Number 21 WEIL

Number 21 WEIL - Clinical md prycholoqical effects of...

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Unformatted text preview: Clinical md prycholoqical effects of marihuana in man — ' ANDREW T.WEIL ' NORMAN E. ZINBERG JUDITH M. NELSEN In the spring of 1968 we conducted a series of pilot experiments on acute mari- huana intoxication in human subjects. The study was not undertaken to prove or dis- prove populariy held convictions about, ' marihuana as an intoxicant, to compare it with other drugs, or to introduce our own opinions. Our concern was simply to col- lect some long overdue pharmacological data. In this article we describe the primi— tive state of knowledge of the drug, the research problems encountered in design- ing a replicable study, and the results of our investigations. . . . Research Problems . That valid basic research on marihuana - is almost nonexistent is not entirely ac- counted for by legislation which restricts even legitimate laboratory investigations or by public reaction sometimes verging on hysteria. A number of obstacles are intrinsic to the study of this drug. We now present a detailed description of our spe- cific experimental approach, but must comment separately on six general prob- lems confronting the investigator who contemplates marihuana research. 1. Concerning the route of administra- tion, many pharmacologists dismiss the possibility of giving marihuana by smoking . 1968) pp. 1234-1242. Coth ' lean Association 101- the Advancement of Science. Re- because, they say, the dose cannot be stan- dardized. We consider it not only passible, but important to administer the drug to . humans by smoking rather than by the oral route for the following reasons. (i) Smoking is the way nearly all Americans use marihuana. (ii) It is possible to have subjects smoke marihuana cigarettes in such a way that drug dosage is reasonably uniform for all subjects. (iii) Standardiza- tion of dose is not assured by giving the drug orally because little is known about gastrointeatinal absorption of the highly water—insoluble cannabinols in man. (iv) There is considerable indirect evidence from users that the quaiity of the intoxi- cation is different when marihuana or preparations of it are ingested rather than _.smoked. In particular, ingestion seems to cause more powerful effects, more “LSD- like" effects, longer-lasting effects, and ' more hangovers. _Further, marihuana smokers are accustomed to a very rapid - onset of action due to efficient absorption through the lungs, whereas the lateiicy for onset of effects may be 45 or 60 minutes after ingestion. . . . 'EClinical and I’chhologicai Enact. of Marihuana in Man" by Andrew 1'. Well. Norman E. Zinber: and Judlfli ll. Nelsen tron SCIENCE, Vol. 162, (December @1968 by the mar printed by permission. _ 2. Until quite recently, it was extremely difficult to estimate the relative potencies of different samples of marihuana by the techniques of analytical chemistry. For this study, we were able to have the mari- huana samples assayed spectrophotomet- rically for THC content. However, since THC has not been established as the sole determinant of marihuana’s activity, we still feel it is important to have chronic, users sample and rate marihuana used in research. Therefore, we assayed our mate- rial by this method as well. 3. One of the major deficiencies in ‘previous studies has been the absence of negative control or placebo treatments, which we consider essential to the design of this kind of investigation. Because mari— huana smoke has a distinctiVe odor and taste, it is difficult to find an effective - ' placebo for use with chronic users. The problem is much less diffith with non- users. Our solution to this dilemma was the use of portions of male hemp stalks, devoid of THC, in the placebo cigarettes. 4. In view of the primitive state of knowledge about marihuana, it is difficult to predict which psychological tests will be sensitive to the effects of the drug. The tests we chose were selected because, in addition to being likely to demonstrate effects, they have been used to evaluate many other psychoactive drugs. 0f the various physiological parametas available, we chose to measure (i) heart rate, because previous studies have consistently reported increases in heart rate after administration of marihtiana; (ii) respiratory rate, because it is an easily measured vital sign, and de- pression has been reported; (iii) pupil size, becatise folklore on effects of marihuana consistently includes reports of pupillary dilatation, although objective experimental evidence of an effect of the drug on pupils has" not been sought; (iv) conjunctival ap- pearance, because both marihuana smokers and eaters are said to develop red eyes; and (v) blood sugar, because hypoglycemia has been invoked as a cause of the hunger and hyperphagia commonly reported by mari- huana users, but animal and human evi- dence of this effect is contradictory. We did not measure blood pressure because previous studies have failed to demonstrate any consistent effect on blood pressure in man, and we were unwilling to subject our volunteers to a nonessential annoyance. 5. It is necessary to control set and setting. “Set” refers to the subject’s psy- - chological expectations of what a drug will do to him in relation to his general personality structure. The total environ- ment in which the drug is taken is the setting. All indications are that the form of marihuana intoxication is particularly dependent on the interaction of drug, set, and setting. Because of recent increases in the extent of use and in attention given this use by the mass media, it is difficult to find subjects with a neutral set toward - marihuana. Our method of selecting sub- jects (described below), at the least, en- abled us to identify the subjects’ attitudes. Unfortunately, too many researchers have succumbed to the temptation to have sub- jects take drugs in “psychedelic” environ- ments or have influenced the response to the drug by asking questions that disturb the setting. Even a question as simple as, “How do you feel?” contains an element of suggestion that alters the drug-set-setting interaction. We took great pains to keep our laboratory setting neutral by strict ad- herence to an experimental timetable and ' to a prearranged set of conventions gov- erning interactions between subjects and experimenters. ' 6. Medical, social, ethical, and legal concerns about the welfare of subjects are a major problem in a project of this kind. Is it ethical to introduce people to mari- huana? When can subjects safely be sent home from the laboratory? What kind of followup care, if any, should be given? -.Thesa are only a few specific questions with which the investigator must wrestle. Examples of some of the precautions we took are as follows. (i) All subjects were volunteers. All were given psychiatric screening interviews and were clearly in- formed that they might be asked to smoke marihuana. All nonusers tested were per- sons who had reported that they had been planning to try marihuana. (ii) All subjects were driven home by an experimenter; they agreed not to engage in unusual ac. tivity or operate machinery until the next morning and to report any unusual, de- layed effects. (iii) All subjects agreed to report for follow-up interviews" 6 months after the experiment. Among other things, the check at 6 months should answer the question whether participation in the ex- periment encouraged further drug Use. (iv) All subjects were protected from pos sible legal repercussions of their participa- tion in these experiments by specific agree- ments with the Federal Bureau of Narcotics, the Office of the Attorney General of Mas- sachusetts Bureau of Drug Abuse and Drug Control. Subjects The central group of subjects consisted of nine healthy, male volunteers, 21 to 26 years of age, all of whom smoked tobacco cigarettes regularly but had never tried _marihuana previously. Eight chronic users of marihuana also participated, both to “assay” the quality of marihuana received from the Federal Bureau of Narcotics and to enable the experimenters to standardize the protocol, using subjects familiar with their responses to the drug. The age range _ for users was also 21 to 26 years. They all smoked marihuana regularly, most of them every day or every other day. The nine “naive” subjects were selected after a careful screening process. An initial pool of prospective subjects was obtained by placing advertisements in the student newspapers of a number of universities in the Boston area. These advertisements sought “male volunteers, at least 21 years old, for psychological experiments." After nonsmokers were eliminated from this pool, the remaining volunteers were. inter- viewed individually by a psychiatrist who determined their histories of use of alco- hol and other intoxicants as well as their general personality types. In addition to serving as a potential screening te<:hnique to eliminate volunteers with evidence of psychosis, or of serious mental or person- - ality disorder, these interviews served as the basis for the psychiatrist’s prediction - of the type of response an individual sub- ject might have after smoking marihuana. (It should be noted that no marihuana— naive volunteer had to be disqualified on psychiatric grounds.) Only after a prospec- tive subject passed the interview was he informed that the “psychological experi- ment" for which hehad volunteered was a marihuana study. If he consented to participate, he was asked to sign a release, informing him that he would be “expected to smoke cigarettes containing marihuana or an inert substance.” He was also re- quired to agree to a number of conditions, among them that he would “during the course of the experiment take no psycho- active drugs, including alcohol, other than those drugs administered in the course of the experiment.” It proved extremely difficult to find marihuana-naive persons in the student population of Boston, and nearly 2 mouths of interviewing were required to obtain nine men. All those interviewed who had already tried marihuana volunteered this information quite freely and were de- lighted to discuss their use of drugs with the psychiatrist. Nearly all persons encoun— tered who had not tried marihuana ad- mitted this somewhat apologetically. Sev- eral said they had been meaning to try the drug but had not got around to it. A few said they had no access to it. Only one "person cited the current laws as his reason for not having experimented with mari- huana. It seemed clear in the interviews that many of these persons were actually afraid of how they might react to mari- huana; they therefore welcomed a chance to smoke it under medical supervision. . . . The eight heavy users of marihuana were obtained with much less difficulty. They were interviewed in the same manner ' as the other subjects and were instructed not to smoke any marihuana on the day - of their appointment in'the laboratory. Subjects were questioned during screen- ing interviews and at the conclusion of the experiments to determine their knowledge of marihuana effects. None of the nine naive subjects had ever watched anyone smoke marihuana or observed anyone high on marihuana. Most of them knew of the effects of the drug only through reports in the popular press. Two subjects had friends who used marihuana frequently; one of these (No. 4) announced his intention to “prove” in the experiments that marihuana really did not do anything; the other (No. 3) was extremely eager to get'high because “everyone I know is always talking about it very positively.” Setting Greatest effort was made to create a . neutral setting. That is, subjects were made comfortable and secure in a pleasant suite of laboratories and offices, but the experi- mental staff carefully avoided encouraging any person to have an enjoyable experience. Subjects were never asked how they felt, and no subject was permitted to discuss the experiment with the staff until he had completed all four sessions. Verbal inter- actions between staff and subjects were minimum and formal. At the end of each session, subjects were asked to complete a brief form asking whether they thought they had smoked mar'ihuana that night; if so, whether a high dose or a low dose; and how confident they were of their answers. The experimenters completed similar forms on each subject. Marihuana Marihuana used in these experiments was of Mexican origin, supplied by the Federal Bureau of Narcotics. It consisted of finely chopped leaves of Cannabis, largely free of seeds and stems. An initial batch, which was judged to be of low potency by the experimenters on the basis of the doses needed to produce symptoms of intoxication in the chronic users, was subsequently found to contain only 0.3 percent of THC by weight. A second batch, assayed at 0.9 percent THC, was rated by the chronic users to be “good, average” marihuana, neither exceptionally strong nor exceptionally weak compared to their usual supplies. Users consistently reported symptoms of intoxication after smoking about 0.5 gram of the material with a vari- ation of only a few puffs from subject to subject. This second batch of marihuana was used in the experiments described be- low; the low dose was 0.5 gram, and the high dose was 2.0 grams. ' All marihuana was administered in the form or cigarettes of standard size made with a hand-operated rolling machine. In any given experimental session, each per- son was required to smoke two cigarettes in succession (Table 1_). Table 1. Composition of the dose. The placebo ciga- rette consisted of placebo material. tobacco filler. and mint leaves for masking flavor. The low do9e was made up of marihuana, tobacco filler, and mint leaves. The h‘gh dose consisted of marihuana and mint leaves. —-———.—.~__.___...____._____.__ Mai-manna Total dose Approxi- in each mar-thum- mu 9°“ cigarette (2 cin- done {I} testes) (a) THC —_—"-_—‘—'——--——I—‘_p__-_.__ Placebo '" — Law 0.25 0.5 4.5 mg High 1.0 2.0 18 mg -—-——'——————.'.__—_._____.___ Placebomaterial consisted of the chopped outer covering of mature stalks of male hemp plants; it contained no THC. . All cigarettes had a tiny plug of tobacco at one end and a plug of paper at the other end so that the contents were not visible. The length to which each cigarette was to be smoked was indicated by an ink line. Marihuana and placebos were administered to the naive subjects in double-blind fash- ion. Scented aerosols were sprayed in the . laboratory before smoking, to mask the odor of_marihuana. The protocol during an experimental session was as follows. The sessions began at approximately 5:30 pm. Time Procedure 0:00 Physiological measurements; blood sample drawn 0:05 Psychological test battery No. 1 ( base line) 0:35 Verbal sample No. 1 0:40 Cigarette smoking 1:00 Rest period, 1:1 5 Physiological measurements; blood sample drawn 1:20 Psychological test battery No. 2 1:50 Verbal sample No. 2 1 :55 Rest period (supper) 2:30 Physiological measurements 2:35 Psychological test battery No. 3 3:05 End of testing Experimental Sessions Chronic users were tested only on high doses of marihuana with no practice ses- sions. Each naive subject was required to come to four sessions, spaced aboutaweek apart. The first was always a practice ses- sion, in which the Subject learned the proper smoking technique and during which he became thoroughly acquainted with the tests and the protocol. In the practice session, each subject completed the entire protocol, smoking two hand- rolled tobacco cigarettes-He was instructed to take a long puff, to inhale deeply, and to maintain inspiration for 20 seconds, as timed by an experimenter with a stop- watch. Subjects were allowed 8 to 12 minutes to smoke each of the two ciga- rettes. One purpose of this practice smok- ing was to identify and eliminate individ- uals who were not tolerant to high doses ' of nicotine, thus reducing the effect of nicotine on the variables measured during subsequent drug sessions. A surprising number (five) of volunteers who had de- scribed themselves in screening interviews as heavy cigarette smokers, “inhaling” up to two packs of cigarettes a day, developed acute nicotine reactions when they smoked two tobacco cigarettes by the required method. Occurrence of such a reaction dis- qualified a subject from participation in the experiments. In subsequent sessions, when cigarettes centained either drug or placebo, all smok- ing was similarly supervised by an experi- menter with a stopwatch. Subjects Were not permitted to smoke tobacco cigarettes while the experiment was in progress. They were assigned to one of the three treatment groups listed in Table 2. . . . Table 2. Order of treatment. Dru. session Group 1 2 3 High Placebo Low II Low High Placebo III ' Placebo Low High [Results and] Discussion Several results from this study raise important questions about the action of marihuana and suggest directions for future research. Our finding that subjects who were naive to marihuana did not become subjectively “high” after a high dose of marihuana in a neutral setting is interest- ing when contrasted with the response of regular users who consistently reported and exhibited highs. It agrees with the re- ports of chronic users that many, if not most, peeple do not become high on their first exposure to marihuana even if they smoke it correctly. This puzzling phenom- enon can be discussed from either a phys- iological or psychosocial point of view. Neither interpretation is entirely satisfac- tory. The physiological hypothesis suggests that getting high on marihuana occurs only after some sort of pharmacological sensiti- zation takes place.’ The psychosocial inter- pretation is that repeated exposure to marihuana reduces psychological inhibi- tion, as part of, or as the result of a learn- ing process. Indirect evidence makes the psycho- logical hypothesis attractivel Anxiety about drug use in this country is suffi- ciently great to make worthy of careful consideration the possibility of an uncon- scious psychological inhibition or block on the part of naive drug takers. The sub- jective responses of our subjects indicate that they had imagined a marihuana effect to be much more profoundly disorganizing than what they experienced. For example, subject No. 4, who started with a bias against the possibility of becoming high on marihuana, was able to control subjectively the effect of the drug and report that he had received a placebo when he had actu- ally gotten a high dose. As anxiety about the drug is lessened with experience, the block may decrease, and the subject may permit himself to notice the drug’s effects. It is well known that marihuana users, in introducing friends to the drug, do actu- ally “teach” them to notice subtle effects of the drug on consciousness. The appar- ently enormous influence of set and setting on the form of the marihuana response is consistent with this hypothesis, as is the testimony of users that, as use becomes more frequent, the amount of drug re- quired to produce intoxication decreases— a unique example cf “reverse tolerance.” (Regular use of many intoxicants is accom- panied by the need for increasing doses to achieve the same effects.) On the other hand, the suggestion aris- ing from this study that users and nonuse'rs react differently to the drug, not only subjectively but also physiologically, in- creases the plausibility of the pharmaco- logical—sensitization hypothesis. Of course, reverse tolerance could equally well be a manifestation of this sensitization. It would be useful to confirm the sug- gested differences between users and non- users and then to test in a systematic man- ner the hypothetical explanations of the phenomenon. One possible approach would be to continue to administer high doses of marihuana to the naive subjects according to the protocol described. If subjects begin reporting high responses to the drug only after several exposures, in the absence of psychedelic settings, sug- gestions, or manipulations of mood, then the likelihood that marihuana induces a true physiological sensitization or that experience reduces psychological inhibi- tions, permitting real drug effects to appear, would be increased. If subjects fail to become high, we could conclude that learning to respond to marihuana re- quires some sort of teaching or suggestion. An investigation of the literature of countries where anxieties over drug use are less prominent would be useful. If this dif- ference between responses of users and nonusers is a uniquely American phenom- enon, a psychological explanation would be indicated, although it would not ac- countfor greater effects with smaller doses after the initial, anxiety-reducing stage. One impetus for reporting the finding of differences between chronic and naive subjects on some of the tests, despite the fact that the experimental designs were not the same, is that this finding agrees with thestatements of many users. They sayihat the effects of marihuana are easily suppressed—much more so than those of alcohol. Our observation, that the chronic Users after smoking marihuana performed on some tests as well as or better than they did before taking the drug, reinforced the argument advanced by chronic users that maintaining effective levels of performance for many tasks—driving, for example—is much easier under the influence of mari- huana than under that of other psycho- active drugs. Certainly the surprise that the chronic users expressed when they found they were performing more effec- tively on the . . . tests than they thought they would is remarkable. It is quite the opposite of the false sense of improvement subjects have under some psychoactive drugs that actually impair performance. What might be the basis of this sup- pressibility? Possibly, the actions of mari- huana are confined to higher cortical func-' tions without any general stimulatory or depressive effect on lower brain centers. The relative absence of neurological-as opposed to psychiatric—symptoms in mari- huana intoxication suggests this possibility. Our failure to detect any changes in blood sugar levels of subjects after they . had' smoked marihuana forces us to look elsewhere for an explanation of the hunger and hyperphagia commonly reported by users. A first smp would be careful inter— viewing of users to determine whether _ they really become hungry after smoking marihuana or whether they simply find eating more pleasurable. Possibly, the basis of this effect is also central rather than due tosome peripheral physiological change. Lack of any change in pupil size of I subjects after they had smoked marihuana is an enlightening finding especially be- cause so many users and law-enforcement agents firmly believe that marihuana dilates pupils. (Since users generally ob- serve each other in dim surroundings, it is not surprising that they see large pupils.) This negative finding emphasizes the need for data from carefully controlled investi- gations rather than from casual observa- tion or anecdotal reports in the evaluation of marihuana. It also agrees with the find- ings of others that synthetic THC does not alter pupil size. Finally, we would like to comment on the fact that marihuana appears to be a relatively mild intoxicant in our studies. If these results seem to differ from those of earlier experiments, it must be remem- bered that other experimenters have given marihuana orally, have given doses much higher than those commonly smoked by users, have administered potent synthetics, and have not strictly controlled the labora- tory setting. As noted in our introduction, more powerful effects are often reported by users who ingest preparations of mari- huana. This may mean that some active constituents which enter the body when the drug is ingested are destroyed by com- bustion, a suggestion that must be investi- gated in man. Another priority considera- tion is the extent to which synthetic THC reproduces marihuana intoxication—a problem that must be resolved before marihuana research proceeds with THC instead of the naim‘al resin of the whole plant. The set, both of subjects and experi- menters, and the setting must be recog- nized as critical variables in studies of mari- huana. Drug, set, and setting interact to shape the form of a marihuana reaction. The researcher who sets out with prior conviction that hemp is psychotomimetic or a “mild hallucinogen" is likely to con; firm his conviction experimentally, but he would probably confirm the opposite hypothesis if his bias were in the opposite direction. Precautions to insure neutrality of set and setting, including use of a double-blind procedure as an absolute minimum, are vitally important if the ob- _ ject of inVestigation is to measure real ' marihua'na-induced responses. , Conclusions 1. It is feasible and safe to study the effects of marihuana on human volunteers who smoke it in a laboratory. 2. In a neutral setting persons who are naive to marihuana do not have strong sub- jective experiences after smoking low or high doses of the drug, and the effects they do report are not the same as those described by regular users of marihuana I who take the drug in the same neutral setting. . , ' 3. Marihuana-naive persons do dem- onstrate impaired performance on simple intellectual and psychomotor tests after smoking marihuana; the impairment is dose-related in some cases. 4. Regular users of marihuana do get high after smoking marihuana in a neutral _ setting but do not show the same degree ' of impairment of performance on the tests as do naive subjects. In some cases, their performance even appears to improve slightly after smoking marihuana. 5. Marihuana increases heart rate moderately. 6. No change in respiratory rate fol- lows administration of marihuana by in- halation. ' 7. No change in pupil size occurs in short term exposure to marihuana. 8. Marihuana administration causes dilatation of conjunctiva! blood veSSels. 9. Marihuana treatment produces no change in blood sugar levels. 10. In a neutral setting the physiolog- ical and psychological effects of a single, inhaled dose of marihuana appear to reach maximum intensity within one-half hour of inhalation, to be diminished after 1 hour, and to be completely dissipated by 3 hours. imagine with us, if you will, that you possess a special kind of psychological calen- dar watch. What makes it special is that it allows you to set it ahead so that it tells only future time, or back so that past time is all that it measures, or even to capture and hold the present in the imperceptible movement of its mechanism. With such a device. you could be the time keeper of yesterdays or tomorrows. or you might pre- fer to prevent the present from slipping into past and the future from ever becom5 ing now. How would-you use it? How would your behavior be affected by the way you chose to operate it? Such a speculation is more than an intriguing fiction. You already own this spe- cial device which has the power of transforming the modes of time. of so readily altering time perspective. Hit; the human mind. There is no construct of human imagination that has a more pervasive. V91 U"- appreciated. effect upon our behavior than that of time. “liberating Behavior from Timrkouud Control: Expanding the Present Through Hypnosis" by Ihilip G. Zimbsrdo. Gun! Marshall and Christina Mulach from JOURNAL OF APPLIED SOCIAL PSYCHOLOGY. Vol. 1. No. 4. (1911) pp. 305—323. Reprinted by pet-mission of Scrip“ Publishirtl Go. ...
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Number 21 WEIL - Clinical md prycholoqical effects of...

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