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.—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 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 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 marihuana 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 < 0.0005) and 31/2 hours (F = 4.94, df 3, P < 0.01). Alcohol significantly increased reaction time at both testing intervals, while the effects of marihuana in increasing reaction time were not apparent until the 31/2-hour time interval.

 

Comment

 

Dextroamphetamine produced the greatest changes in mood, decreasing drowsiness and increasing stimulation and activity. Ethanol and marihuana decreased activity, especially later on. The Clyde Mood Scale was used in two previous experiments. In one, dextroamphetamine increased scores for "friendly" and "clear-thinking" and decreased the "unhappy" score; these items would be reflected in the stimulation and activity factors of the present scale.4 In another, synthetic TI-IC decreased "friendly," "aggressive," and "unhappy" scores, while increasing "sleepy" scores.5 The results of the current study are consonant with earlier studies and consistent with expectations for all three drugs.

 

The NF and FC tests were used in the previous experiment with synthetic THC and both tests were impaired after three hours. In the present study, marihuana decreased performance significantly on the NF test, but to a lesser extent on the FC test. Considering that doses of 30 to 70 mg of THC were used in the earlier study, the results of the present study are consistent with those obtained before. Ethanol has pre-been tested in two recent studies. One, in which two doses, low and high, were smoked, used an estimate of time passed after a five-minute unstructured period of spontaneous speech had been recorded.? Three of nine subjects given low doses and four given high doses of marihuana estimated the period as longer than it actually was. Overestimation of time was found in another study which used oral doses of marihuana extracts Tasks taking 15, 90, and 180 seconds were overestimated as to time spent in accomplishing them. Our subjects, given the rather complex task of estimating 50% of a time period, tended as a rule to underestimate the actual periods, although time was usually estimated as longer during marihuana intoxication as compared with placebo or other drugs. Consequently, the studies seem to agree that subjective time is slowed by marihuana so that a given period of real time seems to be longer than it would be per-

ceived normally. This particular measure was characterized by high variability, as reported by others.s

 

Perception of the vertical in a tilted field was not much affected by any of these drugs, despite the rather large doses. This function may not be influenced until impairment is severe. This measure was also characterized by considerable intra- and inter-individual variability.

 

The DSST was significantly impaired as compared with placebo following both low and high doses of smoked marihuana and at each of two time periods in a previous experiment.? The lack of impairment of this test in the present study by either marihuana or alcohol suggests that further determination of the sensitivity of this test be made before any conclusions are drawn.

 

Simple reaction time has usually been impaired by ethanol, although results have varied due to different doses or times of testing.t The present study revealed unequivocal impairment from ethanol and somewhat less from marihuana. Marihuana has been reported to increase complex visual reaction time, and especially to increase variability in performance due to occasional complete lapses of attention.8 Although dextroamphetamine has been reported to decrease simple reaction time, this effect was not observed in the present study despite its rather striking effects on other tests.8

 

Summary

 

Twelve normal volunteer subjects were treated with marihuana (median dose equivalent to 32 mg tetrahydrocannabinol), ethanol (median dose 57 gm), dextroamphetamine (median dose 15 mg), and a marihuana placebo. Assignment to treatments was random over weekly intervals. Subjective responses based on a mood scale revealed increased stimulation and activity, as well as decreased drowsiness from dextroamphetamine as compared with placebo; ethanol and marihuana decreased activity. Dextroamphetamine tended to improve performance on psychometric tests; the other two drugs tended to impair it. Time estimation was longer with marihuana than with the other treatments, yet because the latter were associated with gross underestimates, marihuana estimates most closely approximated the actual interval being estimated. Dextroamphetamine increased performance on the digit-symbol substitution test. Ethanol and marihuana increased simple reaction time.

 

Marihuana and ethanol were most alike in their effects, with the particular exception of the alteration in time perception produced by the former drug. On the other hand, dextroamphetamine was essentially unlike the other two drugs and was the only one which improved, rather than impaired, performance even in nonfatigued subjects.

 

This study was supported in part by Public Health Service grant MH 03030.

 

References

 

1. Wechsler-Bellevue: Scale for Adolescents and Adults, Record Form II. New York, Psychological Corp, 1947.

2. Free SM, Guthrie M: A methodology using subjective response to discriminate between pharmaceutical preparations. J Clin Pharmacol 8:164-171, 1968.

3. Moran LI: Repetitive Psychodiagnostic Measures. Hogg Foundation for Mental Health. Austin, University of Texas, 1959.

4. Hollister LE, Gillespie HK: A new stimulant, prolintane hydrochloride, compared with dextroamphetamine in fatigued volunteers. J Clin Pharmacol 10:103-109, 1970.

5. Hollister LE, Richards RK, Gillespie HK:Comparison of tetrahydrocannabinol and s}nhexyl in man. Clin Pharmacol Ther 9:783-791, 1968.

6. Carpenter JA: Effects of alcohol on some psychological processes: A critical review with special reference to automobile driving skill. Quart J Stud Alcohol 23:274-314, 1962.

7. Weil AT, Zinberg NE, Nelsen JM: Clinical and psychological effects of marihuana in man. Science 162:1234-1242,1968.

8. Clark ID, Hughes R, Nakashima E: Behavioral effects of marihuana: Experimental studies. Arch Gen Psychiat, 23:193-198, 1970.

9. Lehmann HE, Czank J: Differential screening of phrenotropic agents in man. J Clin Exper Psychopath 18:222-235, 1957.