ALCOHOL AND MARIJUANA, A LESS THAN ADDITIVE INTERACTION?

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1 ALCOHOL AND MARIJUANA, A LESS THAN ADDITIVE INTERACTION? Helen Dauncey, Gregory Chesher, John Crawford, Michael Adena, Kim Horne. Department of Pharmacology, University of Sydney, Australia There have been many studies that have investigated the effects of the interaction between alcohol and marijuana driving or driving related tasks. Most studies have found that the combination produced an additive impairment however a small number have reported less-than-additive results. In a recent paper Perez-Reyes et al, (1988) concluded that the majority of studies found the combination produced additive detrimental effects on performance when the potency of marijuana was high and antagonistic effects when the potency was low. The study reported here was carried out to determine the effects of a combination of alcohol and marijuanan driving related psychomotor skills in a group of regular alcohol and marijuana users, with the objective of defining the nature and extent of the interaction between to two drugs over a range of doses. METHODS AND RESULTS Experimental Design A 4 x 4 randomised, placebo controlled, single blind, no crossover design was used. Four dosage conditions for each drug were tested as well as all possible combinations of doses (0, 2.5, 5 and 10mg THC; 0,.25, 5 and.75g/kg alcohol). There were 20 subjects in each of the 16 dosage groups and each of the 320 subjects in the study was tested only once. In 7 of the cells the volunteers received either marijuana or alcohol in combination with placebo and the data from these cells provided the dose response for alcohol alone and marijuana alone. The remaining 9 cells provided the interaction data. Schedule Drink mins; drink mins; marijuana 30-45mins; HR 45mins; self-assessment scales 47mins; BAC 55 minutes; performance tests 60-85mins; HR 165mins; scales 167mins; BAC 175mins; performance tests mins. Drug administration The maximum tolerated dose of the combination was determined in a pilot study in which nausea and vomiting occurred in 5/6 subjects given alcohol 0.75g/kg followed by 15mg THC and 0/6 given alcohol 0.75g/kg followed by 10mg THC. The alcoholic drinks contained 15% w/v ethanol in sugar-free orange juice to which peppermint oil was added to mask the presence or absence of ethanol. The dose of alcohol was adjusted by a factor of 0.92 for females to correct for the decreased distribution volume of alcohol. BAC was measured by breath analysis using a Drager Alcotest Because of concern over inter-subject variation in marijuana cigarette smoking methods and the possibility that it may cause a serious variation in dose of THC delivered (Perez-Reyes et al, 1982, 1982, 1988) a waterpipe was used. Approximately 100mg marijuana was ignited in the cone of the waterpipe at a time and the smoke was inhaled completely which reduced pyrolysis of THC in the burning zone and prevented loss of THC in side stream smoke. Marijuana leaf was supplied by NIDA. Subjects were given 400mg of marijuana leaf with differing proportions of active leaf and placebo leaf according to their dosage condition. Statistical Methods Large individual differences in performance ability were expected most particularly when subjects were very intoxicated, and this had the potential to made all but gross drug effects. Because the interactions expected were subtle in nature an effort was made to circumvent this potential problem by analysing the performance measures most intensively on a summary performance measure (SPM), derived equally from the five performance tests. The SPM was calculated 620 A lcohol, D rugs and Traffic Safety - T92 Ed. by U tzelm ann / B erghaus / Kroj Verlag TÜV Rheinland GmbH, Köln -1993

2 from 8 of the individual measures which were determined by a factor analysis of all measures recorded during testing and those that contributed the most to predicting poor performance were selected. Measurements taken at times T2 and T3 were analysed using regression models and they were were fitted using GLIM 3.77 (MAG, 1986). Linearity of the Dose Response The regression models first tested for the linear effects of the two drugs, modelled using a regression variable for the use of each drug. Possible non-linearity was modelled by including dummy regression variables in the model for each distinct dose of the drug. Because the measurement at later times depended strongly on the initial measure at Tl, the initial value was included as a covariant in the regression models i.e. the estimates for the other variables in the models were adjusted for the initial skill demonstrated by each subject. Interactions Several forms of specific interaction between the drugs were included in the models as well as the conventional general interaction term. i) There was a test for the general interaction between doses of alcohol and THC after removing their main effects (as in ANOVA analyses). However, since it was based on nine degrees of freedom, the test lacked power and proved to be of little value. ii) The first form of specific interaction was the linear by linear interaction between the two drugs. Such an interaction can reflect either synergism or antagonism and it supposes that the size of the interaction depends on the amount of each drug. iii) Possibility that the double placebo group had a mean response that was not an extrapolation of the response observed for the fifteen combinations of at least one active drug dose was tested by including in the regression model a dummy regression variable. (iv) The third type of interaction tested whether the slope of the response with alcohol differed for subjects receiving no THC compared with those receiving some THC. Another possibility was the converse of this. They were modelled using appropriate regression models. Subjects, set and setting Subjects were recruited from advertisements on a Sydney rock radio station and were accepted if they were over 18 and had smoked marijuana through a waterpipe before. They were excluded if they presented at the laboratory under the influence of a centrally acting drug, including alcohol, or if they admitted recent use of such a drug when completing a drug use questionnaire. No payment was offered but subjects were motivated by explaining the study in a simple nonscientific way and stressing that what was required was a constant, well-motivated effort The setting in the laboratory was a comfortable sitting room with TV, radio, cards and magazines. Subjects were tested in groups of 2-8. Description of the Population Sample Data were collected on one occasion from 320 subjects (256m, 64f) aged between 18 and 70 (median 21yrs, 88% were less than 30 years). 11% had no alcohol in the previous week and 6% had a drink every day, they averaged 3 drinks in each drinking session, 7% having more than 12 drinks. It probably represented a low to normal alcohol consuming population within that age group. On the other hand, 41% of subjects claimed to smoke marijuana daily. Because volunteers were recruited as marijuana smokers, the sample was biased towards a heavy using population. The attitude questionnaire showed that only 1% thought alcohol but 31% thought marijuana a safe drug. 16% saw alcohol as harmful to all who use it but only 2% believed that about marijuana. 97% of volunteers felt that marijuana laws should be relaxed. 621

3 Performance measures Performance ability was measured on four occasions (practice, base line ability, peak of intoxication and three hours after beginning to drink) using tests presented on Apple //e computers. There were 3 reaction time (RT) tasks with increasing central processing load (simple RT with regular and irregular stimulus presentation, complex RT with a high and low stimulus-response compatibility and a mental rotation task with a RT component), a pursuit tracking task and a forward digit span task. The tasks took 25mins to complete. SUMMARY PERFORMANCE MEASURE Eatlaatad dlffaranca froa active drug plus placabo At «0 alnutaa At 180 alnutaa THC Avarag«s.a. THC Avarag«a.a Alcohol Alcohol Avaraga a.a Avaraga s.a At the peak of intoxication a strong linear dose response with alcohol was found on the SPM but the THC dose response relationship could be described equally well by linear and non-linear models. It is likely that for heavy using marijuana smokers the 2.5mg and perhaps the 5mg doses were on the lower end of the dose response curve. As a result of the weak THC dose response, the analyses for interactions had to assume a general drug effect rather than a linear dose response for both drugs. This had the effect of diminishing the chances of achieving statistical significance. Of the three specific interaction models tested on the performance data, none was statistically significant but all three showed substantial trends in the same direction, strongly suggesting de-intensification or antagonism of effect Specifically, these interaction models were a) a linear-by-linear interaction where the effect of each drug was smaller in the presence of a larger amount of the other drug (p = 0.2); b) a flattening of the alcohol dose response slope when subjects received active THC compared with placebo THC (p = 0.15); c) a flattening of the THC dose response when subjects received active alcohol compared with placebo alcohol (p = 0.1). When the interaction analyses were repeated allowing for an assumption of linearity of dose response for both drugs, the dose response slope for THC and placebo alcohol, was statistically significantly different (p =.05) from the slope for THC and active alcohol. The parameter estimates of the slopes from the other two interactions when linearity for both drugs was assumed did not change however they came closer to statistical significance. Driving Scales Subjects were asked to rate on a visual analogue scale As you feel right now, how safely could you drive a car?. The responses were strongly negatively correlated with the dose of alcohol at times T2 and T3, while the dose of marijuana exerted no effect. Those who received marijuana alone responded remarkably differently from those who received alcohol alone. Subjects did not feel that marijuana would affect their safe driving ability at any of the doses given. When 622

4 asked Would you drive a car as you feel right now? there was a strong correlation with alcohol, once again, at times T2 and 13 with a negative response. Again there was no correlation between either answer and marijuana dose. There were no interactions between the drugs. AS YOU FEEL RIGHT MOM HOW SAFELY COULD YOU DRIVE? Rating out of IS at 1 hour THC» Mould you drlva now? Parcant who anawarad yaa at 1 hour THC Estimate of BAC The estimate of BAC correlated reasonably well with the actual dose received. Higher doses tended to be underestimated and lower doses overestimated with BAC 0.05g% (the legal limit in our state) the most accurate. There was no interaction. ESTIMATE Of BAC AT I HOUR Estlaata Actual Laeal H a l t 1n Auatralla 1a 0.05 DISCUSSION Reports of similar results to these have occurred in the literature (MacEvoy & Marks,1975; Chesher et al,1976; Atwood et al,1981; Stein et al,1983; Musty & Saxby,1981). Perez-Reyes et al, (1988) concluded that the majority of studies found the combination produced additive detrimental effects on performance when the potency of marijuana was high and antagonistic effects when the potency was low. Of the studies that have shown antagonism, the doses at which it was observed were BAC.lg% mg THC (MacEvoy & Marks, 1975); BAC 0.054g% + 15mg TOC orally (Chesher et al,1976); BAC.08g% + about 10.5mg and 5.25mg TOC (Atwood et al,1981); BAC.lg% + about 7mg THC (Stein et al,1983); BAC about.07g% + about 7mg THC (Musty & Saxby, 1985). As can be seen they cover a range of doses of both drugs. The present study used both the highest tolerated dose combinations and low doses of both drugs and the degree of de-intensification of effect appeared to be present at the highest dose combination (BAC 0.08g% + 10mg THC) although it appeared to be greatest in the middle to low doses of both drugs. It is probable, therefore, that there are more factors controlling the emergence of 623

5 antagonism than relative doses. A consistent feature among the studies reporting antagonism is the greater extent of previous drug use among subjects. MacEvoy and Marks subjects averaged 3 joints and 43 drinks per week; of Chesher et al s subjects 79% drank and 50% smoked at least once a week and 29% frequently had both drugs together; Stein et al advertised for heavy drinkers who also smoked marijuana; and Musty & Saxby s subjects were regular users. By comparison, Manno et al (1971) used 12 subjects, 8 of whom had not used marijuana before and Perez-Reyes et al (1988) particularly selected volunteers who were not heavy users. They smoked 2.3 ±_ 1.4 marijuana cigarettes per month and drank 5.79 ±_ 2 g/kg alcohol per month. In their study, MacEvoy & Marks compared the results of the subjects with the above drug taking history with an equal number of subjects who had never smoked marijuana and they reported antagonism between alcohol and marijuana among the regular users and synergism from the naive subjects. A further thread of similarity seen in the studies that have shown antagonism was the attempt by investigators to create a relaxed, real world setting rather than a scientific one (Chesher et al,1976; Stein et al,1983; Musty & Saxby,1985). Therefore, it appears that previous drug experience and the set and setting factors may have some influence on whether there is an additive or less than additive impairment of performance when alcohol and marijuana are given together in the laboratory. TTiis study used the maximum tolerated doses for alcohol and marijuana at their peak blood concentrations but people who take these drugs socially rarely use them as they were given in this study because of nausea and vomiting ("spinout"). Studies looking at considerably higher doses of marijuana given an hour or so before alcohol would probably yield results that reflect more accurately the performance ability of road users who take these drugs together and the nature and extent of the drug interaction. 624