# Denial of Petition To Initiate Proceedings To Reschedule Marijuana > Briefs, arguments, decisions, and more. URL: https://www.frixlaw.com/law-library/documents/fr%3A2011-16994 ## Record - **Collection:** Federal Register - **Document type:** Proposed Rule - **Published:** July 8, 2011 - **Citation:** 76 FR 40552 ## Text DEPARTMENT OF JUSTICE Drug Enforcement Administration 21 CFR Chapter II [Docket No. DEA-352N] Denial of Petition To Initiate Proceedings To Reschedule Marijuana AGENCY: Drug Enforcement Administration (DEA), Department of Justice. ACTION: Denial of petition to initiate proceedings to reschedule marijuana. SUMMARY: By letter dated June 21, 2011, the Drug Enforcement Administration (DEA) denied a petition to initiate rulemaking proceedings to reschedule marijuana. 1 Because DEA believes that this matter is of particular interest to members of the public, the agency is publishing below the letter sent to the petitioner (denying the petition), along with the supporting documentation that was attached to the letter. 1 Note that “marihuana” is the spelling originally used in the Controlled Substances Act (CSA). This document uses the spelling that is more common in current usage, “marijuana.” FOR FURTHER INFORMATION CONTACT: Imelda L. Paredes, Office of Diversion Control, Drug Enforcement Administration, 8701 Morrissette Drive, Springfield, Virginia 22152; Telephone (202) 307-7165. SUPPLEMENTARY INFORMATION: June 21, 2011. Dear Mr. Kennedy: On October 9, 2002, you petitioned the Drug Enforcement Administration (DEA) to initiate rulemaking proceedings under the rescheduling provisions of the Controlled Substances Act (CSA). Specifically, you petitioned DEA to have marijuana removed from schedule I of the CSA and rescheduled as cannabis in schedule III, IV or V. You requested that DEA remove marijuana from schedule I based on your assertion that: (1) Cannabis has an accepted medical use in the United States; (2) Cannabis is safe for use under medical supervision; (3) Cannabis has an abuse potential lower than schedule I or II drugs; and (4) Cannabis has a dependence liability that is lower than schedule I or II drugs. In accordance with the CSA rescheduling provisions, after gathering the necessary data, DEA requested a scientific and medical evaluation and scheduling recommendation from the Department of Health and Human Services (DHHS). DHHS concluded that marijuana has a high potential for abuse, has no accepted medical use in the United States, and lacks an acceptable level of safety for use even under medical supervision. Therefore, DHHS recommended that marijuana remain in schedule I. The scientific and medical evaluation and scheduling recommendation that DHHS submitted to DEA is attached hereto. Based on the DHHS evaluation and all other relevant data, DEA has concluded that there is no substantial evidence that marijuana should be removed from schedule I. A document prepared by DEA addressing these materials in detail also is attached hereto. In short, marijuana continues to meet the criteria for schedule I control under the CSA because: (1) Marijuana has a high potential for abuse. The DHHS evaluation and the additional data gathered by DEA show that marijuana has a high potential for abuse. (2) Marijuana has no currently accepted medical use in treatment in the United States. According to established case law, marijuana has no “currently accepted medical use” because: The drug's chemistry is not known and reproducible; there are no adequate safety studies; there are no adequate and well-controlled studies proving efficacy; the drug is not accepted by qualified experts; and the scientific evidence is not widely available. (3) Marijuana lacks accepted safety for use under medical supervision. At present, there are no U.S. Food and Drug Administration (FDA)-approved marijuana products, nor is marijuana under a New Drug Application (NDA) evaluation at the FDA for any indication. Marijuana does not have a currently accepted medical use in treatment in the United States or a currently accepted medical use with severe restrictions. At this time, the known risks of marijuana use have not been shown to be outweighed by specific benefits in well-controlled clinical trials that scientifically evaluate safety and efficacy. You also argued that cannabis has a dependence liability that is lower than schedule I or II drugs. Findings as to the physical or psychological dependence of a drug are only one of eight factors to be considered. As discussed further in the attached documents, DHHS states that long-term, regular use of marijuana can lead to physical dependence and withdrawal following discontinuation as well as psychic addiction or dependence. The statutory mandate of 21 U.S.C. 812(b) is dispositive. Congress established only one schedule, schedule I, for drugs of abuse with “no currently accepted medical use in treatment in the United States” and “lack of accepted safety for use under medical supervision.” 21 U.S.C. 812(b). Accordingly, and as set forth in detail in the accompanying DHHS and DEA documents, there is no statutory basis under the CSA for DEA to grant your petition to initiate rulemaking proceedings to reschedule marijuana. Your petition is, therefore, hereby denied. Sincerely, Michele M. Leonhart, Administrator. Attachments: Marijuana. Scheduling Review Document: Eight Factor Analysis Basis for the recommendation for maintaining marijuana in schedule I of the Controlled Substances Act Date: June 30, 2011 Michele M. Leonhart Administrator Department of Health and Human Services, Office of the Secretary Assistant Secretary for Health, Office of Public Health and Science Washington, D.C. 20201. December 6, 2006. The Honorable Karen P. Tandy Administrator, Drug Enforcement Administration, U.S. Department of Justice, Washington, D.C. 20537 Dear Ms. Tandy: This is in response to your request of July 2004, and pursuant to the Controlled Substances Act (CSA), 21 U.S.C. 811(b), (c), and (f), the Department of Health and Human Services (DHHS) recommends that marijuana continue to be subject to control under Schedule I of the CSA. Marijuana is currently controlled under Schedule I of the CSA. Marijuana continues to meet the three criteria for placing a substance in Schedule I of the CSA under 21 U.S.C. 812(b)(l). As discussed in the attached analysis, marijuana has a high potential for abuse, has no currently accepted medical use in treatment in the United States, and has a lack of an accepted level of safety for use under medical supervision. Accordingly, HHS recommends that marijuana continue to be subject to control under Schedule I of the CSA. Enclosed is a document prepared by FDA's Controlled Substance Staff that is the basis for this recommendation. Should you have any questions regarding this recommendation, please contact Corinne P. Moody, of the Controlled Substance Staff, Center for Drug Evaluation and Research. Ms. Moody can be reached at 301-827-1999. Sincerely yours, John O. Agwunobi, Assistant Secretary for Health. Enclosure: Basis for the Recommendation for Maintaining Marijuana in Schedule I of the Controlled Substances Act BASIS FOR THE RECOMMENDATION FOR MAINTAINING MARIJUANA IN SCHEDULE I OF THE CONTROLLED SUBSTANCES ACT On October 9, 2002, the Coalition for Rescheduling Cannabis (hereafter known as the Coalition) submitted a petition to the Drug Enforcement Administration (DEA) requesting that proceedings be initiated to repeal the rules and regulations that place marijuana in Schedule I of the Controlled Substances Act (CSA). The petition contends that cannabis has an accepted medical use in the United States, is safe for use under medical supervision, and has an abuse potential and a dependency liability that is lower than Schedule I or II drugs. The petition requests that marijuana be rescheduled as “cannabis” in either Schedule III, IV, or V of the CSA. In July 2004, the DEA Administrator requested that the Department of Health and Human Services (HHS) provide a scientific and medical evaluation of the available information and a scheduling recommendation for marijuana, in accordance with the provisions of 21 U.S.C. 811(b). In accordance with 21 U.S.C. 811(b), DEA has gathered information related to the control of marijuana ( Cannabis sativa ) 2 under the CSA. Pursuant to 21 U.S.C. 811(b), the Secretary is required to consider in a scientific and medical evaluation eight factors determinative of control under the CSA. Following consideration of the eight factors, if it is appropriate, the Secretary must make three findings to recommend scheduling a substance in the CSA. The findings relate to a substance's abuse potential, legitimate medical use, and safety or dependence liability. 2 The CSA defines marijuana as the following: all parts of the plant Cannabis Sativa L., whether growing or not; the seeds thereof; the resin extracted from any part of such plant; and every compound, manufacture, salt, derivative, mixture, or preparation of such plant, its seeds or resin. Such term does not include the mature stalks of such plant, fiber produced from such stalks, oil or cake made from the seeds of such plant, any other compound, manufacture, salt, derivative, mixture, or preparation of such mature stalks (except the resin extracted there from), fiber, oil, or cake, or the sterilized seed of such plant which is incapable of germination (21 U.S.C. 802(16)). Administrative responsibilities for evaluating a substance for control under the CSA are performed by the Food and Drug Administration (FDA), with the concurrence of the National Institute on Drug Abuse (NIDA), as described in the Memorandum of Understanding (MOU) of March 8, 1985 (50 FR 9518-20). In this document, FDA recommends the continued control of marijuana in Schedule I of the CSA. Pursuant to 21 U.S.C. 811(c), the eight factors pertaining to the scheduling of marijuana are considered below. 1. ITS ACTUAL OR RELATIVE POTENTIAL FOR ABUSE The first factor the Secretary must consider is marijuana's actual or relative potential for abuse. The term “abuse” is not defined in the CSA. However, the legislative history of the CSA suggests the following in determining whether a particular drug or substance has a potential for abuse: a. Individuals are taking the substance in amounts sufficient to create a hazard to their health or to the safety of other individuals or to the community. b. There is a significant diversion of the drug or substance from legitimate drug channels. c. Individuals are taking the substance on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer such substances. d. The substance is so related in its action to a substance already listed as having a potential for abuse to make it likely that it will have the same potential for abuse as such substance, thus making it reasonable to assume that there may be significant diversions from legitimate channels, significant use contrary to or without medical advice, or that it has a substantial capability of creating hazards to the health of the user or to the safety of the community. Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep. No. 91-1444, 91st Cong., Sess. 1 (1970) reprinted in U.S.C.C.A.N. 4566, 4603. In considering these concepts in a variety of scheduling analyses over the last three decades, the Secretary has analyzed a range of factors when assessing the abuse liability of a substance. These factors have included the prevalence and frequency of use in the general public and in specific sub-populations, the amount of the material that is available for illicit use, the ease with which the substance may be obtained or manufactured, the reputation or status of the substance “on the street,” as well as evidence relevant to population groups that may be at particular risk. Abuse liability is a complex determination with many dimensions. There is no single test or assessment procedure that, by itself, provides a full and complete characterization. Thus, no single measure of abuse liability is ideal. Scientifically, a comprehensive evaluation of the relative abuse potential of a drug substance can include consideration of the drug's receptor binding affinity, preclinical pharmacology, reinforcing effects, discriminative stimulus effects, dependence producing potential, pharmacokinetics and route of administration, toxicity, assessment of the clinical efficacy-safety database relative to actual abuse, clinical abuse liability studies, and the public health risks following introduction of the substance to the general population. It is important to note that abuse may exist independent of a state of tolerance or physical dependence, because drugs may be abused in doses or in patterns that do not induce these phenomena. Animal data, human data, and epidemiological data are all used in determining a substance's abuse liability. Epidemiological data can also be an important indicator of actual abuse. Finally, evidence of clandestine production and illicit trafficking of a substance are also important factors. a. There is evidence that individuals are taking the substance in amounts sufficient to create a hazard to their health or to the safety of other individuals or to the community. Marijuana is a widely abused substance. The pharmacology of the psychoactive constituents of marijuana, including delta 9 -tetrahydrocannabinol (delta 9 -THC), the primary psychoactive ingredient in marijuana, has been studied extensively in animals and humans and is discussed in more detail below in Factor 2, “Scientific Evidence of its Pharmacological Effects, if Known.” Data on the extent of marijuana abuse are available from HHS through NIDA and the Substance Abuse and Mental Health Services Administration (SAMHSA). These data are discussed in detail under Factor 4, “Its History and Current Pattern of Abuse;” Factor 5, “The Scope, Duration, and Significance of Abuse;” and Factor 6, “What, if any, Risk There is to the Public Health?” According to SAMHSA's 2004 National Survey on Drug Use and Health (NSDUH; the database formerly known as the National Household Survey on Drug Abuse (NHSDA)), the latest year for which complete data are available, 14.6 million Americans have used marijuana in the past month. This is an increase of 3.4 million individuals since 1999, when 11.2 million individuals reported using marijuana monthly. (See the discussion of NSDUH data under Factor 4). The Drug Abuse Warning Network (DAWN), sponsored by SAMHSA, is a national probability survey of U.S. hospitals with emergency departments (EDs) designed to obtain information on ED visits in which recent drug use is implicated; 2003 is the latest year for which complete data are available. Marijuana was involved in 79,663 ED visits (13 percent of drug-related visits). There are a number of risks resulting from both acute and chronic use of marijuana which are discussed in full below under Factors 2 and 6. b. There is significant diversion of the substance from legitimate drug channels. At present, cannabis is legally available through legitimate channels for research purposes only and thus has a limited potential for diversion. In addition, the lack of significant diversion of investigational supplies may result from the ready availability of illicit cannabis of equal or greater quality. The magnitude of the demand for illicit marijuana is evidenced by DEA/Office of National Drug Control Policy (ONDCP) seizure statistics. Data on marijuana seizures can often highlight trends in the overall trafficking patterns. DEA's Federal-Wide Drug Seizure System (FDSS) provides information on total federal drug seizures. FDSS reports total federal seizures of 2,700,282 pounds of marijuana in 2003, the latest year for which complete data are available (DEA, 2003). This represents nearly a doubling of marijuana seizures since 1995, when 1,381,107 pounds of marijuana were seized by federal agents. c. Individuals are taking the substance on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer such substances. The 2004 NSDUH data show that 14.6 million American adults use marijuana on a monthly basis (SAMHSA, 2004), confirming that marijuana has reinforcing properties for many individuals. The FDA has not evaluated or approved a new drug application (NDA) for marijuana for any therapeutic indication, although several investigational new drug (IND) applications are currently active. Based on the large number of individuals who use marijuana, it can be concluded that the majority of individuals using cannabis do so on their own initiative, not on the basis of medical advice from a practitioner licensed to administer the drug in the course of professional practice. d. The substance is so related in its action to a substance already listed as having a potential for abuse to make it likely that it will have the same potential for abuse as such substance, thus making it reasonable to assume that there may be significant diversions from legitimate channels, significant use contrary to or without medical advice, or that it has a substantial capability of creating hazards to the health of the user or to the safety of the community. The primary psychoactive compound in botanical marijuana is delta 9 -THC. Other cannabinoids also present in the marijuana plant likely contribute to the psychoactive effects. There are two drug products containing cannabinoid compounds that are structurally related to the active components in marijuana. Both are controlled under the CSA. Marinol is a Schedule III drug product containing synthetic delta 9 -THC, known generically as dronabinol, formulated in sesame oil in soft gelatin capsules. Dronabinol is listed in Schedule I. Marinol was approved by the FDA in 1985 for the treatment of two medical conditions: nausea and vomiting associated with cancer chemotherapy in patients that had failed to respond adequately to conventional anti-emetic treatments, and for the treatment of anorexia associated with weight loss in patients with acquired immunodeficiency syndrome or AIDS. Cesamet is a drug product containing the Schedule II substance, nabilone, that was approved for marketing by the FDA in 1985 for the treatment of nausea and vomiting associated with cancer chemotherapy. All other structurally related cannabinoids in marijuana are already listed as Schedule I drugs under the CSA. 2. SCIENTIFIC EVIDENCE OF ITS PHARMACOLOGICAL EFFECTS, IF KNOWN The second factor the Secretary must consider is scientific evidence of marijuana's pharmacological effects. There are abundant scientific data available on the neurochemistry, toxicology, and pharmacology of marijuana. This section includes a scientific evaluation of marijuana's neurochemistry, pharmacology, and human and animal behavioral, central nervous system, cognitive, cardiovascular, autonomic, endocrinological, and immunological system effects. The overview presented below relies upon the most current research literature on cannabinoids. Neurochemistry and Pharmacology of Marijuana Some 483 natural constituents have been identified in marijuana, including approximately 66 compounds that are classified as cannabinoids (Ross and El Sohly, 1995). Cannabinoids are not known to exist in plants other than marijuana, and most of the cannabinoid compounds that occur naturally have been identified chemically. Delta 9 -THC is considered the major psychoactive cannabinoid constituent of marijuana (Wachtel et al., 2002). The structure and function of delta 9 -THC was first described in 1964 by Gaoni and Mechoulam. The site of action of delta 9 -THC and other cannabinoids was verified with the cloning of cannabinoid receptors, first from rat brain tissue (Matsuda et al., 1990) and then from human brain tissue (Gerard et al., 1991). Two cannabinoid receptors, CB 1 and CB 2 , have subsequently been characterized (Piomelli, 2005). Autoradiographic studies have provided information on the distribution of cannabinoid receptors. CB 1 receptors are found in the basal ganglia, hippocampus, and cerebellum of the brain (Howlett et al., 2004) as well as in the immune system. It is believed that the localization of these receptors may explain cannabinoid interference with movement coordination and effects on memory and cognition. The concentration of CB 1 receptors is considerably lower in peripheral tissues than in the central nervous system (Henkerham et al., 1990 and 1992). CB 2 receptors are found primarily in the immune system, predominantly in B lymphocytes and natural killer cells (Bouaboula et al., 1993). It is believed that the CB 2 -type receptor is responsible for mediating the immunological effects of cannabinoids (Galiegue et al., 1995). However, CB 2 receptors also have recently been localized in the brain, primarily in the cerebellum and hippocampus (Gong et al., 2006). The cannabinoid receptors belong to the family of G-protein-coupled receptors and present a typical seven transmembrane-spanning domain structure. Many G-protein-coupled receptors are linked to adenylate cyclase either positively or negatively, depending on the receptor system. Cannabinoid receptors are linked to an inhibitory G-protein (Gi), so that when the receptor is activated, adenylate cyclase activity is inhibited, which prevents the conversion of adenosine triphosphate (ATP)to the second messenger cyclic adenosine monophosphate (cAMP). Examples of inhibitory-coupled receptors include: opioid, muscarinic cholinergic, alpha 2 -adrenoreceptors, dopamine (D 2 ), and serotonin (5-HT 1 ). It has been shown that CB 1 , but not CB 2 receptors, inhibit N- and P/Q type calcium channels and activate inwardly rectifying potassium channels (Mackie et al., 1995; Twitchell et al., 1997). Inhibition of the N-type calcium channels decreases neurotransmitter release from several tissues and this may be the mechanism by which cannabinoids inhibit acetylcholine, norepinephrine, and glutamate release from specific areas of the brain. These effects might represent a potential cellular mechanism underlying the antinociceptive and psychoactive effects of cannabinoids (Ameri, 1999). When cannabinoids are given subacutely to rats, there is a down-regulation of CB 1 receptors, as well as a decrease in GTPgammaS binding, the second messenger system coupled to CB 1 receptors (Breivogel et al., 2001). Delta 9 -THC displays similar affinity for CB 1 and CB 2 receptors but behaves as a weak agonist for CB 2 receptors, based on inhibition of adenylate cyclase. The identification of synthetic cannabinoid ligands that selectively bind to CB 2 receptors but do not have the typical delta 9 -THC-like psychoactive properties suggests that the psychotropic effects of cannabinoids are mediated through the activation of CB 1 -receptors (Hanus et al., 1999). Naturally-occurring cannabinoid agonists, such as delta 9 -THC, and the synthetic cannabinoid agonists such as WIN-55,212-2 and CP-55,940 produce hypothermia, analgesia, hypoactivity, and cataplexy in addition to their psychoactive effects. In 2000, two endogenous cannabinoid receptor agonists, anandamide and arachidonyl glycerol (2-AG), were discovered. Anandamide is a low efficacy agonist (Breivogel and Childers, 2000), 2-AG is a highly efficacious agonist (Gonsiorek et al., 2000). Cannabinoid endogenous ligands are present in central as well as peripheral tissues. The action of the endogenous ligands is terminated by a combination of uptake and hydrolysis. The physiological role of endogenous cannabinoids is an active area of research (Martin et al., 1999). Progress in cannabinoid pharmacology, including further characterization of the cannabinoid receptors, isolation of endogenous cannabinoid ligands, synthesis of agonists and antagonists with variable affinity, and selectivity for cannabinoid receptors, provide the foundation for the potential elucidation of cannabinoid-mediated effects and their relationship to psychomotor disorders, memory, cognitive functions, analgesia, anti-emesis, intraocular and systemic blood pressure modulation, bronchodilation, and inflammation. Central Nervous System Effects Human Physiological and Psychological Effects Subjective Effects The physiological, psychological, and behavioral effects of marijuana vary among individuals. Common responses to cannabinoids, as described by Adams and Martin (1996) and others (Hollister, 1986 and 1988; Institute of Medicine, 1982) are listed below: 1) Dizziness, nausea, tachycardia, facial flushing, dry mouth, and tremor initially 2) Merriment, happiness, and even exhilaration at high doses 3) Disinhibition, relaxation, increased sociability, and talkativeness 4) Enhanced sensory perception, giving rise to increased appreciation of music, art, and touch 5) Heightened imagination leading to a subjective sense of increased creativity 6) Time distortions 7) Illusions, delusions, and hallucinations, especially at high doses 8) Impaired judgment, reduced co-ordination and ataxia, which can impede driving ability or lead to an increase in risk-taking behavior 9) Emotional lability, incongruity of affect, dysphoria, disorganized thinking, inability to converse logically, agitation, paranoia, confusion, restlessness, anxiety, drowsiness, and panic attacks, especially in inexperienced users or in those who have taken a large dose 10) Increased appetite and short-term memory impairment These subjective responses to marijuana are pleasurable to many humans and are associated with drug-seeking and drug-taking (Maldonado, 2002). The short-term perceptual distortions and psychological alterations produced by marijuana have been characterized by some researchers as acute or transient psychosis (Favrat et al., 2005). However, the full response to cannabinoids is dissimilar to the DSM-IV-TR criteria for a diagnosis of one of the psychotic disorders (DSM-IV-TR, 2000). As with many psychoactive drugs, an individual's response to marijuana can be influenced by that person's medical/psychiatric history and history with drugs. Frequent marijuana users (greater than 100 times) were better able to identify a drug effect from low dose delta 9 -THC than infrequent users (less than 10 times) and were less likely to experience sedative effects from the drug (Kirk and deWit, 1999). Dose preferences have been demonstrated for marijuana in which higher doses (1.95 percent delta 9 -THC) are preferred over lower doses (0.63 percent delta 9 -THC) (Chait and Burke, 1994). Behavioral Impairment 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 to human volunteers of 290 micrograms per kilogram (μg/kg) delta 9 -THC in a smoked marijuana cigarette resulted in impaired perceptual motor speed and accuracy, two skills that are critical to driving ability (Kurzthaler et al., 1999). Similarly, administration of 3.95 percent delta 9 -THC in a smoked marijuana cigarette increased disequilibrium 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 fully resolve until at least 1 day after the acute psychoactive effects have subsided, following repeated administration. Heishman et al. (1990) showed that impairment on memory tasks persists for 24 hours after smoking marijuana cigarettes containing 2.57 percent delta 9 -THC. However, Fant et al. (1998) showed minimal residual alterations in subjective or performance measures the day after subjects were exposed to 1.8 percent or 3.6 percent smoked delta 9 -THC. The effects of chronic marijuana use have also been investigated. Marijuana did not appear to have residual effects on performance of a comprehensive neuropsychological battery when 54 monozygotic male twins (one of whom used marijuana, one of whom did not) were compared 1-20 years after cessation of marijuana use (Lyons et al., 2004). This conclusion is similar to the results from an earlier study of marijuana's effects on cognition in 1,318 participants over a 15-year period, where there was no evidence of long-term residual effects (Lyketsos et al., 1999). In contrast, Solowij et al. (2002) demonstrated that 51 long-term cannabis users did less well than 33 non-using controls or 51 short-term users on certain tasks of memory and attention, but users in this study were abstinent for only 17 hours at time of testing. A recent study noted that heavy, frequent cannabis users, abstinent for at least 24 hours, performed significantly worse than controls on verbal memory and psychomotor speed tests (Messinis et al, 2006). Pope et al. (2003) reported that no differences were seen in neuropsychological performance in early- or late-onset users compared to non-using controls, after adjustment for intelligence quotient (IQ). In another cohort of chronic, heavy marijuana users, some deficits were observed on memory tests up to a week following supervised abstinence, but these effects disappeared by day 28 of abstinence (Harrison et al., 2002). The authors concluded that, “cannabis-associated cognitive deficits are reversible and related to recent cannabis exposure, rather than irreversible and related to cumulative lifetime use.” Other investigators have reported neuropsychological deficits in memory, executive functioning, psychomotor speed, and manual dexterity in heavy marijuana smokers who had been abstinent for 28 days (Bolla et al., 2002). A follow up study of heavy marijuana users noted decision-making deficits after 25 days of abstinence (Bolla et al., 2005). Finally, when IQ was contrasted in adolescents at 9-12 years and at 17-20 years, current heavy marijuana users showed a 4-point reduction in IQ in later adolescence compared to those who did not use marijuana (Fried et al., 2002). 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 age 16 (Ehrenreich et al., 1999). Kandel and Chen (2000) assert that 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. Heavy marijuana users were contrasted with an age matched control group in a case-control design. The heavy users reported lower educational achievement and lower income than controls, a difference that persisted after confounding variables were taken into account. Additionally, the users also reported negative effects of marijuana use on cognition, memory, career, social life, and physical and mental health (Gruber et al., 2003). Association with Psychosis Extensive research has been conducted recently to investigate whether exposure to marijuana is associated with schizophrenia or other psychoses. While many studies are small and inferential, other studies in the literature utilize hundreds to thousands of subjects. At present, the data do not suggest a causative link between marijuana use and the development of psychosis. Although some individuals who use marijuana have received a diagnosis of psychosis, most reports conclude that prodromal symptoms of schizophrenia appear prior to marijuana use (Schiffman et al., 2005). When psychiatric symptoms are assessed in individuals with chronic psychosis, the “schizophrenic cluster” of symptoms is significantly observed among individuals who do not have a history of marijuana use, while “mood cluster” symptoms are significantly observed in individuals who do have a history of marijuana use (Maremmani et al., 2004). In the largest study evaluating the link between psychosis and drug use, 3 percent of 50,000 Swedish conscripts who used marijuana more than 50 times went on to develop schizophrenia (Andreasson et al., 1987). This was interpreted by the authors to suggest that marijuana use increased the risk for the disorder only among those individuals who were predisposed to develop psychosis. A similar conclusion was drawn when the prevalence of schizophrenia was modeled against marijuana use across birth cohorts in Australia between the years 1940 to 1979 (Degenhardt et al., 2003). Although marijuana use increased over time in adults born during the 4-decade period, there was not a corresponding increase in diagnoses for psychosis in these individuals. The authors conclude that marijuana may precipitate schizophrenic disorders only in those individuals who are vulnerable to developing psychosis. Thus, marijuana per se does not appear to induce schizophrenia in the majority of individuals who try or continue to use the drug. However, as might be expected, the acute intoxication produced by marijuana does exacerbate the perceptual and cognitive deficits of psychosis in individuals who have been previously diagnosed with the condition (Schiffman et al., 2005; Hall et al., 2004; Mathers and Ghodse, 1992; Thornicroft, 1990). This is consistent with a 25-year longitudinal study of over 1,000 individuals who had a higher rate of experiencing some symptoms of psychosis (but who did not receive a diagnosis of psychosis) if they were daily marijuana users than if they were not (Fergusson et al., 2005). A shorter, 3-year longitudinal study with over 4,000 subjects similarly showed that psychotic symptoms, but not diagnoses, were more prevalent in subjects who used marijuana (van Os et al., 2002). Additionally, schizophrenic individuals stabilized with antipsychotics do not respond differently to marijuana than healthy controls (D'Souza et al., 2005), suggesting that psychosis and/or antipsychotics do not biochemically alter cannabinoid systems in the brain. Interestingly, cannabis use prior to a first psychotic episode appeared to spare neurocognitive deficits compared to patients who had not used marijuana (Stirling et al., 2005). Although adolescents diagnosed with a first psychotic episode used more marijuana than adults who had their first psychotic break, adolescents and adults had similar clinical outcomes 2 years later (Pencer et al., 2005). Heavy marijuana users, though, do not perform differently than non-users on the Stroop task, a classic psychometric instrument that measures executive cognitive functioning. Since psychotic individuals do not perform the Stroop task well, alterations in executive functioning consistent with a psychotic profile were not apparent following chronic exposure to marijuana (Gruber and Yurgelun-Todd, 2005; Eldreth et al., 2004). Alteration in Brain Structure Although evidence suggests that some drugs of abuse can lead to changes in the density or structure of the brain in humans, there are currently no data showing that exposure to marijuana can induce such alterations. A recent comparison of long-term marijuana smokers to non-smoking control subjects using magnetic resonance imaging (MRI) did not reveal any differences in the volume of grey or white matter, in the hippocampus, or in cerebrospinal fluid volume, between the two groups (Tzilos et al., 2005). Behavioral Effects of Prenatal Exposure The impact of in utero marijuana exposure on performance in a series of cognitive tasks has been studied in children at different stages of development. However, since many marijuana users have abused other drugs, it is difficult to determine the specific impact of marijuana on prenatal exposure. Differences in several cognitive domains distinguished the 4-year-old children of heavy marijuana users. In particular, memory and verbal measures are negatively associated with maternal marijuana use (Fried and Watkinson, 1987). Maternal marijuana use is predictive of poorer performance on abstract/visual reasoning tasks, although it is not associated with an overall lowered IQ in 3-year old children (Griffith et al., 1994). At 6 years of age, prenatal marijuana history is associated with an increase in omission errors on a vigilance task, possibly reflecting a deficit in sustained attention (Fried et al., 1992). When the effect of prenatal exposure in 9-12 year old children is analyzed, in utero marijuana exposure is negatively associated with executive function tasks that require impulse control, visual analysis, and hypothesis testing, and it is not associated with global intelligence (Fried et al., 1998). Marijuana as a “Gateway Drug” The Institute of Medicine (IOM) reported that the widely held belief that marijuana is a “gateway drug,” leading to subsequent abuse of other illicit drugs, lacks conclusive evidence (Institute of Medicine, 1999). Recently, Fergusson et al. (2005) in a 25-year study of 1,256 New Zealand children concluded that use of marijuana correlates to an increased risk of abuse of other drugs, including cocaine and heroin. Other sources, however, do not support a direct causal relationship between regular marijuana and other illicit drug use. In general, such studies are selective in recruiting individuals who, in addition to having extensive histories of marijuana use, are influenced by myriad social, biological, and economic factors that contribute to extensive drug abuse (Hall and Lynskey, 2005). For most studies that test the hypothesis that marijuana causes abuse of harder drugs, the determinative measure of choice is any drug use, rather than DSM-IV-TR criteria for drug abuse or dependence (DSM-IV-TR, 2000). According to Golub & Johnson (2001), the rate of progression to hard drug use by youth born in the 1970's, as opposed to youth born between World War II and the 1960's, is significantly decreased, although overall marijuana use among youth appears to be increasing. Nace et al. (1975) reported that even in the Vietnam-era soldiers who extensively abused marijuana and heroin, there was a lack of correlation of a causal relationship demonstrating marijuana use leading to heroin addiction. A recent longitudinal study of 708 adolescents demonstrated that early onset marijuana use did not lead to problematic drug use (Kandel and Chen, 2000). Similarly, among 2,446 adolescents followed longitudinally, cannabis dependence was uncommon but when it did occur, it was predicted primarily by parental death, deprived socio-economic status, and baseline use of illicit drugs other than marijuana (von Sydow et al., 2002). Animal behavioral effects Self-Administration Self-administration is a method that assesses whether a drug produces rewarding effects that increase the likelihood of behavioral responses in order to obtain additional drug. Drugs that are self-administered by animals are likely to produce rewarding effects in humans, which is indicative of abuse liability. Generally, a good correlation exists between those drugs that are self-administered by rhesus monkeys and those that are abused by humans (Balster and Bigelow, 2003). Interestingly, self-administration of hallucinogenic-like drugs, such as cannabinoids, lysergic acid diethylamide (LSD), and mescaline, has been difficult to demonstrate in animals (Yanagita, 1980). However, when it is known that humans voluntarily consume a particular drug (such as cannabis) for its pleasurable effects, the inability to establish self-administration with that drug in animals has no practical importance in the assessment of abuse potential. This is because the animal test is a predictor of human behavioral response in the absence of naturalistic data. The experimental literature generally reports that naïve animals will not self-administer cannabinoids unless they have had previous experience with other drugs of abuse. However, when squirrel monkeys are first trained to self-administer intravenous cocaine, they will continue to bar-press at the same rate as when delta 9 -THC is substituted for cocaine, at doses that are comparable to those used by humans who smoke marijuana (Tanda et al., 2000). This effect is blocked by the cannabinoid receptor antagonist, SR 141716. New studies show that monkeys without a history of any drug exposure can be successfully trained to self-administer delta 9 -THC intravenously (Justinova et al., 2003). The maximal rate of responding is 4 μg/kg/injection, which is 2-3 times greater than that observed in previous studies using cocaine-experienced monkeys. These data demonstrate that under specific pretreatment conditions, an animal model of reinforcement by cannabinoids now exists for future investigations. Rats will self-administer delta 9 -THC when it is applied intracerebroventricularly (i.c.v.), but only at the lowest doses tested (0.01-0.02 μg/infusion) (Braida et al., 2004). This effect is antagonized by the cannabinoid antagonist SR141716 and by the opioid antagonist naloxone (Braida et al., 2004). Additionally, mice will self-administer WIN 55212, a CB 1 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 that received high doses of WIN 55212 (Chaperon et al., 1998) or delta 9 -THC (Sanudo-Pena et al., 1997). SR 141716 reversed these aversive effects in both studies. Conditioned Place Preference Conditioned place preference (CPP) is a less rigorous method than self-administration of determining whether drugs have rewarding properties. In this behavioral test, animals are given the opportunity to spend time in two distinct environments: one where they previously received a drug and one where they received a placebo. If the drug is reinforcing, animals will choose to spend more time in the environment paired with the drug than the one paired with the placebo, when both options are presented simultaneously. Animals show CPP to delta 9 -THC, but only at the lowest doses tested (0.075-0.75 mg/kg, i.p.) (Braida et al., 2004). This effect is antagonized by the cannabinoid antagonist, SR141716, as well as by the opioid antagonist, naloxone (Braida et al., 2004). However, SR141716 may be a partial agonist, rather than a full antagonist, since it is also able to induce CPP (Cheer et al., 2000). Interestingly, in knockout mice, animals without μ-opioid receptors do not develop CPP to delta 9 -THC (Ghozland et al., 2002). Drug Discrimination Studies Drug discrimination is a method in which animals indicate whether a test drug produces physical or psychic perceptions similar to those produced by a known drug of abuse. In this test, an animal learns to press one bar when it receives the known drug of abuse and another bar when it receives placebo. A challenge session with the test drug determines which of the two bars the animal presses more often, as an indicator of whether the test drug is like the known drug of abuse. 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 delta 9 -THC are pharmacologically specific for marijuana-containing cannabinoids (Balster and Prescott, 1992; Barnett et al., 1985; Browne and Weissman, 1981; Wiley et al., 1993; Wiley et al., 1995). Additionally, the major active metabolite of delta 9 -THC, 11-hydroxy-delta 9 -THC, also generalizes to the stimulus cue elicited by delta 9 -THC (Browne and Weissman, 1981). Twenty-two other cannabinoids found in marijuana also fully substitute for delta 9 -THC. The discriminative stimulus effects of the cannabinoid group appear to provide unique effects because stimulants, hallucinogens, opioids, benzodiazepines, barbiturates, NMDA antagonists, and antipsychotics do not fully substitute for delta 9 -THC. Tolerance and Physical Dependence Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug's effects over time (American Academy of Pain Medicine, American Pain Society and American Society of Addiction Medicine consensus document, 2001). Physical dependence is a state of adaptation manifested by a drug class-specific withdrawal syndrome produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist ( ibid ). The presence of tolerance or physical dependence does not determine whether a drug has abuse potential, in the absence of other abuse indicators such as rewarding properties. Many medications that are not associated with abuse or addiction, such as antidepressants, beta-blockers, and centrally acting antihypertensive drugs, can produce physical dependence and withdrawal symptoms after chronic use. Tolerance to the subjective and performance effects of marijuana has not been demonstrated in studies with humans. For example, reaction times are not altered by acute administration of marijuana in long term marijuana users (Block and Wittenborn, 1985). This may be related to recent electrophysiological data showing that the ability of delta 9 -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, and sleep alterations (Jones et al., 1981). 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). Acute administration of marijuana containing 2.1 percent delta 9 -THC does not produce “hangover effects” (Chait et al., 1985). In chronic marijuana users, though, a marijuana withdrawal syndrome has been described that consists of restlessness, irritability, mild agitation, insomnia, sleep EEG disturbances, nausea, and cramping that resolves within a few days (Haney et al., 1999). However, the American Psychiatric Association's Diagnostic and Statistical Manual (DSM-IV-TR, 2000) does not include a listing for cannabis withdrawal syndrome because, “symptoms of cannabis withdrawal . . . have been described . . . but their clinical significance is uncertain.” A review of all current clinical studies on cannabis withdrawal led to the recommendation by Budney et al. (2004) that the DSM introduce a listing for cannabis withdrawal that includes such symptoms as sleep difficulties, strange dreams, decreased appetite, decreased weight, anger, irritability, and anxiety. Based on clinical descriptions, this syndrome appears to be mild compared to classical alcohol and barbiturate withdrawal syndromes, which can include more serious symptoms such as agitation, paranoia, and seizures. A recent study comparing marijuana and tobacco withdrawal symptoms in humans demonstrated that the magnitude and timecourse of the two withdrawal syndromes are similar (Vandrey et al., 2005). The production of an overt withdrawal syndrome in animals following chronic delta 9 -THC administration has been variably demonstrated under conditions of natural discontinuation. This may be the result of the slow release of cannabinoids from adipose storage, as well as the presence of the major psychoactive metabolite, 11-hydroxy-delta 9 -THC. When investigators have shown such a withdrawal syndrome in monkeys following the termination of cannabinoid administration, the behaviors included transient aggression, anorexia, biting, irritability, scratching, and yawning (Budney et al., 2004). However, in rodents treated with a cannabinoid antagonist following subacute administration of delta 9 -THC, pronounced withdrawal symptoms, including wet dog shakes, can be provoked (Breivogel et al., 2003). Behavioral Sensitization Sensitization to the effects of drugs is the opposite of tolerance: instead of a reduction in behavioral response upon repeated drug administration, animals that are sensitized demonstrate an increase in behavioral response. Cadoni et al. (2001) demonstrated that repeated exposure to delta 9 -THC can induce sensitization to a variety of cannabinoids. These same animals also have a sensitized response to administration of opioids, an effect known as cross-sensitization. Conversely, when animals were sensitized to the effects of morphine, there was cross-sensitization to cannabinoids. Thus, the cannabinoid and opioids systems appear to operate symmetrically in terms of cross-sensitization. Cardiovascular and Autonomic Effects Single smoked or oral doses of delta 9 -THC produce tachycardia and may increase blood pressure (Capriotti et al., 1988; Benowitz and Jones, 1975). However, prolonged delta 9 -THC ingestion produces significant heart rate slowing and blood pressure lowering (Benowitz and Jones, 1975). Both plant-derived cannabinoids and endocannabinoids have been shown to elicit hypotension and bradycardia via activation of peripherally-located CB 1 receptors (Wagner et al., 1998). This study suggests that the mechanism of this effect is through presynaptic CB 1 receptor-mediated inhibition of norepinephrine release from peripheral sympathetic nerve terminals, with possible additional direct vasodilation via activation of vascular cannabinoid receptors. The impaired circulatory responses following delta 9 -THC administration to standing, exercise, Valsalva maneuver, and cold pressor testing suggest that cannabinoids induce a state of sympathetic insufficiency. In humans, tolerance can develop to the orthostatic hypotension (Jones, 2002; Sidney, 2002), possibly related to plasma volume expansion, but does not develop to the supine hypotensive effects (Benowitz and Jones, 1975). During chronic marijuana ingestion, nearly complete tolerance develops to tachycardia and psychological effects when subjects are challenged with smoked marijuana. Electrocardiographic changes are minimal even after large cumulative doses of delta 9 -THC. (Benowitz and Jones, 1975). It is notable that marijuana smoking by older patients, particularly those with some degree of coronary artery or cerebrovascular disease, poses risks related to increased cardiac work, increased catecholamines, carboxyhemoglobin, and postural hypotension (Benowitz and Jones, 1981; Hollister, 1988). Respiratory Effects Transient bronchodilation is the most typical effect following acute exposure to marijuana (Gong et al., 1984). Long-term use of marijuana can lead to an increased frequency of chronic bronchitis and pharyngitis, as well as chronic cough and increased sputum. Pulmonary function tests reveal that large-airway obstruction can occur with chronic marijuana smoking, as can cellular inflammatory histopathological abnormalities in bronchial epithelium (Adams and Martin, 1996; Hollister, 1986). The evidence that marijuana may lead to cancer associated with respiratory effects is inconsistent, with some studies suggesting a positive correlation while others do not (Tashkin, 2005). Several cases of lung cancer have been reported in young marijuana users with no history of tobacco smoking or other significant risk factors (Fung et al., 1999). Marijuana use may dose-dependently interact with mutagenic sensitivity, cigarette smoking and alcohol use to increase the risk of head and neck cancer (Zhang et al., 1999). However, in the largest study to date with 1,650 subjects, no positive association was found between marijuana use and lung cancer (Tashkin et al., 2006). This finding held true regardless of extent of marijuana use, when tobacco use and other potential confounding factors were controlled. The lack of evidence for carcinogenicity related to cannabis may be related to the fact that intoxication from marijuana does not require large amounts of smoked material. This may be especially pertinent since marijuana is reportedly more potent today than a generation ago. Thus, individuals may consume much less marijuana than in previous decades to reach the desired subjective effects, exposing them to less potential carcinogens. Endocrine System The presence of in vitro delta 9 -THC reduces binding of the corticosteroid, dexamethasone, in hippocampal tissue from adrenalectomized rats, suggesting an interaction with the glucocorticoid receptor (Eldridge et al., 1991). Acute delta 9 -THC releases corticosterone, but tolerance develops to this effect with chronic administration (Eldridge et al., 1991). Experimental administration of marijuana to humans does not consistently alter endocrine parameters. In an early study, male subjects who experimentally received smoked marijuana showed a significant depression in luteinizing hormone and a significant increase in cortisol were observed (Cone et al., 1986). However, two later studies showed no changes in hormones. Male subjects who were experimentally exposed to smoked delta 9 -THC (18 mg/marijuana cigarette) or oral delta 9 -THC (10 mg t.i.d. for 3 days and on the morning of the fourth day) showed no changes in plasma prolactin, ACTH, cortisol, luteinizing hormone, or testosterone levels (Dax et al., 1989). Similarly, a study with 93 men and 56 women showed that chronic marijuana use did not significantly alter concentrations of testosterone, luteinizing hormone, follicle stimulating hormone, prolactin, or cortisol (Block et al., 1991). Relatively little research has been performed on the effects of experimentally administered marijuana on female reproductive system functioning. In monkeys, delta 9 -THC administration suppressed ovulation (Asch et al., 1981) and reduced progesterone levels (Almirez et al., 1983). However, when women were studied following experimental exposure to smoked marijuana, no hormonal or menstrual cycle changes were observed (Mendelson and Mello, 1984). Brown and Dobs (2002) suggest that the discrepancy between animal and human hormonal response to cannabinoids may be attributed to the development of tolerance in humans. Recent data suggest that cannabinoid agonists may have therapeutic value in the treatment of prostate cancer, a type of carcinoma in which growth is stimulated by androgens. Research with prostate cancer cells shows that the mixed CB 1 /CB 2 agonist, WIN-55212-2, induces apoptosis in prostate cancer cell growth, as well as decreases in expression of androgen receptors and prostate-specific antigens (Sarfaraz et al., 2005). Immune System Immune functions are altered by cannabinoids, but there can be differences between the effects of synthetic, natural, and endogenous cannabinoids, often in an apparently biphasic manner depending on dose (Croxford and Yamamura, 2005). Abrams et al. (2003) investigated the effect of marijuana on immunological functioning in 62 AIDS patients who were taking protease inhibitors. Subjects received one of the following three times a day: smoked marijuana cigarette containing 3.95 percent delta 9 -THC; oral tablet containing delta 9 -THC (2.5 mg oral dronabinol); or oral placebo. There were no changes in CD4+ and CD8+ cell counts or HIV RNA levels or protease inhibitor levels between groups, demonstrating no short-term adverse virologic effects from using cannabinoids in individuals with compromised immune systems. These human data contrast with data generated in immunodeficient mice showing that exposure to delta 9 -THC in vivo suppresses immune function, increases HIV co-receptor expression, and acts as a cofactor to enhance HIV replication (Roth et al., 2005). 3. THE STATE OF CURRENT SCIENTIFIC KNOWLEDGE REGARDING THE DRUG OR OTHER SUBSTANCE The third factor the Secretary must consider is the state of current scientific knowledge regarding marijuana. Thus, this section discusses the chemistry, human pharmacokinetics, and medical uses of marijuana. Chemistry According to the DEA, Cannabis sativa is the primary species of cannabis currently marketed illegally in the United States of America. From this plant, three derivatives are sold as separate illicit drug products: marijuana, hashish, and hashish oil. Each of these derivatives contains a complex mixture of chemicals. Among the components are the 21 carbon terpenes found in the plant as well as their carboxylic acids, analogues, and transformation products known as cannabinoids (Agurell et al., 1984 and 1986; Mechoulam, 1973). The cannabinoids appear to naturally occur only in the marijuana plant and most of the botanically-derived cannabinoids have been identified. Among the cannabinoids, delta 9 -THC (alternate name delta 1 -THC) and delta-8-tetrahydrocannabinol (delta 8 -THC, alternate name delta 6 -THC) are both found in marijuana and are able to produce the characteristic psychoactive effects of marijuana. Because delta 9 -THC is more abundant than delta 8 -THC, the activity of marijuana is largely attributed to the former. Delta 8 -THC is found only in few varieties of the plant (Hively et al., 1966). Delta 9 -THC is an optically active resinous substance, insoluble in water, and extremely lipid soluble. Chemically delta 9 -THC is (6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo-[b,d]pyran-1-ol or (-)-delta 9 -(trans)-tetrahydrocannabinol. The (-)-trans isomer of delta 9 -THC is pharmacologically 6 to 100 times more potent than the (+)-trans isomer (Dewey et al., 1984). Other cannabinoids, such as cannabidiol (CBD) and cannabinol (CBN), have been characterized. CBD is not considered to have cannabinol-like psychoactivity, but is thought to have significant anticonvulsant, sedative, and anxiolytic activity (Adams and Martin, 1996; Agurell et al., 1984 and 1986; Hollister, 1986). Marijuana is a mixture of the dried flowering tops and leaves from the plant and is variable in content and potency (Agurell et al., 1984 and 1986; Graham, 1976; Mechoulam, 1973). Marijuana is usually smoked in the form of rolled cigarettes while hashish and hash oil are smoked in pipes. Potency of marijuana, as indicated by cannabinoid content, has been reported to average from as low as 1 to 2 percent to as high as 17 percent. The concentration of delta 9 -THC and other cannabinoids in marijuana varies with growing conditions and processing after harvest. Other variables that can influence the strength, quality, and purity of marijuana are genetic differences among the cannabis plant species and which parts of the plant are collected (flowers, leaves, stems, etc.) (Adams and Martin, 1996; Agurell et al., 1984; Mechoulam, 1973). In the usual mixture of leaves and stems distributed as marijuana, the concentration of delta 9 -THC ranges widely from 0.3 to 4.0 percent by weight. However, specially grown and selected marijuana can contain even 15 percent or greater delta 9 -THC. Thus, a 1 gm marijuana cigarette might contain as little as 3 mg or as much as 150 mg or more of delta 9 -THC. 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 a pipe and smoked. DEA reports that cannabinoid content in hashish averages 6 percent. Hash oil is produced by solvent extraction of the cannabinoids from plant material. 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 (DEA, 2005). The lack of a consistent concentration of delta 9 -THC in botanical marijuana from diverse sources complicates the interpretation of clinical data using marijuana. If marijuana is to be investigated more widely for medical use, information and data regarding the chemistry, manufacturing, and specifications of marijuana must be developed. Human Pharmacokinetics Marijuana is generally smoked as a cigarette (weighing between 0.5 and 1.0 gm), or in a pipe. It can also be taken orally in foods or as extracts of plant material in ethanol or other solvents. The absorption, metabolism, and pharmacokinetic profile of delta 9 -THC (and other cannabinoids) in marijuana or other drug products containing delta 9 -THC vary with route of administration and formulation (Adams and Martin, 1996; Agurell et al., 1984 and 1986). When marijuana is administered by smoking, delta 9 -THC in the form of an aerosol is absorbed within seconds. The psychoactive effects of marijuana occur immediately following absorption, with mental and behavioral effects measurable up to 6 hours (Grotenhermen, 2003; Hollister, 1986 and 1988). Delta 9 -THC is delivered to the brain rapidly and efficiently as would be expected of a very lipid-soluble drug. The bioavailability of the delta 9 -THC from marijuana in a cigarette or pipe can range from 1 to 24 percent with the fraction absorbed rarely exceeding 10 to 20 percent (Agurell et al., 1986; Hollister, 1988). The relatively low and variable bioavailability results from the following: significant loss of delta 9 -THC in side-stream smoke, variation in individual smoking behaviors, cannabinoid pyrolysis, incomplete absorption of inhaled smoke, and metabolism in the lungs. A individual's experience and technique with smoking marijuana is an important determinant of the dose that is absorbed (Herning et al., 1986; Johansson et al., 1989). After smoking, venous levels of delta 9 -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 and 1992b). Plasma clearance of delta 9 -THC is approximately 950 ml/min or greater, thus approximating hepatic blood flow. The rapid disappearance of delta 9 -THC from blood is largely due to redistribution to other tissues in the body, rather than to metabolism (Agurell et al., 1984 and 1986). Metabolism in most tissues is relatively slow or absent. Slow release of delta 9 -THC and other cannabinoids from tissues and subsequent metabolism results in a long elimination half-life. The terminal half-life of delta 9 -THC is estimated to range from approximately 20 hours to as long as 10 to 13 days (Hunt and Jones, 1980), though reported estimates vary as expected with any slowly cleared substance and the use of assays of variable sensitivities. Lemberger et al. (1970) determined the half-life of delta 9 -THC to range from 23 to 28 hours in heavy marijuana users to 60 to 70 hours in naïve users. Characterization of the pharmacokinetics of delta 9 -THC and other cannabinoids from smoked marijuana is difficult (Agurell et al., 1986; Herning et al., 1986; Huestis et al., 1992a), in part because a subject's smoking behavior during an experiment is variable. Each puff delivers a discrete dose of delta 9 -THC. 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. For example, under naturalistic conditions, users will hold marijuana smoke in the lungs for an extended period of time, in order to prolong absorption and increase psychoactive effects. The effect of experience in the psychological response may explain why venous blood levels of delta 9 -THC correlate poorly with intensity of effects and level of intoxication (Agurell et al., 1986; Barnett et al., 1985; Huestis et al., 1992a). Additionally, 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 delta 9 -THC in the remaining marijuana increases; thus, each successive puff contains an increasing concentration of delta 9 -THC. In contrast to smoking, the onset of effects after oral administration of delta 9 -THC or marijuana is 30 to 90 min, which peaks after 2 to 3 hours and continues for 4 to 12 hours (Grotenhermen, 2003; Adams and Martin, 1996; Agurell et al., 1984 and 1986). Oral bioavailability of delta 9 -THC, whether pure or in marijuana, is low and extremely variable, ranging between 5 and 20 percent (Agurell et al., 1984 and 1986). Following oral administration of radioactive-labeled delta 9 -THC, delta 9 -THC plasma levels are low relative to those levels after smoking or intravenous administration. There is inter- and intra-subject variability, even when repeated dosing occurs under controlled conditions. The low and variable oral bioavailability of delta 9 -THC is a consequence of its first-pass hepatic elimination from blood and erratic absorption from stomach and bowel. It is more difficult for a user to titrate the oral delta 9 -THC dose than marijuana smoking because of the delay in onset of effects after an oral dose (typically 1 to 2 hours). Cannabinoid metabolism is extensive. Delta 9 -THC is metabolized via microsomal hydroxylation to both active and inactive metabolites (Lemberger et al., 1970, 1972a, and 1972b; Agurell et al., 1986; Hollister, 1988) of which the primary active metabolite was 11-hydroxy-delta 9 -THC. This metabolite is approximately equipotent to delta 9 -THC in producing marijuana-like subjective effects (Agurell et al., 1986; Lemberger and Rubin, 1975). After oral administration, metabolite levels may exceed that of delta 9 -THC and thus contribute greatly to the pharmacological effects of oral delta 9 -THC or marijuana. In addition to 11-hydroxy-delta 9 -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. The majority of the absorbed delta 9 -THC dose is eliminated in feces, and about 33 percent in urine. Delta 9 -THC enters enterohepatic circulation and undergoes hydroxylation and oxidation to 11-nor-9-carboxy-delta 9 -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 delta 9 -THC (Agurell et al., 1986). Medical Uses for Marijuana A NDA for marijuana/cannabis has not been submitted to the FDA for any indication and thus no medicinal product containing botanical cannabis has been approved for marketing. However, small clinical studies published in the current medical literature demonstrate that research with marijuana is being conducted in humans in the United States under FDA-authorized investigational new drug (IND) applications. HHS states in a published guidance that it is committed to providing “research-grade marijuana for studies that are the most likely to yield usable, essential data” (HHS, 1999). The opportunity for scientists to conduct clinical research with botanical marijuana has increased due to changes in the process for obtaining botanical marijuana from NIDA, the only legitimate source of the drug for research in the United States. In May 1999, HHS provided guidance on the procedures for providing research-grade marijuana to scientists who intend to study marijuana in scientifically valid investigations and well-controlled clinical trials (DHHS, 1999). This action was prompted by the increasing interest in determining whether cannabinoids have medical use through scientifically valid investigations. In February 1997, a National Institutes of Health (NIH)-sponsored workshop analyzed available scientific information and concluded that “in order to evaluate various hypotheses concerning the potential utility of marijuana in various therapeutic areas, more and better studies would be needed” (NIH, 1997). In addition, in March 1999, the Institute of Medicine (IOM) issued a detailed report that supported the need for evidence-based research into the effects of marijuana and cannabinoid components of marijuana, for patients with specific disease conditions. The IOM report also emphasized that smoked marijuana is a crude drug delivery system that exposes individuals to a significant number of harmful substances and that “if there is any future for marijuana as a medicine, it lies in its isolated components, the cannabinoids and their synthetic derivatives.” As such, the IOM recommended that clinical trials should be conducted with the goal of developing safe delivery systems (Institute of Medicine, 1999). Additionally, state-level public initiatives, including referenda in support of the medical use of marijuana, have generated interest in the medical community for high quality clinical investigation and comprehensive safety and effectiveness data. For example, in 2000, the state of California established the Center for Medicinal Cannabis Research (CMCR) ( www.cmcr.ucsd.edu ) “in response to scientific evidence for therapeutic possibilities of cannabis and local legislative initiatives in favor of compassionate use” (Grant, 2005). State legislation establishing the CMCR called for high quality medical research that will “enhance understanding of the efficacy and adverse effects of marijuana as a pharmacological agent,” but stressed that the project “should not be construed as encouraging or sanctioning the social or recreational use of marijuana.” CMCR has thus far funded studies on the potential use of cannabinoids for the treatment of multiple sclerosis, neuropathic pain, appetite suppression and cachexia, and severe pain and nausea related to cancer or its treatment by chemotherapy. To date, though, no NDAs utilizing marijuana for these indications have been submitted to the FDA. However, FDA approval of an NDA is not the sole means through which a drug can be determined to have a “currently accepted medical use” under the CSA. According to established case law, a drug has a “currently accepted medical use” if all of the following five elements have been satisfied: a. the drug's chemistry is known and reproducible; b. there are adequate safety studies; c. there are adequate and well-controlled studies proving efficacy; d. the drug is accepted by qualified experts; and e. the scientific evidence is widely available. [ Alliance for Cannabis Therapeutics v. DEA, 15 F.3d 1131, 1135 (D.C. Cir. 1994)] Although the structures of many cannabinoids found in marijuana have been characterized, a complete scientific analysis of all the chemical components found in marijuana has not been conducted. Safety studies for acute or subchronic administration of marijuana have been carried out through a limited number of Phase 1 clinical investigations approved by the FDA, but there have been no NDA-quality studies that have scientifically assessed the efficacy and full safety profile of marijuana for any medical condition. A material conflict of opinion among experts precludes a finding that marijuana has been accepted by qualified experts. At this time, it is clear that there is not a consensus of medical opinion concerning medical applications of marijuana. Finally, the scientific evidence regarding the safety or efficacy of marijuana is typically available only in summarized form, such as in a paper published in the medical literature, rather than in a raw data format. As such, there is no opportunity for adequate scientific scrutiny of whether the data demonstrate safety or efficacy. Alternately, a drug can be considered to have “a currently accepted medical use with severe restrictions” (21 U.S.C. 812(b)(2)(B)), as allowed under the stipulations for a Schedule II drug. However, as stated above, a material conflict of opinion among experts precludes a finding that marijuana has been accepted by qualified experts, even under conditions where its use is severely restricted. Thus, to date, research on the medical use of marijuana has not progressed to the point that marijuana can be considered to have a “currently accepted medical use” or a “currently accepted medical use with severe restrictions.” 4. ITS HISTORY AND CURRENT PATTERN OF ABUSE The fourth factor the Secretary must consider is the history and current pattern of abuse of marijuana. A variety of sources provide data necessary to assess abuse patterns and trends of marijuana. The data indicators of marijuana use include NSDUH, Monitoring the Future (MTF), DAWN, and Treatment Episode Data Set (TEDS), which are described below: National Survey on Drug Use and Health The National Survey on Drug Use and Health (NSDUH, 2004; http://oas.samhsa.gov/nsduh.htm ) is conducted annually by SAMHSA, an agency of HHS. NSDUH provides estimates of the prevalence and incidence of illicit drug, alcohol, and tobacco use in the United States. This database was known until 2001 as the National Household Survey on Drug Abuse. The survey is based on a nationally representative sample of the civilian, non-institutionalized population 12 years of age and older. The survey identifies whether an individual used a drug during a certain period, but not the amount of the drug used on each occasion. Excluded groups include homeless people, active military personnel, and residents of institutions, such as jails. According to the 2004 NSDUH, 19.1 million individuals (7.9 percent of the U.S. population) illicitly used drugs other than alcohol and nicotine on a monthly basis, compared to 14.8 million (6.7 percent of the U.S. population) users in 1999. This is an increase from 1999 of 4.3 million (2.0 percent of the U.S. population). The most frequently used illicit drug was marijuana, with 14.6 million individuals (6.1 percent of the U.S. population) using it monthly. Thus, regular illicit drug use, and more specifically marijuana use, for rewarding responses is increasing. The 2004 NSDUH estimated that 96.8 million individuals (40.2 percent of the U.S. population) have tried marijuana at least once during their lifetime. Thus, 15 percent of those who have tried marijuana on one occasion go on to use it monthly, but 85 percent of them do not. Monitoring the Future MTF (2005, http://www.monitoringthefuture.org ) is a NIDA-sponsored annual national survey that tracks drug use trends among adolescents in the United States. The MTF surveys 8th, 10th, and 12th graders every spring in randomly selected U.S. schools. The MTF survey has been conducted since 1975 for 12th graders and since 1991 for 8th and 10th graders by the Institute for Social Research at the University of Michigan under a grant from NIDA. The 2005 sample sizes were 17,300—8th graders; 16,700—10th graders; and 15,400—12th graders. In all, a total of 49,300 students in 402 schools participated. Since 1999, illicit drug use among teens decreased and held steady through 2005 in all three grades (Table 1). Marijuana remained the most widely used illicit drug, though its use has steadily decreased since 1999. For 2005, the annual prevalence rates for marijuana use in grades 8, 10, and 12 were, respectively, 12.2 percent, 26.6 percent, and 33.6 percent. Current monthly prevalence rates for marijuana use were 6.6 percent, 15.2 percent, and 19.8 percent. (See Table 1). According to Gruber and Pope (2002), when adolescents who used marijuana reach their late 20's, the vast majority of these individuals will have stopped using marijuana. Table 1—Trends in Annual and Monthly Prevalence of Use of Various Drugs for Eighth, Tenth, and Twelfth Graders, From Monitoring the Future. Percentages Represent Students in Survey Responding That They had Used a Drug Either in the Past Year or in the Past 30 Days Annual 2003 2004 2005 30-Day 2003 2004 2005 Any illicit drug (a): 8th Grade 16.1 15.2 15.5 9.7 8.4 8.5 10th Grade 32.0 31.1 29.8 19.5 18.3 17.3 12th Grade 39.3 38.8 38.4 24.1 23.4 23.1 Any illicit drug other than cannabis (a): 8th Grade 8.8 7.9 8.1 4.7 4.1 4.1 10th Grade 13.8 13.5 12.9 6.9 6.9 6.4 12th Grade 19.8 20.5 19.7 10.4 10.8 10.3 Marijuana/hashish: 8th Grade 12.8 11.8 12.2 7.5 6.4 6.6 10th Grade 28.2 27.5 26.6 17.0 15.9 15.2 12th Grade 34.9 34.3 33.6 21.2 19.9 19.8 SOURCE: The Monitoring the Future Study, the University of Michigan. a. For 12th graders only, “any illicit drug” includes any use of marijuana, LSD, other hallucinogens, crack, other cocaine, or heroin, or any use of other opiates, stimulants, barbiturates, or tranquilizers not under a doctor's orders. For 8th and 10th graders, the use of other opiates and barbiturates was excluded. Drug Abuse Warning Network DAWN (2006, http://dawninfo.samhsa.gov/ ) is a national probability survey of U.S. hospitals with EDs designed to obtain information on ED visits in which recent drug use is implicated. The ED data from a representative sample of hospital emergency departments are weighted to produce national estimates. It is critical to note that DAWN data and estimates for 2004 are not comparable to those for any prior years because of vast changes in the methodology used to collect the data. Further, estimates for 2004 are the first to be based on a new, redesigned sample of hospitals. Thus, the most recent estimates available are for 2004. Many factors can influence the estimates of ED visits, including trends in the ED usage in general. Some drug users may have visited EDs for a variety of reasons, some of which may have been life-threatening, whereas others may have sought care at the ED for detoxification because they needed certification before entering treatment. DAWN data do not distinguish the drug responsible for the ED visit from others used concomitantly. As stated in a recent DAWN report, “Since marijuana/hashish is frequently present in combination with other drugs, the reason for the ED contact may be more relevant to the other drug(s) involved in the episode.” For 2004, DAWN estimates a total of 1,997,993 (95 percent confidence interval [CI]: 1,708,205 to 2,287,781) drug-related ED visits for the entire United States. During this period, DAWN estimates 940,953 (CI: 773,124 to 1,108,782) drug-related ED visits involved a major drug of abuse. Thus, nearly half of all drug-related visits involved alcohol or an illicit drug. Overall, drug-related ED visits averaged 1.6 drugs per visit, including illicit drugs, alcohol, prescription and over-the-counter (OTC) pharmaceuticals, dietary supplements, and non-pharmaceutical inhalants. Marijuana was involved in 215,665 (CI: 175,930 to 255,400) ED visits, while cocaine was involved in 383,350 (CI: 284,170 to 482,530) ED visits, heroin was involved in 162,137 (CI: 122,414 to 201,860) ED visits, and stimulants, including amphetamine and methamphetamine, were involved in 102,843 (CI: 61,520 to 144,166) ED visits. Other illicit drugs, such as PCP, MDMA, and GHB, were much less frequently associated with ED visits. Approximately 18 percent of ED visits involving marijuana were for patients under the age of 18, whereas this age group accounts for less than 1 percent of the ED visits involving heroin/morphine and approximately 3 percent of the visits involving cocaine. Since the size of the population differs across age groups, a measure standardized for population size is useful to make comparisons. For marijuana, the rates of ED visits per 100,000 population were highest for patients aged 18 to 20 (225 ED visits per 100,000) and for patients aged 21 to 24 (190 ED visits per 100,000). Treatment Episode Data Set TEDS (TEDS, 2003; http://oas.samhsa.gov/dasis.htm#teds2 ) system is part of SAMHSA's Drug and Alcohol Services Information System (Office of Applied Science, SAMHSA). TEDS comprises data on treatment admissions that are routinely collected by States in monitoring their substance abuse treatment systems. The TEDS report provides information on the demographic and substance use characteristics of the 1.8 million annual admissions to treatment for abuse of alcohol and drugs in facilities that report to individual State administrative data systems. TEDS is an admission-based system, and TEDS admissions do not represent individuals. Thus, a given individual admitted to treatment twice within a given year would be counted as two admissions. Additionally, TEDS does not include all admissions to substance abuse treatment. TEDS includes facilities that are licensed or certified by the States to provide substance abuse treatment and that are required by the States to provide TEDS client-level data. Facilities that report TEDS data are those that receive State alcohol and/or drug agency funds for the provision of alcohol and/or drug treatment services. The primary goal for TEDS is to monitor the characteristics of treatment episodes for substance abusers. Primary marijuana abuse accounted for 15.5 percent of TEDS admissions in 2003, the latest year for which data are available. Three-quarters of the individuals admitted for marijuana were male and 55 percent of the admitted individuals were white. The average age at admission was 23 years. The largest proportion (84 percent) of admissions to ambulatory treatment was for primary marijuana abuse. More than half (57 percent) of marijuana treatment admissions were referred through the criminal justice system. Between 1993 and 2003, the percentage of admissions for primary marijuana use increased from 6.9 percent to 15.5 percent, comparable to the increase for primary opioid use from 13 percent in 1993 to 17.6 percent in 2003. In contrast, the percentage of admissions for primary cocaine use declined from 12.6 percent in 1993 to 9.8 percent in 2003, and for primary alcohol use from 56.9 percent in 1993 to 41.7 percent in 2003. Twenty-six percent of those individuals who were admitted for primary use of marijuana reported its daily use, although 34.6 percent did not use marijuana in the past month. Nearly all (96.2 percent) of primary marijuana users utilized the drug by smoking it. Over 90 percent of primary marijuana admissions used marijuana for the first time before the age of 18. 5. THE SCOPE, DURATION, AND SIGNIFICANCE OF ABUSE The fifth factor the Secretary must consider is the scope, duration, and significance of marijuana abuse. According to 2004 data from NSDUH and MTF, marijuana remains the most extensively used illegal drug in the United States, with 40.6 percent of U.S. individuals over age 12 (96.6 million) and 44.8 percent of 12th graders having used marijuana at least once in their lifetime. While the majority of individuals over age 12 (85 percent) who have used marijuana do not use the drug monthly, 14.6 million individuals (6.1 percent of the U.S. population) report that they used marijuana within the past 30 days. An examination of use among various age cohorts in NSDUH demonstrates that monthly use occurs primarily among college age individuals, with use dropping off sharply after age 25. DAWN data show that marijuana was involved in 79,663 ED visits, which amounts to 13 percent of all drug-related ED visits. Minors accounted for 15 percent of these marijuana-related visits, making marijuana the drug most frequently associated with ED visits for individuals under the age of 18 years. Data from TEDS show that 15.5 percent of all admissions were for primary marijuana abuse. Approximately 90 percent of these primary marijuana admissions were for individuals under the age of 18 years. 6. WHAT, IF ANY, RISK THERE IS TO THE PUBLIC The sixth factor the Secretary must consider is the risk marijuana poses to the public health. The risk to the public health as measured by emergency room episodes, marijuana-related deaths, and drug treatment admissions is discussed in full under Factors 1, 4, and 5, above. Accordingly, Factor 6 focuses on the health risks to the individual user. All drugs, both medicinal and illicit, have a broad range of effects on the individual user that are dependent on dose and duration of use among others. FDA-approved drug products can produce adverse events (or “side effects”) in some individuals even at doses in the therapeutic range. When determining whether a drug product is safe and effective for any indication, FDA performs an extensive risk-benefit analysis to determine whether the risks posed by the drug product's potential or actual side effects are outweighed by the drug product's potential benefits. As marijuana is not FDA-approved for any medicinal use, any potential benefits attributed to marijuana use have not been found to be outweighed by the risks. However, cannabinoids are generally potent psychoactive substances and are pharmacologically active on multiple organ systems. The discussion of marijuana's central nervous system, cognitive, cardiovascular, autonomic, respiratory, and immune system effects are fully discussed under Factor 2. Consequences of marijuana use and abuse are discussed below in terms of the risk from acute and chronic use of the drug to the individual user (Institute of Medicine, 1999). Risks from acute use of marijuana Acute use of marijuana impairs psychomotor performance, including performance of complex tasks, which makes it inadvisable to operate motor vehicles or heavy equipment after using marijuana (Ramaekers et al., 2004). Dysphoria and psychological distress, including prolonged anxiety reactions, are potential responses in a minority of individuals who use marijuana (Haney et al., 1999). Risks from chronic use of marijuana Chronic exposure to marijuana smoke is considered to be comparable to tobacco smoke with respect to increased risk of cancer, lung damage, and poor pregnancy outcome. Although a distinctive marijuana withdrawal syndrome has been identified, indicating that marijuana produces physical dependence, this phenomenon is mild and short-lived (Budney et al., 2004), as described above under Factor 2. The Diagnostic and Statistical Manual (DSM-IV-TR, 2000) of the American Psychiatric Association states that the consequences of cannabis abuse are as follows: [P]eriodic cannabis use and intoxication can interfere with performance at work or school and may be physically hazardous in situations such as driving a car. Legal problems may occur as a consequence of arrests for cannabis possession. There may be arguments with spouses or parents over the possession of cannabis in the home or its use in the presence of children. When psychological or physical problems are associated with cannabis in the context of compulsive use, a diagnosis of Cannabis Dependence, rather than Cannabis Abuse, should be considered. Individuals with Cannabis Dependence have compulsive use and associated problems. Tolerance to most of the effects of cannabis has been reported in individuals who use cannabis chronically. There have also been some reports of withdrawal symptoms, but their clinical significance is uncertain. There is some evidence that a majority of chronic users of cannabinoids report histories of tolerance or withdrawal and that these individuals evidence more severe drug-related problems overall. Individuals with Cannabis Dependence may use very potent cannabis throughout the day over a period of months or years, and they may spend several hours a day acquiring and using the substance. This often interferes with family, school, work, or recreational activities. Individuals with Cannabis Dependence may also persist in their use despite knowledge of physical problems (e.g., chronic cough related to smoking) or psychological problems (e.g., excessive sedation and a decrease in goal-oriented activities resulting from repeated use of high doses). 7. ITS PSYCHIC OR PHYSIOLOGIC DEPENDENCE LIABILITY The seventh factor the Secretary must consider is marijuana's psychic or physiologic dependence liability. Physical dependence is a state of adaptation manifested by a drug class-specific withdrawal syndrome produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist (American Academy of Pain Medicine, American Pain Society and American Society of Addiction Medicine consensus document, 2001). Long-term, regular use of marijuana can lead to physical dependence and withdrawal following discontinuation as well as psychic addiction or dependence. The marijuana withdrawal syndrome consists of symptoms such as restlessness, mild agitation, insomnia, nausea, and cramping that may resolve after 4 days, and may require in-hospital treatment. It is distinct from the withdrawal syndromes associated with alcohol and heroin use (Budney et al., 1999; Haney et al., 1999). Lane and Phillips-Bute (1998) describes milder cases of dependence including symptoms that are comparable to those from caffeine withdrawal, including decreased vigor, increased fatigue, sleepiness, headache, and reduced ability to work. The marijuana withdrawal syndrome has been reported in adolescents who were admitted for substance abuse treatment or in individuals who had been given marijuana on a daily basis during research conditions. Withdrawal symptoms can also be induced in animals following administration of a cannabinoid antagonist after chronic delta 9 -THC administration (Breivogel et al., 2003). Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug's effects over time (American Academy of Pain Medicine, American Pain Society and American Society of Addiction Medicine consensus document, 2001). Tolerance can develop to marijuana-induced cardiovascular and autonomic changes, decreased intraocular pressure, sleep and sleep EEG, and mood and behavioral changes (Jones et al., 1981). Down-regulation of cannabinoid receptors has been suggested as the mechanism underlying tolerance to the effects of marijuana (Rodriguez de Fonseca et al., 1994). Pharmacological tolerance does not indicate the physical dependence liability of a drug. 8. WHETHER THE SUBSTANCE IS AN IMMEDIATE PRECURSOR OF A SUBSTANCE ALREADY CONTROLLED UNDER THIS ARTICLE The eighth factor the Secretary must consider is whether marijuana is an immediate precursor of a controlled substance. Marijuana is not an immediate precursor of another controlled substance. RECOMMENDATION After consideration of the eight factors discussed above, HHS recommends that marijuana remain in Schedule I of the CSA. Marijuana meets the three criteria for placing a substance in Schedule I of the CSA under 21 U.S.C. 812(b)(1): 1) Marijuana has a high potential for abuse: The large number of individuals using marijuana on a regular basis, its widespread use, and the vast amount of marijuana that is available for illicit use are indicative of the high abuse potential for marijuana. Approximately 14.6 million individuals in the United States (6.1 percent of the U.S. population) used marijuana monthly in 2003. A 2003 survey indicates that by 12th grade, 33.6 percent of students report having used marijuana in the past year, and 19.8 percent report using it monthly. In Q3 to Q4 2003, 79,663 ED visits were marijuana-related, representing 13 percent of all drug-related episodes. Primary marijuana use accounted for 15.5 percent of admissions to drug treatment programs in 2003. Marijuana has dose-dependent reinforcing effects, as demonstrated by data that humans prefer higher doses of marijuana to lower doses. In addition, there is evidence that marijuana use can result in psychological dependence in at risk individuals. 2) Marijuana has no currently accepted medical use in treatment in the United States: The FDA has not yet approved an NDA for marijuana. The opportunity for scientists to conduct clinical research with marijuana exists under the HHS policy supporting clinical research with botanical marijuana. While there are INDs for marijuana active at the FDA, marijuana does not have a currently accepted medical use for treatment in the United States, nor does it have an accepted medical use with severe restrictions. A drug has a “currently accepted medical use” if all of the following five elements have been satisfied: a. The drug's chemistry is known and reproducible; b. There are adequate safety studies; c. There are adequate and well-controlled studies proving efficacy; d. The drug is accepted by qualified experts; and e. The scientific evidence is widely available. [ Alliance for Cannabis Therapeutics v. DEA, 15 F.3d 1131, 1135 (D.C. Cir. 1994)] Although the structures of many cannabinoids found in marijuana have been characterized, a complete scientific analysis of all the chemical components found in marijuana has not been conducted. Safety studies for acute or subchronic administration of marijuana have been carried out through a limited number of Phase 1 clinical investigations approved by the FDA, but there have been no NDA-quality studies that have scientifically assessed the efficacy of marijuana for any medical condition. A material conflict of opinion among experts precludes a finding that marijuana has been accepted by qualified experts. At this time, it is clear that there is not a consensus of medical opinion concerning medical applications of marijuana. Finally, the scientific evidence regarding the safety or efficacy of marijuana is typically available only in summarized form, such as in a paper published in the medical literature, rather than in a raw data format. As such, there is no opportunity for adequate scientific scrutiny of whether the data demonstrate safety or efficacy. Alternately, a drug can be considered to have “a currently accepted medical use with severe restrictions” (21 U.S.C. 812(b)(2)(B)), as allowed under the stipulations for a Schedule II drug. However, as stated above, a material conflict of opinion among experts precludes a finding that marijuana has been accepted by qualified experts, even under conditions where its use is severely restricted. To date, research on the medical use of marijuana has not progressed to the point that marijuana can be considered to have a “currently accepted medical use” or a “currently accepted medical use with severe restrictions.” 3) There is a lack of accepted safety for use of marijuana under medical supervision. At present, there are no FDA-approved marijuana products, nor is marijuana under NDA evaluation at the FDA for any indication. Marijuana does not have a currently accepted medical use in treatment in the United States or a currently accepted medical use with severe restrictions. The Center for Medicinal Cannabis Research in California, among others, is conducting research with marijuana at the IND level, but these studies have not yet progressed to the stage of submitting an NDA. Thus, at this time, the known risks of marijuana use have not been shown to be outweighed by specific benefits in well-controlled clinical trials that scientifically evaluate safety and efficacy. 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