The effect of (-) Δ9-tetrahydrocannabinol, alone and in combination with ethanol, on human performance

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<ul><li><p>Psychopharmacology 62, 53-60 (1979) Psychopharmacology 9 by Springer-Verlag 1979 </p><p>The Effect of (--) Trans-A 9-Tetrahydrocannabinol, Alone and in Combination with Ethanol, on Human Performance </p><p>B. E. Belgrave 1, K. D. Bird 1, G. B. Chesher 2, D. M. Jackson 2., K. E. Lubbe 3, G. A. Starmer 2, and R. K. C. Teo 4 </p><p>1 Department of Psychology, University of New South Wales, N.S.W. 2033, Australia 2 Department of Pharmacology, University of Sydney, N.S.W. 2006, Australia 3 Psychiatrist, Brisbane Street Drug Dependence Service, Health Commission of N.S.W., Australia 4 Traffic Accident Research Unit, Department of Motor Transport, Rosebery, N.S.W. 2018, Australia </p><p>Abstract. Twenty five volunteers received (-) trans-A 9- tetrahydrocannabinol (THC) (320 gg/kg) or placebo (both orally, To), and, 60 rain later, they consumed an ethanolic beverage (0.54 g/k~) or placebo. The ef- fects of this medication were measured at T1 (100 rain after THC ingestion), T 2 (160 min), T 3 (220rain) and T~ (280 rain) using a battery of cognitive, perceptual and motor function tests. Factorial analysis indicated that the test procedures could be adequately expressed by four rotated factors: a reaction speed factor (I'), a cognitive factor (II'), a standing steadiness factor (I I I ') and a psychomotor coordination factor (IV'). The first principal component (I) was used as a measure of general performance across the whole test battery. </p><p>Both THC and ethanol produced significant decre- ments in the general performance factor. Ethanol produced significant decrements in standing steadiness and psychomotor coordination, while THC caused a significant deterioration in performance on all the four rotated factors. In all cases the peak effect of ethanol occurred at T 1 and by T 4 the effect had worn off. The performance decrements induced by THC were slower in onset and lasted longer than those induced by ethanol. In general, the peak effect of THC occurred at T 1 and T 2. There was no evidence of any interaction between THC and ethanol, and the effects of a combi- nation of THC and ethanol were no more than additive. THC (but not ethanol) produced a significant rise in pulse rate. Prior administration of THC did not significantly affect the blood ethanol levels obtained. The subjects were able to identify correctly which of the treatments they had received. </p><p>Key words: (-) Trans-A9-tetrahydrocannabinol - Ethanol - Human per fo rmance- Cognitive - Perceptual - Motor </p><p>* To whom offprint requests should be sent </p><p>In two previous experiments, we examined the effects of orally administered A9-tetrahydrocannabinol (THC) (137 and 214 ~tg/kg), alone and in combination with ethanol (0.54 g/kg), on the performance of a series of perceptual, cognitive and motor function tests in human volunteers (Chesher et al., 1976, 1977). In the first experiment, neither THC (137 lag/kg) nor ethanol produced significant performance decrements when given alone, but deterioration did occur after the administration of the combination. In the second experiment, THC (214 ~tg/kg) did produce a signifi- cant effect, which was accentuated in the presence of ethanol. In addition, Chesher et al. (1977) reported some evidence of an antagonism between THC and ethanol which occurred approximately 2 - 3 h after the ingestion of THC. </p><p>This paper reports the findings of a study in which the dose of THC was increased to 320 ~tg/kg and the time of measurement was extended to 5 h. </p><p>Materials and Methods </p><p>Subjects. The subjects were healthy, paid (mainly University stu- dents) volunteers of both sexes (12 male, 13 female), aged 18- 35 years (median 22.3 years), with body weights of 51 - 81 kg (median 62.5 kg). All were 'social' drinkers of ethanol and were non-naive as regards cannabis. The drug experience of the subjects was as follows: a) ethanol; a median consumption of 1.4 'standard' drinks (285ml beer, 30 ml whisky, or 230 ml table wine) per day (range 1 - 20) for a median duration of 9.6 years (range 1-23); b) cannabis; a median rate of use of two occasions per day, (range of &lt; 1 to &gt; 5) for a median duration of 6 years (range i - 14). The detailed drug-use history of these volunteers and of others in subsequent experiments is being compiled. Before admission to the experiment, all subjects were medically examined by one of us (K. E. L.) to ensure that no past or present disease precluded their participation. Six subjects of an initial 31 were excluded; two because of hypertension, two because they had measurable blood alcohol when they first attended, one because of obvious psychiatric disturbance and one because of recent regular use of bronchodilators. The purpose and design of the experiment was fully explained to the subjects and their informed consent obtained. </p><p>0033-3158/79/0062/0053/$ 01.60 </p></li><li><p>54 Psychopharmacology 62 (1979) </p><p>Drugs. Both THC and ethanol were administered orally. THC was dissolved in sesame oil and sealed into capsules containing 2.5, 5.0 or 10.0 mg. Each subject was given four capsules and the dosage was adjusted to deliver approximately 320 gg/kg according to the following schedule: subjects weighing 51 - 58 kg received 17.5 mg; 59 - 66 kg, 20.0 rag; 67- 74 kg, 22.5 mg; and 75 - 82 kg, 25.0 mg. The median dose was 320 Ixg/kg (range 302-343 gg/kg). Placebo capsules contained only sesame oil. Ethanol (0.54 g/kg) was presented as a beverage containing 20 ~o v/v ethanol in lemon squash. Ethanol was omitted from the placebo beverage. The dose of ethanol was the same as that used in our previous studies (Chesher et aI., 1976, 1977). </p><p>Test Battery </p><p>Standing Steadiness. The apparatus consisted of a platform beneath which a displacement transducer was mounted. The actual movement of the platform in the vertical plane was less than 1 gm. The subject stepped on to the platform and was instructed to relax and to stand as still as possible without talking or moving his head. Any shift in position created an electrical impulse that was amplified and recorded on a Grass Polygraph. The impulses were integrated to give an overall measure of body sway, based on frequency and amplitude, under two conditions: eyes open and eyes closed. </p><p>Simple and Complex Reaction Time. The timer used was made by Schfihfried, Stuttgart, West Germany. The subject sat with his finger poised over a 1-cm 2 response button and reacted to signals by pressing as quickly as possible. The signals consisted of red and white lights (2.5 cm in diameter, separated by a distance of 8 cm and positioned 6.5 cm from the response button) and a sound (acoustic power 0.1 W, 1250Hz); these were presented in programmed se- quence. A timing device measured the interval between the ap- pearance of the stimulus and the subject's response in milliseconds. For simple visual and auditory reaction time, the subjects were required to respond to a presentation of the white light or the sound. For complex reaction time, they were to respond only when the white light and auditory stimulus occurred simultaneously although the other stimuli, alone and in combination, were also presented. In the experimental sessions, each subject responded to five visual, five auditory and five complex stimuli. </p><p>The Vienna Determination Apparatus (VDA). This apparatus (Schfihfried, Stuttgart, West Germany) generates a sequence of visual and auditory stimuli and records button and foot pedal responses. The correct and incorrect responses to the signals were recorded. A correct response was registered when the appropriate response was made during the presentation of the signal. In this experiment, the subjects were required to respond to a series of 100 randomized signals of 1.22-s duration. </p><p>Pursuit Rotor. The Motorische Leistungsserie (Schfihfried, Stuttgart, West Germany) apparatus was used and the test was basically one of hand-arm coordination. The task required the subject to track, with a photocell stylus, a 15-mm square lighted area on a horizontal work plate, which rotated at 15 revolutions per minute in a clockwise direction. The number of times the stylus went offthe target and the total time it was off target were automatically recorded. The test time was 32 s. </p><p>Arithmetic. This is a concentration and attention test. The apparatus used was the Arbeit und Konzentration Testger/ite (Zak, Simbach am Inn, West Germany). The subject was presented with a series of random single digit addition and subtraction displays. The subject was required to key in the answers by pressing one of the ten buttons situated just below the displays. Each response generated another display and the number of correct responses was automatically recorded. The test time was 2 min. </p><p>The 'Boggles' Word Construction Test. In this test subjects were presented with a 4 x 4 matrix of 16 letters, and asked to construct as many English words as possible in 3 rain by rearranging letters from unbroken groups of adjacent letters (adjacent by row, column or diagonal). A different form of this test was given on each of the twenty testing occasions. The raw scores on each form were corrected for differences in difficulty level. </p><p>Blood Ethanol Concentrations. These were measured by breath analysis using the Alcotmeter (Model AE-D, Lion Laboratories, Cardiff, U.K.). A sample of deep alveolar air is collected when the exhalation pressure is falling and any ethanol present is oxidised by an electro chemical sensor (fuel cell) at 40 ~ The resultant signal is amplified and presented as a peak-reading digital display. The apparatus is calibrated by means of a standard aerosol of ethanol in argon (Nalco, Lion Laboratories, Cardiff, U.K.). In a preliminary experiment, correlation coefficients for the relationship between capillary blood ethanol concentrations determined by gas-liquid chromatography (Franks et al., 1976) and as shown by the Alcolmeter were calculated for four samples of ten pairs of readings. .The correlation coefficients were between 0.93 and 0.97 (P &lt; 0.001). </p><p>Procedure </p><p>The experiment was conducted on four successive week-ends. Each subject was randomly assigned to one of four groups and each group received each of the following treatments according to a 4 x 4 Latin square: THC + ethanol; THC placebo ethanol; THC placebo + ethanol placebo; ethanol placebo + THC. The experiment was conducted double blind in that neither the subjects nor the observers were aware of which treatment had been administered until the series was complete. The subjects arrived at the laboratory approximately 2 h after consuming a light breakfast. The test battery was adminis- tered to each subject before any drug treatment was given. After the control run (To), the subjects received THC or placebo. One hour later, the subjects were given their ethanolic or placebo beverages and they consumed them under supervision over a 20-min period at a constant rate. Twenty minutes after drinking finished (i.e. 100 min after THC administration), the subjects went through the test battery again (T1) and at hourly intervals thereafter (T2, T3, T4). Pulse rate and blood ethanol were determined at the mid-point of each test sequence and the subjects were asked to estimate the nature and degree of their intoxication. The subjects were allowed to mingle freely, but the tests were conducted in separate cubicles to reduce subject-subject interaction. A light lunch of sandwiches and de- caffeinated coffee was consumed after the second (i.e. T z, 100 min) post-ethanol trial. </p><p>In summary, a three factor within-subjects design was used (Table 1). </p><p>Analysis o f Data </p><p>In view of the relatively large number of outcome measures employed in this study, it was decided to base the statistical analysis of the data on linear combinations of measures defined by factor analysis (Butler et al., 1972). A principal components analysis carried out across total experimental variation (Horst, 1963) suggested that systematic var- iance in the test battery could be summarised adequately in terms of scores on four rotated factors, which jointly accounted for 76.8 ~ of total test battery variance. Scores on the first unrotated principal com- ponent were also analysed, since it was expected that this particular linear combination would be more reliable than either the rotated factors or the individual measures (Cattell, 1966). Interpretations of the factors was based on the pattern off actor loadings given in Table 2. All variables in this table are scaled (after reflection if necessary) in such a way that a high score indicates superior performance. The first </p></li><li><p>B. E. Belgrave et al.: (-) Trans-A9-Tetrahydrocannabinol 55 </p><p>principal component (I), which accounted for 36.0 % of total test battery variance, is simply an efficient measure of general level of performance on the test battery as a whole. The following in- terpretations of rotated factors are based on common features of variables with substantial loadings (italicised in Table 2): </p><p>Factor I' - reaction speed factor incorporates visual reaction time, auditory reaction time and complex reaction time data. </p><p>Factor II' - cognitive factor incorporates word construction ('Boggles') and arithmetic. </p><p>Factor III' - standing steadiness factor incorporates standing steadiness (eyes open and eyes closed) data. </p><p>Factor IV' - psychomotor coordination factor incorporates pursuit rotor and Vienna determination data. </p><p>From the correlations between the rotated factors (Table 3), it is clear that the factors represent relatively independent dimensions of test battery performance. </p><p>Results </p><p>Blood Ethanol Levels. There were no significant differ- ences in ethanol levels at any time between the THC </p><p>Table 1. Experimental design </p><p>Factor Factor levels </p><p>THC (A) </p><p>Ethanol (B) </p><p>Time of testing (C) </p><p>al, 320 gg/kg a2, Placebo </p><p>bl, 0.54 g/kg b2, Placebo </p><p>c o - First reading before drug adminis- tration, To c 1 - First reading after drug adminis- tration, T 1 c2 - Second reading after drug adminis- tration, T 2 % - Third reading after drug adminis- tration, T 3 c4 - Fourth reading after drug adminis- tration, T 4 </p><p>placebo-ethanol group and the THC-ethanol group (Table 4). </p><p>Performance Data. The mean factor scores obtained in the various experimental conditions are shown graphi- cally in Figs. 1 - 5. Scores on each factor were subjected to a 4 x 2 x 2 x 5 analysis of variance with repeated measures on the last three factors (Winer, 1962), where the first factor is concerned with the order in which the drug treatments were presented. The resulting F ratios for tests of interest (excluding effects related to order) are presented in Table 5. Since all tests were carried out at the 0.01 significance level, the Bonferroni inequality (Harris, 1975) ensures that the overall type I error rate for each effect cannot exceed 0.05. From Table 5 and Figs. 1 - 5, the following conclusions can be drawn: </p><p>1. The first principal component provides a good summary of the trends across the four rotated factors...</p></li></ul>