|
Federal Register Notices > Notices - 2001 > Denial of Petition Notices - 2001Central Nervous System Effects Human Behavioral Effects As with other psychoactive drugs, the response that an individual has to marijuana is dependent on the set (psychological and emotional orientation) and setting (circumstances) under which the individual takes the drug. Thus, if an individual uses marijuana while in a happy state of mind among good friends, the responses are likely to be interpreted as more positive than if that individual uses the drug during a crisis while alone. The mental and behavioral effects of marijuana can vary widely among individuals, but common responses, described by Wills (1998) and others (Adams and Martin 1996; Hollister 1986a, 1988a; Institute of Medicine 1982) are listed below:
Animal Behavioral Effects
One indicator of whether a drug will be reinforcing in humans is the self-administration test in animals. Self- [[Page 20043]] administration of marijuana, LSD, sigma receptor
agonists, or cholinergic antagonists is difficult to demonstrate in animals.
However, when it is known that humans voluntarily consume a particular drug for its pleasurable effects, the inability to establish self-administration with that drug in animals has no practical importance.
This is because the animal test is only useful as a rough predictor of human behavioral response in the absence of naturalistic data. Thus,
the petitioner is incorrect that the accepted legal convention for abuse potential is self-administration in animals and that because
marijuana does not induce self-administration in animals, it has a lower abuse potential than drugs that easily induce self-administration
in animals. Similarly, the petitioner is incorrect that the difficulty in inducing self-administration of marijuana in animals is due to a Naive animals will not typically self-administer cannabinoids when they must choose between saline and a cannabinoid. However, a recent report shows that when squirrel monkeys are first trained to self-administer intravenous cocaine, they will continue to bar-press at the same rate when THC is substituted for cocaine, at doses that are comparable to those used by humans who smoke marijuana (Tanda et al., 2000). This effect was blocked by the cannabinoid receptor antagonist, SR 141716. These data demonstrate that under specific pretreatment conditions, an animal model of reinforcement by cannabinoids now exists for future investigations. Additionally, mice have been reported to self-administer WIN 55212, a CB1 receptor agonist with a non-cannabinoid structure (Martellotta et al., 1998). There may be a critical dose-dependent effect, though, since aversive effects, rather than reinforcing effects, have been described in rats with high doses of WIN 55212 (Chaperon et al., 1998) as well as delta9-THC (Sanudo-Pena et al., 1997). The cannabinoid antagonist, SR 141716, counteracted these aversive effects. The conditioned place preference (CPP) test also functions as a predictor of reinforcing effects. Animals show CPP to cannabinoids, but only at mid-dose levels. However, cannabinoid antagonists also induce CPP, suggesting that occupation of the cannabinoid receptor itself, may be responsible.
Animals, including monkeys and rats (Gold et al., 1992) as well as humans (Chait, 1988) can discriminate cannabinoids from other drugs or placebo. Discriminative stimulus effects of delta9-THC are pharmacologically specific for marijuana-containing cannabinoids (Balster and Prescott, 1992, Barrett et al., 1995, Browne and Weissman, 1981, Wiley et al., 1993, Wiley et al., 1995). Additionally, the major active metabolite of delta9-THC, 11-OH-delta9-THC, also generalized to the stimulus cue elicited by delta9-THC (Browne and Weissman, 1981). Twenty-two other cannabinoids found in marijuana also fully substituted for delta9-THC. The discriminative stimulus effects of the cannabinoid group appear to provide unique effects because stimulants, hallucinogens, opioids, benzodiazepines, barbiturates, NMDA antagonists and antipsychotics have not been shown to substitute for delta9-THC. Pharmacodynamics of CNS Effects Psychoactive effects occur within seconds after smoking marijuana, while the onset of effects after oral administration is 30-60 min. After a single moderate smoked dose, most mental and behavioral effects are measurable for approximately 4 to 6 hours (Hollister 1986, 1988). Venous blood levels of delta9-THC or other cannabinoids correlate poorly with intensity of effects and character of intoxication (Agurell et al. 1986; Barnett et al. 1985; Huestis et al. 1992a). There does not appear to be a "hangover'' syndrome following acute administration of marijuana containing 2.1% delta9-THC (Chait, 1985). We agree with the petitioner that clinical studies do not demonstrate tolerance to the "high'' from marijuana. This may be related to recent electrophysiological data showing that the ability of THC to increase neuronal firing in the ventral tegmental area (a region known to play a critical role in drug reinforcement and reward) is not reduced following chronic administration of the drug (Wu and French, 2000). On the other hand, tolerance can develop in humans to marijuana-induced cardiovascular and autonomic changes, decreased intraocular pressure, sleep and sleep EEG, mood and certain behavioral changes (Jones et al., 1981). Repeated use of many drugs leads to the normal physiological adaptations of tolerance and dependence and is not a phenomenon unique to drugs of abuse. Down-regulation of cannabinoid receptors has been suggested as the mechanism underlying tolerance to the effects of marijuana (Rodriguez de Fonseca et al., 1994, Oviedo et al., 1993). By pharmacological definition, tolerance does not indicate the physical dependence liability of a drug. Physical dependence is a condition resulting from the repeated consumption of certain drugs. Discontinuation of the drug results in withdrawal signs and symptoms known as withdrawal or abstinence syndrome. It is believed that the withdrawal syndrome probably reflects a rebound of certain physiological effects that were altered by the repeated administration of the drug. These pharmacological events of physical dependence and withdrawal are not associated uniquely with drugs of abuse. Many medications such as antidepressants, beta-blockers and centrally acting antihypertensive drugs that are not associated with addiction can produce these effects after abrupt discontinuation. Some authors describe a marijuana withdrawal syndrome consisting of restlessness, irritability, mild agitation, insomnia, sleep EEG disturbances, nausea and cramping that resolves in days (Haney et al., 1999). This syndrome is mild compared to classical alcohol and barbiturate withdrawal phenomena, which may include agitation, paranoia, and seizures. Marijuana withdrawal syndrome has more frequently been reported in adolescents who were admitted for substance abuse treatment or under research conditions upon discontinuation of daily administration. According to the American Psychiatric Association, Diagnostic and Statistical Manual (DSM-IV-TRTM, 2000), the distinction between occasional use of cannabis and cannnabis dependence or abuse can be difficult to make because social, behavioral, or psychological problems may be difficult to attribute to the substance, especially in the context of use of other substances. Denial of heavy use is common, and people appear to seek treatment for cannabis dependence or abuse less often than for other types of substance-related disorders. Although pronounced withdrawal symptoms can be provoked from the administration of a cannabinoid antagonist in animals who had received chronic THC administration, there is no overt withdrawal syndrome behaviorally in animals under conditions of natural discontinuation following chronic THC administration. [[Page 20044]] This may be the result of slow release of cannabinoids from adipose storage, as well as the presence of the major metabolite, 11-OH- delta9-THC, which is also psychoactive. Cognitive Effects Acute administration of smoked marijuana impairs performance on tests of learning, associative processes, and psychomotor behavior (Block et al., 1992). These data demonstrate that the short-term effects of marijuana can interfere significantly with an individual's ability to learn in the classroom or to operate motor vehicles. Administration of 290 ug/kg delta9-THC in a smoked marijuana cigarette by human volunteers impaired perceptual motor speed and accuracy, two skills that are critical to driving ability (Kurzthaler et al., 1999). Similarly, administration of 3.95% delta9-THC in a smoked marijuana cigarette increased dysequilibrium measures as well as the latency in a task of simulated vehicle braking at a rate comparable to an increase in stopping distance of 5 feet at 60 mph (Liguori et al., 1998). The effects of marijuana may not resolve fully until at least a day after the acute psychoactive effects have subsided. A study at the National Institute on Drug Abuse (NIDA) showed residual impairment on memory tasks 24 hours after volunteer subjects had smoked 0, 1, or 2 marijuana cigarettes containing 2.57% delta9-THC on two occasions the previous day (Heishman et al., 1990). However, later studies at NIDA showed that there were no residual alterations in subjective or performance measures the day after subjects were exposed to 1.8%, or 3.6% smoked delta9-THC, indicating that the residual effects of smoking a single marijuana cigarette are minimal (Fant et al., 1998). A John Hopkins study examined marijuana's effects on cognition on 1,318 participants over a 15-year period and reported there were no significant differences in cognitive decline between heavy users, light users, and nonusers of cannabis, nor any male-female differences. The authors concluded that "these results * * * seem to provide strong evidence of the absence of a long-term residual effect of cannabis use on cognition.'' (Lyketsos et al., 1999). Age of first use may be a critical factor in persistent impairment resulting from chronic marijuana use. Individuals with a history of marijuana-only use that began before the age of 16 were found to perform more poorly on a visual scanning task measuring attention than individuals who started using marijuana after that age (Ehrenreich et al., 1999). However, the majority of early-onset marijuana users do not go on to become heavy users of marijuana, and those that do tend to associate with delinquent social groups (Kandel and Chen, 2000). An individual's drug history may play a role in the response that person has to marijuana. Frequent marijuana users (greater than 100 times) were better able to identify a drug effect from low dose delta9-THC than infrequent users (less than 10 times) and were less likely to experience sedative effects from the drug (Kirk and deWit, 1999). This difference in experiential history may account for data showing that reaction times are not altered by acute administration of marijuana in long term marijuana users (Block and Wittenborn, 1985), suggesting that behavioral adaptation or tolerance can occur to the acute effects of the drug in the absence of evidence for dependence. The impact of in utero marijuana exposure on a series of cognitive tasks had been studied in children at different stages of development. Differences in several cognitive domains distinguished the 4-year-old children of heavy marijuana users. In particular, memory and verbal measures were negatively associated with maternal marijuana use (Fried and Watkinson, 1987). Maternal marijuana use was predictive of poorer performance on abstract/visual reasoning tasks, although it was not associated with an overall lowered IQ in 3-year old children (Griffith et al., 1994). At 6 years of age, prenatal marijuana history was associated with an increase in omission errors on a vigilance task, possibly reflecting a deficit in sustained attention, was noted (Fried et al., 1992). Recently, it had been speculated that prenatal exposure may affect certain behaviors and cognitive abilities that fall under the construct termed executive function, that is, not associated with measures of global intelligence. It was postulated that when tests evaluate novel problem-solving abilities as contrasted to knowledge, there is an association between executive function and intelligence. In a recent study (Fried et al., 1998), the effect of prenatal exposure in 9-12 year old children was analyzed, and similarly to what was shown in other age groups, in utero marijuana exposure was negatively associated with executive function tasks that require impulse control, visual analysis and hypothesis testing and it was not associated with global intelligence. Cardiovascular and Autonomic Effects Single smoked or oral doses of delta9-THC ingestion produce tachycardia and unchanged or increased blood pressure (Capriotti et al., 1988, Benowitz and Jones, 1975). However, prolonged delta9-THC ingestion produces significant heart rate slowing and blood pressure lowering (Benowitz and Jones, 1975). Both plant-derived cannabinoids and the endogenous ligands have been shown to elicit hypotension and bradycardia via activation of peripherally located CB1 receptors (Wagner et al., 1998). The mechanism of these effects were suggested in that study to include presynaptic CB1 receptor mediated inhibition of norepinephrine release from peripheral sympathetic nerve terminals, with the possibility of additional direct vasodilation via activation of vascular cannabinoid receptors. Impaired circulatory responses to standing, exercise, Valsalva maneuver, and cold pressor testing following THC administration suggest a state of sympathetic insufficiency. Tolerance developed to the orthostatic hypotension, possibly related to plasma volume expansion, but did not develop to the supine hypotensive effects. During chronic marijuana ingestion, nearly complete tolerance was shown to have developed to the tachycardia and psychological effects when subjects were challenged with smoked marijuana. Electrocardiographic changes were minimal despite the large cumulative dose of THC. (Benowitz and Jones, 1975) Cardiovascular effects of smoked or oral marijuana have not been shown to result in any health problems in healthy and relatively young users. However, marijuana smoking by older patients, particularly those with some degree of coronary artery or cerebrovascular disease, is postulated to pose greater risks, because of the resulting increased cardiac work, increased catecholamines, carboxyhemoglobin, and postural hypotension (Benowitz and Jones 1981; Hollister 1988). As a comparison, the cardiovascular risks associated with use of cocaine are quite serious, including cardiac arrhythmias, myocardial ischemia, myocarditis, aortic dissection, cerebral ischemia, stroke and seizures. Respiratory Effects Transient bronchodilation is the most typical effect following acute exposure to marijuana. The petitioner is correct that marijuana does not suppress respiration in a manner that leads to death. With long-term use of marijuana, there can be an increased frequency of pulmonary illness from chronic bronchitis and pharyngitis. Large-airway obstruction, as evident on pulmonary function tests, can also occur with [[Page 20045]] chronic marijuana smoking, as can cellular inflammatory histopathological abnormalities in bronchial epithelium (Adams and Martin 1996; Hollister 1986). The low incidence of carcinogenicity may be related to the fact that intoxication from marijuana does not require large amounts of smoked material. This may be especially true today since marijuana has been reported to be more potent now than a generation ago and individuals typically titrate their drug consumption to consistent levels of intoxication. Several cases of lung cancer in young marijuana users with no history of tobacco smoking or other significant risk factors have been reported (Fung et al. 1999). However, a recent study (Zhang et al., 1999) has suggested that marijuana use may dose-dependently interact with mutagenic sensitivity, cigarette smoking and alcohol use to increase the risk of head and neck cancer. The association of marijuana use with carcinomas remains controversial. Endocrine System Effects In male human volunteers, neither smoked THC (18 mg/marijuana cigarette) nor oral THC (10 mg t.i.d. for 3 days and on the morning of the fourth day) altered plasma prolactin, ACTH, cortisol, luteinizing hormone or testosterone levels (Dax et al., 1989). Reductions in male fertility by marijuana are reversible and only seen in animals at concentrations higher than those found in chronic marijuana users. Relatively little research has been performed on the effects of experimentally administered marijuana on human female endocrine and reproductive system function. Although suppressed ovulation and other ovulatory cycle changes occur in nonhuman primates, a study of human females smoking marijuana in a research hospital setting did not find hormone or menstrual cycle changes like those in monkeys that had been given delta9-THC (Mendelson et al., 1984a). THC reduces binding of the corticosteroid dexamethasone in hippocampal tissue from adrenalectomized rats, suggesting a direct interaction with the glucocorticoid receptor. Chronic THC administration also reduced the number of glucocorticoid receptors. Acute THC releases corti-costerone, but tolerance developed with chronic THC administration. (Eldridge et al., 1991) Immune System Effects Immune functions can be enhanced or diminished by cannabinoids, dependent on experimental conditions, but the effects of endogenous cannabinoids on the immune system are not yet known. The concentrations of THC that are necessary for psychoactivity are lower than those that alter immune responses. A study presented by Abrams and coworkers at the University of California, San Francisco at the XIII International AIDS Conference investigated the effect of marijuana on immunological functioning in 62 AIDS patients who were taking protease inhibitors. Subjects received one of three treatments, three times a day: Smoked marijuana cigarette containing 3.95% THC; oral tablet containing THC (2.5 mg oral dronabinol); or oral placebo. There were no changes in HIV RNA levels between groups, demonstrating no short-term adverse virologic effects from using cannabinoids. Additionally, those individuals in the cannabinoid groups gained more weight than those in the placebo group (3.51 kg from smoked marijuana, 3.18 kg from dronabinol, 1.30 kg from placebo) (7/13/00, Durban, South Africa). 3. The State of Current Scientific Knowledge Regarding the Drug or Other Substance This section discusses the chemistry, human pharmacokinetics, and medical uses of marijuana. Chemistry According to the DEA, three forms of cannabis (that is, Cannabis sativa L. and other species) are currently marketed illicitly in the U.S.A. These cannabis derivatives include marijuana, hashish and hashish oil. Each of these forms contains a complex mixture of chemicals. Among
these components the twenty-one carbon terpenes found in the plant as well as their carboxylic acids, analogues, and transformation products
are known as cannabinoids (Agurell et al., 1984, 1986; Mechoulam, 1973). The cannabinoids appear to be unique to marijuana and most of Marijuana is a mixture of the dried flowering tops and leaves from the plant (Agurell et al. 1984; Graham 1976; Mechoulam 1973) and is variable in content and potency (Agurell et al. 1986; Graham 1976; Mechoulam 1973). Marijuana is usually smoked in the form of rolled cigarettes. The other cannabis forms are also smoked. Potency of marijuana, as indicated by cannabinoid content, has been reported to average from as low as one to two percent to as high as 17 percent. Delta9-THC is an optically active resinous substance, insoluble in water and extremely lipid soluble. Chemically is known as (6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl -dibenzo-[b,d]pyran-1-ol or (-)-delta9-(trans)-tetrahydrocannabinol. The pharmacological activity of delta9-THC is stereospecific; the (-)-trans isomer is 6-100 times more potent than the (+)-trans isomer (Dewey et al., 1984). The concentration of delta9-THC and other cannabinoids in
marijuana varies greatly depending on growing conditions, parts of the plant collected (flowers, leaves stems, etc), plant genetics, and
processing after harvest (Adams and Martin , 1996; Agurell et al.,
1984; Mechoulam, 1973). Thus, there are many variables that can influence the strength, quality and purity of marijuana as a botanical
substance. In the usual mixture of leaves and stems distributed as marijuana, the concentration of
delta9-THC ranges from 0.3 to 4.0 percent by weight. However, specially grown and selected marijuana can
contain 15 percent or even more delta9-THC. Thus, a one-gram
marijuana cigarette might contain as little as 3 milligrams or as much as 150 milligrams or more of
delta9-THC among several other cannabinoids. As a consequence, the clinical pharmacology of pure
delta9-THC may not always be expected to have the same clinical
pharmacology of smoked marijuana containing the same amount of delta9-THC (Harvey, 1985). Also, the lack of consistency of [[Page 20046]] describes the data and information that should be included in the chemistry, manufacturing and controls section of a new drug application (NDA) to be reviewed by FDA. Hashish consists of the cannabinoid-rich resinous material of the cannabis plant, which is dried and compressed into a variety of forms (balls, cakes etc.). Pieces are then broken off, placed into pipes and smoked. Cannabinoid content in hashish has recently been reported by DEA to average 6 percent. Hash oil is produced by extracting the cannabinoids from plant material with a solvent. Color and odor of the extract vary, depending on the type of solvent used. Hash oil is a viscous brown or amber-colored liquid that contains approximately 15 percent cannabinoids. One or two drops of the liquid placed on a cigarette purportedly produce the equivalent of a single marijuana cigarette. Human Pharmacokinetics Marijuana is generally smoked as a cigarette (weighing between 0.5 and 1.0 gram), or in a pipe. It can also be taken orally in foods or as extracts of plant material in ethanol or other solvents. Pure preparations of delta9-THC and other cannabinoids can be administered by mouth, rectal suppository, intravenous injection, or smoked. The absorption, metabolism, and pharmacokinetic profile of delta9-THC (and other cannabinoids) in marijuana or other drug products containing delta9-THC are determined by route of administration and formulation (Adams and Martin 1996; Agurell et al. 1984, 1986). When marijuana is administered by smoking, delta9-THC in the form of an aerosol in the inhaled smoke is absorbed within seconds. The delta9-THC is delivered to the brain rapidly and efficiently as would be expected of a very lipid-soluble drug. The delta9-THC bioavailability from smoked marijuana, i.e., the actual absorbed dose as measured in blood, varies greatly among individuals. Bioavailability can range from one percent to 24 percent with the fraction absorbed rarely exceeding 10 to 20 percent of the delta9-THC in a marijuana cigarette or pipe (Agurell et al. 1986; Hollister 1988a). This relatively low and quite variable bioavailability results from significant loss of delta9-THC in side-stream smoke, from variation in individual smoking behaviors, from cannabinoid pyrolysis, from incomplete absorption of inhaled smoke, and from metabolism in the lungs. A smoker's experience is likely an important determinant of the dose that is actually absorbed (Herning et al. 1986; Johansson et al. 1989). Venous blood levels of delta9-THC or other cannabinoids correlate poorly with intensity of effects and character of intoxication (Agurell et al. 1986; Barnett et al. 1985; Huestis et al. 1992a). After smoking, venous levels of delta9-THC decline precipitously within minutes, and within an hour are about 5 to 10 percent of the peak level (Agurell et al., 1986, Huestis et al., 1992a, 1992b). Plasma clearance of delta9-THC is approximately 950 mL/min or greater, thus approximating hepatic blood flow. The rapid disappearance of delta9-THC from blood is largely due to redistribution to other tissues in the body, rather than to metabolism (Agurell et al., 1984, 1986). Metabolism in most tissues is relatively slow or absent. Slow release of delta9-THC and other cannabinoids from tissues and subsequent metabolism results in a long elimination half-life. The terminal half-life of delta9-THC is estimated to range from approximately 20 hours to as long as 10 to 13 days, though reported estimates vary as expected with any slowly cleared substance and the use of assays of variable sensitivities. In contrast, following an oral dose of
delta9-THC or marijuana, maximum delta9-THC and other cannabinoid blood
levels are attained after 2 to 3 hours (Adams and Martin 1996; Agurell et
al. 1984, 1986). Oral bioavailability of delta9-THC,
whether pure or in marijuana, is low and extremely variable, ranging between 5 and 20 percent (Agurell
et al. 1984, 1986). There is inter-and intra-subject variability, even when repeatedly dosed under
controlled and ideal conditions. The low and variable oral bioavailability of
delta9-THC is a consequence of its first-pass hepatic elimination from blood and erratic absorption from stomach
and bowel. Because peak effects are slow in onset, typically one or two hours after an oral dose, and variable in intensity, it is more
difficult for a user to titrate the oral delta9-THC dose
than with marijuana smoking. When smoked, the active metabolite, 11-hydroxy-delta9-THC, probably contributes little to the
effects since relatively little is formed, but after oral administration, metabolite levels produced may exceed that of
delta9-THC and thus contribute greatly to the
pharmacological effects of oral delta9-THC or marijuana.
Delta9-THC is metabolized via microsomal hydroxylation to
more than 80, active and inactive, metabolites (Lemberger et al., 1970,
Lemberger et al., 1972a, 1972b) of which the primary active metabolite
was 11-OH-delta9-THC. This metabolite is approximately
equipotent to delta9-THC in producing marijuana-like
subjective effects (Agurell et al., 1986, Lemberger and Rubin, 1975).
Following oral administration of radioactive-labeled delta9-THC, it has been confirmed that
delta9-THC plasma levels attained by the oral route are low relative to those levels after
smoking or intravenous administration. The half-life of delta9-THC has been determined to be 23-28 hours in heavy Characterization of the pharmacokinetics of delta9-THC and other cannabinoids from smoked marijuana is difficult (Agurell et al., 1986, Herning et al., 1986, Heustis et al., 1992a) in part because a subject's smoking behavior during an experiment cannot be easily controlled or quantified by the researcher. An experienced marijuana smoker can titrate and regulate the dose to obtain the desired acute psychological effects and to avoid overdose and/or minimize undesired effects. Each puff delivers a discrete dose of delta9-THC to the body. Puff and inhalation volume changes with phase of smoking, tending to be highest at the beginning and lowest at the end of smoking a cigarette. Some studies found frequent users to have higher puff volumes than less frequent marijuana users. During smoking, as the cigarette length shortens, the concentration of delta9-THC in the remaining marijuana increases; thus, each successive puff contains an increasing concentration of delta9-THC. Cannabinoid metabolism is extensive. There are at least 80 probable biologically inactive, but not completely studied, metabolites formed from delta9-THC (Agurell et al., 1986; Hollister, 1988a). In addition to the primary active metabolite, 11-hydroxy-delta9-THC, some inactive carboxy metabolites have terminal half-lives of 50 hours to 6 days or more. The latter substances serve as long term markers of earlier marijuana use in urine tests. Most of the absorbed delta9-THC dose is eliminated in feces, and about 33 percent in urine. Delta9-THC enters enterohepatic circulation and undergoes hydroxylation and oxidation to 11-nor-9-carboxy-delta9-THC. The glucuronide is excreted as the major urine metabolite along with about 18 nonconjugated metabolites. Frequent and infrequent marijuana users are similar in the way they metabolize delta9-THC (Agurell et al., 1986).
Previous Page | Back to Top | Next Page Registration
Support
|
