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Notices - 2001

Respiratory Effects

Marijuana smoking produces inflammation, edema, and cell injury in the tracheobronchial mucosa of smokers and may be a risk factor for lung cancer (Sarafian et al., 1999). Smoke from marijuana has been shown to stimulate intermediate levels of reactive oxygen species. A brief, 30-minute exposure to marijuana smoke, regardless of the THC content, also induced necrotic cell death that increased steadily up to 48 hours after administration. Sarafian et al., concluded that marijuana smoke containing THC is a potent source of cellular oxidative stress that could contribute significantly to cell injury and dysfunction in the lungs of smokers. 

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. However, several cases of lung cancer in young marijuana users with no have been reported (Fung et al., 1999). 

However, a recent study (Zhang et al., 1999, below) 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. THC is known to suppress macrophage natural killer cells and T-lymphocytes and reduce resistance to viral and bacterial infections. As shown below, Zhu et al., demonstrated that THC probably interacts with the T-cell cannabinoid CB2 receptor to produce these effects. As shown in the figure, below, these researchers found that THC promoted tumor growth in two immunocompetent mice lines. In two different weakly immunogenic murine lung cancer models, intermittent administration of THC led to accelerated growth of tumor implants compared with treatment with placebo alone. The immune inhibitory cytokines IL-10 and TGF-beta were augmented, while IFN-gamma was down-regulated at both the tumor site and in the spleens of THC- treated mice. This has been the first clear demonstration that THC promotes tumor growth and supports the epidemiological evidence of an increased risk of cancer among marijuana smokers. 

In a recent comprehensive review of the existing literature base, Carriot & Sasco (2000) reported that users under the age of 40 years of age were more susceptible to squamous-cell carcinoma of the upper aerodigestive tract, particularly of the tongue and larynx, and possibly the lung. Others tumors being suspected are non-lymphoblastic acute leukemia and astrocytoma. In head and neck cancer carcinogenicity was observed for regular (i.e. more than once a day for years) cannabis smokers. Moreover, cannabis increases the risk of head and neck cancer in a dose-response manner for frequency and duration of use. THC seems to have a specific carcinogenic effect different from that of the
pyrolysis products produced by (nicotine) cigarette smoking. 

(3) The State of Current Scientific Knowledge Regarding the Drug or Other Substance 

In general, the petitioner argues that the chemistry, toxicology and pharmacology of marijuana has been subjected to extensive study and peer review, and have been well characterized in the scientific literature. In addition, the discovery of the cannabinoid receptor has shed new light on the effects of marijuana and its mechanism of action.

The literature cited by the petitioner (Tashkin et al., 1987, 1988, 1990, 1991, 1993; Barbers et al., 1991; Sherman et al., 1991a, 1991b; Wu et al., 1992) provide data about the effects of marijuana smoke on the lungs, which, by the petitioner's own admission, is inherently unhealthy. Data show that smoking marijuana is associated with more tar than cigarettes and holding your breath (a common practice of marijuana smokers) increases carbon monoxide concentration. His assertion that Schedule I policy makes promoting safer marijuana smoking habits impossible has no basis in law (exact citations are found in petition). 

Pulmonary effects of smoked marijuana include bronchodilation after acute exposure. Chronic bronchitis and pharyngitis are associated with repeated pulmonary illness. With chronic marijuana smoking, large airway obstruction and cellular inflammatory abnormalities appear in bronchial epithelium (Adams and Martin, 1996). Chronic marijuana use is associated with the same types of health problems as cigarette smoking:
increased frequency of bronchitis, emphysema and asthma. The ability of alveolar macrophages to inactivate bacteria in the lung is impaired. Local irritation and narrowing of airways also contribute to problems in these patients. Work by Perez-Reyes et al. (1991) and Agurell et al. (1989) provides data about the pharmacokinetics of THC from smoked marijuana. 

When marijuana is smoked, THC in the form of an aerosol in the inhaled smoked is absorbed within seconds and delivered to the brain rapidly and efficiently. Peak venous blood levels 75-150 ng/ml usually occur by the end of smoking a cigarette and level of THC

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in the arterial system is probably much higher (Agurell et al., 1986). 

Toxicity by definition is the ability of an agent to produce injury or cause harm (morbidity/mortality). It is not clear that the effects of marijuana use are "well-established," but what is known about the psychoactive effects, lung effects, endocrine effects etc. would
suggest that smoking marijuana is not benign.

The cardiovascular effects of smoked or oral marijuana have not presented any health problems for healthy and relatively young users. However, marijuana smoking by older patients, particularly those with some degree of coronary artery disease, is likely to pose greater risks because of the resulting increased cardiac work, increased catecholamines, carboxyhemoglobin and postural hypotension (Benzowitz and Martin, 1996; Hollister, 1988). 

The endocrine system effects include moderate depression of spermatogenesis and sperm motility and decrease in plasma testosterone on males. Prolactin, FSH, LH, and GH levels are decreased in females (Mendelson and Mello, 1984). Relatively little study has been done on human female endocrine or reproductive function. 

THC and other cannabinoids in marijuana have immunosuppressant properties producing impaired cell-mediated and humoral immune system responses. THC and other cannabinoids suppress antibody formation, cytokine production, leukocyte migration and killer-cell activity (Adams and Martin, 1996). 

Marijuana may cause membrane perturbations in cells. At the marijuana conference in July, 1995 sponsored by NIH, NIDA and DHHS, Dr. Cabral stated that THC effects body functions by accumulating in fatty tissue. While a receptor-based mechanism of action has been determined, localized and characterized it is not clear that this necessarily negates membrane (high fatty acids) effects.

Mechanisms for marijuana's psychoactive effects were thought to be through interactions of the lipid component of cell membranes. The discovery of the cannabinoid receptor has changed that thinking and it is now believed that most of the effects of marijuana are mediated through cannabinoid receptors. Receptors are located in brain areas concerned with memory, cognition and motor coordination. An endogenous ligand, anandamide, has been identified but not studied in humans (Thomas et al. 1996). A specific THC antagonist, SR141716A, produces intense withdrawal signs and behaviors in rodents that have been exposed to THC for even a relatively short period of time (Adams and Martin, 1996). Clinical pharmacology of the antagonist has not been studied in humans. 

Most of what is known about human pharmacology of smoked marijuana comes from experiments with plant material containing about 2 percent THC or less. Very few controlled studies have been done with elderly, inexperienced or unhealthy users and data suggest that adverse effects may differ from healthy volunteers (Hollister 1986, 1988).

 Most of what is written about the pharmacological effects of marijuana is inferred from experiments on pure THC. The amount of Cannabidiol and other cannabinoids in smoked marijuana could modify the effects of THC. 

Tolerance to marijuana's psychoactive effect probably results from down regulation of cannabinoid receptors which is a form of desensitization of neuronal cells. In general, tolerance to marijuana's effects is often associated with an increased dependence liability.
Data indicate that people escalate the amount of marijuana they smoke and continue to use marijuana despite negative consequences. These are classic signs of developing dependence. 

After repeated smoked or oral marijuana doses, marked tolerance is rapidly acquired to many of marijuana's effects: cardiovascular, autoimmune and many subjective effects. After exposure is stopped, tolerance is lost with similar rapidity (Jones et al., 1981).

 Withdrawal symptoms and signs appearing within hours after cessation of repeated marijuana use have been reported in clinical settings (Duffy and Milan, 1996; Mendelson et al., 1984). Typical symptoms and signs were restlessness, insomnia, irritability, salivation, diarrhea, increased body temperature and sleep disturbances (Jones et al., 1981). 

Data on the immune system indicates that marijuana does effect the body's ability to resist microbes including bacteria, viruses and fungi and decreases the body's antitumor activity. THC effects macrophages, T-lymphocytes and B-lymphocyts. A THC receptor has been found in the spleen. These effects may be receptor mediated. In a person with compromised immune function marijuana could pose a health risk. 

Acute effects of transient anxiety, panic, feelings of depression and other dysphoric moods have been reported by 17 percent of regular marijuana users in a large study (Tart, 1971). Whether marijuana can produce lasting mood disorders or schizophrenia is less clear (IOM, 1982).  Chronic marijuana use can be associated with behavior characterized by apathy and loss of motivation along with impaired educational performance (Pope and Yurgelun-Todd, 1996). 

DEA has found that since HHS's last medical and scientific evaluation on marijuana (1986), there have been a significant number of new findings relating to THC:

  1. Cannabinoid receptors have been identified in the brain and spleen;
  2. The CNS cannabinoid receptor has been cloned; 
  3. An endogenous arachidonic acid derivative ligand (anandamide) has been identified;
  4. A high density of cannabinoid receptors have been located in the cerebral cortex, hippocampus, striatum and cerebellum; and 
  5. An antagonist to the cannabinoid receptor has been developed 

In addition, a significant body of literature has been amassed regarding the effects of marijuana.

For example:

  1. Studies on the acute and chronic effects of marijuana on the endocrine system;
  2. Effect of marijuana on learning and memory;
  3. Effect of marijuana on pregnant females and their offspring development;
  4. Effect on the immune system;
  5. Effect on the lungs; and
  6. Effects of chronic use with regard to tolerance, dependence and "amotivational syndrome."

While many of the petitioner's arguments are based on new research findings, the interpretation of those findings requires clarification. 

As was pointed out by the NIH expert committee on the medical utility of marijuana, marijuana is not a single drug. It is a variable and complex mixture of plant parts with a varying mix of biologically active material. Characterizing the clinical pharmacology is difficult especially when the plant is smoked or eaten. Some of the inconsistency or uncertainty in scientific reports describing the clinical pharmacology of marijuana results from the inherently variable potency of the plant material. Inadequate control over drug dose together with the use of research subjects with variable experience in using marijuana contributes to the uncertainty about what marijuana does or does not do. 

There are studies in the scientific literature that have evaluated dose-related subjective and reinforcing effects of Cannabis sativa in humans. These

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studies have assessed the subjective and reinforcing effects of cannabis cigarettes containing different potencies of THC and/or which have manipulated the THC dose by varying the volume of THC smoke inhaled (Azorlosa et al., 1992; Lukas et al., 1995; Chait et al., 1988; Chait and Burke, 1994; Kelly et al., 1993; Kipplinger et al, 1971, Manno et al., 1970).

Chait et al. (1988) studied the discriminative stimulus effects of smoked marijuana cigarettes containing THC contents of 0%, 0.9%, 1.4%, 2.7%. Marijuana smokers were trained to discriminate smoked marijuana from placebo using 4 puff of a 2.7%-THC cigarettes. Subjective ratings of "high", mean peak "high" scores, and physiological measures (i.e., heart rate) were significantly and dose-dependently increased after smoking the 0.9%, 1.4%, 2.7%. Marijuana cigarettes containing 1.4% THC completely substituted for 2.7%-THC on drug identification tasks, however, 0.9%-THC did not. The authors found that the onset of discriminative stimulus effects was within 90 seconds after smoking began (after the first two puffs). Since the 1.4%-THC cigarette substituted for 2-puffs of the 2.7%-THC cigarette, the authors estimate that an inhaled dose of THC as low as 3 mg can produce discriminable subjective effects.

Similarly, Lukas et al. (1995) reported that marijuana cigarettes containing either 1.26% or 2.53% THC produced significant and dose-dependent increases in level of intoxication and euphoria in male occasional marijuana smokers. Four of the six subjects that smoked the 1.26%-THC cigarette reported marijuana effects and 75% of these subjects reported euphoria. All six of the subjects that smoked 2.53% THC reported marijuana effects and euphoria. Peak levels of self-reported intoxication occurred at 15 and 30 minutes after smoking and returned to control levels by 90-105 minutes. There was no difference between latency to or duration of euphoria after smoking either the 1.26% or 2.53% THC cigarettes. The higher dose-marijuana cigarette produced a more rapid onset and longer duration of action than the lower dose marijuana cigarette (1.26% THC). Plasma THC levels peaked 5-10 minutes after smoking began; the average peak level attained after the low- and high-dose marijuana cigarette was 36 and 69 ng/ml respectively.

In order to determine marijuana dose-effects on subjective and performance measures over a wide dose range, Azorlosa et al. (1992) evaluated the effects of 4, 10, or 25 puffs from marijuana cigarettes containing 1.75 or 3.55% THC in seven male moderate users of marijuana. Orderly dose-response curves were produced for subjective drug effects, heart rate, and plasma concentration, as a function of THC content and number of puffs. After smoking the 1.75% THC cigarette, maximal plasma THC levels were 57 ng/ml immediately after smoking, 18.3 ng/ml 15 minutes after smoking, 10.3 ng/ml 30 minutes after smoking, and 7.7 ng/ ml 45 minutes after smoking. 

The study also show that subjects could smoke more of the low THC cigarette to produced effects that were similar to the high THC dose  cigarette (Azorlosa et al., 1992). There were nearly identical THC levels produced by 10-puff low-THC cigarette (98.6 ng/ml) and 4-puff high THC cigarette (89.4 ng/ml). Similarly, the subjective effects ratings, including high, stoned, impaired, confused, clear-headed and sluggish, produced under the 10 puff low- and high-THC and 25 puff low-THC conditions did not differ significantly from each other.

As with most drugs of abuse, higher doses of marijuana are preferred over lower dose. Although not preferred, these lower doses still produce cannabimimetic effects. Twelve regular marijuana smokers participated in a study designed to determine the preference of a low potency (0.64%-THC) vs. a high potency (1.95%-THC) marijuana cigarette (Chait and Burke, 1994). The subjects first sampled the marijuana of two different potencies in one session, then chose which potency and how much to smoke. During sampling sessions, there were significant dose-dependent increases in heart rate and subjective effects, including ratings of peak "high", strength of drug effects, stimulated, and drug liking. During choice sessions, the higher dose marijuana was chosen over the lower dose marijuana on 87.5% of occasions. Not surprising, there was a significant positive correlation between the total number of cigarettes smoked and the ratings of subjective effects, strength of drug effect, drug "liking", expired air carbon monoxide, and heart rate increases. The authors state it is not necessary valid to assume that the preference observed in the present study for the high-potency marijuana was due to greater CNS effects from its higher THC content. The present study found that the low- and high-potency marijuana cigarettes also differ on several sensory dimensions; the high-potency THC was found to "fresher" and "hotter". Other studies found that marijuana cigarettes containing different THC contents varied in sensory dimensions (cf., Chait et al., 1988; Nemeth-Coslett et al., 1986). 

As described above in Factors 1 and 2, there are data to show that the effects of THC are dose-dependent and several studies have found that low-potency THC is behaviorally active and can produce cannabimimetic-like subjective and physiological effects. Preclinical and clinical experimental data demonstrate that marijuana and D9-THC have similar abuse liabilities (i.e., drug discrimination, self-administration, subjective effects). Both preclinical and clinical studies show that discontinuation of either marijuana and D9-THC administration produces a mild withdrawal syndrome. Most of what is known about human pharmacology of smoked marijuana comes from experiments with plant material containing about 2-3% percent THC or less, in cigarette form provided by NIDA (cf., NIDA, 1996). Very few controlled studies have been done with elderly, inexperienced or unhealthy users and data suggests that adverse effects may differ from healthy volunteers (Hollister 1986, 1988). 

Cannabidiol (CBD) does not have psychotomimetic properties and does not appear to produce a subjective "high" in human subjects (Musty, 1984). This does not mean that CBD does not have CNS effects or that it does not contribute to the subjective high produced by the cannabinoids. CBD has been clearly shown to have anti-convulsant effects as demonstrated by several techniques such as electroshock-induced seizures, kindled seizures, pentylenetetrazole-induced seizures (Carlini et al., 1973; Izquierdo & Tannhauser, 1973). The suggestion that CBD does not have abuse liability is based in part on the findings that CBD does not produce THC-like discriminative stimulus effects in animals (Ford, Balster, Dewey, Rosecrans, & Harris, 1984; but see below). However, these tests were conducted with CBD administered alone and at only one or two time-points (however, see Jarbe below). The normal route of administration of THC and CBD in humans is by smoking. This mode of administration provides a variable proportion of cannabinoid ratios to the individual subject. As stated above, the chemistry of marijuana is not just the chemistry of D9-THC , but at a minimum, a combination of cannabinoids. According to Turner (1980) kinetic interactions have been reported to occur among the cannabinoids since the early 1970s. Control studies with varying ratios of cannabinoid administrations and

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complete time-effect functions have still not been conducted. 

Domino, Domino, & Domino (1984) have shown that the rate-of-change of the subjective high after marijuana administration does not follow the rate-of-change of plasma or brain THC levels. While plasma THC function show a sharp ascending limb and exponential decline after administration, the subjective "high" peaks after the peak in THC and shows a protracted slow decline. The proportional ratios between the cannabinoids and their metabolites in inhaled marijuana, acting as entourage substances, may have emergent properties that cannot be ascribed to any one component of the complex stimulus administered in the smoke (Gauvin & Baird, 1999). These cannabinoid ratios may play a critical role in the initiation, maintenance, and relapse of marijuana smoking. 

CBD has been clearly shown to have anxiolytic (Guimares et al, 1990, 1994; Musty, 1984; Onaivi, Green, & Martin, 1990; Zuardi et al., 1982) and antipsychotic (Zuardi et al., 1995; Zuardi, Antunes Rodrigues, & Cunha, 1991) effects in both animal and man. In the sense that many studies which have examined the subjective profiles of marijuana have demonstrated an "anxiety" component to THC and marijuana use, it should not be surprising that CBD's anxiolytic effects block some of these discriminative properties. However, it should not be concluded from these results that CBD's anxiolytic properties do not have or cannot acquire reinforcing efficacy. It has been suggested that the affective baseline of the drug abuser plays a critical role in the stimulus properties of drugs (Gauvin, Harland, & Holloway, 1989). The anxiolytic properties of CBD may serve to diminish the anxiety states associated with many psychopathological states, thus effectively functioning as a "negative reinforcer". As such, CBD may function to increase the likelihood of its administration by its ability to remove the negative affective states in anxious patients. A number of authors have summarized the process by which marijuana smokers "learn to get high" (cf. Jones, 1971, 1980; Cappell & Pliner, 1974). Karniol et al., (1974) have clearly demonstrated that the co-administration of CBD with THC actually blocks the anxiety induced by D9-THC, leaving the subjects less tense and potentiating the reinforcing effects of the THC as demonstrated by the subjects verbal reports of enjoying the experience even more. Very few experienced marijuana smokers report symptoms of anxiety (cf Jones, 1971, 1980; Petersen, 1980). The relief of the anxiety and/or psychotomimetic properties of THC by the co-administration of CBD may effectively function as a "negative reinforcer", increasing the likelihood of continued abuse. 

Other studies have reported that cannabidiol has cannabinoid properties, including anticonvulsant effects in animal and human models (Consroe et al., 1981; Carlini et al., 1981; Doyle and Spence, 1995), hypnotic effects (Monti et al., 1977), and rate-decreasing effects on operant behavior (Hiltunen et al., 1988). Experiments with cannabidiol in combination with THC have found that certain behavioral responses induced by THC (i.e., operant, schedule-controlled responding) were attenuated by cannabidiol (Borgen and Davis, 1974; Brady and Balster, 1980; Consroe et al., 1977; Dalton et al., 1976; Karniol and Carlini, 1973; Karniol et al., 1974; Welburn et al., 1976; Zuardi and Karniol, 1983; Zuardi et al., 1981, 1982; Hiltunen et al., 1988). However, other affects produced by THC are augmented or prolonged by the combined administration of CBD and THC or marijuana extract (Chesher and Jackson, 1974; Hine et al., 1975a,b; Fernandes et al., 1974; Karniol and Carlini, 1973; Musty and Sands, 1978; Zuardi and Karniol, 1983; Zuardi et al., 1984). Still other studies did not report any behavioral interaction between the CBD and THC (Bird et al., 1980; Browne and Weissman, 1981; Hollister and Gillespie, 1975; Jarbe and Henricksson, 1974; Jarbe et al., 1977; Mechoulam et al., 1970; Sanders et al., 1979; Ten Ham and DeLong, 1975). 

A study to characterize the interaction between CBD and THC was conducted using preclinical drug discrimination procedures. Rats and pigeons trained to discriminate the presence or absence of THC, and tested with CBD administered alone and in combinations with THC (Hiltunen and Jarbe, 1986). Specifically, in rats trained to discriminate 3.0 mg/kg, i.p. THC, CBD (30.0 mg/kg) was administered alone and in combination with THC (0.3 and 1.0 mg/kg, i.p.). In pigeons trained to discriminate 0.56 mg/kg, i.m. THC, CBD (17.5 mg/kg) was administered alone and in combination with THC (0.1, 0.3, and 0.56 mg/ kg, i.m.). CBD prolonged the discriminative stimulus effects of THC in rats, but did not change the time-effect curve for THC in pigeons. In pigeons, the administration of CBD did not produce any differential effect under a fixed ratio schedule of reinforcement (Hiltunen and Jarbe, 1986). 

These data suggest that CBD may somehow augment or prolong the actions of THC in rats and had no effect in pigeons. In the present study, the CBD/THC ratios ranged from 30:1 to 100:1 in rats and enhanced the stimulus effects of THC. However, similar CBD/THC ratios in pigeons (31:1, 58:1 and 175:1) did not result in any changes to THC's discriminative stimulus or response rate effects (Hiltunen and Jarbe, 1986).

In conclusion, although cannabidiol does contribute to the other effects of cannabis, it appears to lack cannabimimetic properties. In addition, there does not appear to be a scientific consensus that cannabidiol pharmacologically antagonizes, in a classic sense, the effects of THC. Certain functional blockades have been demonstrated. As presented in the scientific literature cited above, the ability of cannabidiol to modify the effects of THC may be specific to only some effects of THC. Most importantly, CBD appears to potentiate the euphorigenic and reinforcing effects of THC which suggests that the interaction between THC and CBD is synergistic and may actually contribute to the abuse of marijuana. 

(4) Its History and Current Pattern of Abuse 

The federal databases documenting the actual abuse of marijuana are distributed and maintained by the HHS, therefore, we acknowledge and concur with HHS's review of this factor analysis.

(5) The Scope, Duration, and Significance of Abuse 

The basis of the petition to remove marijuana from Schedules I and II is not based on data required by 21 U.S.C. 811 (c) (i.e., the scope, duration, and significance of use of the substances).

The petitioner seems to assume that the concept, use of an illegal substance is abuse of that substance, is a concept which is universally held to the exclusion of any other definition of abuse of a substance. While this concept is valid in general terms because marijuana is not a legitimately marketed product therefore it has no legitimate use, holding that all adhere to this definition of abuse denigrates the intellectual capacity of all researchers who investigate the topic. The petitioner neglects to recognize the efforts of the DHHS and many groups which expend a great deal of time and money in research efforts directed toward developing and implementing drug-abuse prevention programs. The petitioner also rejects the notion that there are individuals who abuse marijuana even though the National Household Survey, to which the

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petitioner refers, would indicate that is the case.

It has not been established that marijuana is effective in treating any medical condition. (NIH Workshop on the Medical Utility of Marijuana, 1997) At this time, there is no body of knowledge to which a physician can turn to learn which medical condition in which patient will be ameliorated at which dosage schedule of smoked marijuana nor can he/she determine in which patient the benefits will exceed the risks associated with such treatment. The petitioner, therefore, is advocating that individuals become their own physicians, a notion that even primitive man found unsatisfactory.

There is nothing absolute in the placement of a substance into a particular CSA schedule. The placement of a substance in a CSA schedule is the government's mechanism for seeing that the availability of certain psychoactive substances is limited to the industrial, scientific and medical needs which are accepted as being legitimate. 

The placement of a substance into Schedule I does not preclude research of that substance, nor does it preclude development of a marketable product. The National Institute on Drug Abuse, an element of the Department of Health and Human Services, convened a conference in 1995 and with NIDA's parent organization, the National Institutes of Health, assembled an ad hoc group of experts in 1997 to address issues related to the use, abuse, and medical utility of marijuana. With regard to the medical utility of marijuana, the experts concluded that the scientific process should be allowed to evaluate the potential therapeutic effects of marijuana for certain disorders, dissociated from the societal debate over the potential harmful effects of nonmedical marijuana use. All decisions on the ultimate usefulness of a medical intervention are based on a benefit/risk calculation, and marijuana should be no exception to this generally accepted principle.

The cause and effect relationship which the petitioner poses is neither substantiated nor relevant. Estimates are useful when attempting to allocate resources but they are not necessary for effective eradication of marijuana. Each year, millions of plants are destroyed before their product reaches the market. In addition, federal law enforcement activities result in the seizure of another million or more pounds of product annually.

As reviewed by Gledhill, Lee, Strote, & Wechsler (2000), rates of illicit drug use, especially marijuana, have risen uniformly among the youth in the United States in the past decade and remained steady at the end of the 1990s despite efforts to reduce prevalence. Between 1991 and 1997, rates of past 30-day marijuana use had more than doubled among U.S. 10th grade secondary school students and more than tripled among seniors, after a decade of decline. Between 1997 and 1999, rates of marijuana use among secondary school students declined for the first time in the 1990s mainly among the older students (16-17 yrs old). 

Disturbing are the findings that marijuana use is steadily increasing among 8th, 10th and 12th graders at all prevalence levels. According to the 1996 survey results from the Monitoring the Future Study, 45% of seniors and 35% of 10th graders claimed to have used marijuana at least once. Among eighth graders, annual prevalence rates more nearly tripled 1992 to 1996. Accompanying the increased use of marijuana among High School seniors is a decreasing perceived risk or harm of marijuana use (Johnston et al., 1996). In reality, the harm associated with the abuse of marijuana is increasing; the marijuana emergency room and treatment admission rates continue to increase in recent years. 

Gledhill-Hoyt, Lee, Strote, & Wechsler (2000) examined rates and patterns of marijuana use among different types of students and colleges in 1999, and changes in use since 1993. 15,403 students in 1993, 14,724 students in 1997, and 14,138 students in 1999 were assessed. The prevalence of past 30-day and annual marijuana use increased in nearly all student demographic subgroups, and at all types of colleges. Nine out of 10 students (91%) who used marijuana in the past 30 days had used other illicit drugs, smoked cigarettes, and/or engaged in binge drinking. Twenty-nine percent of past 30-day marijuana users first used marijuana and 34% began to use marijuana regularly at or after the age of 18, when most were in college. 

Coffey, Lynskey, Wolfe, & Patton (2000) examined predictors of cannabis use initiation, continuity and progression to daily use in adolescents. Over 2,000 students were examined. Peer cannabis use, daily smoking, alcohol use, antisocial behavior and high rates of school-level cannabis use were associated with middle-school cannabis use and independently predicted high-school uptake. Cannabis use persisted into high-school use in 80% of all middle-school users. Middle-school use independently predicted incidents in high-school daily use in males, while high-dose alcohol use and antisocial behavior predicted incidence of daily use in high school females. The authors also found that cigarette smoking was an important predictor of both initiation and persisting cannabis use.

Farrelly et al., (2001) reviewed the NHSDA from 1990 through 1996 and compared those statistics with State law enforcement policies and prices that affect marijuana use in the general public. These authors found evidence that both higher fines for marijuana possession and increased probability of arrest decreased the probability that a young adult will use marijuana. These new data refute the petitioner's suggestion that legal control of marijuana does not have a dampening effect on its use.

(6) What, if any, Risks are There to Public Health

There are human data demonstrating that marijuana and D9-THC produce an increase in heart rate, an increase in systolic blood pressure while supine, and decreases in blood pressure while standing (cf., Jaffe, 1993). The increase in heart rate is dose-dependent and its onset and duration correlate with levels of D9-THC in the blood.

When DEA evaluates a drug for control or rescheduling, the question of whether the substance creates dangers to the public health, in addition to, or because of, its abuse potential must be considered. A drug substances' risk to the public health manifests itself in many ways. Abuse of a substance may affect the physical and/or psychological functioning of an individual abuser. In addition, 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 specific factor of the CSA 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. 

Adverse effects associated with marijuana and THC as determined by clinical trials, FDA adverse drug effects and World Health Organization data, are described elsewhere (cf., Chait and Zacny, 1988; Chait and Zacny, 1992; Cone et al., 1988; and Pertwee, 1991). A recent press release from the Substance Abuse and Mental Health Service Administration reported that adolescents, age 12 to 17, who use

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marijuana weekly are nine times more likely than non-users to experiment with illegal drugs or alcohol; six times more likely to run away from home; five times more likely to steal; nearly four times more likely to engage in violence; and three times more likely to have thoughts about committing suicide. It was also reported that adolescents also associated social withdrawal, physical complaints, anxiety, and depression, attention problems, and thoughts of suicide with past-year marijuana use (SAMHSA, 1999). 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.

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