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EFFECTS OF MARIJUANA ON THE BRAIN The most clearly established effects of cannabis are upon behavior. These effects, described in Chapter 6, indicate that major actions of cannabinoids are upon the brain. The ways in which marijuana alters the brain to produce its behavioral effects are not known. Efforts to discover the causes of the behavioral effects have included studies on brain morphology, physiology, and chemistry to be reviewed in this chapter. Effects of marijuana on brain electrical activity and on brain chemistry have been measured, but their significance for brain function is not known because of our limited knowledge of brain-behavior relations. Marijuana causes temporary intoxication and results in changes in brain physiology and chemistry similar to those caused by other intoxicating drugs. Although these kinds of studies may ultimately shed light on the way marijuana produces its behavioral changes, they do not provide answers to important clinical questions. Does marijuana cause long-term changes in the brain that lead to chronic psychiatric or neurological disorders? So far, the studies reviewed below provide no convincing evidence for long-term changes because of use of marijuana. BRAIN MORPHOLOGY There is substantial controversy about whether marijuana causes changes in brain structure or in brain cells. Two studies have reported that marijuana produces changes in brain morphology. Both suffer sufficiently from methodologic and interpretational defects that their conclusions cannot be accepted. Furthermore, other studies have not found changes in morphology. Gross Morphology Data suggesting that use of marijuana causes brain atrophy were obtained by pneumoencephalography (injection of air into spaces in and surrounding the brain) on l0 users of marijuana who had sought medical attention because of neurologic complaints (Campbell et al., l97l). The size of the largest brain cavities (ventricles) was 80
81 mee-sured to determine whether loss of brain tissue had occurred. The authors interpreted their data as showing that atrophy was present. One of the first critics of this report questioned the interpretation of the radiologic techniques used (Bull, l97l). The results also have been seriously criticized because of the marijuana users studied. They had neurological symptoms or signs sufficient to justify an invasive and painful diagnostic test, but there is no evidence that such neurological complaints occur with greater frequency in users of marijuana than in the general population. Further, Campbell's patients did not only use marijuana, but also used such behavior-altering drugs, as lysergic acid diethylamide (LSD) and amphetamines. More recent evidence has been provided by computed tomography (CT) scans of the brain. This technique, which is noninvasive, painless, and yields more precise and quantifiable measures of brain atrophy, has replaced pneumoencephalography as a diagnostic test. Using CT methods, two studies failed to find evidence of cerebral atrophy in healthy chronic marijuana users (Co et al., l977; Keuhnle et al., l977). These latter results suggest that the earlier findings were attributable to the imprecision of conventional pneumoencephalography, or to the fact that a group with neurologic complaints was studied, or to the use of multiple psychoactive drugs by these individuals. This last possibility is reinforced by CT scans of animals who received a variety of psychoactive drugs. Marijuana alone produced no evidence of brain atrophy, whereas other drugs, such as amphetamines, did produce changes (Rumbaugh et al., l980). Microscopic Morphology Three post mortem studies on monkeys in the same laboratory have reported changes in the microscopic morphology of the brain at the ultrastructural level (Harper et al., l977; Meyers and Heath, l979; Heath et al., l980). No similar studies on human beings have been reported. The monkeys received either chronic exposure to marijuana smoke or chronic injections of A-9-THC. Changes reported to have occurred in the brains included alteration in synaptic* cleft width, increased density of synaptic cleft material, a decrease in volume of rough endoplasmic reticulum, presence of clumping of synaptic vesicles in axon terminals (where impulses travel away from the cell body), and an increase in intranuclear inclusions. These changes appear dramatic, but they must be interpreted with caution. The three studies are based principally upon examination of two limited brain areas only in three treated monkeys, two receiving marijuana smoke *A synapse is the region of communication between nerve cells, forming the place where a nervous impulse is transmitted from one nerve cell to another.
82 and one intravenous A-9-THC; a fourth treated animal was added to the last study and more brain areas were analyzed in it (Heath et al., l980). Further, although the material was evaluated "doubleblind" after electron micrographs had been made, it would appear that fixation, tissue preparation, and photography were carried out before these safeguards against bias were applied. It is possible that unknown but systematic differences occurred between experimental (treated) and control animals in fixation and preparation of tissue or in selection of samples for micrography. In addition, it should be noted that at least one of the changes noted, clumping of synaptic vesicles (Harper et al., l977), is a normal variant in the synaptic morphology of axon terminals in mammalian brain (Sipe and Moore, l977) and does not represent a pathological change. Also, these studies have not been replicated and, because the basis for interpretation is such a limited sample, it is con- cluded that no definitive interpretation can be made at this time. However, the possibility that marijuana may produce chronic, ultra- structural changes in brain has not been ruled out and should be investigated. NEUROPHYSIOLOGY One source of information on the mechanisms of action of a drug, such as marijuana, is the study of its physiological effects. Effects of marijuana on the electrical activity of the brain have been demonstrated by means of the electroencephalogram (EEG). The standard, or clinical, EEG measures tiny variations at the scalp of voltages produced by the electrical activity of the brain. Voltage differences between two points on the scalp, or between the scalp and an inactive reference site, are recorded on moving paper, producing a graph of voltage over time. The waves observed are classified according to frequencies as delta, theta, alpha, and beta. While the changes in EEG described below are of interest, their biological significance is unknown. Acute (Short-Term) Effects in Waking EEG Ingested marijuana or A-9-THC produces rather slight effects on the EEG of an awake subject. Relatively high doses (2l0 mg A-9-THC or its equivalent/day) have failed to produce measurable changes even though marked behavioral effects were observed. The EEG effect most frequently reported in recent studies has been an increased abundance of alpha waves associated with a slight slowing (about 0.25 Hz) of the alpha frequency (Rodin et al., l970; Volavka et al., l97l; Fink, l976). However, reduced alpha abundance and increased fast frequency activity (beta) have also been reported (Wikler and Lloyd, l945; Jones and Stone, l970). Most studies which report EEG changes have noted that tolerance develops with repeated drug administration. No significance with respect to hazard can be inferred from the effects
83 of cannabis on the waking EEG. For a further review of this literature, see Fried (l977). Persistent Effects in Waking EEG The occurrence of persistent (long-lasting) changes in EEG with use of marijuana would cause concern even if their significance for brain function was unknown. However, in attempting to investigate the question of whether such changes occur, there inevitably arise crucial issues of subject selection. If one selects only chronic marijuana users who are in good health, one may be eliminating systematically those who have been adversely affected by use of the drug and who might have shown EEG changes. On the other hand, if one includes in such studies marijuana users who suffer from various illnesses or behavioral disturbances, one might find abnormalities of the EEG that result from these conditions rather than from the marijuana. Long-term use of marijuana, either in the modest doses custom- arily used in this country or the heavy doses of hashish and ganga used by certain studied populations abroad, has not been shown to produce changes in the EEG. No abnormalities were found in the EEG of l0 healthy students who had smoked marijuana regularly for l year (Rodin et al., l970). Another study compared clinical EEG records of 46 hashish users and 40 matched controls in Greece (Fink, l976). Each record was evaluated independently by four qualified neurologist- electroencephalographers. No differences were observed in the incidence of abnormal records in the users and controls, a result consistent with the absence of significant differences between the two groups in various tests of neurological function. Essentially, the same negative results were obtained in studies of ganga users in Jamaica (Rubin and Comitas, l975) and marijuana users in Costa Rica (Karacan et al., l976). In these later studies subjects were carefully selected to include only those in good health who were functioning adequately in the community. As mentioned above, this method of selection runs the risk of eliminating subjects whose health or behavior were adversely affected by marijuana and who might have shown EEG changes. This methodological difficulty cannot be eliminated in any small sample investigation of marijuana users. Acute Effects in Event-Related Potentials One can employ computer averaging to retrieve from the EEG certain information that is not detectable by visual inspection. In this way, the electrical events that follow a stimulus may be studied in subjects who are at rest, asleep, or carrying out certain tasks. These computer-averaged potentials provide clues to the sequential processing of information by the brain. Although the literature is inconsistent, it is clear that cannabis can produce effects on event-related potentials (EPs) (Herning et al., l979). Effects on amplitude are more often reported than effects
84 on latency of the event-related waves. Several studies with inconsistent results have appeared; these inconsistencies result from differences in task, dose, or duration of administration. Thus, EPs in response to sensory stimuli are unaffected or even increased by cannabis if the subject is passive, but are decreased in amplitude if the subject is performing a task. One study found the first negative wave, a component of the auditory EP, was reduced at a dose of l80-2l0 mg per day, but not at a dose of 70-90 mg per day during acute (l to 3 days) administration (Herning et al., l979). After 2 weeks at the higher dosage, this effect was observed only for the more difficult tasks. This study demonstrates differences in marijuana effects on EPS according to dose, duration of administration, and task complexity. Acute Effects in Sleep EEG Drugs often produce marked effects on the BEG during sleep, but producing little or no change in the waking EEG. This is the case with marijuana and A-9-THC. In relatively high doses (70-2l0 mg/day), A-9-THC and marijuana extract produced marked effects on sleep EEG (Feinberg et al., l975, l976). On initial administration, the time spent in REM sleep* (stage REM duration) was reduced below baseline levels (placebo) by l8 percent and the number of eye movements by 49 percent. Some tolerance (return toward baseline levels) was apparent during the period (l2-l6 days) of drug administration. On withdrawal, REM duration was increased above baseline by 49 percent and rapid eye movements were increased by 67 percent. While these effects are quite large, their clinical significance is unknown. They were not accompanied by such unusual behavioral changes as hallucinations or disorientation, although there was evidence of withdrawalâ irritability, increased reflexes, and mild agitation. With much smaller doses of A-9-THC, either a small reduction in REM sleep (Pivik et al., l972; Freemon, l974) or no change has been reported (Barratt et al., l974; Hosko et al., l973; Pranikoff et al., l973). Persistent Effects in Sleep EEG We are not aware of any investigation of sleep in abstinent long-term marijuana users. However, 32 male chronic marijuana users and matched controls were studied in Costa Rica (Karacan et al., l976). The users habitually smoked 2.5 to 23.3 cigarettes per day (mean = 9.2) and had used the drug for l0 to 27 years; they continued their usual intake during the study (Costa Rican cigarettes contain about 200 mg *A stage in sleep during which Rapid Eye Movements may be detected and vivid dreaming usually occurs.
85 of marijuana). The subjects selected for this study had normal medical, neurologic, and laboratory evaluations. Sleep was recorded for 8 consecutive nights. Prior to each night's recording, the users described their marijuana intake during the previous 24 hours. This intake was not directly monitored or controlled by the experimenters, because the goal was to observe sleep patterns under "naturalistic" conditions. The subjects were forbidden to use marijuana during the 2-3 hours prior to sleep recording. (For further details of this extensive study, see Karacan et al., l976.) All of the major variables derived from visual sleep stage classification were examined. The only statistically significant differences between marijuana users and their matched controls were in one of the sleep latency measures and in REM percentage of total sleep and average REM period length. The differences were quite small and may have been due to the subjects experiencing early withdrawal at the time their sleep was recorded. This is a likely explanation for these findings according to studies described previously (Feinberg et al., l975, l976). The Costa Rican study concluded there was a lack of evidence of major disturbances of EEG sleep patterns in user subjects studied in situ (Karacan et al., l976). Thus, long-term marijuana use has not been demonstrated to cause marked and consistent abnormalities of sleep EEG that can be demonstrated in studies with small samples. Electrophysiological Studies in Animals Sleep Studies The findings of several animal studies carried out to investigate the effects of marijuana on EEG differ in some respects to those in human beings. Species differences are thought to be responsible for some of the variations found from species to species. For example, 5 and l0 mg/kg A-9-THC administered acutely to rats suppressed REM, reduced slow-wave sleep, and increased wakefulness (Moreton and Davis, l973). Chronic administration caused an initial suppression of REM, which returned to baseline after 4 days and remained at baseline levels for a further l6 days. In contrast to the human studies, there was no withdrawal increase in REM above baseline during a l0-day withdrawal period. Similar results were obtained in a short-term study that employed intravenous doses of A-9-THC (0.5 and l.0 mg/kg) to rabbits (Fujuimori and Himwich, l973). Appreciable qualitative differences in sleep EEG response to A-9-THC have also been detected in primates when compared with human studies. When l.2 mg/kg A-9-THC is administered to squirrel monkeys in a single oral dose, daily for 60 days, no significant effects on REM sleep duration occurred; instead, a decrease in EEG stages 3 and 4 was noted (Adams and Barratt, l975).
86 BEG Studies in Subcortical Structures Electrode implantation is rarely possible in man, but is a routine and essential technique for the study of brain electrophysiology in animals. Animal experiments also permit use of higher doses and more prolonged administration than is possible with human subjects. For these reasons, animal experiments can yield important data that cannot be obtained in human studies. In general, EEG recordings after short-term administration of marijuana are similar from surface (cortex) or from deep brain (subcortex) regions. However, after chronic administration of high doses of A-9-THC, abnormal recordings have been observed in subcortical regions of some animals, readings not seen in the cortex. Although these findings have not been replicated, they are of particular concern, because they raise the possibility that chronic exposure to high doses of marijuana produces long-lasting effects on brain physiology. After intravenous administration of a range of A-9-THC doses (from 0.05 to l2.8 mg/kg) to rhesus monkeys, a general increase in EEG synchrony was observed; and at higher dose ranges, there were specific EEG changes in the limbic system, frontal cortex, thalamus and fastigial nuclei (Martinez et al., l972). In this study, the increase in high-voltage activity showed a good dose-response relationship. In a second study, oral dosing of three rhesus monkeys with a crude marijuana extract containing 25 percent A-9-THC produced dose-related EEG changes, including slow waves in the hippocampus, amygdala, and septum (Stadnicki et al., l974). Tolerance to the behavioral and EEG changes occurred with daily treatment, which was stopped after 5l days. Behavioral withdrawal effects were noted, but EEG changes during withdrawal were minimal and there was no evidence of EEG changes persisting beyond the period of A-9-THC ingestion. Two studies that monitored EEG recording from deep brain sites after chronic administration of high doses of marijuana found changes in EEGs from deep brain sites that were not observed in surface areas after drug withdrawal (Fehr et al., l976; Heath, l976; Heath et al., l979). Studies of two rats with electrodes implanted in the anterior neocortex, dorsal hippocampus, and mesencephalic reticular formation l year after exposure to 20 mg/kg for 6 months (Fehr et al., l976) yielded hippocampal recordings with "epileptiform" abnormalities, in contrast to one control and two alcohol-treated animals. The second study was carried out on thirteen feral-raised rhesus monkeys (Heath l976; Heath et al., l979). Ten monkeys had electrodes implanted in deep sites and in brain cortex. Four monkeys were made to smoke marijuana three times a day, 5 days per week for 6 months; two other monkeys with implants were given 0.6 mg/kg A-9-THC each day, 5 days per week for 6 months; still other monkeys were used as controls or received smaller doses of marijuana. In three high-dose monkeys, two smoking and one ingesting A-9-THC, changes in EEG could be detected in recordings from deep brain sites; the changes continued 7 months after cessation of marijuana exposure. No EEG abnormalities were present in recordings from the brain surface.
87 One of the major criticisms of both these studies is their use of small numbers of animals. Furthermore, there have been no attempts at replication by other workers. Nevertheless, because these findings provide some of the only evidence for a possible irreversible effect of chronic high doses of marijuana, they are mentioned here with a strong urging for additional studies in an effort to replicate these findings. EPILEPSY Because of the effects of marijuana on brain electrical activity, questions have been raised about its association with epilepsy. Two questions are raised in the literature. First, does marijuana produce seizures? Second, does marijuana or a derivative prevent seizures? The first question will be discussed here. The second is reviewed in Chapter 1, which is concerned with the potential therapeutic uses of cannabis. There are anecdotal reports in the literature that suggest seizures may be induced by marijuana in some persons with a known seizure disorder. A rigorous study, using adequate numbers of patients with documented seizure patterns, has not been done. Reports of experimental animal studies are conflicting and varied (Feeney et al., l973, l979; Lemberger, l980). There are some circumstances in which cannabis administration does not alter certain types of seizures such as the photosensitive seizures in the baboon (Meldrum et al., l974), and others in which it seems that seizures are induced. A single rabbit that responded to A-9-THC adminis- tration with seizures was bred to establish a colony of rabbits with similar response (Consroe and Fish, l98l). It will be of consider- able interest to determine mechanisms of seizure induction and pharmacologic response patterns in this unusual animal model. However, as described further in Chapter 7, the bulk of the animal literature and some data from human studies suggest that the more prominent effect of marijuana derivatives, especially cannabinol and cannabidiol, is to decrease rather than increase seizure suscepti- bility (see Karler and Turkanis, l981, for review). NEUROCHEMISTRY Our knowledge of the effects of marijuana on brain chemistry has come largely from studies in animals. Cannabis and some of its derivatives have been shown to cause chemical effects in the brain, as demonstrated by effects on neurotransmitters and on nucleic acids. The evidence is reviewed below. Neurotransmitters The brain is composed of many information-processing networks of nerve cells. Within each of these networks the transfer of informa-
88 tion from one nerve cell to another is dependent upon chemicals called neurotransmitters. These substances are produced by nerve cells, released when the cells are stimulated and act to alter the excitability of neighboring nerve cells. Neurotransmitters play an essential role in the transmission and processing of information, and it is not surprising that many drugs that alter behavior do so by their actions on neurotransmitters. The understanding of the effects of marijuana on the brain must include knowledge of its effects on neurotransmitter systems. Several different classes of chemicals act as neurotransmitters. The first chemical to be demonstrated to have this function was acetylcholine, and it is now established that acetylcholine is the neurotransmitter for several nerve cell networks in the brain. A number of studies in animals have examined the effect of marijuana on brain acetylcholine (see Domino, l98l, for a brief review of the extensive literature). The most clear-cut effects have been on acetylcholine turnover, a measure of the level of activity of neurons producing the chemical. Small doses of A-9-THC cause a reduction in acetylcholine turnover in the hippocampus (Domino et al., l978; Revuelta et al., l978; Domino, l98l) and this results from reduced activity of the acetylcholine neurons. It is noteworthy that the effect is produced by small doses and only by cannabinoids. Administration of physostigmine, a drug that enhances acetylcholine action by partially blocking its breakdown, to five healthy human volunteers (2 hours after ingestion of 20 to 40 mg of A-9-THC) produced enhancement of the lethargy and somnolence occurring late in the course of the A-9-THC intoxication (Freemon et al., l975). The results of this study, and others in man and animals (El-Yousef et al., l973; Low et al., l973; Drew and Miller, l974; Freemon et al., l975), have led to the conclusion that A-9-THC acts to inhibit acetylcholine nerve cell networks. The exact nature of this action is not known, but it may be related to the memory deficits produced (Domino, l98l). There have been studies of cannabinoids on several other neurotransmitters in brain, including catecholamines, serotonin, and gamma aminobutyric acid (Banerjee et al., l975; Braes et al., l975). Although some effects have been reported, they either are produced by a very high dose or are so fragmentary that their implications are unclear. The effects of cannabinoids on neurotransmitters that have been studied to date, other than acetylcholine, are not striking. In particular, there is no evidence for any significant, long-term toxic effect of cannabinoids on any of the nerve cell networks that produce identified neurotransmitters. Proteins, Enzymes, Nucleic Acids A very few studies have examined the effects of marijuana on neurochemical variabless other than neurotransmitters (Luthra and Rosenkrantz, l974; Luthra et al., l975, l976). After chronic administration to rats either of A-9-THC or marijuana smoke (for
89 periods from 28 to l80 days), these investigators examined brain lipid, protein, and ribonucleic acid (RNA) content. With very high doses of A-9-THC (up to 500 mg/kg/day), some decrease in brain protein and RNA was noted; no decrease was noted in lipid content. However, with smaller doses, or administration of marijuana smoke, no consistent or marked changes were noted. The significance of these effects is unknown. Whether additional effects might be observed with more sophisticated and sensitive methods directed to more restricted analytical problems cannot be answered at present. SUMMARY There is no persuasive evidence that marijuana causes morphological changes in the brain. Computer tomography studies on users of marijuana reveal no gross changes in brain structure. Electron micrographic studies of monkey brains indicating morphologic changes are methodologically flawed and cannot be used as evidence for an effect of marijuana on brain cell morphology. Clear effects on brain electrical activity in human beings and in animals have been found after drug exposure. These effects have not been demonstrated to persist in human beings after the drug has been discontinued. Studies of EEG from deep brain structures in chronically treated animals have shown changes after the withdrawl of the drug. These limited findings need to be confirmed by further studies. Studies in human beings and animals indicate that, despite the neurophysiologic effects demonstrated in EEG studies, marijuana does not appear to increase epileptic seizure susceptibility. Current evidence has shown marijuana causes some chemical changes in brain. Cannabinoids affect several neurotransmitter systems, especially the cholinergic system. At high doses marijuana also has been shown to affect nucleoprotein synthesis. The significance of these findings for brain function as demonstrated by human behavior or their clinical relevance is unknown. RECOMMENDATIONS FOR RESEARCH In view of the widespread use of cannabis, it would be worthwhile to carry out further and more systematic studies of the effects of cannabis on brain structure, chemistry, and electrophysiology. Such studies should be closely correlated with behavior, e.g., learning, psychomotor coordination (see Chapter 6). One useful approach might be to investigate the effects of medium and high doses of cannabis (defined in terms of the patterns of human consumption) on juvenile and adult monkeys during and after long-term exposure. Juvenile monkeys should be included because the immature nervous system may be more sensitive to harmful drug effects; this issue is of great clinical concern, because marijuana use by human beings now begins quite early in life (see Chapter 2). Observations also should be made during long-term abstinence after previous long-term exposure to
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