcohol contentrations (BACs) greater than 0.10. Williams et al (1985) investigated the relationship between alcohol and cannabis use and driver responsibility for fatal accidents (as judged from police investigations of each accident) involving young men in California. Using the small drug-free group as the comparison, they found that both alcohol (OR=4.7 [95 per cent CI: 2.1, 10.3]) and alcohol and marijuana in combination (OR=8.6 [95 per cent CI: 3.3, 22.2]) significantly increased the odds of the driver being adjudged to be responsible for the accident. Marijuana-only drivers, however, were less likely to be adjudged responsible for their accident (OR=0.5 [95 per cent CI: 0.2, 1.3]), although numbers were small (N=19). There is also indirect evidence that cannabis use produces an increase in the risk of accidents, from surveys of self-reported accidents among adolescent drug users. Two such surveys have found a statistically significant relationship between marijuana use and self-reported involvement in accidents, with marijuana smokers having approximately twice the risk of being involved in accidents of non-marijuana smokers (Hingson et al, 1982; Smart and Fejer, 1976). More direct evidence of an association between cannabis use and accidents is provided by two epidemiological studies, one of cannabis use and mortality (Andreasson and Allebeck, 1990), and the other of cannabis use and health service utilisation (Polen et al, 1993). Andreasson and Allebeck reported a prospective study of mortality over 15 years among 50,465 Swedish military conscripts. They found an increased risk of premature mortality among men who had smoked cannabis 50 or more times by age 18 (RR=4.6, 95 per cent CI: 2.4, 8.5). Violent deaths were the major cause of death contributing to this excess mortality, with 26 per cent of deaths being motor vehicle and 7 per cent other accidents (e.g. drownings and falls). The increased risk was no longer statistically significant (RR=1.2 [95 per cent CI: 0.7, 1.9]) after multivariate statistical adjustment for confounding variables such as anti-social behaviour, and alcohol and other drug use in adolescence (Andreasson and Allebeck, 1990), reinforcing Gieringer's suggestion that the combination of cannabis and alcohol may be the important risk factor for accidents. Polen et al (1993) compared health service utilisation by non-smokers (N=450) and daily cannabis-only smokers (N=450) screened at Kaiser Permanente Medical centres between July, 1979 and December, 1985. They reported an increased rate of medical care utilisation by cannabis-only smokers for respiratory conditions and accidental injury over a one to two-year follow-up. There was also an interaction between cannabis and alcohol use, in which cannabis users who were the heaviest alcohol users showed the highest rates of utilisation. This result is suggestive but minimally informative about the risks of motor vehicle accidents, because all forms of accidental injury were aggregated. 5.4.6 Conclusions on cannabis and driving There is no doubt that cannabis adversely affects the performance of a number of psychomotor tasks, an effect which is related to dose, and which is larger, more consistent and persistent in difficult tasks involving sustained attention. The acute effects on performance of typical recreational doses of cannabis are similar to, if smaller than, those of intoxicating doses of alcohol. Alcohol and cannabis differ in their effects on the apparent willingness of intoxicated users to take risks when driving, with persons intoxicated by cannabis engaging in less risky behaviour than persons intoxicated by alcohol. While cannabis produces decrements in performance under laboratory and controlled on-road conditions, it has been difficult, for technical and ethical reasons, to establish conclusively whether cannabis intoxication increases the risk of involvement in motor vehicle accidents. There is sufficient consistency and coherence in the evidence from studies of cannabinoid levels among accident victims, and a small number of epidemiological studies, to infer that there probably is an increased risk of motor vehicle accidents among persons who drive when intoxicated with cannabis. A crude estimate of the risk is of the order of two to four times for persons driving under the influence of cannabis. This increased risk may be largely explained by the combined use of cannabis with intoxicating doses of alcohol. Further research is required to elucidate this issue, although it will not be easily resolved because of the technical obstacles to such research. In the meantime, cannabis users should be urged not to drive while intoxicated by cannabis, and they should be particularly warned of the dangers of driving after combining alcohol and cannabis use. 5.5 Interactions between cannabis and other drugs Cannabis is often taken in combination with other drugs. This is most likely among those who use it frequently and in large quantities (Tec, 1973). The predominant drug of choice for use with cannabis is alcohol (e.g. Carlin & Post, 1971; Hochhauser, 1977; McGlothlin et al, 1970; Norton and Colliver, 1988) which supports the popular notion that this combination enhances the degree of intoxication. Barbiturates, in contrast, appear to produce an aversive intoxication when combined with cannabis (Johnstone et al, 1975). The interactions of cannabis with each type of drug will be considered in three ways; interactions of toxicity, psychotropic effects and psychomotor impairment. 5.5.1 Other cannabinoids There are slight interactions of THC with other cannabinoids found in cannabis preparations. The two major cannabinoids other than THC which have been extensively tested for interactions with THC and other drugs are cannabidiol and cannabinol. Both of these compounds have been found to have little psychoactivity when administered alone (Hollister, 1986). In rather high doses (15-60mg), cannabidiol has been reported to abolish the effects of 30mg of oral THC (Karniol et al, 1975), whereas cannabinol had no apparent effect (Hollister & Gillespie, 1975). Comparisons of smoked THC and smoked cannabis, the latter containing the usual small amounts of cannabinol and cannabidiol, indicate that there is, if anything, a slightly greater psychoactive effect from the cannabis than from THC (Galanter et al, 1973; Lemberger et al, 1976). The psychotropic effects of THC also appear to be slightly enhanced by the minor constituent cannabinoids found in natural products when smoked (Galanter et al, 1973). No such differences have been reported in the behavioural effects of smoked cannabis. 5.5.2 Alcohol Alcohol and cannabis have a number of effects in common, although the mechanisms of these actions appear to be different. The recent identification of the cannabinoid receptor (Howlett et al, 1990), and an endogenous ligand for that receptor, have confirmed the hypothesis that the central activity of cannabis is receptor-mediated (see pp 29-31 above). While the mechanism of action of alcohol is still in question, most explanations are concerned with the effects of alcohol upon the structure and chemistry of the cell membrane. Both drugs are considered to be CNS depressants, especially in high doses, and both have substantial analgesic properties. Since these effects of the two drugs appear to be approximately additive (Siemens, 1980) it is possible that the toxicity of high doses of Æ9-tetrahydrocannabinol (THC) (Rosencrantz, 1983) may be potentiated by alcohol, although there is very little evidence to support this conjecture. Neither the metabolism of alcohol nor that of THC appears to be altered by the presence of the other drug (Siemens & Khanna, 1977). Alcohol and THC also appear to have similar psychotropic effects. The perceived stimulation and euphoria at low doses are common effects, as well as a tendency toward behavioural disinhibition over a range of doses (Hollister & Gillespie, 1970). This interaction is generally perceived by users as enhancing the intoxication produced by either drug alone (Chesher et al, 1976), although contrary results have been reported (Manno et al, 1971). However, larger doses in combination are often reported to be aversive (Sulkowski & Vachon, 1977; Chesher et al, 1986). The effects of alcohol and cannabis combinations on psychomotor performance are more complex. The majority of studies have reported that both drugs produce impairment on a variety of psychomotor tasks, and that the interaction is approximately additive. However, a number of studies have reported that at low doses there is less than an additive effect. Chesher et al (1976, 1977) found a reduction in impairment late in intoxication after a combination of oral THC (0.14-0.21mg/kg) and alcohol (0.5-0.6g/kg). A further study in which the THC (0.32mg/kg) was administered one hour before the alcohol (0.54g/kg) found no apparent antagonism (Belgrave et al, 1979). Another study using three doses of smoked marijuana in combination with alcohol showed a lower-than-expected impairment in the group which received the lowest dose of THC (5mg) and the lowest dose of alcohol (0.54g.kg) (Chesher et al, 1986). Peck et al (1986) also reported an apparent antagonism, but only on a composite "stopping" variable derived from driving performance. In most of their measures, the combination of alcohol and cannabis produced additive impairments. Siemens (1980) has proposed that alcohol may reduce the availability of THC through a pharmacokinetic interaction demonstrated in animals (Siemens & Khanna, 1977). Given that there is substantial evidence for cross-tolerance between alcohol and THC (Newman et al, 1972), it is possible that low doses of THC and alcohol in combination may enhance the acute tolerance to alcohol (Hurst & Bagley, 1972) late in intoxication. 5.5.3 Psychostimulants The most characteristic effect of psychostimulants such as amphetamine and cocaine is their activation of the sympathetic branch of the autonomic nervous system, as indicated by increases in arousal, blood pressure and respiratory rate. There are few actions which appear to be common between cannabis and stimulants. The few effects on the cardiovascular system, such as amphetamine-induced hypertension, and THC-induced tachycardia, seem to occur independently (Zalcman et al, 1973). It is in the combined effect upon cardiac action that toxic interactions of THC and stimulants could be dangerous, but there are no clear indications in the literature for humans, and the evidence from animal studies is mixed (Siemens, 1980). The psychotropic effects of the combination of 0.14mg/kg amphetamine and 0.05mg/kg THC have been reported as a longer and more intense "high" (Evans et al, 1976), although a similar study using only 0.025mg/kg THC found no effect of the combination (Forney et al 1976). While the concurrent use of cannabis and cocaine is often reported (Miller et al, 1990), systematic study of their interaction is lacking. There is some evidence that amphetamine may antagonise the behavioural impairments produced by cannabis (Zalcman et al, 1973), as a number of stimulants appear to do in some animals (Consroe et al, 1976). The infrequency of stimulant/cannabis combinations in recreational use (Hollister, 1986) may be due to as yet unspecified negative interactions experienced by users. It may be, for example, that stimulants increase the probability of occurrence, or severity of the acute panic reaction which sometimes occurs after cannabis use. 5.5.4 Depressants A great deal of experimentation in animals has shown that cannabis in general increases the depressant action of drugs such as the barbiturates over a range of doses (Siemens, 1980). This is also the case with oxymorphone (Johnstone et al, 1975) and diazepam (Smith & Kulp, 1976). As with alcohol, it is likely that interactions between these acute effects of depressant drugs would lead to the greatest danger of acute toxicity. There is little human evidence at present, however, to support this speculation. The psychotropic effects produced by combinations of barbiturates with cannabis appear to be additive (Dalton et al, 1975). As mentioned previously, this intoxication is more likely to be aversive to the user (Johnstone et al, 1975). The behavioural effects of the interaction of depressant drugs with cannabis are, in almost all reports, also additive. 5.5.5 Miscellaneous drugs A number of other substances have been reported to antagonise various effects of cannabis in animals, including phenitrone (Kudrin & Davydova, 1968), pemoline (Howes, 1973) and even tamarind (Hollister, 1986). Only pemoline is acknowledged to counter the reduced motor activity and hypoalgesia due to THC. Physostigmine has shown a complex interaction which includes increasing the motor depression produced by THC and antagonising the tachycardia (Freemon et al, 1975). Propanolol, which would be expected to antagonise the tachycardia characteristic of cannabis intoxication, also appears to abolish the reduction in learning capacity produced by cannabis (Sulkowski et al, 1977), although an earlier study using smaller, spaced doses found no effect (Drew et al, 1972). Recently, it has been reported that indomethacin, a non-steroidal anti-inflammatory, reduced or eliminated a number of physiological effects of THC, and attenuated the "high", but did not affect the acute memory impairment (Perez-Reyes et al, 1991). 5.5.6 Conclusions on drug interactions At present, the interactions between the effects of cannabis and other drugs are what would be predicted from their separate actions, and are generally relatively innocuous in recreational doses. There have been a number of reports in which cannabis use has accompanied serious consequences, typically when used in combination with one or more other drugs in high doses, or over extended periods of intoxication. However, there appears to be no evidence that cannabis is particularly implicated in cases of heavy intoxication with other drugs. The concurrent intoxication with alcohol and cannabis, which is the most common combination of drugs, may have greatest relevance in motor vehicle accidents. The separate impairments induced by the two drugs appear to be approximately additive, and there are indications that users of both drugs are over-represented among motor vehicle accidents. References Andreasson, S. and Allebeck, P. (1990) Cannabis and mortality among young men: A longitudinal study of Swedish conscripts. Scandinavian Journal of Social Medicine, 18, 9-15. Belgrave, B. E., Bird, K. D., Chesher, G. B., Jackson, D. M., Lubbe, K. E., Starmer, G. A. & Teo, R. K. C. 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