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Notices - 2001

Toxic Effects of Marijuana and THC

Although a median lethal dose (LD50) of THC has not been established in humans, it has been found in laboratory animals (Phillips et al., 1971). In mice, the LD50 for THC was 481.9, 454.9 and 28.6 mg/kg after oral, intraperitoneal, and intravenous routes of administration. In rats, the LD50 for THC (extracted from marijuana) was 666.0, 372.9 and 42.5 mg/kg after oral, intraperitoneal, and intravenous routes of administration. Another study examined the toxicity of THC in rats, dogs and monkeys (Thompson et al., 1972). Similarly this study found that in rats, the LD50 for THC was 1140.0, 400.0 and 20.0 mg/kg after oral, intraperitoneal, and intravenous routes of administration. There was no LD50 attained in monkeys and dogs by the oral route. Over 3000 mg/kg of THC was administered without lethality to dogs and monkeys. A dose of about 1000 mg/kg was the lowest dose that caused death in any animal. Behavioral changes in the survivors included sedation, huddled postures, muscle tremors, hypersensitivity to sound and immobility. 

The cause of death in the rats and mice after oral THC was profound depression leading to dyspnea, prostration, weight loss, loss of righting reflex, ataxia, and severe decreases in body temperature leading to cessation of respiration from 10 to 40 hours after a single oral dose (Thompson et al., 1972). No consistent pathologic changes were observed in any organs. The cause of death in dogs or monkeys (when it rarely occurred) did not appear to be via the same mechanism as in the rats.

In humans, the estimated lethal dose of intravenous dronabinol [(-)-D9-THC] is 30 mg/kg (2100 mg/70 kg). In antiemetic studies, significant CNS symptoms were observed following oral doses of 0.4 mg/kg (28 mg/70 kg) (PDR, 1997). Signs and symptoms of mild dronabinol intoxication include drowsiness, euphoria, heightened sensory awareness, altered time perception, reddened conjunctiva, dry mouth and tachycardia. Following moderate dronabinol intoxication patients may experience memory impairment, depersonalization, mood alterations, urinary retention, and reduced bowel motility. Signs and symptoms of severe dronabinol intoxication include decreased motor coordination, lethargy, slurred speech, and postural hypotension. Dronabinol may produce panic reactions in apprehensive patients or seizures in those with an existing seizure disorder (PDR, 1997).

Thus, large doses of THC ingested by mouth were not often associated with toxicity in dogs, nonhuman primates and humans. However, it did produce fatalities in rodents as a result of profound CNS depression. Thus, the evidence from studies in laboratory animals and human case reports indicates that the lethal dose of THC is quite large. The adverse effects associated with THC use are generally extensions of the CNS effects of the drug and are similar to those reported after administration of marijuana (cf., Chait and Zacny, 1988; Chait and Zacny, 1992; Cone et al., 1988; and Pertwee, 1991).

Health and Safety Risks of D9 -THC Use

The recent Institute of Medicine report on the scientific basis for the medicinal use of cannabinoid products stated the following:

Not surprisingly, most users of other illicit drugs have used marijuana first. In fact, most drug users begin with alcohol and nicotine before marijuana--usually before they are of legal age. In the sense that marijuana use typically precedes rather than follows initiation of other illicit drug use, it is indeed a "gateway" drug (Institute of Medicine Report 1999, p. ES.7).

Golub and Johnson (1994) examined the developmental pathway followed by a sample of persons who became serious drug abusers. Of the 837 persons sampled 84% had onset to more serious drugs by the time of the interviews. Most of the sample reported having used marijuana (91%). Two-thirds of the drug abusers reported having used marijuana prior to onset to more serious drugs and an additional 19% reported having onset to marijuana and more serious drugs in the same year. These data strongly suggest that marijuana does plan an important role on the pathway to more serious drugs use. Further, the proportion who onset to marijuana before or in the same year as more serious drugs was reported to have increased substantially with time from a low of 78% for persons born from 1928 to 1952 to 95% for the most recent birth cohort of the study (1968-1973). These findings further suggest that marijuana's role as a gateway to more serious substance sue has become more pronounced over time.

Ferguson & Horwood (2000) have examined the relationship between cannabis use in adolescence and the onset of other illicit drug use. Data were gathered over the course of a 21 year longitudinal study of a birth cohort of 1,265 children. By the age of 21, just over a quarter of this cohort reported using various forms of illicit drugs on at least one occasion. In agreement with the predictions of a "stage-theory" of the "gateway hypothesis" there was strong evidence of a temporal sequence in which the use of cannabis preceded the onset of the use of other illicit drugs. Of those reporting the use of illicit drugs, all but three (99%) had used cannabis prior to the use of other illicit drugs. However, the converse was not true and the majority (63%) of those using cannabis did not progress to the use of other forms of illicit drugs. In addition, to these findings there was a strong dose-response relationship between the extent of cannabis use and the onset of illicit drug use. The analysis suggested that those using cannabis in any given year on at least 50 occasions had hazards of using other illicit drugs that were over 140 times higher than those who did not use in the year. Furthermore, hazards of the onset of other illicit drug use increased steadily with increasing cannabis use. The very strong gradient in risk reflected the facts that: (1) Among non-users of cannabis the use of other forms of illicit drugs was almost non-existent and (2) among regular users of cannabis the use of other illicit drugs was common. To address the issue of "confounding factors", the associations between cannabis use and the onset of illicit drug use were adjusted for a series of

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prospectively measured confounding factors that included measures of social disadvantage, family functioning, parental adjustment, individual characteristics, attitudes to drug use and early adolescent behavior. After adjustments for these factors, there was still evidence of strong dose-response relationships between the extent of cannabis use in a given year and the onset of illicit drug use--the hazards of the onset of illicit drug use was 100 times those of non-users. 

Critics of the "gateway theory" point to the presence of other confounding factors and processes that encourage both cannabis use and other forms of illicit drug use. Despite these factors, the Ferguson & Horwood (2000) study provide a compelling set of results that support the hypothesis that cannabis use may encourage other forms of illicit drug use, including the following:

  1. Temporal sequence: There was clear evidence that the use of cannabis almost invariably preceded the onset of other forms of illicit drug use.
  2. Dose-Response: There was clear evidence of a very strong and consistent dose-response relationship in which increasing cannabis use was associated with increasing risks of the onset of illicit drug use.
  3. Resilience to control for confounding: Even following control for a range of prospectively measured social, family and individual factors, strong and consistent associations remained between cannabis use and the onset of other forms of illicit drug use. And,
  4. Specificity of associations: The association could not be explained as reflecting a more general process of transition to adolescent deviant behavior since even after control for contemporaneously assessed measures of juvenile offending, alcohol use, cigarette smoking, unemployment and related measures, strong and consistent relationships between cannabis use and the onset of other forms of illicit drugs remained.

A suggested view of the "gateway hypothesis" states that the use of cannabis may be associated with increasing risks of other forms of illicit drug use, with this relationship being mediated by affiliations with deviant peers and other non-observed processes that may encourage those who use cannabis (and particularly heavy users) to experiment with, and use, other illicit drugs.

While marijuana is clearly not the only gateway to the use of other illicit drugs it is one of the three most typical drugs in the adolescent's armamentarium. The increased avenues to imported and "home-grown" marijuana which contain behaviorally-active doses of THC and CBD pose a serious threat to the health and well-being of this dimension of society.

 Taylor et al. (2000) evaluated the relationship between cannabis dependence and respiratory symptoms and lung function in young adults, 21 years of age, while controlling for the effects of cigarette smoking. The researchers found significant respiratory symptoms and changes in spirometry occur in cannabis-dependent individuals at age 21 years, even though the cannabis smoking history is of relatively short duration. The likelihood of reporting a broad range of respiratory symptoms was significantly increased in those who were either cannabis-dependent or smoked tobacco or both compared to non-smokers. The symptoms most frequently and significantly associated with cannabis dependence were early morning sputum production (144% greater prevalence than non-smokers). Overall, respiratory symptoms in study members who met strict criteria for cannabis dependence were comparable to those of tobacco smokers consuming 1-10 cigarettes daily. In subjects who were both tobacco users and were cannabis-dependent, some effects seem to be additive, notably early morning sputum production, which occurred 8 times more frequently than non-smokers. 

One of the greatest concerns to society regarding D9-THC is the behavioral toxicity produced by the drug. D9-THC intoxication is associated with impairments in memory, motor coordination, cognition, judgement, motivation, sensation, perception and mood (cf., Jaffe, 1993). The consequences produced by D9- THC-induced behavioral impairments can greatly impact the individual and society in general. These impairments result in occupational, household, or airplane, train, truck, bus or automobile accidents, given that individuals may be attending school, working, or operating a motor vehicle under the influence of the drug. In the most general sense, impaired driving can be seen as a failure to exercise the expected degree of prudence or control necessary to ensure road safety. The operations of a motor vehicle are clearly a skilled performance that requires controlled and flexible use of a person's intellectual and perceptual resources. Cannabis interferes with resource allocations in both cognitive and attentional tasks. 

In 1999, Ehrenreich et al., examined the detrimental effects of chronic interference by cannabis with the endogenous cannabinoid systems during peripubertal development in humans. As an index of cannabinoid action, visual scanning and other attentional factors were examined in 99 individuals who exclusively used cannabis. Early-onset cannabis use (onset before the age of 16) showed significant impairments in attention in adulthood. These persistent attentional deficits may interact with the activities of daily living, such as operating an automobile. 

Kurzthaler et al., (1999) examined the effects of cannabis on a cognitive test battery and driving performance skills. The demonstrated significant impairments in the verbal memory and the trail making tests in this study reflect parallel compromises in associative control that is acknowledged as a cognitive process inherent in memory function immediately after smoking cannabis. Applied to the question of driving ability, the authors suggest that the missing functions would signify that a driver under acute cannabis influences would not be able to use acquired knowledge from earlier experiences adequately to ensure road safety. 

Recently, the National Highway Traffic Safety Administration (NHTSA; 1998, 1999, 2000) conducted a study with the Institute for Human Psychopharmacology at Maastricht University in The Netherlands. Low dose and high dose THC administered alone, and with alcohol were examined in two on-road driving situations: (1) The Road Tracking Test, measuring a driver's ability to maintain a constant speed of 62 mph and a steady lateral position between the boundaries of the right traffic lane; and (2) the Car Following Test, measuring a drivers' reaction times and ability to maintain distance between vehicles while driving 164 ft. behind a vehicle that executed a series of alternating accelerations and decelerations. Both levels of THC alone, and alcohol alone, significantly impaired performances on BOTH road tests compared with baseline. Alcohol and the high dose of THC produced 36% decrements in reaction time; because the test vehicles were traveling at 59 mph, the delayed reaction times meant that the vehicle traveled, on average, an additional 139 feet beyond the point where the subjects began to decelerate. Even the lower dose of THC by itself retarded reaction times by 0.9 seconds. The NHTSA concluded that even in low to moderate doses, marijuana impairs driving performance.

In a related analysis, Yesavage, Leirer, Denari, & Hollister (1985) examined the acute and delayed effects of smoking one marijuana cigarette containing 1.9% THC (19 mg of THC) on aircraft pilot performance. Ten private pilot licensed subjects were trained in a flight simulator prior to marijuana exposure. Flight simulator performance was

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measured by the number of aileron (lateral control), elevator (vertical control) and throttle changes; the size of these control changes; the distance off the center of the runway on landing; and the average lateral and vertical deviation from an ideal glideslope and center line over the final mile of the approach. Compared to baseline performance, significant differences occurred in all variables at 1 and 4 hours after smoking, except for the numbers of throttle and elevator changes at 4 hours. Most importantly, at 24 hours after a single marijuana cigarette, there were significant impairments in the number and size of aileron (lateral control) changes, size of elevator changes, distance off-center on landing, and vertical and lateral deviations on approach to landing. Interestingly, despite these performance deficits, the pilots reported no significant subjective awareness of their impairments at 24 hours. It is noteworthy that a fatal crash in which a pilot had a positive THC screen involved similar landing misjudgments. 

In addition to causing unsafe conditions, marijuana use results in decreased performance and lost productivity in the workplace, including injuries, absenteeism, and increased health care costs. A NIDA report on drugs in the workplace summarized the prevalence of marijuana use in the workplace and its impact on society. This report found that in 1989, one in nine working people (11%) reported current use of marijuana (Gust and Walsh, 1989). Recent DAWN data and other surveys indicate that marijuana use is increasing, especially among younger and working age individuals. 

Bray, Zarkin, Ringwalt, & Qi (2000) estimated the impact of age of dropout on the relationship between marijuana use and high school dropouts using four longitudinal surveys from students in the Southeastern U.S. public school system. Their results suggested that marijuana initiation was positively related to high school dropout. Although the magnitude and the significance of the relationship varied with age of dropout and the other substances used, the overall effect represented an odds-ratio of approximately 2.3. These data suggest that an individual is approximately 2.3 times more likely to drop out of school than an individual who has not initiated marijuana use.

When DEA evaluates a drug for control or rescheduling, whether the substance creates dangers to the public health, in addition to or because of its abuse potential, must be considered. The risk to the public health of a substance may manifest itself in many ways. Abuse of a substance may affect the physical and/or psychological functioning of an individual abuser, it may have disruptive effects on the abuser's family, friends, work environment, and society in general. Abuse of certain substances leads to a number of antisocial behaviors, including violent behavior, endangering others, criminal activity, and driving while intoxicated. Data examined under this factor ranges from preclinical toxicity to postmarketing adverse reactions in humans. DEA reviews data from many sources, including forensic laboratory analyses, crime laboratories, medical examiners, poison control centers, substance abuse treatment centers, and the scientific and medical literature.

In its official report titled "Marijuana and Medicine: Assessing the Science Base", the Institute of Medicine highlighted a number of risks to the public health as a result of cannabis consumption: 

  1. Cognitive impairments associated with acutely administered marijuana limit the activities that people would be able to do safely or productively. For example, no one under the influence of marijuana or THC should drive a vehicle or operate potentially dangerous equipment (Page 107).
  2. The most compelling concerns regarding marijuana smoking in HIV/AIDS patients are the possible effects of marijuana on immunity. Reports of opportunistic fungal and bacterial pneumonia in AIDS patients who used marijuana suggest that marijuana smoking either suppresses the immune system or exposes patients to an added burden of pathogens. In summary, patients with pre-existing immune deficits due to AIDS should be expected to be vulnerable to serious harm caused by smoking marijuana. The relative contribution of marijuana smoke versus THC or other cannabinoids is not known. (Page 116-117) 
  3. DNA alterations are known to be early events in the development of cancer, and have been observed in the lymphocytes of pregnant marijuana smokers and in those of their newborns. This is an important study because the investigators were careful to exclude tobacco smokers; a problem in previous studies that cited mutagenic effects of marijuana smoke. (Page 118-119) 
  4. * * * factors influence the safety of marijuana or cannabinoid drugs for medical use: the delivery system, the use of plant material, and the side effects of cannabinoid drugs. (1) Smoking marijuana is clearly harmful, especially in people with chronic conditions, and is not an ideal drug delivery system. (2) Plants are of uncertain composition, which renders their effects equally uncertain, so they constitute an undesirable medication.  (Page 127)

(7) Its Psychic or Physiological Dependence Liability

The "dopaminergic hypothesis of drug abuse" is not the only explanation for the neurochemical actions of drugs. The nucleus accumbens/ventral striatum areas of the brain, typically referred to as simply the Nucleus Accumbens (NAc), represents a critical site for mediating the rewarding or hedonic properties of several classes of abused drugs, including alcohol, opioids, and psychomotor stimulants (Gardner & Vorel, 1998; Koob, 1992; Koob et al., 1998; Wise, 1996; Wise & Bozarth, 1987). It is generally appreciated that all of these drugs augment extracellular dopamine levels in the NAc and that this action
contributes to their rewarding properties. However, recent evidence also suggests that many drugs of abuse have dopamine-independent interactions with Nac neuronal activity (Carlezon & Wise, 1996; Chieng & Williams, 1998; Koob, 1992; Martin et al., 1997; Yuan et al., 1992). 

Recent studies conducted at the Cellular Neurobiology Branch of the NIDA by Hoffman & Lupica (2001) concluded that THC modulates NAc glutamatergic functioning of dopamine. These authors suggested that increases in Nac dopamine levels may be a useful neurochemical index of drug reward but do not fully account for the complex processing of fast synaptic activity by this neuromodulator in the Nac. Moreover, because both glutamatergic and GABAergic inputs to medium spiny neurons are directly inhibited by dopamine, as well as by drugs of abuse. It is likely that these effects contribute to the abuse liability of marijuana.

In addition, the petitioner's global statements about the role of dopamine, the reinforcing effects of marijuana and other drugs, and the predictive validity of animal self-administration studies with marijuana and abuse potential in humans are not supported by the scientific literature. For example:

  1. There are drugs that do not function through dopaminergic systems that are self-administered by animals and humans (i.e., barbiturates, benzodiazepines, PCP).
  2. There are drugs that are readily self-administered by animals that are not abused by man (antihistamines)
  3. There are drugs that are abused by humans that are not readily self-administered by animals (hallucinogens and hallucinogenic phenethylamines, nicotine, caffeine).
  4. There are drugs that have no effect on dopamine that are self-administered

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by animals and not abused by humans (i.e., antihistamines).

Physical Dependence in Animals

Abrupt withdrawal from D9-THC can produce a mild spontaneous withdrawal syndrome in animals, including increased motor activity and grooming in rats, decreased seizure threshold in mice and increased aggressiveness, irritability and altered operant performance in rhesus monkeys (cf., Pertwee, 1991). The failure to observe profound withdrawal signs following abrupt discontinuation of D9-THC may be due to (1) its long half-life in plasma and (2) slowly waning levels of D9-THC and its metabolites that continue to permit receptor adaptation.

Recently the discovery of a cannabinoid receptor antagonist demonstrates that a profound precipitated withdrawal syndrome can be produced in D9-THC tolerant animals after twice
daily injections (Tsou et al., 1995) or continuous infusion (Aceto et al., 1995, 1996). In rats continuously infused with low doses D9-THC for four days, the cannabinoid antagonist precipitated a behavioral withdrawal syndrome, including scratching, face rubbing, licking, wet dog shakes, arched back and ptosis (Aceto et al., 1996). This chronic low dose regimen consisted of 0.5, 1, 2, 4 mg/kg/day D9-THC on days 1 through 4; 5 and 25-fold higher D9-THC doses were used for the medium and high dose regimens, respectively. The precipitated withdrawal syndrome was dose-dependently more severe in the medium and high THC dose groups.

Physical Dependence in Humans

Signs of withdrawal have been demonstrated after studies with D9-THC. Although the intensity of the withdrawal syndrome is related to the daily dose and frequency of administration, in general, the signs of D9-THC withdrawal have been relatively mild (cf., Pertwee, 1991). This withdrawal syndrome has been compared to that of a short-term, low dose treatment with an opioid or ethanol, and includes changes in mood, sleep, heart rate body temperature, and appetite. Other signs such as irritability, restlessness, tremor mild nausea, hot flashes and sweating have also been noted (cf., Jones, 1983). 

A withdrawal syndrome was reported after the discontinuation of oral THC in volunteers receiving dronabinol dosages of 210 mg/day for 12 to 16 consecutive days (PDR, 1997). This was 42-times the recommended dose of 2.5 mg, b.i.d. Within 12 hours after discontinuation, these volunteers manifested withdrawal symptoms such as irritability, insomnia, and restlessness. By approximately 24 hours after THC discontinuation, there was an intensification of withdrawal symptoms to include "hot flashes", sweating, rhinorrhea, loose stools, hiccoughs, and anorexia. These withdrawal symptoms gradually dissipated over the next 48 hours. EEG changes consistent with the effects of drug withdrawal (hyperexcitation) were recorded in patients after abrupt challenge. Patients also complained of disturbed sleep for several weeks after discontinuation of high doses of dronabinol. The intensity of the cannabinoid withdrawal syndrome is related by the chronic dose and by the frequency of chronic administration. There is also evidence that the cannabinoid withdrawal symptoms can be reversed by the administration of marijuana and D9-THC, or by treatment with a barbiturate (hexobarbital) or ethanol (Pertwee, 1991).

An acute withdrawal syndrome or "hangover" has been reported by Chait, Fischman, & Schuster (1985) developing approximately 9 hours after smoking a 1 g marijuana cigarette containing 2.9% THC. Five of twelve subjects reported themselves as "dopey and hung over" the morning after smoking the single cigarette. In a 10 second and 30 second time-production task significant marijuana hangover effects were found. The effect on the time production task is of interest since the effect obtained the morning after smoking marijuana was opposite to that observed acutely after smoking marijuana. These data may suggest an opponent compensatory rebound which may underlie the development of tolerance over periods of chronic marijuana exposure. Scores on the benzedrine-group (BG) scale, a stimulant scale of the Addiction Research Center Inventory (ARCI) consisting mainly of terms relating to intellectual efficiency and energy, were significantly higher the morning after marijuana smoking, as well. Chait, Fischman, & Schuster also reported increases on the amphetamine (A) scale of the ARCI, a measure of the dose-related effects of d-amphetamine. Cousens & DiMascio (1973) have previously reported a similar "hangover" and "speed of thought alterations" in subjects the morning after they had received a 30 mg oral dose of D9-THC. Like the "hangover" associated with high dose ethyl alcohol consumption, the hangover from marijuana may be qualitatively identical to, and differ only on an intensity dimension from, the withdrawal syndrome produced from chronic consumption (cf. Gauvin, Cheng, Holloway, 1993). 

As described above, Haney et al. have recently described abstinence symptoms of an acute withdrawal syndrome following high (30 mg q.i.d.) and low (20 mg q.i.d) dose administrations of oral THC (Haney et al., 1999a) and following 5 puffs of high (3.1%) and low (1.8%) THC-containing smoked marijuana cigarettes (Haney et al., 1999b). Both of these studies have delineated a withdrawal syndrome from concentrations of THC significantly lower than those reported in any other previous study and, for the first time, clearly identified a marijuana withdrawal syndrome detected at low levels of THC exposure that do not produce tolerance. These data suggest that dependence on THC may in fact be an important consequence of repeated, daily exposure to cannabinoids and that daily marijuana use may be maintained, at least in part, by the alleviation of abstinence symptoms.

As stated above, Budney, Novy, & Hughes (1999) have recently examined the withdrawal symptomology in chronic marijuana users seeking treatment for their dependence. The majority of the subjects (85%) reported that they had experienced symptoms of at least moderate severity and 47% experienced greater than four symptoms rated as severe. The most reported mood symptoms associated with the withdrawal state were irritability, nervousness, depression, and anger. Some of the behavioral characteristics of the marijuana withdrawal syndrome were craving, restlessness, sleep disruptions, strange dreams, changes in appetite, and violent outbursts. These data clearly support the validity and clinical significance of a marijuana withdrawal syndrome in man. Large-scale population studies have also reported significant rates of cannabis dependence (Kessler et al., 1994; Farrell et al., 1998), particularly in prison and homeless populations. Similar reports of cannabis dependence in withdrawal in other populations have been previously discussed (above; Crowley et al. (1998); Kouri & Pope (2000)).

Psychological Dependence in Humans

In addition to the physical dependence produced by abrupt withdrawal from D9-THC, psychological dependence on D9-THC can also be demonstrated. Case reports and clinical studies show that frequency of D9-THC use (most often as marijuana) escalates over time, there is evidence that individuals increase the number, doses, and potency of marijuana cigarettes. Data have clearly shown that tolerance

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to the stimulus effects of the drug develops which could lead to drug seeking behavior (Pertwee, 1991; Aceto et al., 1996; Kelly et al., 1993, 1994; Balster and Prescott, 1992; Mendelson et al., 1976; Mendelson and Mello, 1985; Mello, 1989). Several studies have reported that patterns of marijuana smoking and increased quantity of marijuana smoked were related to social context and drug availability (Kelly et al., 1994; Mendelson and Mello, 1985; Mello, 1989). There have been, however, other studies which have demonstrated that the magnitude of many of the behavioral effects produced by D9-THC and other synthetic cannabinoids lessens with repeated exposure while also demonstrating that tolerance did not develop to the euphorigenic activity, or the "high" from smoked marijuana (Dewey, 1986; Perez-Reyes et al., 1991). Recent electrophysiological data from animals suggests that the response of VTA dopamine neurons do not diminish during repeated exposure to cannabinoids, and that this may underlie the lack of tolerance to the euphoric effects of marijuana even with chronic use (Wu & French, 2000).

The problems of psychological dependence associated with marijuana (THC) abuse are apparent from DAWN reports and survey data from the National Household Survey on Drug Abuse and the Monitoring the Future study. These databases show that the incidence of chronic daily marijuana use and adverse events associated with its use are increasing, especially among the young. At the same time, perception of risk has decreased and availability is widespread (cf., NIDA, 1996). These factors contribute to perpetuating the continued use of the marijuana. 

(8) Whether The Substance Is an Immediate Precursor of a Substance Already Controlled Under This Subchapter.

According to the legal definition, marijuana (Cannabis sativa L.) is not an immediate precursor of a scheduled controlled substance. However, cannabidiol is a precursor for delta-9-tetrahydrocannabinol, a Schedule I substance under the CSA.

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