Marihuana, Ethanol, and Dextroamphetamine Mood and Mental Function Alterations

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1 From the Veterans Administration Hospital and Stanford University School of Medicine, Palo Alto, Calif MARIHUANA, ethanol, and dextroamphetamine are three widely used social drugs with somewhat different actions. Marihuana is a sedative somewhat like ethanol, but also has perceptual effects resembling those of hallucinogens. Ethanol is primarily a sedative, while dextroamphetamine is a stimulant. As it has been seldom possible to compare these three drugs in the same subjects, using quantified doses, we measured their effects on mood and selected mental functions. Methods Twelve normal young volunteers were chosen primarily on the basis of their being in good physical and emotional health and intelligent and cooperative enough to carry out the required procedures. All but one were men. Although most subjects had had prior experience with small doses of marihuana and amphetamines, and all with alcoholic beverages, none were chronic or recent users of any of these drugs, except for mild use of beverage alcohol. Subjects were told that these three drugs were to be given, and that one might be given twice. Four trials were run at weekly intervals, with random assignment of the following four treatments: (1) marihuana prepared as an extract and calibrated for 1-1-tetrahydrocannabinol (THC) content, 0.5 mg/kg; (2) 95% ethanol, 1 ml/kg; (3) dextroamphetamine sulfate, 0.2 mg/ kg; and (4) a placebo made by reextracting marihuana from which all cannabinoids had previously been extracted. Subjects varied in weight from 66 kg (146 lb) to 91 kg (200 lb). Doses of drugs were as follows: marihuana as THC, median dose 32 mg, range 27 to 39 mg; dextroamphetamine, median dose 15 mg, range 13 to 18 mg; ethanol, median dose 57 gm, range 50 to 68 gm. Doses of each drug were given orally in 180 ml of a flavored, noncaloric soft drink. To mask taste differences further, the subject was blindfolded and his nostrils occluded. To the greatest extent possible, double-blind control was exercised, although various circumstances (distinctive taste and effects of alcohol and marihuana) made this difficult. Subjects were given the doses of drug at 8 AM, while in a fasting state. One hour later they were given a battery of tests which included the rod-and-frame test, the digit-symbol substitution test, and simple reaction time. These tests were repeated 31/2 hours after drug administration. Rod-and-Frame Test 1 / 5

2 . This test used a portable, electrically operated apparatus (Model 12010, Stoelting). The subject looked into the enclosed box where he saw a white disk with a black rod inside a black square. The square was tilted first to the right then to the left, the rod being off vertical. The subject was allowed to direct movement of the rod until he saw it as vertical. Eight trials were done, with the setting of the frame to the right or left being equally divided but randomly ordered after the first two presentations. Deviation of the adjusted rod from vertical was recorded to the nearest 0.5 degree. All deviations were summed. Digit-Symbol Substitution Test (DSST). This test was part of the Wechsler-Bellevue Scale for Adults.' After some explanation and practice, the subject was instructed to begin when signalled to match the appropriate symbol to each digit in order, working as rapidly as possible. A test period of 90 seconds was used. The score was the number of correct substitutions completed in the allotted time. Simple Reaction Time. The subject was instructed to depress a telegraph key and keep it depressed until a tone which he would shortly hear stopped. A tone at 300 cycles per second at 70 db was generated for periods of 2, 7, and 12 seconds randomly over 19 trials (7, 6, and 6, for each time period respectively). Reaction time was expressed as the mean time to release the key on the 19 trials. Two hours and four hours after the drug was given, the following additional tests were dory.:,: Adjective Checklist Mood Scale. The subject was given a checklist of 50 adjectives which describe different feelings or moods.2 He rated them on a four-point scale, ranging from "not a bit" to "extremely," based on his current feelings. Three factors, scores for "active," "stimulated," and "drowsy" were obtained by summing the ratings on 12 adjectives contributing to the "active" factor, 7 adjectives contributing to the "stimulation" factor, and 5 adjectives contributing to the "drowsy" factor. Repetitive Psychometric Measures. Two tests were chosen from a series of psychometric tests designed for repeated measures, the Number Facility (NF) test and the Flexibility of Closure (FC) test.'3 The NF test consists of a 2 / 5

3 series of 'simple arithmetic problems. The FC test consists of a task of retracing in a field of dots a figure drawn in a similar field, the point of origin being designated in the open field. Both tests were available in numerous variations equated for difficulty so that no subject received the same set of problems twice. The number of correct problems completed in a five-minute period was the basis for the score for each test. Time Estimation. Subjects were instructed to pay close attention to the duration of a tone, try to conceive of a period of time exactly one half the duration of the tone and then, after a lapse of four seconds, to match that interval by depressing a telegraph key the appropriate length of time. The tones were the same as used above for the simple reaction time, once again being randomly presented. Each was separated by an interval during which the estimate of one half the time period was made. Thus, seven estimates of a 1-second interval, six of a 3.5-second interval, and six of a 6-second interval were required. Deviations from each time interval were summed algebraically and the mean score for each was calculated. Results The clinical effects of the drugs were about what might be expected, and to some extent were recognized by the subjects. Ethanol ingestion, in the large amounts given in the fasting state, had an immediate and profound effect, readily recognized as alcoholic intoxication. Most subjects were also able to distinguish the effect of marihuana, which occurred more slowly and was characterized by euphoria and sleepiness. The effects of dextroamphetamine were less readily evident and the placebo had no discernible effect, other than its noxious taste which resembled the active marihuana extract. Mean scores from the three mood-scale factors were compared for the three drugs and placebo two and four hours after the dose was given. Treatments were shown by two-way analysis of variance to differ in regard to drowsiness at two hours (F = 5.54, df 3, P < 0.005), due to less drowsiness from dextroamphetamine than from the other treatments (Table 1). Although this relationship held at four hours, differences between treatments just missed being significant. Stimulation is not necessarily the converse of drowsiness, and all three drugs tended to increase this factor as compared with placebo. Analysis of variance again revealed a significant difference between treatments after two hours (F = 3.00, df 3, P < 0.05), due to the greater degree of stimulation from dextroamphetamine at both time intervals. The activity factor was differently affected by treatments, both after two hours (F = 5.68, df 3, P < 0.005) and after 3 / 5

4 four hours (F = 6.04, df 3, P < 0.005). After two hours, the difference was due to increased activity from dextroamphetamine, while at four hours it was due to decreased activity from alcohol and marihuana. All changes in mood-scale factors were in directions postulated from known actions of the drugs. The Repetitive Psychometric Measures revealed differences between treatments (Table 2). Differential effects on the FC test were observed after two hours (F = 5.10, df 3, P < 0.01) due to improved performance following dextroamphetamine. After four hours, this difference was lost. A relative decrease in performance from mari huana was noted, although not statistically significant. The NF test revealed differences between treatments at both two hours (F = 5.33, df 3, P < 0.005) and four hours (F = 3.90, df 3, P < 0.025). Although dextroamphetamine also increased performance on this test, it did not account for the treatment differences. Rather it was marihuana, which decreased performance at both times. After two hours alcohol also decreased performance, to a degree which was not quite significant. The treatments differed on their effects on time estimate only on that for the 3.5-second interval (Table 3). The difference between treatments was significant both at two hours (F = 3.64, df 3, P < 0.025) and at four hours (F= 6.05, df 3, P < 0.005). In both instances it was marihuana which accounted for the differences in two distinct ways: toward a longer estimate of time and a closer approximation of the actual time interval. This marihuana effect was rather consistent, regardless of the time interval being estimated or the time of testing. No differences between treatments were observed in the amount of error on the rodand-frame test, either by analysis of variance (F = 1.45, df 3, NS) or by comparing each drug with placebo (Table 4). The digit-symbol substitution test revealed a difference between treatments after 1 hour (F = 3.15, df 3, P < 0.05), but not at 31/2 hours (F = 1.27, df 3, NS). This early difference was attributable to an increase in performance following dextroamphetamine. Differences beween treatments were observed on the simple reaction time at both 1 hour (F = 8.62, df 3, P < ) and 31/2 hours (F = 4.94, df 3, P < 0.01). Alcohol significantly increased reaction time at both testing inter vals, while the effects of marihuana in increasing reaction time were not apparent until the 31/2-hour time interval. 4 / 5

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TI-IC reflected of for period extracts greatest test. low with four the was "friendly" Overestimation Ethanol and longer Considering decreased present given synthetic and increasing of used them. Tasks high, changes spontaneous consistent during high and study Our were stimulation two taking "friendly," THC marihuana performance doses "clear-thinking" "sleepy" that subjects, of marihuana previous are smoked, mood, and time with 15, doses speech of consistent both 90, and scores.5 doses each present sensitivity ceived Perception The by rather is seems of DSST others.s of slowed two study normally. smoked was large of with time was of this also by be by the placebo doses. significantly high either longer This characterized vertical be variability, particular This marihuana made than other a function and so a impaired previous it before tilted would that drugs. measure by report considerable field a may alcohol any be given experiment.? Consequently, per- was not compared conclusions was period suggests be not influenced intra- much of The with real are that and affected lack placebo studies drawn. further until inter-individual of impairment by following seem determination any of to these agree variability. both of is this severe. low drugs, of that test and subjective was This despite given high of used the and tests had 30 to ethanol visual complete simple effects Summary mg), Subjective well psychometric marihuana underestimates, estimated. Ethanol alteration dextroamphetamine improved, Simple Twelve Marihuana different tetrahydrocannabinol), as and reaction and normal a lapses other Dextroamphetamine responses decreased than doses somewhat and marihuana tests; time, tests.8 with volunteer of ethanol or drowsiness attention.8 and times the this based has activity. placebo. less increased other especially were effect subjects usually of ethanol estimates from on testing.t two most treatments, from Dextroamphetamine Although was Assignment increased a marihuana. drugs mood been simple (median were to dextroamphetamine alike not The increase most impaired tended observed scale treated reaction present performance yet dose their closely to Marihuana revealed because treatments variability to with effects, by 57 impair time. study approximated tended ethanol, the gm), marihuana the increased present has revealed with it. dextroamphetamine was latter Time to compared performance been has although improve digit-symbol random study (median were estimation particular been unequivocal stimulation reported actual with results associated performance despite reported over due dose placebo; exception substitution to was interval weekly and to have increase (median its impairment equivalent to occasional longer rather activity, with decrease varied intervals. ethanol being of gross dose complex with test. striking theto as due from References Psychological pharmaceutical Austin, This Wechsler-Bellevue: Free Moran study University SM, rather LI: was time Guthrie Repetitive Corp, preparations. supported perception of Texas, was M: impaired, Scale Psychodiagnostic A essentially methodology produced J part for Clin performance Adolescents by Pharmacol unlike Public by using the Measures. Health former even and subjective other 8: , Adults, Service drug. two nonfatigued Hogg drugs response On Record grant Foundation the MH other subjects. Form to was discriminate hand, the for II. New Mental only York, one between Health. which and dextroamphetamine 5. Comparison special Science Arch Psychopath Hollister Carpenter Weil Clark Lehmann Gen reference 162: ,1968. AT, ID, Psychiat, LE, 18: , LE, of Zinberg Hughes JA: HE, tetrahydrocannabinol Richards Gillespie Effects to Czank 23: , automobile NE, R, fatigued Nakashima of RK, J: Nelsen HK: alcohol Differential Gillespie A volunteers. driving new JM: on E: and stimulant, Clinical some HK: screening Behavioral skill. s}nhexyl J psychological Quart Clin and prolintane of Pharmacol psychological effects J phrenotropic Stud man. Alcohol of hydrochloride, processes: Clin marihuana: 10: , Pharmacol effects agents 23: , A of critical Experimental in compared marihuana Ther man review 9: , J Clin with in studies. with Exper man. 5 / 5