Behavioral and electroencephalographic correlates of the chronic use of marijuana—A review

BEHAVIORALBIOLOGY21, 163-196 (1977)

Behavioral and Electroencephalographic Correlates of the Chronic Use of Marijuana--A Review' P. A . FRIED Carleton University, Ottawa, Canada

Research and discussion related to the behavioral and electroencephalographic effects of long-term use of marijuana or its constituents are reviewed. It is

concluded that tolerance develops to the behavioral and electroencephalographic depressant aspects of the cannabis drugs but little attentuation develops to the stimulant effects. The rate of tolerance development is considerably influenced by learning factors such as the opportunity or necessity to make behavioral responses that counteract the decrements in performance resulting from the drug's influence. Evidence is presented indicating that the animal and human literature are in considerable agreement if socially acquired cues and expectancies and dosage/ frequency parameters are taken into consideration. R e c e n t l y , M i l l e r a n d D r e w (1974) r e v i e w e d t h e r e s e a r c h c o n c e r n e d with b e h a v i o r a l effects o f c a n n a b i s in a n i m a l s . B y c h o i c e , t h e s e a u t h o r s did n o t c o n s i d e r , in a n y d e p t h , t h e c o n s i d e r a b l e l i t e r a t u r e p e r t a i n i n g s p e c i f i c a l l y to t h e r e p e a t e d u s e o f m a r i j u a n a a n d t h e r e l a t e d t o p i c o f t o l e r a n c e . It is t h e o b j e c t i v e o f this p a p e r to e x t e n d t h e m a t e r i a l c o n s i d e r e d b y M i l l e r a n d D r e w b y r e v i e w i n g a n d i n t e g r a t i n g d a t a p e r t a i n i n g to t h e c h r o n i c u s e o f marijuana. A l a r g e b o d y o f l i t e r a t u r e h a s b e e n d e v o t e d to s t u d i e s i n v e s t i g a t i n g t o l e r a n c e to m a r i j u a n a a n d m a r i j u a n a c o n s t i t u e n t s a n d , a l t h o u g h t h e e m e r g i n g p i c t u r e is a n y t h i n g b u t c l e a r , it is a p p a r e n t t h a t t h e u n d e r s t a n d ing o f this p h e n o m e n o n is a k e y f a c t o r in u n d e r s t a n d i n g the e f f e c t s o f r e p e a t e d m a r i j u a n a u s e . " C h r o n i c " t o l e r a n c e is s a i d to o c c u r w h e n , as a r e s u l t o f n u m e r o u s a d m i n i s t r a t i o n s o f a d r u g , an i n c r e a s e d a m o u n t o f t h e d r u g is r e q u i r e d to p r o d u c e t h e effects o b s e r v e d with t h e original d o s e l e v e l , o r w h e n a l e s s e r e f f e c t is p r o d u c e d b y t h e s a m e r e p e a t e d d o s e 1 Research leading to the present paper was supported by Grant No. MRC-DA-13 from the Medical Research Council of Canada and by Grant No. 494-74B from the Ontario Mental Health Foundation. Portions of this paper were presented at the Canadian Psychological Association-Non-Medical Use of Drugs Symposium on Behavioral Models of Drug Dependence at Windsor in 1974. The author thanks R. Stretch and H. Anisman for their critical comments. Requests for reprints should be sent to P. A. Fried, Department of Psychology, Carleton University, Ottawa, Ontario, Canada, K1S 5B6. 163 Copyright © 1977 by Academic Press, Inc All rights of reproduction m any form reserved

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(Kalant et al., 1971). The term " a c u t e " tolerance is used in cannabis research to denote a decrease in drug effect after one exposure to the drug (e.g., Black et al., 1970; Domino, 1971; McMillan et al., 1971). It is appropriate to emphasize at the beginning of the paper that tolerance, as defined previously, is "valid only for a specified individual drug action, and not necessarily for the composite picture of all actions of a given drug on the whole organism" (Kalant et al., 1971, p. 137). This is an important point as many of the controversial issues concerning tolerance (e.g., mechanisms involved, whether or not it occurs in humans, inconsistent findings with animals) revolve around the dependent variables chosen for observation rather than on overall drug action. SPONTANEOUS MOTOR ACTIVITY AND REACTIVITY Animals

The acute administration of marijuana-like compounds or constituents of marijuana has been found to affect spontaneous motor activity in a large number of species including the rhesus monkey (Scheckel et al., 1968: Grunfeld and Edery, 1969), dog (Dewey et al., 1970; Grunfeld and Edery, 1969), cat (Hockman et al., 1971; Lipparini et al., 1969), rabbit (Lipparini et al., 1969), gerbil (Grunfeld and Edery, 1969), mouse (Garattini, 1965; Holtzman et al., 1969), and rat (Potvin and Fried, 1972; Sjoden et al., 1973). The general, although not consistent, picture that emerges from these and other similar studies is that there exists a dose-related depressant effect manifested as a decrease in spontaneous activity. Confounding this generalization are the reports that at lower dose levels the reduction in activity is often preceded by excitation (c.f. Gershon, 1970), and, on occasion at higher doses, it is followed by an increase in activity (Garriott, et al., 1967; Davis, et al., 1972). The relatively few studies which have examined spontaneous activity following repeated cannabinoid administrations have reported that after a number of administrations of delta-9-tetrahydrocannibinol (Ag-THC) an attenuation of the depressant aspect occurs in the rat and is expressed as a return to predrug or control levels of ambulation (Davis et al., 1972; Fried and Husband, 1973: Glick and Milloy, 1972; Moreton and Davis, 1970), a return to predrug grooming and rearing activity when either A~-THC or cannabis extract was used (Masur et al., 1971), and even an increase in activity relative to controls (Potvin and Fried, 1972). In dogs, the ataxia and trance-like status which characterizes the effects of initial injections of both delta-8 (AS)_ and Ag-THC are considerably lessened after subsequent administrations (Dewey et al., 1969; Dewey et al., 1972).' Recently Rosenkrantz and others have described the activity of rats that were exposed to marijuana smoke for up to 87 days (Rosenkrantz and Braude, 1974: Luthra et al., 1976) or cannabinoids given orally for more

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than 100 days (Thompson et al., 1973; Luthra et al., 1975). In all cases there was a dose-related decrease in activity which lasted a week or two with subsequent tolerance developing to this reduced activity. After approximately 3 weeks of treatment 40% of the animals receiving 0.7 mg/kg of Ag-THC via inhalation became hyperactive in that they displayed increased grooming, circling, and gnawing. At higher doses of 2 and 4 mg/kg, however, the increase in activity was not observed. A reverse dose relationship was observed with oral doses. Hyperactivity was noted in an unspecified number of rats by Luthra et al. (1975) at doses of 10 and 50 mg/kg but not at the low dose of 2 mg/kg. Thompson et al. reported hyperactivity in all rats at all oral dose levels used which ranged from 50 to 500 mg/kg. It should be noted that an inhaled dose of zXg-THC produces effects that are two to three times greater than those produced by an equal amount of Ag-THC administered orally (Isbell et al., 1967; Kiplinger and Manno, 1970; Fried and Nieman, 1973). With oral treatment, all of the rats in Thompson's et al. study (1973) and half of the animals in Luthra's et al. study (1975) were not tolerant to the hyperactive effects of the cannabinoids after 90 days of drug ingestion. When cannabis was administered by inhalation, the hyperactivity that had been observed in 40% of the subjects had attenuated in virtually all rats after 23 exposures in one instance (Rosenkrantz and Braude, 1974) and 87 exposures in the other (Luthra et al., 1976). The lesser amount of hyperactivity observed in the inhalation studies may be due to small amounts of cannabinol and cannabidiol present in the marijuana. Both of these cannabinoids have been reported to attenuate the excitatory effects and/or potentiate the depressant effects of Ag-THC (Fernandes et al., 1974; Karniol and Carlini, 1973; Krantz et al., 1971; Takahashi and Karniol, 1975). Sjoden et al. (1973), using low doses of A8- and Ag-THC, tested rats in an open field apparatus nine times during a 19-day period of drug injections after the animals had been acclimatized to the laboratory for several months. The reduced activity measures following initial treatment attenuated in those animals receiving chronic Ag-THC. In the same study, other rats were tested in a similar fashion 30 min after receiving drug injections, except that they were placed in an open field within 24 hr of arriving at the laboratory. These subjects were as active or more active than vehicle-injected controls during the testing days, and there was no evidence of tolerance to this increased activity. Several authors have observed that lack of acclimation to the laboratory lessened the depressant action of acute injection of A~-THC (Barry and Kubena, 1969; Consroe et al., 1975; Fried, 1974). In fact at a dose level of 4 mg/kg the drug has been observed to result in initial increased activity when measured by an actophotometer (Barry and Kubena, 1969) and by activity wheel revolutions (Fried, 1974). However, at a higher dose of 8 mg/kg, the absence of laboratory acclimation did not attenuate the depressant effect

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of Ag-THC in activity wheels (Fried, 1974). This evidence of a doserelated interaction between acclimation and increased or lessened activity is consistent with Abel's (1970b) report of biphasic dose effect on ambulatory scores obtained when using a marijuana homolog, pyrahexyl. At 2.5 and 5 mg/kg of pyrahexyl he found increased motor scores, at 10 mg/kg there was no apparent effect, and at 15 mg/kg activity was depressed. Similarly, Glick and Milloy (1972) reported that acute low doses of Ag-THC (0.25 mg/kg) increased activity relative to controls, and Davis et al. (1972) observed increases activity following 5 mg/kg of Ag-THC and lessened activity after 15 and 30 mg/kg. Thus, it would appear that at relatively low doses some cannabinoids possess an excitatory or stimulant property and that this aspect of the drug's effect is potentiated in situations that are somewhat arousing (e.g., a novel apparatus or environment). These results also indicate that at higher dose levels the environmental variables are less of a factor in influencing the drug effect. The finding of Sjoden et al. (1973), that animals demonstrated signs of tolerance only in those situations in which cannabinoids originally reduced activity but not when the drugs originally increased activity, suggests that the consequences of administering cannabinoids repeatedly may differ as a function of whether one is considering excitatory or depressant aspects of the drug's effects. This theme will l~e developed further in other portions of this paper. In Potvin and Fried's (1972) study, rats that received 4 mg/kg of Ag-THC every second day for at least 50 days exhibited an increase in activity in an open field apparatus relative to appropriate control groups. A unique feature of this study was that the animals which received multiple administrations of the drug were tested in an open-field only once, after at least 25 injections. Presumably, the novel test situation was more arousing than the typical procedure in which animals receive repeated testing as well as repeated injections. Thus, the increase in activity is quite consistent with the hypothesis that the stimulant properties of Ag-THC do not attenuate with chronic Ag-THC administrations and that these same stimulant properties are potentiated in arousing situations. In the same study, a parallel observation was made using a swimming task. Two aspects of these observations appear particularly relevant. First, this increased activity cannot be attributed to a deficit in rate of habituation given the one-trial nature of the tasks. Second, there was no opportunity for the subjects to learn the motor response in either task while under the influence of Ag-THC. Thus, the difference between the significantly reduced activity of rats receiving just one injection of the drug prior to testing compared to the attenuation of this depressed activity in those animals receiving 25 injections is not attributable to such factors as practice, memory, or state dependency. However, it is important to emphasize that in other situations, aspects of tolerance to cannabinoid

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effects following repeated administrations may be highly contingent upon such variables as state dependency. This will be considered in a later portion of the paper. The data pertaining to temperature and cannabinoids are strikingly parallel to the reports described previously. As in the activity studies, low doses of Ag-THC (up to 5 mg/kg) in rats result in a stimulant effect reflected as hyperthermia (Sofia, 1972, Johansson et al., 1975). At higher doses there is a dose-dependent fall in temperature (Abel, 1972; Adams et al., 1976; Yagiela et al., 1974). After repeated administrations, tolerance is reported to develop to the hypothermic effect (Anderson et al., 1975) and, in a number of instances, is succeeded by hyperthermia (Lomax, 1971; Johansson et al., 1975). No tolerance has been found to develop to the hyperthermic response following low doses of Ag-THC (Johansson et al., 1975). Thus, these studies, in the same manner as the activity data, indicate the dose-related dual nature of cannabinoids, the absence of tolerance to the stimulant effects which are manifested at the outset at low doses, and the unmasking of the stimulant effects when tolerance develops to the depressant aspects of higher doses of cannabinoids. A further aspect of the Potvin and Fried (1972) study which is pertinent to this discussion was the observation of a dramatic change in the reactivity of animals that received chronic administrations of 4 mg/kg of Ag-THC. After approximately 15 injections these animals became very difficult to handle, reacting with exaggerated responses to a puff of air or light touch. In this study, the animals were maintained on a limited ration of food. From the results of other laboratories stress, induced in this case by partial food deprivation, would appear to be an important variable in producing an increase in reactivity following chronic administrations of various cannabinoids. There are numerous reports that relate chronic cannabis administrations to an increase in different forms of reactivity in rats. In most studies chronic administration of cannabinoids resulted in intraspecies aggression only if an additional stress factor was added. This stress could take many forms including food deprivation (Carlini and Masur, 1969; 1970), morphine withdrawal (Carlini and Gonzalez, 1972), or cold (Carlini et al., 1972). Consistent with this apparent interaction of stress and cannabis producing aggression are the reports by Carder and Olson (1972) and Alves et al., (1973). In the study by Carder and Olson rats treated with acute low doses of marijuana extract fought more than controls when provoked by foot shock. If, however, the animals were familiarized with the test apparatus (with no shock present), thereby removing the arousal associated with a novel situation, the drug plus shock did not produce an increase in aggression. In the study by Alves et al. (1973) acute administrations of 5-40 mg/kg of Ag-THC resulted in aggression in rats if they had previously been deprived of rapid eye movement sleep.

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Miczek (1976) failed to find intraspecies aggression in rats over a wide range of dose levels of injected Ag-THC which was administered for up to 8 weeks. In his study the animals were only slightly food-deprived as they were restricted to 20 g a day. Some workers have found aggression to occur in the absence of any intentional experimenter-introduced stress if the chronic administration is carried on for a very extensive period (Thompson et al., 1973; Luthra et al., 1975, 1976). In these instances the aggression was found more consistently at higher doses. Thus, it would appear that intraspecies aggression may arise following chronic administration, but its onset is more rapid if additional stressors are present. Mouse-killing behavior (muricide) in previous "nonkiller" rats has been induced by chronic administration of Ag-THC and typically is potentiated by stressful manipulations such as hunger (Alves and Carlini, 1973; Ueki et al., 1972) or isolation (Ueki et al., 1972). Miczek (1976) reported muricidal behavior in rats following chronic injections of Ag-THC with no experimenter-introduced stress. It is noteworthy that in this latter study the occurrence of mouse killing was considerably delayed compared to those in which stress was manipulated. Both Ueki et al. (1972) and Miczek (1976) indicate that the muricide induced by Ag-THC differed from mouse killing observed in natural "killer" rats. The development of irritability concurrent with the development of tolerance has also been observed in group-living macaques (Sassenrath and Chapman, 1975). Monkeys that had received THC daily for several months exhibited increased aggressiveness in situations in which the group dominance structure was unstable or when animals were intentionally housed in high density conditions. The data reviewed above, coupled with the reports that acute doses of cannabinoids suppress intraspecies aggression (Miczek, 1976) and muricidal behavior in "killer" rats (Alves and Carlini, 1973), are consistent with the findings discussed earlier pertaining to spontaneous activity. The dose-dependent depressant effect of cannabinoids attenuate with chronic administration, and as tolerance develops excitatory behavior manifests itself. Little, if any, tolerance develops to this aspect of the drug's effect. Palermo Neto (Palermo Neto and Carvalho, 1973; Palermo Neto et al., 1975) has suggested that the lowered levels of brain 5-hydroxytriptamine (5-HT, serotonin) which he found following chronic cannabis treatment are involved in the appearance of aggressive behavior. Chronic injections of Ag-THC have been shown by others to reduce the turnover of brain 5-HT, although there was no decrease in levels of serotonin (Ho et al., 1973, 1974). The report that prolonged stress reduces 5-HT (Curson and Green, 1968) and that ovariectomized rats with lowered 5-HT due to estrogen treatment become aggressive following cannabis injections sooner than animals receiving only cannabis supports this hypothesis. Also consistent with this proposal are the data reporting a relationship

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between muricidal behavior and lowered 5-HT (Kulkarni, 1968; Karli et al., 1972). Humans

In humans, the question of the effect of chronic use of marijuana or marijuana-constituents upon general motor activity and reactivity is difficult to assess as the profound influence of psychosocial factors such as socially acquired cues and expectancies with respect to drug effects (e.g., Carlin et al., 1974; Hollister, 1971; Hollister et al., 1975; Jones, 1971 a and b) confound any interpretation. Even at quite high doses, by North American standards, psychosocial factors play an important role (Rubin and Comitas, 1975). A second problem associated with the specific topic of spontaneous motor activity is that most of the reports in the literature are obtained from "regular" users in an indirect manner. Typically, a self-rating and/or symptom check list is utilized (e.g., Galanter et al., 1973; Waskow et al., 1970) in which parameters of drug effect such as dizziness and lethargy are itemized. The picture that emerges is the "amotivational syndrome" (McGlothin and West, 1968), one of a general reduction in physical activity following cannabis use, a loss of desire to work, to compete, and to face challenges (Le Dain Commission, 1972). However, it is very difficult to distinguish socially acquired cues and/or expectancies which may make a chronic user more "sensitive" to the drug from attenuation of drug effect typically reported in most of the animal literature. Jones (1971, a and b) controlled psychological variables to a degree by administering Ag-THC either in conventional cigarettes or in an oral form which eliminated many of the cues normally associated with "smoking up." Jones' subject pool was divided into infrequent and frequent users. The former smoked fewer than two cigarettes a month, whereas the latter smoked at least seven cigarettes a week. The level of a subjective, self-rating assessment of intoxication, presumably including such variables as lethargy, was lower in the frequent user group than in the infrequent user group when the drug was given orally. However, when the Ag-THC was smoked, the two groups reported virtually the same degree of intoxication. Thus, in the situation which limited psychological cues, tolerance appeared in the chronic subjects. In the control portion of these studies (Jones, 1971 a and b) the role of psychological variables was demonstrated in a striking fashion. The frequent users reported a greater degree of intoxication than the infrequent users when a placebo was given in cigarette form, but no differences were reported between the two groups when the placebo was given orally. Data from a study by Meyer et al. (1971) is in striking accord with much of the animal literature reviewed previously. Casual smokers (less than one cigarette per week) were contrasted to heavy smokers (daily use of marijuana) on a variety of tasks. Both groups were instructed to smoke

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an amount of marijuana that caused them to reach a "high" that they usually got when smoking. The two groups did not differ in the amount consumed. On a subjective rating scale the heavy users rated themselves as higher than the casual users after 30 min and they came " d o w n " sooner than the light users. What is of particular interest is that heavy users were less impaired on psychomotor tasks than the casual smokers, and on a "vigor" assessment of these tasks the heavy smokers scored higher indicating a stimulant effect. A few workers have looked at psychomotor functions such as ataxia (Morrow, 1944) and motor coordination (e.g., Morrow, 1944; Clark et aI., 1970; Klonoff et al., 1973; Milstein et al., 1975) in nonnaive subjects. The work by Milstein et al. (1975) compared naive to regular but not heavy users (averaging approximately twice a month) in motor, perceptual motor, and visual recognition tasks after each subject smoked cigarettes with approximately 8 mg of Aa-THC and control cigarettes made from placebo material (marijuana with Ag-THC extracted). No effect of Ag-THC was observed in either group on simple motor tasks, although in the perceptual motor tasks there were impairments in both naive and regular user groups in the experimental condition. Interestingly, and uniquely, these authors found that the naive users were less impaired than the experienced group. On the other hand, Feinberg et al. (1975) found " m a r k e d " tolerance on unspecified motor tasks after 5 or 6 days of very high oral doses of 210 mg of Ag-THC [equivalent to two (Jones and Stone, 1970)-10 (Isbell et al., 1967) cigarettes] administered to heavy users with habits of one to two cigarettes a day. The contrasting findings between these two studies with respect to the absence or presence of tolerance may be attributable to the quantitative differences in marijuana consumption between the two " u s e r " groups prior to being placed in the test situation. In a study by Miles et al. (1972), six regular marijuana users (the average frequency of use was once a week for 2 years) volunteered to spend 70 days in a closed-off annex next to a hospital. The subjects smoked a mandatory amount (16 mg of 2~9-THC each for 4 weeks) during the study and were also allowed to purchase additional marijuana if they wished. The six individuals could engage in productive work (building stools) for which they would be paid. Out of their earnings they were expected to pay for such items as food, cigarettes, beer, and toiletries. Of particular relevance here were the observations made on the subjects' activity. The authors "tentatively conclude that in this study, an 'amotivational' syndrome showed up in terms of decrease in the amount of time spent in productive work and a roughly corresponding increase in time spent being passively entertained and in resting in bed doing nothing" (p. 33). This description parellels one in a report by Williams et al. (1946). These authors observed six prisoners, former marijuana users who were

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placed in a research ward and permitted to smoke marijuana ad libitum for 39 days. Initially these subjects demonstrated exhilaration but after several days this "was replaced by general lassitude and indifference which resulted in . . . a lack of productive activity" (p. 1082). The reasons for the occurrence of this often-described syndrome are numerous and speculative (Marihuana and Health, 1971; Le Dain, 1972). Whatever approach is taken, the critical role of cultural and socioeconomic factors in determining at least this aspect of chronic cannabis use have to be recognized. For example, in Jamaica, individuals often smoke prior to the performance of a heavy task so as to provide themselves with energy and strength (Bowman and Pihl, 1973" Rubin and Comitas, 1975; Comitas, 1976). Thus, in that particular culture, cannabis is used as an aid to work. Even within our Western culture the amotivational syndrome cannot be ascribed to marijuana in a casual manner. Contributing to the difficulty is the complexity of the interaction of drug use and the general lifestyle of the user and the critical importance of socialization experiences that antedate marijuana usage (Carter and Doughty, 1976; Mellinger et al., 1976). A vivid demonstration of this was obtained in the study of Miles et al. (1972) described previously. Near the end of that experiment, the subjects staged a form of strike, insisting upon higher wages. This, in itself, is not consistent with an amotivational attitude. When the subjects did, in fact, receive an increase in wage, their productivity increased despite a continued intake of marijuana. Thus, it would appear that under an appropriate incentive, the lethargy and general disinterest induced by cannabis can be overcome. Similarly, Casswell (1975) reported that monetary incentives tended to reduce the effect of cannabis on numerical and reaction-time tasks. This incentive factor may account for the failure to find consistent differences in academic performances between cannabis users and nonusers (Le Dain, 1972). In a paradigm quite similar to Miles et al. (1972), Mendelson and others (1974, 1976) found that work was sustained during marijuana smoking. The study on ataxia reported by Morrow (1944) is particularly relevant to the question of the influence of chronic cannabis use and its effect on unlearned motor tasks. In essence, the results were that static equilibrium was upset in a dose-dependent manner, with marijuana nonusers being considerably more affected than the users at comparable doses. A similar observation, using the same subjects, was made in a hand steadiness task. An interesting footnote in Morrow's report stated that, for most of the nonusers, the high dose (5ml of marijuana extract) was " t o o much," with ingestion often being followed by nausea. This was not noted by the subjects who had been regular users prior to the study. In summary, the work with humans suggests that if objective measurements are taken and psychological variables are controlled, the motor

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impairments which are apparent after the initial administration of the drug attenuate after heavy repeated use. Obviously, however, in the natural environment, psychological variables exist and therefore the self-reports, anecdotal statements, and results from observational studies describing lethargy and other motor effects in chronic users are important in the assessment of the long-term use of cannabis. With humans in experimental situations where stress was not obvious, aggressive behavior was not found during the repeated use of marijuana (Abel, 1977; Le Dain, 1972; Miles et al., 1972; Mayor's Committee Report, 1944; Williams et al., 1946). Virtually all governmental and official reports conclude that there is little or no relationship between aggressive criminal acts and the chronic use of cannabis (Indian Hemp Drugs Commission Report [1893-1894], 1969; Le Dain, 1972; Marihuana and Health, 1971, 1972, 1975), and self-reports of very heavy users in Jamaica indicate that no aggressive feelings arose as a function of their smoking experience (Rubin and Comitas, 1975). Although a detailed discussion of psychologically adverse effects of the chronic use of cannabis is beyond the scope of this review, it would seem appropriate to discuss briefly certain aspects of this topic since it may be somewhat analogous to the already described unusual animal behavior in stressful situations. It is interesting that a number of authors have noted the relatively large number of North American individuals coming to psychiatrists' attention following cannabis use (usually acute) in Vietnam, a presumably stressful environment (Talbot and Teague, 1969). Most psychological, adverse reactions to cannabis in North America are of an acute nature following an initial high dose of cannabis, and are typified by anxiety and panic reactions (Weil, 1970). As the cannabis in Vietnam is more potent than that usually available in North America, Talbot and Teague's (1969) observations may be due to a potency variable. In regular cannabis users, long-lasting psychological changes (including the amotivational syndrome mentioned above) have been repeatedly cited in the literature (e.g., Spencer, 1970; Mirin et al., 1971). However, in most reports, the mental health of the individuals prior to chronic cannabis use is either abnormal or not known (Kolansky and Moore, 1971, 1972). In addition, many patients are multiple drug users, and thus the specific role of cannabis cannot be determined. One aspect of psychological disturbance and chronic marijuana use which does seem relatively clear is that there exists a correlation between the extent of marijuana use and the time it takes to recover from the mental disorder (Paton et al., 1973). However, this finding can be interpreted as being consistent with the belief that cannabis use is a consequence of the psychological disorder and not the cause of it. In brief, at the present time the clinical literature indicates that psychological disorders arising directly from chronic cannabis use are

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-elatively rare in North America, but that the drug appears to be a zomplicating factor for particular individuals by contributing to and exacerbating previously existing chronic mental disorders. Reports of clinical findings from societies in which chronic users smoke more potent and greater amount of cannabis are varied. From research n India and Africa, numerous authors cite cannabis as a cause of many ~sychotic reactions, labeled collectively as "Hemp psychosis" (e.g., Chopra, 1969; Chopra and Smith, 1974; Lambo, 1965). This literature is fifficult to interpret and relate to the North American situation because of ;uch factors as the enormous amount of very potent cannabis consumed ~y most of the subjects considered, the absence of controlled compari;ons with nonusers having the same socioeconomic and philosophical ~ackground, and the interpretation of what is psychotic behavior. Recent ;tudies conducted in Jamaica by Bowman and Pihl (1973) and Rubin and 2omitas (1975) examined chronic users (at least 10 years of daily con~umption) of very potent cannabis and compared these subjects to conrols from the same environment who had never used the drug but who vere matched in terms of social class, alcohol use, and general intelli;ence. Unlike the reports cited above, there was no evidence of impairnent on any of the numerous psychological tests. A similar observation Las been made within a subculture of heavy cannabis users in }reece (J. Volavka, personal communication) and Costa Rica (Satz, et l., 1976). Unfortunately, whether the differences obtained in the studies of heavy Lsers of cannabis from the East and West are due to pharmacological, ociological, or methodological factors cannot be ascertained at this time. LEARNED BEHAVIOR nimals

One of the most striking effects of the repeated administration of ?-THC, synthetic derivatives such as pyrahexyl, or cannabis extract is in ehaviors which are maintained by positive reinforcement delivered nder various schedules. Whereas initial drug administrations interfere lith or abolish responding (depending upon the species and dose level), absequent injections result in a marked tolerance to the disruptive effect. 'his phenomenon has been reported in a variety of species such as the himpanzee (Ferraro, 1972; Ferraro and Grisham, 1972), pigeon (e.g., lack et al., 1970; Ford and McMillan, 1971; McMillan and Dewey, 1972), ad rat (e.g., Carlini, 1968; Frankenheim et al., 1971; Silva et al., 1968). Even though this attenuation of the initial effect is a robust phenomeon, a number of studies have reported that under particular circumances tolerance does not appear to develop equally to all facets of the isrupted behavior.

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One example of such an exception was described by Ferraro et al. (1971). The authors reported that a low dose of marijuana extract containing 1.0 mg/kg of Ag-THC disrupted a fixed ratio 40 schedule (the subject was required to make 40 consecutive responses in order to receive a reinforcement) in chimpanzees. This disruption did not attenuate after 18 administrations. What is particularly intriguing about this report is that the disruptive effect of Ag-THC was an increase in responding rather than the typical decrease. Thus, as in some studies cited earlier in the paper, tolerance did not seem to develop to the stimulant action of the drug. Other work by Ferraro (Ferraro, 1972; Ferraro and Grisham, 1972) suggests that tolerance is present if the experimenter defines it in terms of a return to a no-drug level rate of reinforcement. If, however, the criterion is in terms of rate of response, the animal's behavior, after many administrations of cannabis extract or Ag-THC, either does not return or takes longer to return to the no-drug level. For example, Ferraro (1972) used monkeys in a 45-sec variable interval task. Under this schedule each reinforcement was separated by a temporal interval averaging 45 sec with a food pellet being obtained following the first response after the 45-sec inter-reinforcement time had elapsed. The monkey could respond during the 45 sec, but this had no effect upon the number of reinforcements received. Ferraro found that the response rate was largely suppressed (and therefore the rate of reinforcement) during the first two days of 2 mg/kg of Ag-THC administered orally. As the daily regimen continued, the rate of responding increased sufficiently so that the number of reinforcements was similar to the no-drug condition, but the number of responses did not reach the no-drug level. In a parallel fashion, initial doses of marijuana extract distillate or synthetic Ag-THC caused chimpanzees in a DRL task (one in which a subject must withold a response for a specific temporal interval in order to obtain reinforcement, differential reinforcement of low response rate) to shorten their inter-response time (IRT) and therefore decrease the number of obtained reinforcements. Chronic administrations of these drugs resulted in tolerance with respect to reinforcement within the fifth and sixth testing session, but only by sessions 9 and 10 was the IRT similar to the ones observed during the no-drug period of study (Ferraro and Grisham, 1972). Very similar results have also been recently reported by Elsmore (1976). These observations, that subjects modified their behavior during repeated drug administrations in such a way so as to normalize the rate of reinforcement, was interpreted (Ferraro and Grisham, 1972) as evidence for the hypothesis that the development of behavioral tolerance involved a learning process. That is, some sort of behavioral adjustment or compensatory response is developed under the influence of the drug that permits the animal to counteract drug effects in performance. According to this hypothesis, repeated exposures to the drug per se would not result

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in tolerance (Ferraro et al., 1974) or at least slow its development (Ferraro, 1972; Sodetz, 1972; Manning, 1972, 1976 a and b). Several recent studies using schedule-controlled behavior have provided unquestionable evidence indicating that learning has some role in the development of tolerance. Manning (1973), using rhesus monkeys, examined the development of tolerance in a DRL task. Each monkey was tested on a previously learned task either 3 or 4 hr after the administration of an oral dose of Ag-THC. Within I hr of being in the test situation, the reinforcement rate had become similar to that observed during the nodrug portion of the study. The important aspect of this study was that the development of tolerance within one session was not a function of time elapsing between drug ingestion and testing. Both the group that was tested 3 hr and the group that was tested 4 hr after drug administration took 1 hr in the test situation to demonstrate tolerance. It was the actual performance of the response in the drug state that was critical in the recovery of the disruptive effects of Ag-THC. The evidence of learning being an important aspect of tolerance development is not restricted to data from primates. Carder and Olson (1973) gave marijuana extract to rats that had previously been trained to bar-press for either water or food reinforcement. One group of animals received the drug 1 hr prior to being placed in the test situation, whereas Lhe other group received the drug 45 min after bar-pressing. The drug~efore group was initially impaired in bar-pressing ability, but by the sixth Jay of drug administration the animals appeared tolerant. However, the drug-after animals, following 6 days of receiving marijuana extract after ~ar-pressing, showed virtually no evidence of tolerance when given the Jrug for the first time before testing. These authors (Olson and Carder, 1974) reported a parallel finding using starting time in an alley as a iependent measure. The rate of tolerance was a function of the amount of ~redrug training. These results are a persuasive argument for the role of earning in the development of tolerance. A further study implicating learning in an indirect manner is an experinent by Bueno and Carlini (1972). In this work, rats that were impaired in t rope climbing task following initial injections of cannabis extract were nade tolerant following 14 injections. The animals were then trained to wess one of two simultaneously presented Skinner bars; whether the right ~r left bar was correct was determined by whether the subject had been njected with cannabis extract or placebo 45 min previously. After 30 njections of cannabis alternating with an equal number of placebo adminstrations the subjects were able to perform the task successfully, apparntly on the basis of some sort of discriminative cue arising from the qarijuana extract. This is in spite of the fact that the animals appeared uite tolerant when tested on the rope climbing task throughout the final ~hase of this study.

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The ability of the rats to discriminate the drugged state from the undrugged state, even when tolerant to certain of the drug's effects, is consistent with the hypothesis that behavioral tolerance involves a learning process. The state within the organism which is induced by the cannabis extract can serve as a discriminative cue for the subject. During its presence, the animal can learn to develop a particular compensatory response to counteract the drug's effect. Once the new response is learned, tolerance is said to have occurred. From the above series of studies it is quite apparent that a learning mechanism is involved in at least some aspects of tolerance to cannabis or its constituents. But there is also incontrovertible evidence that tolerance can occur without the opportunity for the animal to learn to respond under the influence of the drug. Using rats, Potvin and Fried (1972) found tolerance manifested on a variety of one-trial tasks. One group of animals was placed in the test situation only once after receiving 25 injections of zXg-THC, and another group was placed in the same apparatus after receiving 24 control injections followed by one drug injection. The animals receiving chronic injections of 2~9-THC were equal to or superior to nondrug control groups, whereas the animals that had received just one injection of Ag-THC were severely impaired. Consistent with this is the report of Black e t al. (1970) that tolerance to the suppressive effect of Ag-THC on various schedules of key-pecking behavior in pigeons developed even when the response was not performed in the presence of the drug effect. Furthermore, it does not seem possible that learning could account for the ability of a pigeon to perform in a normal fashion after receiving gradually increasing amounts of Ag-THC in a schedule-controlled task at dose levels which, had they been injected initially, would have been lethal (Ford and McMillan, 1971; McMillan and Dewey, 1972). In summary, then, the result of chronic administration of cannabis constituents upon animal behavior in positively reinforced, schedulecontrolled tasks, is to reinstate the reinforcement rate to predrug levels but not always doing the same to response patterns. There is evidence that, in certain circumstances, tolerance involves a learning process. However, the generality of this and the relative importance of learning and pharmacological factors in tolerance is a matter of conjecture. Kalant e t a l. (1971) have suggested that the same mechanisms may be involved in both learning and pharmacological aspects of tolerance, but that they differ in their rate of development. Furthermore, these authors suggest that learned or behavioral tolerance should be considered as "behaviorally augmented" tolerance. This terminology would emphasize the fact that tolerance can develop at a pharmacological level but that it is relatively slow and can be accelerated by behavioral variables. The data described above strongly support this view.

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There have been relatively few studies which have examined the per'ormance of animals, after chronic cannabis or marijuana constituent administration, on tasks other than the schedule type discussed above. In conditioned avoidance task at doses of 2~9-THC above 7.5 mg/kg rats lisplay reduced rates of avoidance initially (Henriksson and Jarbe, 1971; ~¢aser et al., 1976), but if injections are continued tolerance develops to ;he suppressive effects with the drugged animals preforming at a higher •ate after 10 administrations (Waser et al., 1976). Webster et al. (1973) "ound that tolerance to Ag-THC developed in rats injected either before or ffter daily Sidman avoidance sessions, a task in which an animal must hake an avoidance response within a certain time limit after a cue stimuus appears. In complete agreement with the proposal of Kalant et al. 1971), described previously, those rats receiving their injections after the ask took longer to develop tolerance than those receiving their injections ~rior to training. Also consistent with Kalant's proposal is the work by 3lick and Milloy (1972) who manipulated the amount of experience rats lad with an activity wheel prior to repeated drug injections. They found hat predrug experience in the monitoring devices increased the rate of olerance development. Harris et al. (1972) found that repeated intravelous injections of Ag-THC in rhesus monkeys resulted in tolerance de~eloping in an avoidance task somewhat similar to that used by Webster 't al. (1973). Interestingly, only a slight degree of tolerance was observed n the monkeys' general behavior, suggesting that a specific compensatory 'esponse was developed for the avoidance task. Workers have examined the effects of repeated Ag-THC administrations m a delayed matching-to-sample problem (Ferraro and Grilly, 1973) and a [elayed oddity discrimination problem (Zimmerberg et al., 1971). These asks, which examine short-term memory, require subjects to choose rom among several alternatives a stimulus which has either presented delayed matching) or not presented (delayed oddity) some time predeermined previously. In the Ferraro and Grilly study, chimpanzees were ound to have diminished in accuracy and speed of performance with no olerance developing to this drug effect after 21 days of I mg/kg of Ag-THC ,nd 42 days of 4 mg/kg. When the drug portion of the study was termilated, the subjects' behavior returned to baseline levels of performance, n Zimmerberg's et al. (1971) work rhesus monkeys were given six oral loses of Ag-THC ranging from 0.5 to 2.0 mg/kg with each ingestion eparated by 3 days. As in the previous study, there was an initial ecrement in accuracy and rate of performance which did not attenuate ¢ith repeated drug administrations. In this latter work, the longer the nposed delay in the task, the greater the impairment in accuracy relative the control condition. The lack of tolerance in these relatively complex asks is interesting because it is in such contrast to the literature describlg the attenuation of the drug effect in simpler problems. However, these

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differences are in accord with the hypothesis that tolerance is more likely to occur (and to occur sooner) if some sort of compensatory response can be made to counteract the drug effect. Whereas this is ~ossible by changing response rates in schedule-controlled tasks and avoidance tasks, it is difficult to imagine that behavioral compensatory response can be made in problems which test short-term retention capabilities (Ferraro, 1972). A further study which supports the hypothesis that behavioral augmentation can be important to tolerance development is the experiment by Elsmore (1972) in which temporal and auditory discrimination performances of macaque monkeys were investigated. Both the accuracy and the rate of responding decreased with initial doses of AS-THC~ but following chronic oral administrations both disruptive aspects of the drug effect attenuated. Of particular interest for purposes of this discussion is that the rate of responding (a form of behavioral augmentation) returned to baseline levels before accuracy did. Humans

In humans, the effect of repeated use of cannabis or its constituents on learned behavior has been considered in a relatively wide range of tasks and situations. One example is time perception studies which are somewhat analogous to those animal studies in which reinforcement occurs with the first response after a fixed time interval. The data derived from human subjects are quite consistent; the experienced users' subjective feeling of time being faster than the actual time, resulting in an overestimate of the real time (Hollister and Gillespie, 1970; Le Dain, 1972; Jones and Stone, 1970). This relationship was found to be dose-dependent (Le Dain, 1972), occurring in both moderate (Hollister and Gillespie, 1970; Le Dain, 1972) and heavy users (Jones and Stone, 1970) with no evidence of tolerance as the drug effect was as great in users as in naive subjects (e.g., Clark et al., 1970; Weil et al., 1968). This absence of attenuation of the speeding up of an "internal clock" is consistent with the animal data described previously which related an absence of tolerance to the stimulant effects of low doses of cannabis constituents. It is particularly interesting that Ferraro et a l. (1971) noted that chimps receiving a food pellet after every 40 responses shortened their interresponse time and maintained this alteration throughout 18 injections of low doses of Ag-THC, thus again demonstrating an absence of tolerance to a stimulant effect of the drug. In a direct, operant examination of time perception Cappell et al. (1972) tested 12 "experienced" users in a problem requiring subjects to space their responses by at least 20 sec (DRL-20) in a key-pressing task after smoking Ag-THC. There was found to be a dose-related, shortened interresponse time and thus fewer reinforcements compared to a no-drug condition, suggesting a speeding up of subjective time. Unfortunately, there was no breakdown of subjects into heavy and light users (e.g. Jones,

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1971 a and b), although the term "experienced users" usually refers to a regular but relatively infrequent (typically, twice a week; e.g., Cappell, et al. 1973) habit. In addition, as there were no nonusers employed in the task, it is not possible to discuss these results in terms of acute and chronic cannabis use. The literature examining the effect of repeated cannabis use, intellectual performance, and higher cognitive function falls into three general categories. There are those studies which report the result of laboratory experiments utilizing "experienced" or "regular" users, those studies which have used a survey approach, and those studies in which heavy users have been compared to suitable controls either in experimental or natural settings. The first category, which comprises the bulk of the recent literature, typically involves tasks which require attentional and short-term memory mechanisms. Volunteers are used and their marijuana habit varies considerably, but, when the habit is reported, it is stated to be approximately once a week or less. With this subject pool cannabis has been found to effect cognitive tasks in a dose-related fashion with the degree of impairment being a function of the complexity and familiarity of the task. Thus, relatively simple tasks (e.g., digit span) are virtually unaffected at low and moderate doses (Casswell and Marks, 1973; Waskow et al., 1970), as are !asks which have been well learned prior to testing, such as counting ~ackwards (Waskow et al., 1970). In tests that make somewhat more ~.axing demands upon short-term memory and attention, such as serial nanipulation of information (Casswell and Marks, 1973: Melges et al., 1970), rearranging random numbers (Tinklenberg et al., 1970), and vari?us verbal learning tasks (Abel, 1970 a and b, 1971), the administration of zannabis results in an impairment of performance. In a series of studies, ight users (Rickles et al., 1973) and heavy users (Cohen and Rickles, 1974) were given a paired associate verbal learning task in an experimenal design which permitted testing for state-dependent learning. State tependency is the hypothesis that a drug may give rise to discernable, nternal cues, and when a task is learned under the influence of that drug, he internal cues become an important component of the acquired task. ~uccessful recall is hypothesized to be, in part, contingent upon the "einstatement of the internal cues. In the Cohen and Rickles study, the ight users (no more than three times a week), when tested after smoking narijuana, required significantly more trials to reach criterion than conrol subjects and, during recall 10 days later, demonstrated a significant ;tate-dependent effect. On the other hand, the heavy users (more than hree times per week) were not impaired during the original learning bUowing smoking nor was there any evidence of state dependency on the 'ecall trials. These differences between the light and heavy users strongly ;uggest the presence of tolerance in the latter group. The underlying

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causes of the impairment in the light users are not clearly established. Abel (1970 a and b, 1971, 1973), and Darley et al. (1973) present evidence that cannabis may affect the storage of information (not input or retrieval), perhaps because of a failure of concentration which impairs rehearsal of information. The work of Miller et al. (1972) on recalling a story generally supports this view. Attentional and motivational factors (Tinklenberg et al., 1970; Casswell and Marks, 1973) also play a role in this drug effect and probably underlie the reported episodic nature of this impairment (Tinklenberg et al., 1970). The duration of the cognitive changes appear to be usually less than 5 hr (Le Dain, 1972; Tinklenberg et al., 1970). Overall, the experimental reports using subjects who probably represent, in terms of frequency of habit, the majority of cannabis users in North America reveal an impairment in relatively complex tasks that waxes and wanes and is susceptible to attentional and motivational factors. A number of commissioned works and review articles which survey both clinical and experimental evidence from various populations differ in their conclusions. Greek subjects who averaged 25 years of heavy cannabis use, when tested after smoking 78-180 mg of Ag-THC, were very similar to North American casual users (previously described) who were tested after smoking up to 25 mg of Ag-THC (Dornbush and Kokkevi, 1976). Reports from the East (e.g., Indian Hemp Drug Commission Report [1893-1894], 1969; Chopra, t969) conclude that moderate use of the drug does not cause intellectual deterioration but excessive use does. These and similar reports have to be interpreted with caution, since, as noted earlier, the potency of the drug is much greater than typically used in North America, intermittent use is rarely defined, the population sample of chronic users is usually drawn from a very low socioeconomic group with its representiveness being difficult to ascertain, and there are seldom adequate control groups. The commissioned works which survey the situation in North American society with respect to intellectual functioning and long-term " h e a v y " use of cannabis all report that, except in rare cases, no evidence of cognitive impairment can be attributed to the drug (Le Dain, 1972; Mayor's Committee on Marihuana, 1944; Marihuana and Health, 1971, 1975). Of course, the term '~heavy" has quite different meanings in the East and West and thus some of the differences, although not all, may be accounted for in terms of degree of chronicity. Other factors which contribute to the discrepancy were discussed during the consideration of the "amotivational syndrome." A recent study conducted in Jamaica (Bowman and Pihl, 1973) found no indication of intellectual impairment in chronic, heavy users when contrasted with appropriate matched controls. The length of the habit and the strength of the smoked material is comparable to that used in India. The

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tbsence of cannabis-related effects on cognitive ability in the Jamaican ;ociety in contrast to the reports from the East highlights the complexity ~f the issue. In the Jamaican study, experimental subjects were tested when "not ligh." When the users were observed while consuming large amounts of ~otent marijuana, only minimal effects were seen, suggesting the presence )f tolerance. Attenuation of the drug effect and performance on a cognitive task were '.xamined directly by Jones (1971 a and b) and Jones and Stone (1970) who :ompared the performance of infrequent users (less than two cigarettes a nonth) to chronic users (more than seven times per week) on a digit ubstitution test. After smoking 1 g of marijuana (9 mg of Ag-THC), the requent users were not affected compared to the placebo condition, vhereas the infrequent users were impaired. This is quite consistent with he literature cited earlier in which relatively infrequent users were afected by cannabis. Additional evidence for tolerance is derived from the )ornbush et al. (1972) study in which 14 mg of Ag-THC was administered ally for 21 days to volunteer, experienced users. Subjects were tested in number of ways, including an assessment of short-term memory. The ,articipants were impaired at the start, but by the end of the experiment )e predrug performance level was reached.

ELECTROPHYSIOLOGICAL STUDIES The cortical electroencephalographic (EEG) changes that result from ~e acute administration of marijuana, its constituents, or synthetic THC erivatives are qualitatively quite similar across a number of species. ypical reports describe a generalized reduction in cortical EEG voltage. At the subcortical level, gross slow wave changes have been observed L a number of sites including the brain stem and midbrain reticular cstem in cats (Barratt and Adams, 1972) and amygdala and cerebellar eduncle in the monkey (Martinez et al., 1972). In the rabbit (Lipparini et '., 1969; Willinsky et al., 1973) and rat (Fried and Mclntyre, 1973) a isruption of hippocampal theta activity follows an acute administration cannabis constituents. In rats hippocampal theta activity is associated ith voluntary movement (Vanderwolf, 1969). In humans, recent reports (Hollister et al., 1970; Low et al., 1973; odin et al., 1970; Volavka et al., 1971; Fink, 1976) have typically found 1 increase in alpha activity, a slight decrease in the peak frequence of pha rhythm, and an increase in beta activity (Fink, 1976) following an itial administration of cannabis in the test situation. The behavioral ld/or biological importance of this shift is unknown. There have been a w reports of marijuana resulting in a desynchronized EEG (Ames, 1958; rues and Stone, 1970; Wikler and Lloyd, 1945; Williams et al., 1946). he explanation of these disparate data is not apparent, and the whole

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issue is confounded by the fact that, in all cases in which details with respect to subjects are provided, the subjects had previous experience with marijuana. In rats, repeated administrations of 2¢-THC or marijuana extract distillate results in a reduction of a drug effect on those aspects of EEG that are associated with lowered arousal and reduced activity (Klemm, 1969; Vanderwolf, 1969). Following chronic administrations the following effects are attenuated, slowing of peak alpha activity (Pirch et al., 1973, 1972), disruption of hippocampal theta (Fried and McIntyre, 1973), and anticonvulsant properties (Fried and McIntyre, 1973). In contrast, those aspects of EEG associated with central nervous system activation (the spike wave complexes) did not change during chronic administration (Fried and McIntyre, 1973; Masur and Khazan, 1970; Pirch et al., 1972; Stadnicki, Schaeppi, Rosenkrantz and Braude, 1974). These electrophysiological results are in striking accord with the behavioral data described previously, which indicated that the depressant and stimulant effect of cannabis constituents are differentially affected by chronic administrations. In species other than the rat, the data available pertaining to EEG changes following repeated administrations of Ag-THC is very limited. Lipparini et al. (1969) found no attenuation of EEG effects of 3 mg/kg of Ag-THC in a rabbit when it was given six daily injections. The use of a single subject and the limited number of injections makes any generalization difficult. Barratt and Adams (1972) administered Ag-THC to cats for 60-180 consecutive days and found no lessening of either slow wave changes or of the presence of spike-wave complexes. Heath (1973) presented marijuana smoke to six rhesus monkeys up to five times and recorded EEG from a number of cortical and subcortical sites. The most marked changes occurred in the septal region where delta waves at a frequency of 3-4 cycles per second and bursts of high amplitude spindles (approximately 16 cycles per second) were observed. Other sites which exhibited changes were cerebellar nuclei, hippocampus, and posteroventral lateral thalamus. Ninety minutes after administration of the smoke, the EEG resembled predrug recordings. Unfortunately, it is not possible from the report to determine whether or not the number of times a subject was given marijuana smoke differentially affected the EEG. It is quite apparent that further work, particularly of a comparative nature, is needed in this area. Data obtained from experiments with humans in which cannabis is administered daily indicate that EEG changes are minimal. Williams et al. (1946) reported that EEG changes were no longer present after 4 to 6 days, Miles and his associates (in Le Dain, 1972) in a preliminary report found no alterations in EEG during the course of a 4-week study, and Volavka et al. (1971) stated that a tendency toward "'increased synchronization" occurred in their subjects, this change lasting for 48-72 hr. Rodin

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't al. (1970) reported no abnormalities in the EEG of 10 healthy students

~¢ho had smoked marijuana regularly for at least a year. When the subects inhaled cannabis in the laboratory until they achieved their usual 'high," there occurred a slight but statistically significant shift toward ;lower alpha frequencies. Fink (1976) noted that chronic hashish smokers ,'xhibited the same EEG changes as occasional users following marijuana nhalation in an experimental situation. However, the heavy users retuired more Ag-THC prior to exhibiting the EEG alterations. In one phase ff the study occasional users were observed smoking for 21 consecutive lays. Fink found an attenuation of the originally observed alpha enlancement, but no alteration in the increased beta activity was noted in he 3 weeks. This is in accord with the hypothesis that tolerance develops [ifferentially to the excitatory and sedative properites of A9-THC.

SOME GENERAL CONSIDERATIONS Although much descriptive data are available with respect to the ironic use of cannabis, there are still many gaps in our knowledge. For ~ample, the question of the duration of tolerance has not been examined ~tensively in a systematic manner. In rats, Webster et al. (1973) found a ~ss of tolerance 9 days after drug administration ceased, but other work-s have found tolerance to last at least 8 days (Silva et al., 1968) or 11 ~ys (Davis et al., 1972). Barnes and Fried (1974) recently examined derance development in immature and adult rats. Rats, which had re~ived chronic injections of Ag-THC when immature and were then reincted with repeated doses of A9-THC when adults, developed tolerance )oner than those subjects which had their initial chronic experience hen mature. Related to this evidence is Abel's (1972) finding that the ~fects of A9-THC on body temperature is much greater in 12-hr-old ticks than in 15- and 25-day-old chickens and Nozaki et a l ' s (1975) .,port that the rate of tolerance to morphine was faster in 4-week-old rats an in 12-week-old animals. It has been suggested that the age-related aJg effect may be attributed to a lessened effectiveness of the blood"ain barrier in young animals (Abel, 1972). In dogs, (Dewey et al., 1969; Dewey et al., 1972), pigeons (McMillan et ., 1971), and monkeys (Harris et al., 1972) tolerance lasts at least 3 eeks. No systematic data are available on this topic with humans, though Jones et al. (1976) allude to a "rapid disappearance of tolerIce."

The issue of the mechanism(s) underlying the attenuation of the effect 'cannabis is a very complex one (e.g., McMillan and Dewey, 1972; artin et al., 1976) and still at a speculative state. It is beyond the scope 'this paper to consider this topic in detail, but certain aspects are trticularly relevant to the data described earlier. As mentioned preously, some aspects of attenuated drug effects are attributable to a

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learning phenomenon, but other facets involve some sort of pharmacodynamic system at the cellular level. Although the rate of metabolism of Ag-THC into 11-hydroxy-THC differs in users and nonusers (Lemberger et al., 1970, 1971), it is unlikely that this enzymatic change is the basis of tolerance, since this metabolite is pharmacologically active (Christensen et al., 1971; Lemberger et al., 1972; Wall, 1971). A further argument against the idea that increased microsomal breakdown of Ag-THC causes tolerance is the fact that if this were the underlying mechanism, then all aspects of the drug effect should demon~strate tolerance, and the rate of attenuation to different effects should be similar at similar dose levels. From the data reviewed previously, it is apparent that this does not occur. If tolerance is not due to an increased breakdown of Ag-THC by metabolizing enzymes, what are the alternatives? One possibility is that constituents may be distributed differentially in tolerant and nontolerant animals. Although the evidence is not conclusive (Shannon and Fried, 1972), the distribution of cannabinoids within the brain does not appear to differ as a function of the number of drug injections (Dewey et al., 1973; McMillan et al., 1973; Sprague and Craigmill, 1976). As a modification to this theory, a nonspecified cellular mechanism of tolerance has been proposed by a number of workers (McMillan and Dewey, 1972; Nazar et al., 1974; Sprague and Craigmill, 1976). Specific evidence that is supportive of this approach has recently been reported. Martin et al. (1976) found that synaptic vesicles function of tolerant dogs contained less Aa-THC or its metabolites than a similar homoginate derived from nontolerant animals. Magour et al. (1977) noted in subcellular fractions an accelerated shift, in tolerant animals, of Ag-THC toward highly polar (and behaviorally inactive) metabolites. Related to the question of tolerance is the presence or absence of withdrawal symptoms following the discontinuation of the drug. With rats, some behavioral changes have been noted when chronic administrations of various cannabis constitutents have been stopped. Pirth et al. (1972) noted a marked increase in EEG voltage and Sjoden et al. (1973) observed an increase in grooming responses. On the other hand, ambulatory behaviors (Sjoden et ah, 1973), sleep rhythms (Moreton and Davis, 1973), and pentylenetetrazol convulsive thresholds (Cheser and Jackson, 1974) were unaffected by withdrawal. During a 30-day withdrawal period following 6 months of Ag-THC administration, rats were observed to "behave normally" by Luthra et al. (1975). Furthermore, after ingesting cannabis extract for 126 days, rats did not exhibit any withdrawal symptoms nor did they self administer after this length of time (Leite and Carlini, 1974). In pigeons the data are inconsistent as McMillan et al. (1971) reported no abstinence syndromes, whereas Ford and McMillan (1972) found a disruption in schedule-controlled key-pecking 2 days after

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Aa-THC was withdrawn. The interpretation of the latter study is not clear, since stable responding did not return with an injection of the drug. Using dogs, Dewey et al. 0972) observed no signs of withdrawal, but with monkeys that were administered Ag-THC every six hr, Kaymakcalan (Deneau and Kaymakcalan, 1971; Kaymakcalan, 1973) noted depression and irritability 12 hr after withdrawal. In addition, the monkeys exhibited muscle tremors and autonomic disturbances such as yawning, piloerection, and erection of the penis. The authors reported that the THC abstinance syndrome also included behaviors which suggested the presence of hallucinations. The continuous intoxication of these animals may be of critical importance as Harris et al. (1972) did not report such observations with his rhesus monkeys that were given Ag-THC no more than once a day. In man there have been occasional reports of acute abstinence symptoms lasting 2 or 3 days following heavy chronic use of marijuana (e.g., Jones, 1971 a and b; Paton et al., 1973). These symptoms which include loss of appetite, irritability, headaches, and mild gastrointestinal upsets are relatively infrequent (Le Dain, 1972) and not severe (Nahas, 1973). In controlled "subchronic" studies in which marijuana was administered daily for at least 3 weeks, no objective withdrawal symptoms were observed (Miles et al., 1972; Williams et al., 1946), although the latter workers reported that subjects stated that they felt jittery after abrupt cessation of a 39-day period of marijuana smoking. Jones et al. (1976) observed experienced users in an experimental setting in which Aa-THC was administered every 4 hr for 12 days. As with the monkeys that were continuously intoxicated, these subjects exhibited withdrawal symptoms but they were mild and short-lived. Reports based on anecdotes and interviews suggest that the abstinence syndrome following the termination of a long-term hashish smoking habit appears to be more pronounced (Kaymakcalan, 1973; Soueif, 1967) with mood depression, irritability, and disturbed sleep characterizing the withdrawal period. However, in a controlled setting, long-term Greek hashish users did not display any objectively measured withdrawal symptoms during a 3-day abstinence period (Stefanis et al., 1976). Repeated marijuana usage has been reported by some to interact with the immunosuppressant system. Thymus-derived lymphocytes (T cells) have been shown to be decreased in their activity (Nahas et al., 1974) and numbers (Gupta et al.~ 1974; Cushman and Khurana, 1976) in chronic smokers. Others, hov~ever, have failed to find any effect of long-term marijuana smoking on T-cell activation (Silverstein and Lessin, 1974; White et al., 1975; Lau et al., 1976). Recently Petersen et al. (1976) reported a depression in T-cell activity in some chronic users after they had smoked in the laboratory. The effect was transitory and contingent upon the time elapsing between the last cigarette and sampling. This

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transitory, reversible effect was also described by Nahas (1975) in an in vitro test. The temporary nature of the phenomenon plus the intersubject variability presumably are major factors underlying the conflicting results obtained in the different laboratories. In addition, it is noteworthy that there is no evidence that sickness is more prevalent in animals or humans that have been exposed to marijuana or Ag-THC chronically (e.g., Coggins et al., 1976). This would suggest that, even if the lymphocytes are functionally reduced, the remaining numbers are sufficient to permit the immunosuppressant system to perform adequately (Tinklenberg, 1975). Consistent with this notion of a large reserve of lymphocytes is Cushman and Khurana's (1976) observation that marijuana affects only a subpopulation of T cells that may represent about 10% of the total. Conflicting data has also been reported with respect to plasma testosterone levels in chronic marijuana smokers. Kolodny, et al. (1974) reported a dose-related reduction in testosterone levels in chronic users, and Cohen (1976) noted a lowering of plasma testosterone in regular users during a 94-day controlled study. In this latter work testosterone levels recovered during a nonsmoking, 1-week period. On the other hand, Mendelson et al. (t974) examining heavy users for a month in a controlled environment, Cushman (1975) using marijuana smoking university students, Schaeffer et al. (1975) observing habitual and occasional users for 5 days in a hospital ward, and Coggins et al. (1976) investigating chronic, heavy users in Costa Rica failed to find lowered testosterone levels. In part because of the large number of factors that influence plasma testosterone levels including diurnal variations, other hormones, and drugs, it is not possible to reconcile these disparate data. Again, as with the lymphocyte data described above, in cases in which a reduction in circulating testosterone levels are found, the biological significance of the amount of the reduction remains to be assessed. CONCLUSIONS AND SUMMARY The studies and reviews described in this paper provide evidence that many of the acute effects of cannabis or its constituents are altered if the drug is administered in a chronic fashion. Two main themes were developed. First, the chronic use of cannabis influences the depressant and excitatory effects of marijuana differentially. Whereas tolerance develops to the behavioral and electrophysiological depressant aspects of the drug, there is no attenuation, in fact, maybe even a potentiation, of the stimulant effects. The failure to find tolerance to the rate-increasing effects of cannabis is not unique to this drug as lack of tolerance development to the enhancing effects of mescaline (Bridget, et al., 1973) and amphetamine (Schuster et al., 1966) have also been reported. The rate of tolerance development to marijuana is affected by learning

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factors; in particular, the opportunity or necessity to make a compensa tory response while under the drug's influence is important. This "behavioral augmentation" (Kalant et al., 1971), in a manner somewhat parallel to Held's (e.g., Held and Hein, 1963) reafference theory, is thought to provide feedback which facilitates adaptive behavior. The second theme developed in this paper is that to a large degree, the animal and human literatures are in agreement if socially acquired cues and expectancies and the dosage/frequency parameters are taken into consideration. The importance of psychosocial variables was emphasized both as a manipulatable, experimental variable and as functioning in the nonlaboratory milieu. The phenomenon of "reverse tolerance" (Weil et al., 1968) appears to be a product of such variables, since in many studies cited the heavy users were functionally not greatly impaired by an administration of marijuana, but subjectively rated themselves as "high." Emphasis was also placed upon the wide range of frequency of use by "~regular" or "'experienced" subjects employed in experiments and surveys. The smoker who consumes a couple of cigarettes a week (probably the mode of North American use) cannot be contrasted to the subject of animal studies to which marijuana is administered daily for an extended period of time. REFERENCES Abel, E. L. (1970a). Marihuana and memory. Nature (London) 227, 1151-1152. Abel, E. L. (1970b). Effects of the marihuana h omologue, pyrahexyl, on open field behavior in the rat. J. Pharm. Pharmacol. 22, 785. Abel, E. L. (1971). Retrieval of information after use of marihuana. Nature (London) 231, 58-59. Abel, E. L. (1973). Marihuana and memory: Acquisition or retrieval? Science 173, 10381040. Abel, E. L. (1972). Comparative effects of Ag-THC on thermoregulation. In W. D. M. Paton and J. Crown (Eds.), "Cannabis and its Derivatives." London: Oxford University Press. Abel, E. L. (1977). The relationship between Cannabis and violence: A review. Psychol. Bull. 84, 193-211. Adams, M. D., Chait, L. D., and Earnhardt, J. T. (1976), Tolerance to the cardiovascular effects of A~-tetrahydrocannabinol in the rat. Brit. J, Pharmacol. 56, 43-48. Alves, C. N., and Carlini, E. A. (1973). Effects of acute and chronic administration of Cannabis sativa extract on the mouse-killing behavior of rats. Life Sei. 13, 75-85. Ames, F. (1958). A clinical and metabolic study of acute intoxication with Cannabis sativa and its role in the model psychosis. J. Ment. Sci. 104, 972-999. Anderson. P. F., Jackson, D. M., Chesher, G. B., and Malor, R. (1975). Tolerance to the effects of •9-tetrahydrocannabinol in mice on intestinal motility, temperature, and locomotor activity. Psychopharmacologia 43, 31-36, Barnes, C., and Fried, P. A. (1974). Tolerance to Ag-THC in adult rats with differential Ag-TCH exposure when immature or during early adulthood. Psychopharmacologia 34, 181-190. Barratt, E. S., and Adams, P. (1972). The effects of chronic marijuana administration on brain functioning in cats. In J. M. Singh, L. Miller, and H. Lal (Eds.), "'Drug Addiction: Volume 1 Experimental Pharmacology," New York: Futura.

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