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5. The accute effects of cannabis intoxication
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.
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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.
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.
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.
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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.