Federal Register/Vol. 81, No. 156/Friday, August 12, 2016

53688 Federal Register / Vol. 81, No. 156 / Friday, August 12, 2016 / Proposed Rules

DEPARTMENT OF JUSTICE recommendation that the HHS submitted to Preliminary Note Regarding Treaty the DEA is enclosed with this letter. Considerations Drug Enforcement Administration Based on the HHS evaluation and all other Cover Letter from HHS to DEA relevant data, the DEA has concluded that Summarizing the Scientific and Medical 21 CFR Chapter II there is no substantial evidence that Evaluation and Scheduling Recommendation marijuana should be removed from Schedule for Marijuana. [Docket No. DEA–426] I. A document prepared by the DEA U.S. Department of Health and Human addressing these materials in detail also is Services (HHS)—Basis for the Denial of Petition To Initiate enclosed. In short, marijuana continues to Recommendation for Maintaining Marijuana Proceedings To Reschedule Marijuana meet the criteria for Schedule I control under in Schedule I of the Controlled Substances the CSA because: Act AGENCY: Drug Enforcement (1) Marijuana has a high potential for U.S. Department of Justice—Drug Administration, Department of Justice. abuse. The HHS evaluation and the Enforcement Administration (DEA), ACTION: Denial of petition to initiate additional data gathered by the DEA show Schedule of Controlled Substances: Maintaining Marijuana in Schedule I of the proceedings to reschedule marijuana. that marijuana has a high potential for abuse. Controlled Substances Act, Background, (2) Marijuana has no currently accepted Data, and Analysis: Eight Factors SUMMARY: By letter dated July 19, 2016 medical use in treatment in the United Determinative of Control and Findings the Drug Enforcement Administration States. Based on the established five-part test Pursuant to 21 U.S.C. 812(b) (DEA) denied a petition to initiate for making such determination, marijuana rulemaking proceedings to reschedule has no ‘‘currently accepted medical use’’ Dated: July 19, 2016. marijuana. Because the DEA believes because: As detailed in the HHS evaluation, Chuck Rosenberg, that this matter is of particular interest the drug’s chemistry is not known and Acting Administrator, Preliminary Note to members of the public, the agency is reproducible; there are no adequate safety Regarding Treaty Considerations. publishing below the letter sent to the studies; there are no adequate and well- As the Controlled Substances Act petitioner which denied the petition, controlled studies proving efficacy; the drug (CSA) recognizes, the United States is a along with the supporting is not accepted by qualified experts; and the party to the Single Convention on documentation that was attached to the scientific evidence is not widely available. Narcotic Drugs, 1961 (referred to here as (3) Marijuana lacks accepted safety for use the Single Convention or the treaty). 21 letter. under medical supervision. At present, there DATES: August 12, 2016. are no marijuana products approved by the U.S.C. 801(7). Parties to the Single FOR FURTHER INFORMATION CONTACT: U.S. Food and Drug Administration (FDA), Convention are obligated to maintain Michael J. Lewis, Office of Diversion nor is marijuana under a New Drug various control provisions related to the Control, Drug Enforcement Application (NDA) evaluation at the FDA for drugs that are covered by the treaty. Administration; Mailing Address: 8701 any indication. The HHS evaluation states Many of the provisions of the CSA were Morrissette Drive, Springfield, Virginia that marijuana does not have a currently enacted by Congress for the specific 22152; Telephone: (202) 598–6812. accepted medical use in treatment in the purpose of ensuring U.S. compliance United States or a currently accepted medical with the treaty. Among these is a SUPPLEMENTARY INFORMATION: use with severe restrictions. At this time, the scheduling provision, 21 U.S.C. July 19, 2016 known risks of marijuana use have not been 811(d)(1). Section 811(d)(1) provides Dear Ms. Raimondo and Mr. Inslee: shown to be outweighed by specific benefits that, where a drug is subject to control On November 30, 2011, your predecessors, in well-controlled clinical trials that under the Single Convention, the DEA The Honorable Lincoln D. Chafee and The scientifically evaluate safety and efficacy. Administrator (by delegation from the Honorable Christine O. Gregoire, petitioned The statutory mandate of Title 21 United the Drug Enforcement Administration (DEA) Attorney General) must ‘‘issue an order States Code, Section 812(b) (21 U.S.C. 812(b)) controlling such drug under the to initiate rulemaking proceedings under the is dispositive. Congress established only one rescheduling provisions of the Controlled schedule, Schedule I, for drugs of abuse with schedule he deems most appropriate to Substances Act (CSA). Specifically, your ‘‘no currently accepted medical use in carry out such [treaty] obligations, predecessors petitioned the DEA to have treatment in the United States’’ and ‘‘lack of without regard to the findings required marijuana and ‘‘related items’’ removed from accepted safety for use . . . under medical by [21 U.S.C. 811(a) or 812(b)] and Schedule I of the CSA and rescheduled as supervision.’’ 21 U.S.C. 812(b). without regard to the procedures medical cannabis in Schedule II. Although the HHS evaluation and all other prescribed by [21 U.S.C. 811(a) and Your predecessors requested that the DEA relevant data lead to the conclusion that (b)].’’ remove marijuana and related items from marijuana must remain in schedule I, it Marijuana is a drug listed in the Schedule I based on their assertion that: (1) Cannabis has accepted medical use in should also be noted that, in view of United Single Convention. The Single the United States; States obligations under international drug Convention uses the term ‘‘cannabis’’ to (2) Cannabis is safe for use under medical control treaties, marijuana cannot be placed refer to marijuana.1 Thus, the DEA supervision; in a schedule less restrictive than schedule (3) Cannabis for medical purposes has a II. This is explained in detail in 1 Under the Single Convention, ‘‘cannabis plant’ relatively low potential for abuse, especially accompanying document titled ‘‘Preliminary means any plant of the genus Cannabis.’’ Article in comparison with other Schedule II drugs. Note Regarding Treaty Considerations.’’ 1(c). The Single Convention defines ‘‘cannabis’’ to In accordance with the CSA rescheduling Accordingly, and as set forth in detail in include ‘‘the flowering or fruiting tops of the cannabis plant (excluding the seeds and leaves provisions, after gathering the necessary data, the accompanying HHS and DEA documents, when not accompanied by the tops) from which the the DEA requested a scientific and medical there is no statutory basis under the CSA for resin has not been extracted, by whatever name evaluation and scheduling recommendation the DEA to grant your predecessors’ petition they may be designated.’’ Article 1(b). This from the Department of Health and Human to initiate rulemaking proceedings to definition of ‘‘cannabis’’ under the Single Services (HHS). The HHS concluded that reschedule marijuana. The petition is, Convention is slightly less inclusive than the CSA marijuana has a high potential for abuse, has therefore, hereby denied. definition of ‘‘marihuana,’’ which includes all parts no accepted medical use in the United States, of the cannabis plant except for the mature stalks, and lacks an acceptable level of safety for use sterilized seeds, oil from the seeds, and certain Sincerely, derivatives thereof. See 21 U.S.C. 802(16). Cannabis even under medical supervision. Therefore, Chuck Rosenberg, and cannabis resin are included in the list of drugs the HHS recommended that marijuana in Schedule I and Schedule IV of the Single remain in Schedule I. The scientific and Acting Administrator. Convention. In contrast to the CSA, the drugs listed medical evaluation and scheduling Attachments: in Schedule IV of the Single Convention are also

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Administrator is obligated under section petition and keep marijuana in schedule Marijuana meets the three criteria for 811(d) to control marijuana in the I. placing a substance in Schedule I of the CSA schedule that he deems most As indicated, where section 811(d)(1) under 21 U.S.C. 812(b)(1). As discussed in appropriate to carry out the U.S. applies to a drug that is the subject of the enclosed analyses, marijuana has a high a rescheduling petition, the DEA potential for abuse, no currently accepted obligations under the Single medical use in treatment in the United Convention. It has been established in Administrator must issue an order States, and a lack of accepted safety for use prior marijuana rescheduling controlling the drug under the schedule under medical supervision. Accordingly, proceedings that placement of he deems most appropriate to carry out HHS recommends that marijuana be marijuana in either schedule I or United States obligations under the maintained in Schedule I of the CSA. schedule II of the CSA is ‘‘necessary as Single Convention, without regard to Enclosed are two documents prepared by well as sufficient to satisfy our the findings required by sections 811(a) FDA’s Controlled Substance Staff (in international obligations’’ under the or 812(b) and without regard to the response to petitions filed in 2009 by Mr. Single Convention. NORML v. DEA, 559 procedures prescribed by sections Bryan Krumm and in 2011 by Governors F.2d 735, 751 (D.C. Cir. 1977). As the 811(a) and (b). Thus, since the only Lincoln D. Chafee and Christine O. Gregoire) that form the basis for the recommendation. United States Court of Appeals for the determinative issue in evaluating the Pursuant to the requests in the petitions, FDA DC Circuit has stated, ‘‘several present scheduling petition is whether broadly evaluated marijuana, and did not requirements imposed by the Single marijuana has a currently accepted focus its evaluation on particular strains of Convention would not be met if medical use in treatment in the United marijuana or components or derivatives of cannabis and cannabis resin were States, DEA need not consider the marijuana. placed in CSA schedule III, IV, or findings of sections 811(a) or 812(b) that FDA’s Center for Drug Evaluation and V.’’ 2 Id. Therefore, in accordance with have no bearing on that determination, Research’s current review of the available section 811(d)(1), DEA must place and DEA likewise need not follow the evidence and the published clinical studies marijuana in either schedule I or procedures prescribed by sections on marijuana demonstrated that since our 811(a) and (b) with respect to such 2006 scientific and medical evaluation and schedule II. scheduling recommendation responding to a Because schedules I and II are the irrelevant findings. Specifically, DEA previous DEA petition, research with only possible schedules in which need not evaluate the relative abuse marijuana has progressed. However, the marijuana may be placed, for purposes potential of marijuana or the relative available evidence is not sufficient to of evaluating this scheduling petition, it extent to which abuse of marijuana may determine that marijuana has an accepted is essential to understand the lead to physical or psychological medical use. Therefore, more research is differences between the criteria for dependence. needed into marijuana’s effects, including placement of a substance in schedule I As explained below, the medical and potential medical uses for marijuana and its and those for placement in schedule II. scientific evaluation and scheduling derivatives. Based on the current review, we These criteria are set forth in 21 U.S.C. recommendation issued by the Secretary identified several methodological challenges in the marijuana studies published in the 812(b)(1) and (b)(2), respectively. As of Health and Human Services concludes that marijuana has no literature. We recommend they be addressed indicated therein, substances in both in future clinical studies with marijuana to schedule I and schedule II share the currently accepted medical use in ensure that valid scientific data are generated characteristic of ‘‘a high potential for treatment in the United States, and the in studies evaluating marijuana’s safety and abuse.’’ Where the distinction lies is DEA Administrator likewise so efficacy for therapeutic use. For example, we that schedule I drugs have ‘‘no currently concludes. For the reasons just recommend that studies need to focus on accepted medical use in treatment in the indicated, no further analysis beyond consistent administration and reproducible United States’’ and ‘‘a lack of accepted this consideration is required. dosing of marijuana, potentially through the safety for use of the drug . . . under Nonetheless, because of the widespread use of administration methods other than smoking. A summary of our review of the medical supervision,’’ while schedule II public interest in understanding all the facts relating to the harms associated published literature on the clinical uses of drugs do have ‘‘a currently accepted marijuana, including recommendations for medical use in treatment in the United with marijuana, DEA is publishing here future studies, is attached to this document. States.’’ 3 the entire medical and scientific FDA and the National Institutes of Health’s Accordingly, in view of section analysis and scheduling evaluation National Institute on Drug Abuse (NIDA) also 811(d)(1), this scheduling petition turns issued by the Secretary, as well as believe that work continues to be needed to on whether marijuana has a currently DEA’s additional analysis. ensure support by the federal government for the efficient conduct of clinical research accepted medical use in treatment in the Department of Health and Human Services, United States. If it does not, DEA must, Office of the Secretary Assistant Secretary using marijuana. Concerns have been raised pursuant to section 811(d), deny the for Health, Office of Public Health and about whether the existing federal regulatory Science, Washington, DC 20201. system is flexible enough to respond to increased interest in research into the listed in Schedule I of the Single Convention and June 25, 2015. potential therapeutic uses of marijuana and are subject to the same controls as Schedule I drugs The Honorable Chuck Rosenberg marijuana-derived drugs. HHS welcomes an as well as additional controls. Article 2, par. 5 Acting Administrator, Drug Enforcement opportunity to continue to explore these 2 The Court further stated: ‘‘For example, [article 31 paragraph 4 of the Single Convention] requires Administration, U.S. Department of Justice, concerns with DEA. import and export permits that would not be 8701 Morrissette Drive, Springfield, VA Should you have any questions regarding obtained if the substances were placed in CSA 22152. theses recommendations, please contact schedules III through V. In addition, the quota and Dear Mr. Rosenberg: Corinne P. Moody, Science Policy Analyst, [recordkeeping] requirements of Articles 19 through Pursuant to the Controlled Substances Act Controlled Substances Staff, Center for Drug 21 of the Single Convention would be satisfied only (CSA, 21 U.S.C. § 811(b), (c), and (f)), the Evaluation and Research, FDA, at (301) 796– by placing the substances in CSA schedule I or II.’’ Department of Health and Human Services 3152. Id. n. 71 (internal citations omitted). 3 (HHS) is recommending that marijuana Sincerely yours, As DEA has stated in evaluating prior marijuana continue to be maintained in Schedule I of rescheduling petitions, ‘‘Congress established only Karen B. DeSalvo, MD, MPH, MSc the CSA. one schedule, schedule I, for drugs of abuse with Acting Assistant Secretary for Health. ‘no currently accepted medical use in treatment in The Food and Drug Administration (FDA) the United States’and ‘lack of accepted safety for has considered the abuse potential and Enclosure: Basis for the Recommendation for use . . . under medical supervision.’ 21 U.S.C. dependence-producing characteristics of Maintaining Marijuana in Schedule I of the 812(b).’’ 76 FR 40552 (2011); 66 FR 20038 (2001). marijuana. Controlled Substances Act

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Basis for the Recommendation for Schedule I of the CSA. Pursuant to 21 on what is known about the range of Maintaining Marijuana in Schedule I of U.S.C. 811(c), the eight factors these constituents across all cultivated the Controlled Substances Act pertaining to the scheduling of strains. On November 30, 2011, Governors marijuana are considered below. Determining the abuse potential of a Lincoln D. Chafee of Rhode Island and substance is complex with many 1. Its Actual or Relative Potential for dimensions, and no single test or Christine O. Gregoire of Washington Abuse submitted a petition to the Drug assessment provides a complete Enforcement Administration (DEA) Under the first factor the Secretary characterization. Thus, no single requesting that proceeding be initiated must consider marijuana’s actual or measure of abuse potential is ideal. to repeal the rules and regulations that relative potential for abuse. The CSA Scientifically, a comprehensive place marijuana 4 in Schedule I of the does not define the term ‘‘abuse.’’ evaluation of the relative abuse Controlled Substances Act (CSA). The However, the CSA’s legislative history potential of a substance can include petition contends that cannabis has an suggests the following in determining consideration of the following elements: accepted medical use in the United whether a particular drug or substance Receptor binding affinity, preclinical States, is safe for use under medical has a potential for abuse: 6 pharmacology, reinforcing effects, supervision, and has a relatively low a. There is evidence that individuals discriminative stimulus effects, abuse potential compared to other are taking the drug or drugs containing dependence producing potential, Schedule II drugs. The petition requests such a substance in amounts sufficient pharmacokinetics, route of that marijuana and ‘‘related items’’ be to create a hazard to their health or to administration, toxicity, data on actual rescheduled in Schedule II of the CSA. the safety of other individuals or to the abuse, clinical abuse potential studies, In June 2013, the DEA Administrator community. and public health risks. Importantly, requested that the U.S. Department of b. There is a significant diversion of abuse can exist independently from Health and Human Services (HHS) the drug or drugs containing such a tolerance or physical dependence provide a scientific and medical substance from legitimate drug because individuals may abuse drugs in evaluation of the available information channels. doses or patterns that do not induce and a scheduling recommendation for c. Individuals are taking the drug or these phenomena. Additionally marijuana, in accordance with the drugs containing such a substance on evidence of clandestine population and provisions of 21 U.S.C. 811(b). their own initiative rather than on the illicit trafficking of a substance can shed In accordance with 21 U.S.C. 811(b), basis of medical advice from a light on both the demand for a DEA has gathered information related to practitioner licensed by law to substance as well as the ease of the control of marijuana (Cannabis administer such drugs in the course of obtaining a substance. Animal and sativa) 5 under the CSA. Pursuant to 21 his professional practice. human laboratory data and U.S.C. 811(b), the Secretary of HHS is d. The drug or drugs containing such epidemiological data are all used in required to consider in a scientific and a substance are new drugs so related in determining a substance’s abuse medical evaluation eight factors their action to a drug or drugs already potential. Moreover, epidemiological determinative of control under the CSA. listed as having a potential for abuse to data can indicate actual abuse. Following consideration of the eight make it likely that the drug will have The petitioners compare the effects of factors, if it is appropriate, the Secretary the same potentiality for abuse as such marijuana to currently controlled must make three findings to recommend drugs, thus making it reasonable to Schedule II substances and make scheduling a substance in the CSA. The assume that there may be significant repeated claims about their comparative findings relate to a substance’s abuse diversions from legitimate channels, effects. Comparisons between marijuana and the diverse array of Schedule II potential, legitimate medical use, and significant use contrary to or without substances is difficult, because of the safety or dependence liability. medical advice, or that it has a pharmacologically dissimilar actions of Administrative responsibilities for substantial capability of creating substances of Schedule II of the CSA. evaluating a substance for control under hazards to the health of the user or to For example, Schedule II substances the CSA are performed by the Food and the safety of the community. include stimulant-like drugs (e.g., Drug Administration (FDA), with the In the development of this scientific cocaine, methylphenidate, and concurrence of the National Institute on and medical evaluation for the purpose amphetamine), opioids (e.g., oxycodone, Drug Abuse (NIDA), as described in the of scheduling, the Secretary analyzed fentanyl), sedatives (e.g., pentobarbital, Memorandum of Understanding (MOU) considerable data related to the of March 8, 1985 (50 FR 9518–20). amobarbital), dissociative anesthetics substance’s abuse potential. The data (e.g., PCP), and naturally occurring In this document, FDA recommends include a discussion of the prevalence the continued control of marijuana in plant components (e.g., coca leaves and and frequency of use, the amount of the poppy straw). The mechanism(s) of substance available for illicit use, the 4 action of the above Schedule II Note that ‘‘marihuana’’ is the spelling originally ease of obtaining or manufacturing the used in the Controlled Substances Act (CSA). This substances are wholly different from document uses the spelling that is more common substance, the reputation or status of the one another, and they are different from in current usage, ‘‘marijuana.’’ substance ‘‘on the street,’’ and evidence 5 tetrahydrocannabinol (THC) and The CSA defines marijuana as the following: relevant to at-risk populations. marijuana as well. For example, All parts of the plant Cannabis Sativa L., whether Importantly, the petitioners define growing or not; the seeds thereof; the resin Schedule II stimulants typically extracted from any part of such plant; and every marijuana as including all Cannabis function by increasing monoaminergic compound, manufacture, salt, derivative, mixture, cultivated strains. Different marijuana tone via an increase in dopamine and or preparation of such plant, its seeds or resin. Such samples derived from various cultivated norepinephrine (Schmitt et al., 2013). In term does not include the mature stalks of such strains may have very different chemical plant, fiber produced from such stalks, oil or cake contrast, opioid analgesics function via made from the seeds of such plant, any other constituents, thus the analysis is based mu-opioid receptor agonist effects. compound, manufacture, salt, derivative, mixture, These differing mechanism(s) of action or preparation of such mature stalks (except the 6 Comprehensive Drug Abuse Prevention and resin extracted therefrom), fiber, oil, or cake, or the Control Act of 1970, H.R. Rep. No. 91–1444, 91st result in vastly different behavioral and sterilized seed of such plant which is incapable of Cong., Sess. 1 (1970) reprinted in U.S.C.C.A.N. adverse effect profiles, making germination (21 U.S.C. 802(16)). 4566, 4603. comparisons across the range of

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pharmacologically diverse C–II probability survey of U.S. hospitals with publically available (DEA Domestic substances inappropriate. emergency departments (EDs) and was Drug Seizures, n.d.). In addition, many substances designed to obtain information on ED c. Individuals are taking the substance scheduled under the CSA are reviewed visits in which marijuana was on their own initiative rather than on and evaluated within the context of mentioned, accounting for 36.4 percent the basis of medical advice from a commercial drug development, using of illicit drug related ED visits. There practitioner licensed by law to data submitted in the form of a new are some limitations related to DAWN administer such substances. drug application (NDA). A new data on ED visits, which are discussed Because the FDA has not approved an analgesic drug might be compared to a in detail in Factor 4, ‘‘Its History and NDA or BLA for a marijuana drug currently scheduled analgesic drug as Current Pattern of Abuse;’’ Factor 5, product for any therapeutic indication, part of the assessment of its relative ‘‘The Scope, Duration, and Significance the only way an individual can take abuse potential. However, because the of Abuse;’’ and Factor 6, ‘‘What, if any, marijuana on the basis of medical petitioners have not identified a specific Risk There is to the Public Health.’’ advice through legitimate channels at indication for the use of marijuana, These factors contain detailed the federal level is by participating in identifying an appropriate comparator discussions of these data. research under an IND application. That based on indication cannot be done. A number of risks can occur with both said, numerous states and the District of a. There is evidence that individuals acute and chronic use of marijuana. Columbia have passed state-level are taking the substance in amounts Detailed discussions of the risks are medical marijuana laws allowing for sufficient to create a hazard to their addressed in Factor 2, ‘‘Scientific individuals to use marijuana under health or to the safety of other Evidence of its Pharmacological Effect, certain circumstances. However, data individuals or to the community. if Known,’’ and Factor 6, ‘‘What, if any, are not yet available to determine the Evidence shows that some individuals Risk There is to the Public Health.’’ number of individuals using marijuana are taking marijuana in amounts b. There is significant diversion of the under these state-level medical sufficient to create a hazard to their substance from legitimate drug marijuana laws. Regardless, according to health and to the safety of other channels. the 2012 NSDUH data, 18.9 million individuals and the community. A large There is a lack of evidence of American adults currently use number of individuals use marijuana. significant diversion of marijuana from marijuana (SAMHSA, 2013). Based on HHS provides data on the extent of legitimate drug channels, but this is the large number of individuals marijuana abuse through NIDA and the likely due to the fact that marijuana is reporting current use of marijuana and Substance Abuse and Mental Health more widely available from illicit the lack of an FDA-approved drug Services Administration (SAMHSA). sources rather than through legitimate product in the United States, one can According to the most recent data from channels. Marijuana is not an FDA- assume that it is likely that the majority SAMHSA’s 2012 National Survey on approved drug product, as an NDA or of individuals using marijuana do so on Drug Use and Health (NSDUH), which biologics license application (BLA) has their own initiative rather than on the estimates the number of individuals not been approved for marketing in the basis of medical advice from a licensed who have used a substance within a United States. Numerous states and the practitioner. month prior to the study (described as District of Columbia have state-level d. The substance is so related in its ‘‘current use’’), marijuana is the most medical marijuana laws that allow for action to a substance already listed as commonly used illicit drug among marijuana use within that state. These having a potential for abuse to make it Americans aged 12 years and older, state-level drug channels do not have likely that it will have the same with an estimated 18.9 million sufficient collection of data related to potential for abuse as such substance, Americans having used marijuana medical treatment, including efficacy thus making it reasonable to assume that within the month prior to the 2012 and safety. there may be significant diversions from NSDUH. Compared to 2004, when an Marijuana is used by researchers for legitimate channels, significant use estimated 14.6 million individuals nonclinical research as well as clinical contrary to or without medical advice, reported using marijuana within the research under investigational new drug or that it has a substantial capability of month prior to the study, the estimated (IND) applications; this represents the creating hazards to the health of the user rates in 2012 show an increase of only legitimate drug channel in the or to the safety of the community. approximately 4.3 million individuals. United States. However, marijuana used FDA has approved two drug products The 2013 Monitoring the Future (MTF) for research represents a very small containing cannabinoid compounds that survey of 8th, 10th, and 12th grade contribution of the total amount of are structurally related to the active students also indicates that marijuana is marijuana available in the United States, components in marijuana. These two the most widely used illicit substance in and thus provides limited information marketed products are controlled under this age group. Specifically, current about diversion. In addition, the lack of the CSA. Once a specific drug product month use was at 7.0 percent of 8th significant diversion of investigation containing cannabinoids becomes graders, 18.0 percent of 10th, graders supplies is likely because of the approved, that specific drug product and 22.7 percent of 12th graders. widespread availability of illicit may be moved from Schedule I to a Additionally, the 2011 Treatment marijuana of equal or greater amounts of different Schedule (II–V) under the Episode Data Set (TEDS) reported that delta9-THC. The data originating from CSA. Firstly, Marinol—generically primary marijuana abuse accounted for the DEA on seizure statistics known as dronabinol—is a Schedule III 18.1 percent of non-private substance- demonstrate the magnitude of the drug product containing synthetic abuse treatment facility admissions, availability for illicit marijuana. DEA’s delta9-THC. Marinol, which is with 24.3 percent of those admitted System to Retrieve Information from formulated in sesame oil in soft gelatin reporting daily use. However, of these Drug Evidence (STRIDE) provides capsules, was first placed in Schedule II admissions for primary marijuana information on total domestic drug under the CSA following its approval by abuse, the criminal justice system seizures. STRIDE reports a total the FDA. Marinol was later rescheduled referred 51.6 percent to treatment. domestic seizure of 573,195 kg of to Schedule III under the CSA because SAMHSA’s Drug Abuse Warning marijuana in 2011, the most recent year of low numbers of reports of abuse Network (DAWN) was a national with complete data that is currently relative to marijuana. Dronabinol is

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listed in Schedule I under the CSA. FDA been identified chemically. New and CB1 receptors are found in the immune approved Marinol in 1985 for the minor cannabinoids and other new system and numerous other peripheral treatment of nausea and vomiting compounds are continuously being tissues (Petrocellis and Di Marzo, 2009). associated with cancer chemotherapy in characterized (Pollastro et al., 2011). So However, the concentration of CB1 patients who failed to respond far, only two cannabinoids receptors is considerably lower in adequately to conventional anti-emetic (cannabigerol and its corresponding peripheral tissues than in the central treatments. In 1992, FDA approved acid) have been obtained from a non- nervous system (Herkenharn et al., 1990 Marional for anorexia associated with Cannabis source. A South African and 1992). weight loss in patients with acquired Helichrysum (H. umbraculigerum) CB2 receptors are found primarily in immunodeficiency syndrome (AIDS). accumulates these compounds the immune system, but are also present Secondly, in 1985, FDA approved (Appendino et al., 2011). The chemistry in the central nervous system and other Cesamet, a drug product containing the of marijuana is described in more detail peripheral tissues. In the immune Schedule II substance nabilone, for the in Factor 3, ‘‘The State of Current system, CB2 receptors are found treatment of nausea and vomiting Scientific Knowledge Regarding the predominantly in B lymphocytes and associated with cancer chemotherapy. Drug or Other Substance.’’ natural killer cells (Bouaboula et al., Besides the two cannabinoid-containing The site of cannabinoid action is at 1993). CB2 receptors may mediate drug products FDA approved for the cannabinoid receptors. Cloning of cannabinoids’ immunological effects marketing, other naturally occurring cannabinoid receptors, first from rat (Galiegue et al., 1995). Additionally, CB2 cannabinoids and their derivatives brain tissue (Matsuda et al., 1990) and receptors have been localized in the (from Cannabis) and their synthetic then from human brain tissue (Gerard et brain, primarily in the cerebellum and equivalents with similar chemical al., 1991), has verified the site of action. hippocampus (Gong et al., 2006). The structure and pharmacological activity Two cannabinoid receptors, CB1 and distribution of CB2 receptors throughout are included in the CSA as Schedule I CB2, were characterized (Battista et al., the body is less extensive than the substances. 2012; Piomelli, 2005). Evidence of a distribution of CB1 receptors (Petrocellis third cannabinoid receptor exists, but it and Di Marzo, 2009). However, both CB 2. Scientific Evidence of Its 1 has not been identified (Battista et al., and CB2 receptors are present in Pharmacological Effects, if Known 2012). numerous tissues of the body. Under the second factor, the Secretary The cannabinoid receptors, CB1 and Cannabinoid receptors have must consider the scientific evidence of CB2, belong to the family of G-protein- endogenous ligands. In 1992 and 1995, marijuana’s pharmacological effects. coupled receptors, and present a typical two endogenous cannabinoid receptor Abundant scientific data are available seven transmembrane-spanning domain agonists, anandamide and arachidonyl on the neurochemistry, toxicology, and structure. Cannabinoid receptors link to glycerol (2-AG), respectively, were pharmacology of marijuana. This an inhibitory G-protein (Gi), such that identified (Di Marzo, 2006). section includes a scientific evaluation adenylate cyclase activity is inhibited Anandamide is a low efficacy agonist of marijuana’s neurochemistry; when a ligand binds to the receptor. (Breivogel and Childers, 2000) and 2-AG pharmacology; and human and animal This, in turn, prevents the conversion of is a high efficacy agonist (Gonsiorek et behavioral, central nervous system, ATP to the second messenger, cyclic al., 2000). Cannabinoid endogenous cognitive, cardiovascular, autonomic, AMP (cAMP). Examples of inhibitory ligands are present in central as well as endocrinological, and immunological coupled receptors include opioid, peripheral tissues. A combination of system effects. The overview presented muscarinic cholinergic, alpha2- uptake and hydrolysis terminate the below relies upon the most current adrenoreceptors, dopamine (D2), and action of the endogenous ligands. The research literature on cannabinoids. serotonin (5-HT1). endogenous cannabinoid system is a Cannabinoid receptor activation locally active signaling system that, to Neurochemistry and Pharmacology of inhibits N- and P/Q-type calcium help restore homeostasis, is activated Marijuana channels and activates inwardly ‘‘on demand’’ in response to changes to Marijuana is a plant that contains rectifying potassium channels (Mackie the local homeostasis (Petrocellis and Di numerous natural constituents, such as et al., 1995; Twitchell et al., 1997). N- Marzo, 2009). The endogenous cannabinoids, that have a variety of type calcium channel inhibition cannabinoid system, including the pharmacological actions. The petition decreases neurotransmitter release from endogenous cannabinoids and the defines marijuana as including all several tissues. Thus, calcium channel cannabinoid receptors, demonstrate Cannabis cultivated strains. Different inhibition may be the mechanism by substantial plasticity in response to marijuana samples derived from various which cannabinoids inhibit several physiological and pathological cultivated strains may have very acetylcholine, norepinephrine, and stimuli (Petrocellis and Di Marzo, 2009). different chemical constituents glutamate release from specific areas of This plasticity is particularly evident in including delta9-THC and other the brain. These effects may represent a the central nervous system. cannabinoids (Appendino et al., 2011). potential cellular mechanism Delta9-THC and cannabidiol (CBD) are As a consequence, marijuana products underlying cannabinoids’ two abundant cannabinoids present in from different strains will have different antinociceptive and psychoactive effects marijuana. Marijuana’s major biological and pharmacological profiles. (Ameri, 1999). psychoactive cannabinoid is delta9-THC According to ElSohly and Slade CB1 receptors are found primarily in (Wachtel et al., 2002). In 1964, Gaoni (2005) and Appendino et al. (2011), the central nervous system, but are also and Mechoularn first described delta9- marijuana contains approximately 525 present in peripheral tissues. CB1 THC’s structure and function. In 1963, identified natural constituents, receptors are located mainly in the basal Mechoularn and Shvo first described including approximately 100 ganglia, hippocampus, and cerebellum CBD’s structure. The pharmacological compounds classified as cannabinoids. of the brain (Howlett et al., 2004). The actions of CBD have not been fully Cannabinoids primarily exist in localization of these receptors may studied in humans. Cannabis, and published data suggests explain cannabinoid interference with Delta9-THC and CBD have varying that most major cannabinoid movement coordination and effects on affinity and effects at the cannabinoid compounds occurring naturally have memory and cognition. Additionally, receptors. Delta9-THC displays similar

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affinity for CB1 and CB2 receptors, but monkeys. Naltrexone, a mu-opioid which of the two bars the animal behaves as a weak agonist for CB2 antagonist, partially antagonizes these presses more often. receptors. The identification of rewarding effects of delta9-THC In addition to humans (Lile et al., synthetic cannabinoid ligands that (Justinova et al., 2004). 2009; Lile et al., 2011), it has been noted selectively bind to CB2 receptors but do Additionally, data demonstrate that that animals, including monkeys not have the typical delta9-THC-like under specific conditions, rodents self- (McMahon, 2009), mice (McMahon et psychoactive properties suggests that administer cannabinoids. Rats will self- al., 2008), and rats (Gold et al., 1992), the activation of CB1-receptors mediates administer delta9-THC when applied are able to discriminate cannabinoids cannabinoids’ psychotropic effects intracerebroventricularly (i.c.v.), but from other drugs or placebo. Moreover, (Hanus et al., 1999). CBD has low only at the lowest doses tested (0.01– the major active metabolite of delta9- 9 affinity for both CB1 and CB2 receptors 0.02 mg/infusion) (Braida et al., 2004). THC, 11-hydroxy-delta -THC, also (Mechoulam et al., 2007). According to SR141716 and the opioid antagonist generalizes (following oral Mechoulam et al. (2007), CBD has naloxone can antagonize this effect. administration) to the stimulus cues 9 antagonistic effects at CB1 receptors and However, most studies involve rodents elicited by delta -THC (Browne and some inverse agonistic properties at CB2 self-administrating the synthetic Weissman, 1981). Twenty-two other receptors. When cannabinoids are given cannabinoid WIN 55212, a CB1 receptor cannabinoids found in marijuana also 9 subacutely to rats, CB1 receptors down- agonist with a non-cannabinoid fully substitute for delta -THC. regulate and the binding of the second structure (Deiana et al., 2007; Fattore et However, CBD does not substitute for 9 messenger system coupled to CB1 al., 2007; Martellotta et al., 1998; delta -THC in rats (Vann et al., 2008). receptors, GTPgarnmaS, decreases Mendizabal et al., 2006). Discriminative stimulus effects of (Breivogel et al., 2001). Aversive effects, rather than delta9-THC are pharmacologically specific for marijuana containing Animal Behavioral Effects reinforcing effects, occur in rats that received high doses of WIN 55212 cannabinoids (Balster and Prescott, Self-Administration (Chaperon et al., 1998) or delta9-THC 1992; Browne and Weissman, 1981; Self-administration is a method that (Sanudo-Pena et al., 1997), indicating a Wiley et al., 1993, 1995). The assesses the ability of a drug to produce possible critical dose-dependent effect. discriminative stimulus effects of the rewarding effects. The presence of In both studies, SR141716 reversed cannabinoid group appear to provide rewarding effects increases the these aversive effects. unique effects because stimulants, hallucinogens, opioids, likelihood of behavioral responses to Conditioned Place Preference obtain additional drug. Animal self- benzodiazepines, barbiturates, NMDA administration of a drug is often useful Conditioned place preference (CPP) is antagonists, and antipsychotics do not 9 in predicting rewarding effects in a less rigorous method than self- fully substitute for delta -THC. humans, and is indicative of abuse administration for determining whether Central Nervous System Effects liability. A good correlation is often or not a drug has rewarding properties. observed between those drugs that In this behavioral test, animals spend Human Physiological and Psychological rhesus monkeys self-administer and time in two distinct environments: one Effects those drugs that humans abuse (Balster where they previously received a drug Psychoactive Effects and one where they received a placebo. and Bigelow, 2003). Initially, Below is a list of the common If the drug is reinforcing, animals will researchers could not establish self- subjective responses to cannabinoids choose to spend more time in the administration of cannabinoids, (Adams and Martin, 1996; Gonzalez, 9 environment paired with the drug, including delta -THC, in animal 2007; Hollister 1986, 1988; Institute of rather than with the placebo, when models. However, self-administration of Medicine, 1982). According to 9 presented with both options delta -THC can now be established in Maldonado (2002), these responses to a variety of animal models under s.imultaneously. 9 marijuana are pleasurable to many specific training paradigms (Justinova et Animals show CPP to delta -THC, but humans and are often associated with al., 2003, 2004, 2005). only at the lowest doses tested (0.075– drug-seeking and drug-taking. High Squirrel monkeys, with and without 1.0 mg/kg, intraperitoneal (i.p.)) (Braida levels of positive psychoactive effects prior exposure to other drugs of abuse, et al., 2004). SR141716 and naloxone 9 are associated with increased marijuana self-administer delta -THC under antagonize this effect (Braida et al., use, abuse, and dependence (Scherrer et specific conditions. For instance, Tanda 2004). As a partial agonist, SR141716 al., 2009; Zeiger et al., 2010). et al. (2000) observed that when squirrel can induce CPP at doses of 0.25, 0.5, 2 (1) Disinhibition, relaxation, monkeys are initially trained to self- and 3 mg/kg (Cheer et al., 2000). In increased sociability, and talkativeness. administer intravenous cocaine, they knockout mice, those without m-opioid (2) Increased merriment and appetite, 9 will continue to bar-press delta -THC at receptors do not develop CPP to delta9- and even exhilaration at high doses. the same rate as they would with THC (Ghozland et al., 2002). (3) Enhanced sensory perception, cocaine. The doses were notably Drug Discrimination Studies which can generate an increased comparable to those doses used by appreciation of music, art, and touch. humans who smoke marijuana. Drug discrimination is a method (4) Heightened imagination, which SR141716, a CB1 cannabinoid receptor where animals indicate whether a test can lead to a subjective sense of agonist-antagonist, can block this drug produces physical or psychic increased creativity. rewarding effect. Other studies show perceptions similar to those produced (5) Initial dizziness, nausea, that naı¨ve squirrel monkeys can be by a known drug of abuse. In this test, tachycardia, facial flushing, dry mouth, successfully trained to self-administer an animal learns to press one bar when and tremor. delta9-THC intravenously (Justinova et it receives the known drug of abuse and (6) Disorganized thinking, inability to al., 2003). The maximal responding rate another bar when it receives placebo. To converse logically, time distortions, and is 4 mg/kg per injection, which is 2–3 determine whether the test drug is like short-term memory impairment. times greater than observed in previous the known drug of abuse, a challenge (7) Ataxia and impaired judgment, studies using cocaine-experienced session with the test drug demonstrates which can impede driving ability or

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lead to an increase in risk-tasking potential. Major differences in and cannabinol (CBN) influence delta9- behavior. formulation, availability, and usage THC’s psychoactive effects. Dalton et al. (8) Illusions, delusions, and between marijuana and the drug (1976) observed that smoked hallucinations that intensify with higher product, Marinol, contribute to their administration of placebo marijuana doses. differing abuse potentials. cigarettes containing injections of 0.15 (9) Emotional lability, incongruity of Hollister and Gillespie (1973) mg/kg CBD combined with 0.025mg/kg affect, dysphoria, agitation, paranoia, estimated that delta9-THC by smoking is of delta9-THC, in a 7:1 ratio of CBD to confusion, drowsiness, and panic 2.6 to 3 times more potent than delta9- delta9-THC, significantly decreased attacks, which are more common in THC ingested orally. The intense ratings of acute subjective effects and inexperienced or high-dosed users. psychoactive drug effect achieved, ‘‘high’’ when compared to smoking As with many psychoactive drugs, a rapidly by smoking is generally delta9-THC alone. In contrast, Ilan et al. person’s medical, psychiatric, and drug- considered to produce the effect desired (2005) calculated the naturally taking history can influence the by the abuser. This effect explains why occurring concentrations of CBC and individual’s response to marijuana. abusers often prefer to administer CBD in a batch of marijuana cigarettes Dose preferences to marijuana occur in certain drugs by inhalation, with either 1.8 percent or 3.6 percent that marijuana users prefer higher intravenously, or intranasally rather delta9-THC concentration by weight. For concentrations of the principal than orally. Such is the case with each strength of delta9-THC in psychoactive substance (1.95 percent cocaine, opium, heroin, phencyclidine, marijuana cigarettes, the concentrations delta9-THC) over lower concentrations methamphetamine, and delta9-THC of CBC and CBD were classified in (0.63 percent delta9-THC) (Chait and from marijuana (0.1–9.5 percent delta9- groups of either low or high. The study Burke, 1994). Nonetheless, frequent THC range) or hashish (10–30 percent varied the amount of CBC and CBD marijuana users (>100 times of use) delta9-THC range) (Wesson and within each strength of delta9-THC were able to identify a drug effect from Washburn, 1990). Thus, the delayed marijuana cigarettes, with low-dose delta9-THC better than onset and longer duration of action for administrations consisting of either low occasional users (<10 times of use) Marinol may be contributing factors CBC (between 0.1–0.2 percent CBC while also experiencing fewer sedative limiting the abuse or appeal of Marinol concentration by weight) and low CBD effects from marijuana (Kirk and de Wit, as a drug of abuse relative to marijuana. (between 0.1–0.4 percent CBD 1999). The formulation of Marinol is a factor concentration by weight), high CBC The petitioners contend that many of that contributes to differential (>0.5 percent CBC concentration by marijuana’s naturally occurring scheduling of Marinol and marijuana. weight) and low CBD, or low CBC and cannabinoids mitigate the psychoactive For example, extraction and purification high CBD (>1.0 percent CBD effects of delta9-THC, and therefore that of dronabinol from the encapsulated concentration by weight). Overall, all marijuana lacks sufficient abuse sesame oil mixture of Marinol is highly combinations scored significantly potential to warrant Schedule I complex and difficult. Additionally, the greater than placebo on ratings of placement, because Marinol, which is in presence of sesame oil mixture in the subjective effects, and there was no Schedule III, contains only delta9-THC. formulation may preclude the smoking significant difference between any This theory has not been demonstrated of Marinol-laced cigarettes. combinations. in controlled studies. Moreover, the Additionally, there is a dramatic The oral administration of a concept of abuse potential encompasses difference between actual abuse and combination of either 15, 30, or 60 mg all properties of a substance, including illicit trafficking of Marinol and CBD with 30 mg delta9-THC dissolved its chemistry, pharmacology, and marijuana. Despite Marinol’s in liquid (in a ratio of at least 1:2 CBD pharmacokinetics, as well as usage availability in the United States, there to delta9-THC) reduced the subjective patterns and diversion history. The have been no significant reports of effects produced by delta9-THC alone abuse potential of a substance is abuse, diversion, or public health (Karniol et al., 1974). Additionally, associated with the repeated or sporadic problems due to Marinol. By orally administering a liquid mixture use of a substance in nonmedical comparison, 18.9 million American combining 1 mg/kg CBD with 0.5 mg/kg situations for the psychoactive effects adults report currently using marijuana of delta9-THC (ratio of 2:1 CBD to delta9- the substance produces. These (SAMHSA, 2013). THC) decreased scores of anxiety and psychoactive effects include euphoria, In addition, FDA’s approval of an marijuana drug effect on the Addiction perceptual and other cognitive NDA for Marinol allowed for Marinol to Research Center Inventory (ARCI) distortions, hallucinations, and mood be rescheduled to Schedule II, and compared to delta9-THC alone (Zuardi changes. However, as stated above, the subsequently to Schedule III of the CSA. et al.,1982). Lastly, oral administration abuse potential not only includes the In conclusion, marijuana and Marinol of either 12.5, 25, or 50 mg CBN psychoactive effects, but also includes differ on a wide variety of factors that combined with 25 mg delta9-THC other aspects related to a substance. contribute to each substance’s abuse dissolved in liquid (ratio of at least 1:2 DEA’s final published rule entitled potential. These differences are major CBN to delta9-THC) significantly ‘‘Rescheduling of the Food and Drug reasons distinguishing the higher abuse increased subjective ratings of Administration Approved Product potential for marijuana and the different ‘‘drugged,’’ ‘‘drowsy,’’ ‘‘dizzy,’’ and Containing Synthetic Dronabinol [(–)- scheduling determinations of marijuana ‘‘drunk,’’ compared to delta9-THC alone delta9-(trans)-Tetrahydrocannabinol] in and Marinol. (Karniol et al., 1975). Sesame Oil and Encapsulated in Soft In terms of the petitioners’ claim that Even though some studies suggest that Gelatin Capsules From Schedule II to different cannabinoids present in CBD may decrease some of delta9-THC’s Schedule III’’ (64 FR 35928, July 2, marijuana mitigate the psychoactive psychoactive effects, the ratios of CBD 1999) rescheduled Marinol from effects of delta9-THC, only three of the to delta9-THC administered in these Schedule II to Schedule III. The HHS cannabinoids present in marijuana were studies are not present in marijuana assessment of the abuse potential and simultaneously administered with used by most people. For example, in subsequent scheduling recommendation delta9-THC to examine how the one study, researchers used smoked compared Marinol to marijuana on combinations of these cannabinoids marijuana with ratios of CBD to delta9- different aspects related to abuse such as CBD, cannabichromene (CBC) THC naturally present in marijuana

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plant material and they found out that showed that the morning after exposure marijuana use may impact the duration varying the amount of CBD actually had to 1.8 percent or 3.6 percent smoked of residual impairment. no effect on delta9-THC’s psychoactive delta9-THC, subjects had minimal The effects of chronic marijuana use effects (Ilan et al., 2005). Because most residual alterations in subjective or do not seem to persist after more than marijuana currently available on the performance measures. 1 to 3 months of abstinence. After 3 9 street has high amounts of delta -THC A number of factors may influence months of abstinence, any deficits with low amounts of CBD and other marijuana’s behavioral effects including observed in IQ, immediate memory, cannabinoids, most individuals use the duration of use (chronic or short delayed memory, and information- processing speeds following heavy marijuana with low levels of CBD term), frequency of use (daily, weekly, marijuana use compared to pre-drug use present (Mehmedic et al., 2010). Thus, or occasionally), and amount of use 9 scores were no longer apparent (Fried et any possible mitigation of delta -THC’s (heavy or moderate). Researchers also al., 2005). Marijuana did not appear to psychoactive effects by CBD will not have examined how long behavioral have lasting effects on performance of a occur for most marijuana users. In impairments last following chronic comprehensive neuropsychological contrast, one study indicated that marijuana use. These studies used self- battery when 54 monozygotic male another cannabinoid present in reported histories of past duration, 9 twins (one of whom used marijuana, marijuana, CBN, may enhance delta - frequency, and amount of past THC’s psychoactive effects (Karniol et one of whom did not) were compared 1– marijuana use, and administered a al., 1975). 20 years after cessation of marijuana use variety of performance and cognitive (Lyons et al., 2004). Similarly, following Behavioral Impairment measures at different time points abstinence for a year or more, both light Marijuana induces various following marijuana abstinence. In and heavy adult marijuana users did not psychoactive effects that can lead to chronic marijuana users, behavioral show deficits on scores of verbal behavioral impairment. Marijuana’s impairments may persist for up to 28 memory compared to non-using controls acute effects can significantly interfere days of abstinence. Solowij et al. (2002) (Tait et al., 2011). According to a recent with a person’s ability to learn in the demonstrated that after 17 hours of meta-analysis looking at non-acute and classroom or to operate motor vehicles. abstinence, 51 adult heavy chronic long-lasting effects of marijuana use on Acute administration of smoked marijuana users performed worse on neurocognitive performance, any marijuana impairs performance on memory and attention tasks than 33 deficits seen within the first month learning, associative processes, and non-using controls or 51 heavy, short- following abstinence are generally not psychomotor behavioral tests (Block et term users. Another study noted that present after about 1 month of al., 1992). Ramaekers et al. (2006a) heavy, frequent marijuana users, abstinence (Schreiner and Dunn, 2012). showed that acute administration of 250 abstinent for at least 24 hours, Another aspect that may be a critical mg/kg and 500 mg/kg of delta9-THC in performed significantly worse than the factor in the intensity and persistence of smoked marijuana dose-dependently controls on verbal memory and impairment resulting from chronic impairs cognition and motor control, psychomotor speed tests (Messinis et marijuana use is the age of first use. including motor impulsivity and al., 2006). Additionally, after at least 1 Individuals with a diagnosis of tracking impairments (Ramaekers et al., week of abstinence, young adult marijuana misuse or dependence who 2006b). Similarly, administration of 290 frequent marijuana users, aged 18–28, were seeking treatment for substance mg/kg delta9-THC in a smoked marijuana showed deficits in psychomotor speed, use, who initiated marijuana use before cigarette resulted in impaired sustained attention, and cognitive the age of 15 years, showed deficits in perceptual motor speed and accuracy: inhibition (Lisdahl and Price, 2012). performance on tasks assessing Two skills which are critical to driving Adult heavy, chronic marijuana users sustained attention, impulse control, ability (Kurzthaler et al., 1999). Lastly, showed deficits on memory tests after 7 and general executive functioning administration of 3.95 percent delta9- days of supervised abstinence (Pope et compared to non-using controls. These THC in a smoked marijuana cigarette al., 2002). However, when these same deficits were not seen in individuals not only increased disequilibrium individuals were again tested after 28 who initiated marijuana use after the measures, but also increased the latency days of abstinence, they did not show age of 15 years (Fontes et al., 2011). in a task of simulated vehicle braking at significant memory deficits. The authors Similarly, heavy, chronic marijuana a rate comparable to an increase in concluded, ‘‘cannabis-associated users who began using marijuana before stopping distance of five feet at 60 mph cognitive deficits are reversible and the age of 16 years had greater (Liguori et al., 1998). However, acute related to recent cannabis exposure, decrements in executive functioning administration of marijuana containing rather than irreversible and related to tasks than heavy, chronic marijuana 2.1 percent delta9-THC does not cumulative lifetime use.’’ 7 However, users who started using after the age of produce ‘‘hangover effects’’ (Chait, other researchers reported 16 years and non-using controls (Gruber 1990). neuropsychological deficits in memory, et al., 2012). Additionally, in a In addition to measuring the acute executive functioning, psychomotor prospective longitudinal birth cohort effects immediately following marijuana speed and manual dexterity in heavy study of 1,037 individuals, marijuana administration, researchers have marijuana users abstinent for 28 days dependence or chronic marijuana use conducted studies to determine how (Bolla et al., 2002). Furthermore, a was associated with a decrease in IQ long behavioral impairments last after follow-up study of heavy marijuana and general neuropsychological abstinence. Some of marijuana’s acute users noted decision-making deficits performance compared to pre-marijuana effects may not fully resolve until at after 25 days of supervised abstinence. exposure levels in adolescent onset least one day after the acute (Bolla et al., 2005). However, moderate users (Meier et al., 2012). The decline in psychoactive effects have subsided. marijuana users did not show decision- adolescent-onset user’s IQ persisted Heishman et al. (1990) showed that making deficits after 25 days of even after reduction or abstinence of impairment on memory tasks persists abstinence, suggesting the amount of marijuana use for at least 1 year. In for 24 hours after smoking marijuana contrast, the adult-onset chronic cigarettes containing 2.57 percent 7 In this quotation the term Cannabis is used marijuana users showed no significant delta9-THC. However, Fant et al. (1998) interchangeably for marijuana. changes in IQ compared to pre-exposure

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levels whether they were current users Association of Marijuana Use With (<0.01 percent) received a diagnosis of or abstinent for at least 1 year (Meier et Psychosis schizophrenia within the 14-year period al., 2012). This analysis evaluates only the following military induction from 1969 In addition to the age of onset of use, evidence for a direct link between prior to 1983 (Andreasson et al., 1987). Of the conscripts diagnosed with psychosis, some evidence suggests that the amount marijuana use and the subsequent 7.7 percent (21 of the 274 conscripts of marijuana used may relate to the development of psychosis. Thus, this with psychosis) had used marijuana intensity of impairments. In the above discussion does not consider issues such as whether marijuana’s transient more than 50 times at induction, while study by Gruber et al. (2012), where 72 percent (197 of the 274 conscripts early-onset users had greater deficits effects are similar to psychotic symptoms in healthy individuals or with psychosis) had never used than late-onset users, the early-onset marijuana. Although high marijuana use exacerbate psychotic symptoms in users reported using marijuana twice as increased the relative risk for individuals already diagnosed with often and using three times as much schizophrenia to 6.0, the authors note marijuana per week than the late-onset schizophrenia. Extensive research has been that substantial marijuana use history users. Meier et al. (2012) showed that conducted to investigate whether ‘‘accounts for only a minority of all the deficits in IQ seen in adolescent- cases’’ of psychosis (Andreasson et al., exposure to marijuana is associated with 1987). Instead, the best predictor for onset users increased with the amount the development of schizophrenia or whether a conscript would develop of marijuana used. Moreover, when other psychoses. Although many studies psychosis was a non-psychotic comparing scores for measures of IQ, are small and inferential, other studies psychiatric diagnosis upon induction. immediate memory, delayed memory, in the literature use hundreds to The authors concluded that marijuana and information-processing speeds to thousands of subjects. At present, the use increased the risk for psychosis only pre-drug-use levels, the current, heavy, available data do not suggest a causative among individuals predisposed to chronic marijuana users showed deficits link between marijuana use and the develop the disorder. In addition, a 35- in all three measures while current, development of psychosis (Minozzi et occasional marijuana users did not year follow up to this study reported al., 2010). Numerous large, longitudinal very similar results (Manrique-Garcia et (Fried et al., 2005). studies show that subjects who used al., 2012). In this follow up study, 354 marijuana do not have a greater Behavioral Effects of Prenatal Exposure conscripts developed schizophrenia; of incidence of psychotic diagnoses these 354 conscripts, 32 used marijuana Studies with children at different compared to those who do not use more than 50 times at induction (9 stages of development are used to marijuana (Fergusson et al., 2005; percent, an odds ratio of 6.3), while 255 examine the impact of prenatal Kuepper et al., 2011; Van Os et al., had never used marijuana (72 percent). marijuana exposure on performance in a 2002). Additionally, the conclusion that the series of cognitive tasks. However, many When analyzing the available impact of marijuana may manifest only evidence of the connection between pregnant women who reported in individuals likely to develop psychosis and marijuana, it is critical to marijuana use were more likely to also psychotic disorders has been shown in determine whether the subjects in the many other types of studies. For report use of alcohol, tobacco, and studies are patients who are already cocaine (Goldschmidt et al., 2008). example, although evidence shows that diagnosed with psychosis or individuals marijuana use may precede the Thus, with potential exposure to who demonstrate a limited number of multiple drugs, it is difficult to presentation of symptoms in individuals symptoms associated with psychosis later diagnosed with psychosis determine the specific impact of without qualifying for a diagnosis of the (Schimmelmann et al., 2011), most prenatal marijuana exposure. disorder. For example, instead of using reports conclude that prodromal Most studies assessing the behavioral a diagnosis of psychosis, some symptoms of schizophrenia appear prior effects of prenatal marijuana exposure researchers relied on non-standard to marijuana use (Schiffman et al., included women who, in addition to methods of representing symptoms of 2005). Similarly, a review of the gene- using marijuana, also reported using psychosis including ‘‘schizophrenic environment interaction model for alcohol and tobacco. However, some cluster’’ (Maremmani et al., 2004), marijuana and psychosis concluded that evidence suggests an association ‘‘subclinical psychotic symptoms’’ (Van some evidence supports marijuana use between heavy prenatal marijuana Gastel et al., 2012), ‘‘pre-psychotic as a factor that may influence the exposure and deficits in some cognitive clinical high risk’’ (Van der Meer et al., development of psychosis, but only in domains. In both 4-year-old and 6-year- 2012), and symptoms related to those individuals with psychotic ‘‘psychosis vulnerability’’ (Griffith- old children, heavy prenatal marijuana liability (Pelayo-Teran et al., 2012). Lendering et al., 2012). These groupings use is negatively associated with A similar conclusion was drawn do not conform to the criteria in the when the prevalence of schizophrenia performance on tasks assessing memory, Diagnostic and Statistical Manual was modeled against marijuana use verbal reasoning, and quantitative (DSM–5) or the International across eight birth cohorts in Australia in reasoning (Fried and Watkinson, 1987; Classification of Diseases (ICD–10) for a individuals born between the years 1940 Goldschmidt et al., 2008). Additionally, diagnosis of psychosis. Thus, these to 1979 (Degenhardt et al., 2003). heavy prenatal marijuana use is groupings are not appropriate for use in Although marijuana use increased over associated with deficits in measures of evaluating marijuana’s impact on the time in adults born during the four- sustained attention in children at the development of actual psychosis. decade period, there was not a ages of 6 years and 13–16 years (Fried Accordingly, this analysis includes only corresponding increase in diagnoses for et al., 1992; Fried, 2002). In 9- to 12- those studies that use subjects psychosis in these individuals. The year-old children, prenatal marijuana diagnosed with a psychotic disorder. authors conclude that marijuana may exposure is negatively associated with In the largest study evaluating the link precipitate schizophrenic disorders only executive functioning tasks that require between psychosis and drug use, 274 of in those individuals who are vulnerable impulse control, visual analysis, and the approximately 45,500 Swedish to developing psychosis. Thus, hypothesis (Fried et al., 1998). conscripts in the study population marijuana per se does not appear to

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induce schizophrenia in the majority of current marijuana use but not tobacco women showed that chronic marijuana individuals who have tried or continue use at the time of assessment. Pletcher use did not significantly alter to use marijuana. However, in et al. (2012) found that the occasional concentrations of testosterone, individuals with a genetic vulnerability use of marijuana is not associated with luteinizing hormone, follicle stimulating for psychosis, marijuana use may decreased pulmonary function. hormone, prolactin, or cortisol (Block et influence the development of psychosis. However, some preliminary evidence al., 1991). Additionally, chronic suggests that heavy marijuana use may marijuana use did not affect serum Cardiovascular and Autonomic Effects be associated with negative pulmonary levels of thyrotropin, thyroxine, and Single smoked or oral doses of delta9- effects (Pletcher et al., 2012). Long-term triiodothyronine (Bonnet, 2013). THC produce tachycardia and may use of marijuana can lead to chronic However, in a double-blind, placebo- increase blood pressure (Capriotti et al., cough and increased sputum, as well as controlled, randomized clinical trial of 1988; Benowitz and Jones, 1975). Some an increased frequency of chronic HIV-positive men, smoking marijuana evidence associates the tachycardia bronchitis and pharyngitis. In addition, dose-dependently increased plasma produced by delta9-THC with excitation pulmonary function tests reveal that levels of ghrelin and leptin, and of the sympathetic and depression of the large-airway obstruction can occur with decreased plasma levels of peptide YY parasympathetic nervous systems chronic marijuana smoking, as can (Riggs et al., 2012). (Malinowska et al., 2012). During cellular inflammatory histopathological The effects of marijuana on female chronic marijuana ingestion, a tolerance abnormalities in bronchial epithelium reproductive system functionality differ to tachycardia develops (Malinowska et (Adams and Martin 1996; Hollister between humans and animals. In al., 2012). 1986). monkeys, delta9-THC administration However, prolonged delta9-THC Evidence regarding marijuana suppressed ovulation (Asch et al., 1981) ingestion produces bradycardia and smoking leading to cancer is and reduced progesterone levels hypotension (Benowitz and Jones, inconsistent, as some studies suggest a (Almirez et al., 1983). However, in 1975). Plant-derived cannabinoids and positive correlation while others do not women, smoked marijuana did not alter endocannabinoids elicit hypotension (Lee and Hancox, 2011; Tashkin, 2005). hormone levels or the menstrual cycle and bradycardia via activation of Several lung cancer cases have been (Mendelson and Mello, 1984). Brown peripherally-located CB1 receptors reported in young marijuana users with and Dobs (2002) suggest that the (Wagner et al., 1998). Specifically, the no tobacco smoking history or other development of tolerance in humans mechanism of this effect is through significant risk factors (Fung et al., may be the cause of the discrepancies presynaptic CB1 receptor-mediated 1999). Marijuana use may dose- between animal and human hormonal inhibition of norepinephrine release dependently interact with mutagenic response to cannabinoids. from peripheral sympathetic nerve sensitivity, cigarette smoking, and The presence of in vitro delta9-THC terminals, with possible additional alcohol use to increase the risk of head reduces binding of the corticosteroid, direct vasodilation via activation of and neck cancer (Zhang et al., 1999). dexamethasone, in hippocampal tissue vascular cannabinoid receptors (Pacher However, in a large study with 1,650 from adrenalectomized rats, suggesting et al., 2006). In humans, tolerance can subjects, a positive association was not an interaction with the glucocorticoid develop to orthostatic hypotension found between marijuana and lung receptor (Eldridge et al., 1991). (Jones, 2002; Sidney, 2002) possibly cancer (Tashkin et al., 2006). This Although acute delta9-THC presence related to plasma volume expansion, but finding remained true, regardless of the releases corticosterone, tolerance tolerance does not develop to the supine extent of marijuana use, when develops in rats with chronic hypotensive effects (Benowitz and controlling for tobacco use and other administration (Eldridge et al., 1991). Jones, 1975). Additionally, potential confounding variables. Some studies support a possible electrocardiographic changes are Overall, new evidence suggests that the association between frequent, long-term minimal, even after large cumulative effects of marijuana smoking on marijuana use and increased risk of doses of delta9-THC are administered. respiratory function and carcinogenicity testicular germ cell tumors (Trabert et (Benowitz and Jones, 1975). differ from those of tobacco smoking al., 2011). On the other hand, recent Marijuana smoking by individuals, (Lee and Hancox, 2011). data suggest that cannabinoid agonists particularly those with some degree of may have therapeutic value in the Endocrine System coronary artery or cerebrovascular treatment of prostate cancer, a type of disease, poses risks such as increased Experimental marijuana carcinoma in which growth is cardiac work, catecholamines and administration to humans does not stimulated by androgens. Research with carboxyhemoglobin, myocardial consistently alter many endocrine prostate cancer cells shows that the infarction, and postural hypotension parameters. In an early study, male mixed CB1/CB2 agonist, WIN–55212–2, (Benowitz and Jones, 1981; Hollister, subjects who experimentally received induces apoptosis in prostate cancer 1988; Mittleman et al., 2001; smoked marijuana showed a significant cells, as well as decreases the Malinowska et al., 2012). depression in luteinizing hormone and expression of androgen receptors and a significant increase in cortisol (Cone et Respiratory Effects prostate-specific antigens (Sarfaraz et al., 1986). However, two later studies al., 2005). After acute exposure to marijuana, showed no changes in hormones. Male transient bronchodilation is the most subjects experimentally exposed to Immune System typical respiratory effect (Gong et al., smoked delta9-THC (18 mg/marijuana Cannabinoids affect the immune 1984). A recent 20-year longitudinal cigarette) or oral delta9-THC (10 mg system in many different ways. study with over 5,000 individuals three times per day for 3 days and on Synthetic, natural, and endogenous collected information on the amount of the morning of the fourth day) showed cannabinoids often cause different marijuana use and pulmonary function no changes in plasma effects in a dose-dependent biphasic data at years 0, 2, 5, 10, and 20 (Pletcher adrenocorticotropic hormone (ACTH), manner (Croxford and Yamamura, 2005; et al., 2012). Among the more than 5,000 cortisol, prolactin, luteinizing hormone, Tanasescu and Constantinescu, 2010). individuals who participated in the or testosterone levels (Dax et al., 1989). Studies in humans and animals give study, almost 800 of them reported Similarly, a study with 93 men and 56 conflicting results about cannabinoid

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effects on immune functioning in including cannabinoids. Overall, with weak psychoactivity. Chemically, subjects with compromised immune various Cannabis strains contain more CBN is 6,6,9-trimethyl-3-pentyl- systems. Abrams et al. (2003) than 525 identified natural constituents. benzo[c]chromen-1-ol. investigated marijuana’s effect on Among those constituents, the most Different marijuana samples derived immunological functioning in 62 AIDS important ones are the 21 (or 22) carbon from various cultivated strains may patients taking protease inhibitors. terpenoids found in the plant, as well as differ in chemical constituents Subjects received one of the following their carboxylic acids, analogues, and including delta9-THC and other three times a day: A smoked marijuana transformation products, known as cannabinoids (Appendino et al. 2011). cigarette containing 3.95 percent delta9- cannabinoids (Agurell et al., 1984, 1986; As a consequence, marijuana products THC, an oral tablet containing delta9- Mechoulam, 1973; Appendino et al., from different strains may have different THC (2.5 mg oral dronabinol), or an oral 2011). Thus far, more than 100 safety, biological, pharmacological, and placebo. The results showed no changes compounds classified as cannabinoids toxicological profiles. In addition to in CD4+ and CD8+ cell counts, HIV have been characterized (ElSohly and differences between cultivated strains, RNA levels, or protease inhibitor levels Slade, 2005; Radwan, ElSohly et al., the concentration of delta9-THC and between groups. Thus, the use of 2009; Appendino et al. 2011). other cannabinoids in marijuana may cannabinoids showed no short-term Cannabinoids primarily exist in vary with growing conditions and adverse virologic effects in individuals Cannabis, and published data suggest processing after harvest. In addition to with compromised immune systems. that most major cannabinoid genetic differences among Cannabis However, these human data contrast compounds occurring naturally have species, the plant parts collected—for with data generated in immunodeficient been chemically identified. New and example, flowers, leaves, and stems— mice, which demonstrated that minor cannabinoids and other new can influence marijuana’s potency, exposure to delta9-THC in vivo compounds are continuously being quality, and purity (Adams and Martin, suppresses immune function, increases characterized (Pollastro et al., 2011). So 1996; Agurell et al., 1984; Mechoulam, HIV co-receptor expression, and acts as far, only two cannabinoids 1973). All these variations produce a cofactor to enhance HIV replication (cannabigerol and its corresponding marijuana with potencies, as indicated (Roth et al., 2005). acid) have been obtained from a non- by cannabinoid content, on average Cannabis source. A South African from as low as 1–2 percent to as high 3. The State of Current Scientific Helichrysum (H umbraculigerum) as 17 percent. Knowledge Regarding the Drug or accumulates these compounds Overall, these variations in the Other Substance (Appendino et al. 2011). concentrations of cannabinoids and Under the third factor, the Secretary Among the cannabinoids found in other chemical constituents in must consider the state of current marijuana, delta9-THC (alternate name marijuana complicate the interpretation scientific knowledge regarding delta1-THC) and delta-8- of clinical data using marijuana. The marijuana. Thus, this section discusses tetrahydrocannibinol (delta8-THC, lack of consistent concentrations of the chemistry, human alternate name delta6-THC) produce delta9 -THC and other substances in pharmacokinetics, and medical uses of marijuana’s characteristic psychoactive marijuana from diverse sources makes marijuana. effects. Because delta9-THC is more interpreting the effect of different abundant than delta8-THC, marijuana’s marijuana constituents difficult. In Chemistry psychoactivity is largely attributed to addition to different cannabinoid Marijuana is one of the common the former. Only a few varieties of concentrations having different names of Cannabis sativa L. in the marijuana analyzed contain delta8-THC pharmacological and toxicological family Cannabaceae. at significant amounts (Hively et al., profiles, the non-cannabinoid Cannabis is one of the oldest 1966). Delta9-THC is an optically active components in marijuana, such as other cultivated crops, providing a source of resinous substance, insoluble in water, terpenoids and flavonoids, might also fiber, food, oil, and drug. Botanists still and extremely lipid soluble. contribute to the overall debate whether Cannabis should be Chemically, delta9-THC is (6aR-trans)- pharmacological and toxicological considered as a single (The Plant List, 6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3- profiles of various marijuana strains and 2010) or three species, i.e., C. sativa, C. pentyl-6H-dibenzo-[b,d]pyran-l-ol, or products derived from those strains. indica, and C. ruderalis (Hillig, 2005). (–)-delta9-(trans)-tetrahydrocannabinol. The term marijuana is often used to Specifically, marijuana is developed as The (–)-trans isomer of delta9-THC is refer to a mixture of the dried flowering sativa and indica cultivated varieties pharmacologically 6–100 times more tops and leaves from Cannabis. (strains) or various hybrids. potent than the (+)-trans isomer (Dewey Marijuana in this limiting definition is The petition defines marijuana as et al., 1984). one of three major derivatives sold as including all Cannabis cultivated Other cannabinoids present in separate illicit products, which also strains. Different marijuana samples marijuana include CBD, CBC, and CBN. include hashish and hash oil. According derived from various cultivated strains CBD, a major cannabinoid of marijuana, to the DEA, Cannabis saliva is the may have very different chemical is insoluble in water and lipid-soluble. primary species of Cannabis currently constituents including delta9 -THC and Chemically, CBD is 2-[(1R,6R)-3-methyl- marketed illegally in the United States. other cannabinoids (Appendino et al., 6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5- Marijuana can vary in cannabinoid 2011). As a consequence, marijuana pentylbenzene-1,3-diol. CBD does not content and potency (Agurell et al., products from different strains will have have cannabinol-like psychoactivity 1984, 1986; Mechoulam 1973, Cascini et different safety, biological, (Adams and Martin, 1996; Agurell et al., al., 2012). In the usual mixture of leaves pharmacological, and toxicological 1984, 1986; Hollister, 1986). CBC is and stems distributed as marijuana, the profiles. Thus, all Cannabis strains another major cannabinoid in concentration of delta9-THC averages cannot be considered together because marijuana. Chemically, CBC is 2- over 12 percent by weight. However, of the varying chemical constituents methyl-2-(4-methylpent-3-enyl)-7- specially grown and selected marijuana between strains. pentyl-5-chromenol. CBN, a major can contain 15 percent or greater delta9- Marijuana contains numerous metabolite of delta9-THC, is also a THC (Appendino et al., 2011). Thus, a naturally occurring constituents minor naturally-occurring cannabinoid 1-gram marijuana cigarette might

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contain delta9-THC in a range from as and meet the requirements for new drug significant loss of delta9-THC in side- little as 3 milligrams to as much as 150 approval (See 21 CFR 314.50). stream smoke, variation in individual milligrams or more. Additionally, a smoking behaviors, cannabinoid Human Pharmacokinetics recent systematic review and meta- pyrolysis, incomplete absorption of analysis found that marijuana’s delta9- Marijuana can be taken in a variety of inhaled smoke, and metabolism in the THC content has increased significantly formulations by multiple routes of lungs. An individual’s experience and from 1979–2009 (Cascini et al., 2012). In administration. Individuals smoke technique with smoking marijuana also addition to smoking marijuana, marijuana as a cigarette, weighing determines the dose absorbed (Heming individuals ingest marijuana through between 0.5 and 1.0 gram, or in a pipe. et al., 1986; Johansson et al., 1989). food made with butter or oil infused Additionally, individuals take After smoking, delta9-THC venous with marijuana and its extracts. These marijuana orally in foods or as an levels decline precipitously within marijuana butters are generally made by extract in ethanol or other solvents. minutes, and continue to go down to adding marijuana to butter and heating More recently, access to vaporizers about 5 to 10 percent of the peak level it. The resultant butter is then used to provides another means for abusers to within an hour (Agurell et al., 1986, cook a variety of foods. There are no inhale marijuana, Huestis et al.,1992a, 1992b). published studies measuring the The absorption, metabolism, and pharmacokinetic profile of delta9-THC, Pharmacokinetics for Oral concentrations of cannabinoids in these Administration of Cannabinoids marijuana food products. cannabinoids, and drug products containing delta9-THC vary with route After oral administration of delta9- Hashish consists of the dried and of administratfon and formulation THC or marijuana, the onset of effects compressed cannabinoid-rich resinous (Adams and Martin, 1996; Agurell et al., starts within 30 to 90 minutes, reaches material of Cannabis and comes in a 1984, 1986). its peak after 2 to 3 hours and then variety of forms (e.g. balls and cakes). remains for 4 to 12 hours Individuals may break off pieces, place Pharmacokinetics of Smoked Administration of Cannabinoids (Grotenhermen, 2003; Adams and it into a pipe and smoke it. DEA reports Martin, 1996; Agurell et al., 1984, 1986). that cannabinoid content in hashish Characterization of the Due to the delay in onset of effects, averages six percent (DEA, 2005). With pharmacokinetics of delta9-THC and users have difficulty in titrating oral the development and cultivation of other cannabinoids from smoked delta9-THC doses compared to smoking more high potency Cannabis strains, the marijuana is difficult because a subject’s marijuana. Oral bioavailability of delta9- average cannabinoid content in hashish smoking behavior during an experiment THC, whether pure or in marijuana, is will likely increase. varies (Agurell et al., 1986; Heming et low and extremely variable, ranging Hash oil is produced by solvent al., 1986; Huestis et al., 1992a). Each between 5 and 20 percent (Agurell et al., extraction of the cannabinoids from puff delivers a discrete dose of delta9- 1984, 1986). Following oral plant material. The extract’s color and THC. An experienced marijuana smoker administration of radioactive-labeled odor vary, depending on the solvent can titrate and regulate the dose to delta9-THC, delta9-THC plasma levels type used. Hash oil is a viscous brown- obtain the desired acute psychological are low relative to plasma levels after or amber-colored liquid containing effects and minimize undesired effects. smoking or intravenous administration. approximately 50 percent cannabinoids. For example, under naturalistic Inter- and intra-subject variability One or two drops of the liquid placed conditions, users hold marijuana smoke occurs even with repeated dosing under on a cigarette purportedly produce the in their lungs for an extended period of controlled conditions. The low and equivalent of a single marijuana time which causes prolonged absorption variable oral bioavailability of delta9- cigarette (DEA, 2005). and increases psychoactive effects. The THC is a consequence of its first-pass In conclusion, marijuana has effect of experience in the psychological hepatic elimination from blood and hundreds of cultivars containing response may explain why delta9-THC erratic absorption from stomach and variable concentrations of delta9-THC, venous blood levels correlate poorly bowel. cannabinoids, and other compounds. with intensity of effects and intoxication Cannabinoid Metabolism and Excretion Thus, marijuana is not a single chemical level (Agurell et al. 1986; Barnett et al. with a consistent and reproducible 1985; Huestis et al., 1992a). Puff and Cannabinoid metabolism is complex. chemical profile or predictable and inhalation volumes should be recorded Delta9-THC is metabolized via consistent clinical effects. A guidance in studies as the concentration (dose) of microsomal hydroxylation to both active for industry, entitled Botanical Drug cannabinoids administered can vary at and inactive metabolites (Lemberger et Products,8 provides information on the different stages of smoking. al., 1970, 1972a, 1972b; Agurell et al., approval of botanical drug products. To Smoked marijuana results in 1986; Hollister, 1988). The primary investigate marijuana for medical use in absorption of delta9-THC in the form of active metabolite of delta9-THC a manner acceptable as support for an aerosol within seconds. Psychoactive following oral ingestion is 11-hydroxy- marketing approval under an NDA, effects occur immediately following delta9-THC. This metabolite is clinical studies under an IND of absorption, with mental and behavioral approximately equipotent to delta9-THC consistent batches of a particular effects measurable for up to 6 hours in producing marijuana-like subjective marijuana product for particular disease (Grotenhermen, 2003; Hollister 1986, effects (Agurell et al., 1986, Lemberger indications should be conducted. In 1988). Delta9-THC is delivered to the and Rubin, 1975). After oral addition, information and data brain rapidly and efficiently as expected administration, metabolite levels may regarding the marijuana product’s of a very lipid soluble drug. exceed that of delta9-THC and thus 9 chemistry, manufacturing and control, The bioavailability of the delta -THC, contribute greatly to the pharmacology, and animal toxicology from marijuana in a cigarette or pipe, pharmacological effects of oral delta9- data, among others must be provided can range from 1 to 24 percent with the THC or marijuana. fraction absorbed rarely exceeding 10 to Plasma clearance of delta9-THC 8 This guidance is available on the Internet at 20 percent (Agurell et al.,1986; approximates hepatic blood flow at http://www.fda.gov/Drugs/default.htm under Hollister, 1988). The relatively low and about 950 ml/min or greater. The rapid Guidance (Drugs). variable bioavailability results from disappearance of delta9-THC from blood

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is largely due to redistribution to other potential use for treating multiple evaluate the safety and effectiveness of tissues in the body, rather than to sclerosis, neuropathic pain, appetite drugs, on the basis of which it could be metabolism (Agurell et al., 1984, 1986). suppression and cachexia. However, fairly and responsibly concluded by Metabolism in most tissues is relatively aside from the data produced by CMCR, such experts that the substance will slow or absent. Slow release of delta9- no state-level medical marijuana laws have the intended effect in treating a THC and other cannabinoids from have produced scientific data on specific, recognized disorder.’’ tissues and subsequent metabolism marijuana’s safety and effectiveness. iv. the drug must be accepted by results in a long elimination half-life. FDA approves medical use of a drug qualified experts. The terminal half-life of delta9-THC following a submission and review of an ‘‘The drug has a New Drug ranges from approximately 20 hours to NDA or BLA. The FDA has not Application (NDA) approved by the as long as 10 to 13 days, though approved any drug product containing Food and Drug Administration, reported estimates vary as expected marijuana for marketing. Even so, pursuant to the Food, Drug and with any slowly cleared substance and results of small clinical exploratory Cosmetic Act, 21 U.S.C. 355. Or, a the use of assays with variable studies have been published in the consensus of the national community of sensitivities (Hunt and Jones, 1980). current medical literature. Many studies experts, qualified by scientific training Lemberger et al. (1970) determined the describe human research with and experience to evaluate the safety half-life of delta9-THC to range from 23 marijuana in the United States under and effectiveness of drugs, accepts the to 28 hours in heavy marijuana users to FDA-regulated IND applications. safety and effectiveness of the substance 60 to 70 hours in naive users. In However, FDA approval of an NDA is for use in treating a specific, recognized addition to 11-hydroxy-delta9-THC, not the only means through which a disorder. A material conflict of opinion some inactive carboxy metabolites have drug can have a currently accepted among experts precludes a finding of terminal half-lives of 50 hours to 6 days medical use in treatment in the United consensus.’’ and or more. The latter substances serve as States. In general, a drug may have a v. the scientific evidence must be long-term markers in urine tests for ‘‘currently accepted medical use’’ in widely available. earlier marijuana use. treatment in the United States if the ‘‘In the absence of NDA approval, The majority of the absorbed delta9- drug meets a five-part test. Established information concerning the chemistry, THC dose is eliminated in feces, and case law (Alliance for Cannabis pharmacology, toxicology, and about 33 percent in urine. Delta9-THC Therapeutics v. DEA, 15 F.3d 1131, effectiveness of the substance must be enters enterohepatic circulation and 1135 (D.C. Cir. 1994)) upheld the reported, published, or otherwise undergoes hydroxylation and oxidation Administrator of DEA’s application of widely available, in sufficient detail to to 11-nor-9-carboxy-delta9-THC. The the five-part test to determine whether permit experts, qualified by scientific glucuronide is excreted as the major a drug has a ‘‘currently accepted training and experience to evaluate the urine metabolite along with about 18 medical use.’’ The following describes safety and effectiveness of drugs, to non-conjugated metabolites. Frequent the five elements that characterize fairly and responsibly conclude the and infrequent marijuana users ‘‘currently accepted medical use’’ for a substance is safe and effective for use in metabolize delta9-THC similarly 10 drug: treating a specific, recognized disorder.’’ (Agurell et al., 1986). i. the drug’s chemistry must be known Marijuana does not meet any of the and reproducible. Status of Research Into the Medical ‘‘The substance’s chemistry must be five elements necessary for a drug to Uses for Marijuana scientifically established to permit it to have a ‘‘currently accepted medical State-level public initiatives, be reproduced into dosages which can use.’’ including laws and referenda in support be standardized. The listing of the Firstly, the chemistry of marijuana, as of the medical use of marijuana, have substance in a current edition of one of defined in the petition, is not generated interest in the medical the official compendia, as defined by reproducible in terms of creating a community and the need for high section 201 G) of the Food, Drug and standardized dose. The petition defines quality clinical investigation as well as Cosmetic Act, 21 U.S.C. 321G), is marijuana as including all Cannabis comprehensive safety and effectiveness sufficient to meet this requirement.’’ cultivated strains. Different marijuana data. In order to address the need for ii. there must be adequate safety samples derived from various cultivated high quality clinical investigations, the studies. strains may have very different chemical state of California established the Center ‘‘There must be adequate constituents including delta9-THC and for Medicinal Cannabis Research pharmacological and toxicological other cannabinoids (Appendino et al., (CMCR, www.cmcr.ucsd.edu) in 2000 studies, done by all methods reasonably 2011). As a consequence, marijuana ‘‘in response to scientific evidence for applicable, on the basis of which it products from different strains will have therapeutic possibilities of cannabis 9 could fairly and responsibly be different safety, biological, and local legislative initiatives in favor concluded, by experts qualified by pharmacological, and toxicological of compassionate use’’ (Grant, 2005). scientific training and experience to profiles. Thus, when considering all State legislation establishing the CMCR evaluate the safety and effectiveness of Cannabis strains together, because of called for high quality medical research drugs, that the substance is safe for the varying chemical constituents, that would ‘‘enhance understanding of treating a specific, recognized disorder.’’ reproducing consistent standardized the efficacy and adverse effects of iii. there must be adequate and well- doses is not possible. Additionally, marijuana as a pharmacological agent,’’ controlled studies proving efficacy. smoking marijuana currently has not but stressed the project ‘‘should not be ‘‘There must be adequate, well- been shown to allow delivery of construed as encouraging or sanctioning controlled, well-designed, well- consistent and reproducible doses. the social or recreational use of conducted, and well-documented However, if a specific Cannabis strain is marijuana.’’ The CMCR funded many of studies, including clinical grown and processed under strictly the published studies on marijuana’s investigations, by experts qualified by controlled conditions, the plant scientific training and experience to chemistry may be kept consistent 9 In this quotation the term cannabis is enough to produce reproducible and interchangeable with marijuana. 10 57 FR 10499, 10504–06 (March 26, 1992). standardized doses.

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As to the second and third criteria; these abstracts, a full-text review was judged against the intended use of the there are neither adequate safety studies conducted with 85 papers to assess drug, its known effectiveness, its known nor adequate and well-controlled eligibility. Of the studies identified and potential risks, the severity of the studies proving marijuana’s efficacy. To through the search of the references and illness to be treated, and the availability support the petitioners’ assertion that the 566 abstracts from the PubMed of alternative remedies’’ (57 FR 10504). marijuana has accepted medical use, the search, only 11 studies met all the When determining whether a drug petitioners cite the American Medical criteria for selection (Abrams et al., product is safe and effective for any Association’s (AMA) 2009 report 2007; Corey-Bloom et al., 2012; indication, FDA performs an extensive entitled ‘‘Use of Cannabis for Medicinal Crawford and Merritt, 1979; Ellis et al., risk-benefit analysis to determine Purposes.’’ The petitioners claim the 2009; Haney et al., 2005; Haney et al., whether the risks posed by the drug AMA report is evidence the AMA 2007; Merritt et al., 1980; Tashkin et al., product’s side effects are outweighed by accepts marijuana’s safety and efficacy. 1974; Ware et al., 2010; Wilsey et al., the drug product’s potential benefits for However, the 2009 AMA report clarifies 2008; Wilsey et al., 2013). These 11 a particular indication. Thus, contrary that the report ‘‘should not be viewed as studies were published between 1974 to the petitioner’s assertion that an endorsement of state-based medical and 2013. Ten of these studies were marijuana has accepted safety, in the cannabis programs, the legalization of conducted in the United States and one absence of an accepted therapeutic marijuana, or that scientific evidence on study was conducted in Canada. The indication which can be weighed the therapeutic use of cannabis meets identified studies examine the effects of against marijuana’s risks, marijuana the same and current standards for a smoked and vaporized marijuana for the does not satisfy the element for having prescription drug product.’’ 11 indications of chronic neuropathic pain, adequate safety studies such that Currently, no published studies spasticity related to Multiple Sclerosis experts may conclude that it is safe for conducted with marijuana meet the (MS), appetite stimulation in human treating a specific, recognized disorder. criteria of an adequate and well- immunodeficiency virus (HIV) patients, The fourth of the five elements for controlled efficacy study. The criteria glaucoma, and asthma. All studies used determining ‘‘currently accepted for an adequate and well-controlled adult subjects. medical use’’ requires that the national study for purposes of determining the The 11 identified studies were community of experts, qualified by safety and efficacy of a human drug are individually evaluated to determine if scientific training and experience to defined under the Code of Federal they successfully meet accepted evaluate the safety and effectiveness of Regulations (CFR) in 21 CFR 314.126. In scientific standards. Specifically, they drugs, accepts the safety and order to assess this element, FDA were evaluated on study design effectiveness of the substance for use in conducted a review of clinical studies including subject selection criteria, treating a specific, recognized disorder. published and available in the public sample size, blinding techniques, dosing A material conflict of opinion among domain before February, 2013. Studies paradigms, outcome measures, and the experts precludes a finding of were identified through a search of statistical analysis of the results. The consensus. Medical practitioners who PubMed 12 for articles published from analysis relied on published studies, are not experts in evaluating drugs are inception to February 2013, for thus information available about not qualified to determine whether a randomized controlled trials using protocols, procedures, and results were drug is generally recognized as safe and marijuana to assess marijuana’s efficacy limited to documents published and effective or meets NDA requirements (57 in any therapeutic indication. widely available in the public domain. FR 10499–10505). Additionally, the review included The review found that all 11 studies that There is no evidence that there is a studies identified through a search of examined effects of inhaled marijuana consensus among qualified experts that bibliographic references in relevant do not currently prove efficacy of marijuana is safe and effective for use in systematic reviews and identified marijuana in any therapeutic indication treating a specific, recognized disorder. studies presenting original research in based on a number of limitations in As discussed above, there are not any language. Selected studies needed their study design; however, they may adequate scientific studies that show to be placebo-controlled and double- be considered proof of concept studies. marijuana is safe and effective in blinded. Additionally, studies needed to Proof of concept studies provide treating a specific, recognized disorder. encompass administered marijuana preliminary evidence on a proposed In addition, there is no evidence that a consensus of qualified experts have plant material. There was no hypothesis involving a drug’s effect. For accepted the safety and effectiveness of requirement for any specific route of drugs under development, the effect marijuana for use in treating a specific, administration, nor any age limits on often relates to a short-term clinical recognized disorder. Although medical study subjects. Studies were excluded outcome being investigated. Proof of practitioners are not qualified by that used placebo marijuana concept studies often serve as the link scientific training and experience to supplemented by the addition of between preclinical studies and dose evaluate the safety and effectiveness of specific amounts of THC or other ranging clinical studies. Thus, proof of concept studies generally are not drugs, we also note that the AMA’s cannabinoids. Additionally, studies sufficient to prove efficacy of a drug report, entitled ‘‘Use of Cannabis for administering marijuana plant extracts because they provide only preliminary Medicinal Purposes,’’ does not accept were excluded. that marijuana currently has accepted The PubMed search yielded a total of information about the effects of a drug. In addition to the lack of published medical use. Furthermore, based on the 566 abstracts of scientific articles. Of adequate and well-controlled efficacy above definition of a ‘‘qualified expert’’, studies proving efficacy, the criteria for who is an individual qualified by 11 In this quotation the term cannabis is used interchangeably for marijuana. adequate safety studies has also not scientific training and experience to 12 The following search strategy was used, been met. Importantly, in its discussion evaluate the safety and effectiveness of ‘‘(cannabis OR marijuana) AND (therapeutic use OR of the five-part test used to determine a drug, state-level medical marijuana therapy) AND (RCT OR randomized controlled trial whether a drug has a ‘‘currently laws do not provide evidence of a OR ‘‘systematic review’’ OR clinical trial OR clinical trials) NOT (‘‘marijuana abuse’’[Mesh] OR accepted medical use,’’ DEA said, ‘‘No consensus among qualified experts that addictive behavior OR substance related drug can be considered safe in the marijuana is safe and effective for use in disorders).’’ abstract. Safety has meaning only when treating a specific, recognized disorder.

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As to the fifth part of the test, which use of illicit drugs, including marijuana, between the ages of 18–25, with 18.7 requires that information concerning the is increasing. The 2012 NSDUH percent of this age group currently using chemistry, pharmacology, toxicology, estimates that 23.9 million individuals marijuana. In the 26 and older age and effectiveness of marijuana to be over 12 years of age (9.2 percent of the group, 5.3 percent of individuals reported in sufficient detail, the U.S. population) currently use illicit currently use marijuana. Additionally, scientific evidence regarding all of these drugs, which is an increase of 4.8 in individuals aged 12 years and older, aspects is not available in sufficient million individuals from 2004 when males reported more current marijuana detail to allow adequate scientific 19.1 million individuals (7.9 percent of use than females. scrutiny. Specifically, the scientific the U.S. population) were current illicit NSDUH includes a series of questions evidence regarding marijuana’s drug users. NSDUH reports marijuana as aimed at assessing the prevalence of chemistry in terms of a specific the most commonly used illicit drug, dependence and abuse of different Cannabis strain that could produce with 18.9 million individuals (7.3 substances in the past 12 months.15 In standardized and reproducible doses is percent of the U.S. population) 2012, marijuana was the most common not currently available. currently using marijuana in 2012. This illicit drug reported by individuals with Alternately, a drug can be considered represents an increase of 4.3 million past year dependence or abuse. An to have a ‘‘currently accepted medical individuals from 2004, when 14.6 estimated 4.3 million individuals meet use with severe restrictions’’ (21 U.S.C. million individuals (6.1 percent of the the NSDUH criteria for marijuana 812(b)(2)(B)), as allowed under the U.S. population) were current marijuana stipulations for a Schedule II drug. Yet, users. dependence or abuse in 2012. The estimated rates and number of as stated above, currently marijuana The majority of individuals who try individuals with marijuana dependence does not have any accepted medical use, marijuana at least once in their lifetime or abuse has remained similar from even under conditions where its use is do not currently use marijuana. The 2002 to 2012. In addition to data on severely restricted. 2012 NSDUH estimates that 111.2 dependence and abuse, NSDUH In conclusion, to date, research on million individuals (42.8 percent of the marijuana’s medical use has not includes questions aimed at assessing U.S. population) have used marijuana at 16 progressed to the point where marijuana least once in their lifetime. Based on treatment for a substance use problem. is considered to have a ‘‘currently this estimate and the estimate for the In 2012, an estimated 957,000 persons accepted medical use’’ or a ‘‘currently number of individuals currently using received treatment for marijuana use accepted medical use with severe marijuana, approximately 16.9 percent during their most recent treatment in restrictions.’’ of those who have tried marijuana at the year prior to the survey. 4. Its History and Current Pattern of least once in their lifetime currently use Monitoring the Future (MTF) 17 Abuse marijuana; conversely, 83.1 percent do 18 Under the fourth factor, the Secretary not currently use marijuana. In terms of According to MTF, rates of must consider the history and current the frequency of marijuana use, an marijuana and illicit drug use declined pattern of marijuana abuse. A variety of estimated 40.3 percent of individuals for all three grades from 2005 through sources provide data necessary to assess who used marijuana in the past month 2007. However, starting around 2008, abuse patterns and trends of marijuana. used marijuana on 20 or more days rates of annual use of illicit drugs and The data indicators of marijuana use within the past month. This amount marijuana increased through 2013 for all include the NSDUH, MTF, DAWN, and corresponds to an estimated 7.6 million three grades. Marijuana remained the TEDS. The following briefly describes individuals who used marijuana on a most widely used illicit drug during all each data source, and summarizes the daily or almost daily basis. time periods. The prevalence of annual data from each source. Some characteristics of marijuana and past month marijuana use in 10th users are related to age, gender, and and 12th graders in 2013 is greater than National Survey on Drug Use and criminal justice system involvement. In in 2005. Table 1 lists the lifetime, 13 Health (NSDUH) observing use among different age annual, and monthly prevalence rates of According to 2012 NSDUH 14 data, the cohorts, the majority of individuals who various drugs for 8th, 10th, and 12th most recent year with complete data, the currently use marijuana are shown to be graders in 2013.

13 NSDUH provides national estimates of the based on criteria specified in the Diagnostic and rehabilitation facility (outpatient or inpatient), prevalence and incidence of illicit drug, alcohol Statistical Manual of Mental Disorder, 4th edition mental health center, emergency room, private and tobacco use in the United States. NSDUH is an (DSM–IV). The questions related to dependence ask doctor’s office, prison or jail, or a self-help group, annual study conducted by SAMHSA. Prior to about health and emotional problems associated such as Alcoholics Anonymous or Narcotics 2002, the database was known as the National with substance use, unsuccessful attempts to cut Anonymous.’’ (NSDUH, 2013). Household Survey on Drug Abuse (NHSDA). down on use, tolerance, withdrawal, reducing other 17 Monitoring the Future is a national survey that NSDUH utilizes a nationally representative sample activities to use substances, spending a lot time tracks drug use prevalence and trends among of United States civilian, non-institutionalized engaging in activities related to substance use, or adolescents in the United States. MTF is reported population aged 12 years and older. The survey using the substance in greater quantities or for annually by the Institute for Social Research at the excludes homeless people who do not use shelters, longer time than intended. The questions on abuse University of Michigan under a grant from NIDA. active military personnel, and residents of ask about problems at work, home, and school; Every spring, MTF surveys 8th, 10th, and 12th institutional group quarters such as jails and problems with family or friends; physical danger; graders in randomly selected U.S. schools. MTF has hospitals. The survey identifies whether an and trouble with the law due to substance use. been conducted since 1975 for 12th graders and individual used a drug within a specific time Dependence is considered to be a more severe since 1991 for 8th and 10th graders. The MTF period, but does not identify the amount of the drug substance use problem than abuse because it survey presents data in terms of prevalence among used on each occasion. NSDUH defines ‘‘current involves the psychological and physiological effects the sample interviewed. For 2012, the latest year use’’ as having used the substance within the month of tolerance and withdrawal.’’ (NSDUH, 2013). with complete data, the sample sizes were 15,200— prior to the study. 16 ‘‘Estimates . . . refer to treatment received for 8th graders; 13,300—10th graders; and 13,200— 14 2013; http://www.samhsa.gov/data/ illicit drug or alcohol use, or for medical problems 12th graders. In all, a total of about 41,700 students NSDUH.aspx. associated with the use of illicit drugs or alcohol. of 389 schools participated in the 2013 MTF. 15 ‘‘These questions are used to classify persons This includes treatment received in the past year at 18 2013; http://www.monitoringthefuture.org/ as dependent on or abusing specific substances any location, such as a hospital (inpatient), index.html.

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Drug Abuse Warning Network 2,462,948 ([CI]: 2,112,868 to 2,813,028) marijuana, the rates of ED visits per (DAWN) 19 visits involved drug misuse or abuse. 100,000 population were highest for During the same period, DAWN patients aged 18 to 20 (443.8 ED visits Importantly, many factors can estimates that 1,252,500 (CI: 976,169 to per 100,000) and for patients aged 21 to influence the estimates of ED visits, 1,528,831) drug related ED visits 24 (446.9 ED visits per 100,000). including trends in overall use of a involved illicit drugs. Thus, over half of substance as well as trends in the While DAWN provides estimates for all drug-related ED visits associated ED visits associated with the use of reasons for ED usage. For instance, some with drug misuse or abuse involved an medical marijuana for 2009–2011, the drug users may visit EDs for life- illicit drug. For ED visits involving validity of these estimates is threatening issues while others may illicit drugs, 56.3 percent involved questionable. Because the drug is not visit to seek care for detoxification multiple drugs while 43.7 percent approved by the FDA, reporting medical because they needed certification before involved a single drug. entering treatment. Additionally, Marijuana was involved in 455,668 marijuana may be inconsistent and DAWN data do not distinguish the drug ED visits (CI: 370,995 to 540,340), while reliant on a number of factors including responsible for the ED visit from other cocaine was involved in 505,224 (CI: whether the patient self-reports the drugs that may have been used 324,262 to 686, 185) ED visits, heroin marijuana use as medicinal, how the concomitantly. As stated in a DAWN was involved in 258,482 (CI: 205,046 to treating health care provider records the report, ‘‘Since marijuana/hashish is 311,918) ED visits and stimulants marijuana use, and lastly how the frequently present in combination with including amphetamine and SAMHSA coder interprets the report. other drugs, the reason for the ED visit methamphetamine were involved in All of these aspects will vary greatly may be more relevant to the other 159,840 (CI: 100,199 to 219,481) ED between states with medical marijuana drug(s) involved in the episode.’’ visits. Other illicit drugs, such as PCP, laws and states without medical For 2011, DAWN 20 estimates a total MDMA, GHB and LSD were much less marijuana laws. Thus, even though of 5,067,374 (95 percent confidence frequently associated with ED visits. estimates are reported for medical interval [CI]: 4,616,753 to 5,517,995) The number of ED visits involving marijuana related ED visits, medical drug-related ED visits from the entire marijuana has increased by 62 percent marijuana estimates cannot be assessed United States. Of these, approximately since 2004. with any acceptable accuracy at this Marijuana-related ED visits were most time, as FDA has not approved marijuana treatment of any medical 19 DAWN is a national probability survey of the frequent among young adults and U.S. hospitals with ED designed to obtain minors. Individuals under the age of 18 condition. These data show the information on drug related ED visits. DAWN is accounted for 13.2 percent of these difficulty in evaluating abuse of a sponsored by SAMHSA. The DAWN system marijuana-related visits, whereas this product that is not currently approved provides information on the health consequences of drug use in the United States, as manifested by age group accounted for approximately by FDA, but authorized for medical use, drug-related visits to ED. The ED data from a 1.2 percent of ED visits involving albeit inconsistently, at the state level. representative sample of hospital emergency cocaine, and less than 1 percent of ED Thus, we believe the likelihood of the departments are weighted to produce national treating health care provider or estimates. Importantly, DAWN data and estimates, visits involving heroin. However, the starting in 2004, are not comparable to those for age group with the most marijuana- SAMHSA coder attributing the ED visit prior years because of vast changes in the related ED visits was between 25 and 29 to ‘‘medical marijuana’’ versus methodology used to collect the data. Furthermore, years old. Yet, because populations ‘‘marijuana’’ to be very low. Overall, the estimates for 2004 are the first to be based on a redesigned sample of hospitals, which ended in differ between age groups, a available data are inadequate to 2011. standardized measure for population characterize its abuse at the community 20 2011; http://www.samhsa.gov/data/dawn.aspx. size is useful to make comparisons. For level.

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Treatment Episode Data Set (TEDS) 21 5. The Scope, Duration, and Approximately 61.5 percent of primary Significance of Abuse marijuana admissions in 2011 were for Primary marijuana abuse accounted individuals under the age of 25 years. for 18.1 percent of all 2011 TEDS 22 Under the fifth factor, the Secretary must consider the scope, duration, and admissions. Individuals admitted for 6. WHAT, if Any, Risk There Is to the significance of marijuana abuse. primary marijuana abuse were nearly Public Health According to 2012 data from NSDUH three-quarters (73.4 percent) male, and and 2013 data from MTF, marijuana Under the sixth factor, the Secretary almost half (45.2 percent) were white. remains the most extensively used must consider the risks posed to the The average age at admission was 24 illegal drug in the United States, with public health by marijuana. Factors 1, 4, years old, and 31.1 percent of 42.8 percent of U.S. individuals over age and 5 include a. discussion of the risk individuals admitted for primary 12 (111.2 million) and 45.5 percent of to the public health as measured by marijuana abuse were under the age of 12th graders having used marijuana at emergency room episodes and drug 18. The reported frequency of marijuana least once in their lifetime. Although the treatment admissions. Additionally, use was 24.3 percent reporting daily majority of individuals over age 12 (83.1 Factor 2 includes a discussion of use. Almost all (96.8 percent) primary percent) who have ever used marijuana marijuana’s central nervous system, marijuana users utilized the substance in their lifetime do not use the drug cognitive, cardiovascular, autonomic, by smoking. Additionally, 92.9 percent monthly, 18.9 million individuals (7.3 respiratory, and immune system effects. reported using marijuana for the first percent of the U.S. population) report Factor 6 focuses on the health risks to the individual user in terms of the risks time before the age of 18. that they used marijuana within the past from acute and chronic use of An important aspect of TEDS 30 days. An examination of use among various age cohorts through NSDUH marijuana, as well as the ‘‘gateway admission data for marijuana is of the hypothesis.’’ referral source for treatment. demonstrates that monthly use occurs primarily among college-aged Specifically, primary marijuana Risks From Acute Use of Marijuana individuals, with use dropping off admissions were less likely than all Acute use of marijuana impairs sharply after age 25. Additionally, psychomotor performance, including other admissions to either be self- NSDUH data show the number of complex task performance, which referred or referred by an individual for individuals reporting past-month use of makes operating motor vehicles or treatment. Instead, the criminal justice marijuana has increased by 4.3 million heavy equipment after using marijuana system referred more than half (51.6 individuals since 2004. Data from MTF inadvisable (Ramaekers et al., 2004; percent) of primary marijuana shows that annual prevalence of Ramaekers et al., 2006a). A meta- admissions. marijuana use declined for all three analysis conducted by Li et al. (2011) grades from 2005 through 2007, then Since 2003, the percent of admissions showed an association between began to rise through 2013. for primary marijuana abuse increased marijuana use by the driver and a Additionally, in 2013, 1.1 percent of 8th from 15.5 percent of all admissions in significantly increased risk of graders, 4.0 percent of 10th graders, and 2003 to 18.1 percent in 2011. This involvement in a car accident. 6.5 percent of 12th graders reported increase is less than the increase seen Additionally, in a minority of daily use of marijuana, defined as use for admissions for primary opioids other individuals who use marijuana, some on 20 or more days within the past 30 than heroin, which increased from 2.8 potential responses include dysphoria percent in 2003 to 7.3 percent in 2011. days. The 2011 DAWN data show that and psychological distress, including In contrast, the admissions for primary marijuana use was mentioned in prolonged anxiety reactions (Haney et cocaine abuse declined from 9.8 percent 455,668 ED visits, which amounts to al., 1999). in 2003 to 2.0 percent in 2011. approximately 36.4 percent of all illicit Risks From Chronic Use of Marijuana drug-related ED visits.23 21 A distinctive marijuana withdrawal The TEDS system is part of SAMHSA’s Drug TEDS data for 2011 show that 18.1 and Alcohol Services Information System (Office of syndrome following long term or percent of all admissions were for Applied Science, SAMHSA). The TEDS report chronic use has been identified. The primary marijuana abuse.24 Between presents information on the demographic and withdrawal syndrome indicates that 2003 and 2011, there was a 2.6 percent substance use characteristics of the 1.8 million marijuana produces physical annual admissions to treatment for alcohol and increase in the number of TEDS dependence that is mild, short-lived, drug abuse in facilities that report to individual admissions for primary marijuana use. state administrative data systems. Specifically, and comparable to tobacco withdrawal TEDS includes facilities licensed or certified by the 23 Many factors can influence the estimates of ED (Budney et al., 2008). Marijuana states to provide substance abuse treatment and is withdrawal syndrome is described in required by the states to provide TEDS client-level visits, including trends in the reasons for ED usage. data. Facilities that report TEDS data are those For instance, some drug users may visit EDs for life- detail below under Factor 7. threatening issues while others may visit to seek receiving State alcohol and drug agency funds for The following states how the DSM–V care for detoxification because they needed the provision of alcohol and drug treatment certification before entering treatment. (2013) of the American Psychiatric services. Since TEDS is based only on reports from Additionally, DAWN data do not distinguish the Association describes the consequences these facilities, TEDS data do not represent the total drug responsible for the ED visit from other drugs of Cannabis 25 abuse: national demand for substance abuse treatment or that may have been used concomitantly. As stated Individuals with cannabis use the prevalence of substance abuse in the general in a DAWN report, ‘‘Since marijuana/hashish is population. The primary goal for TEDS is to frequently present in combination with other drugs, disorder may use cannabis throughout monitor the characteristics of treatment .episodes the reason for the ED visit may be more relevant to the day over a period of months or for substance abusers. Importantly, TEDS is an the other drug(s) involved in the episode.’’ years, and thus may spend many hours admissions-based system, where admittance to 24 An important aspect of TEDS admission data a day under the influence. Others may treatment is counted as an anonymous tally. For for marijuana is of the referral source for treatment. use less frequently, but their use causes instance, a given individual who is admitted to Specifically, primary marijuana admissions were treatment twice within a given year would be less likely than all other admissions to either be recurrent problems related to family, counted as two admissions. The most recent year self-referred or referred by an individual for with complete data is 2011. treatment. Instead, the criminal justice system 25 Cannabis is the term used in the DSM–V to 22 2011; http://www.samhsa.gov/data/ referred more than half (51.6 percent) of primary refer to marijuana. In the following excerpt the term DASIS.aspx?qr=t#TEDS. marijuana admissions. Cannabis is interchangeable for the term marijuana.

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school, work, or other important marijuana use leading to heroin drugs, this fact does not correctly lead activities (e.g., repeated absences at addiction. Additionally, in another to the reverse inference that most work; neglect of family obligations). longitudinal study of 2,446 adolescents, individuals who used marijuana will Periodic cannabis use and intoxication marijuana dependence was uncommon inherently go on to try or become can negatively affect behavioral and but when it did occur, the common regular users of other illicit drugs. cognitive functioning and thus interfere predictors of marijuana dependence Specifically, data from the 2011 NSDUH with optimal performance at work or were the following: Parental death, survey illustrates this issue (SAMHSA, school, or place the individual at deprived socio-economic status, and 2012). NSDUH data estimates 107.8 increased physical risk when baseline illicit drug use other than million individuals have a lifetime performing activities that could be marijuana (von Sydow et al., 2002). history of marijuana use, which physically hazardous (e.g., driving a car; When examining the association indicates use on at least one occasion, playing certain sports; performing between marijuana and illicit drugs, compared to approximately 36 million manual work activities, including focusing on drug use versus abuse or individuals having a lifetime history of operating machinery). Arguments with dependence, different patterns emerge. cocaine use and approximately 4 spouses or parents over the use of For example, a study examining the million individuals having a lifetime cannabis in the home, or its use in the possible causal relationship of the history of heroin use. NSDUH data do presence of children, can adversely gateway hypothesis found a correlation not provide information about each impact family functioning and are between marijuana use in adolescents individual’s specific drug history. common features of those with cannabis and other illicit drug use in early However, even if one posits that every use disorder. Last, individuals with adulthood and, adjusting for age-linked cocaine and heroin user previously used cannabis use disorder may continue experiences, did not effect this marijuana, the NSDUH data show that using marijuana despite knowledge of correlation (Van Gundy and Rebellon, marijuana use at least once in a lifetime physical problems (e.g., chronic cough 2010). However, when examining the does not predict that an individual will related to smoking) or psychological association in terms of development of also use another illicit drug at least problems (e.g., excessive sedation or drug abuse; age-linked stressors and once. exacerbation of other mental health social roles moderated the correlation Finally, a review of the gateway problems) associated with its use. between marijuana use in adolescents hypothesis by Vanyukov et al. (2012) and other illicit drug abuse. Similarly, notes that because the gateway Marijuana as a ‘‘Gateway Drug’’ Degenhardt et al. (2009) examined the hypothesis only addresses the order of Kandel (1975) proposed nearly 40 development of drug dependence and drug use initiation, the gateway years ago the hypothesis that marijuana found an association that did not hypothesis does not specify any is a ‘‘gateway drug’’ that leads to the use support the gateway hypothesis. mechanistic connections between drug or abuse of other illicit drugs. Since that Specifically, drug dependence was ‘‘stages’’ following exposure to time, epidemiological research explored significantly associated with the use of marijuana and does not extend to the this premise. Overall, research does not other illicit drugs prior to marijuana risks for addiction. This concept support a direct causal relationship use. contrasts with the concept of a common between regular marijuana use and Interestingly, the order of initiation of liability to addiction that involves other illicit drug use. The studies drug use seems to depend on the mechanisms and biobehavioral examining the gateway hypothesis are prevalence of use of each drug, which characteristics pertaining to the entire limited. First, in general, studies recruit varies by country. Based on the World course of drug abuse risk and disorders. individuals influenced by a myriad of Health Organization (WHO) World social, biological, and economic factors Mental Health Survey that includes data 7. Its Psychic or Physiologic that contribute to extensive drug abuse from 17 different countries, the order of Dependence Liability (Hall & Lynskey, 2005). Second, most drug use initiation varies by country Under the seventh factor, the studies that test the hypothesis that and relates to prevalence of drug use in Secretary must consider marijuana’s marijuana use causes abuse of illicit each country (Degenhardt et al., 2010). psychic or physiological dependence drugs use the determinative measure Specifically, in the countries with the liability. any use of an illicit drug, rather than lowest prevalence of marijuana use, use Psychic or psychological dependence DSM–5 criteria for drug abuse or of other illicit drugs before marijuana has been shown in response to dependence on an illicit drug (DSM–5, was common. This sequence of marijuana’s psychoactive effects. 2013). Consequently, although an initiation is less common in countries Psychoactive responses to marijuana are individual who used marijuana may try with higher prevalence of marijuana pleasurable to many humans and are other illicit drugs, the individual may use. A study of 9,282 households in the associated with drug-seeking and drug- not regularly use drugs, or have a United States found that marijuana use taking (Maldonado, 2002). Moreover, diagnosis of drug abuse or dependence. often preceded the use of other illicit high levels of psychoactive effects, Little evidence supports the drugs; however, prior non-marijuana notably positive reinforcement, are hypothesis that initiation of marijuana drug dependence was also frequently associated with increased marijuana use leads to an abuse disorder with correlated with higher levels of illicit use, abuse, and dependence (Scherrer et other illicit substances. For example, drug abuse (Degenhardt et al., 2009). al., 2009; Zeiger et al., 2010). one longitudinal study of 708 Additionally, in a large 25-year Epidemiological data support these adolescents demonstrated that early longitudinal study of 1,256 New findings through 2012 NSDUH statistics onset marijuana use did not lead to Zealand children, the author concluded that show that of individuals years 12 or problematic drug use (Kandel & Chen, that marijuana use correlated to an older who used marijuana in the past 2000). Similarly, Nace et al. (1975) increased risk of abuse of other drugs, month, an estimated 40.3 percent used examined Vietnam-era soldiers who including cocaine and heroin marijuana on 20 or more days within extensively abused marijuana and (Fergusson et al., 2005). the past month. This equates to heroin while they were in the military, Although many individuals with a approximately 7.6 million individuals and found a lack of correlation of a drug abuse disorder may have used aged 12 or older who used marijuana on causal relationship demonstrating marijuana as one of their first illicit a daily or almost daily basis.

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Additionally, the 2013 MTF data report 2005; Rodriguez de Fonseca et al., 1994; Recommendation the prevalence of daily marijuana use, Oviedo et al., 1993). After consideration of the eight factors Importantly, pharmacological defined as use on 20 or more days discussed above, FDA recommends that tolerance alone does not indicate a within the past 30 days, in 8th, 10th, marijuana remain in Schedule I of the drug’s physical dependence liability. In and 12th graders is 1.1 percent, 4.0 CSA. NIDA concurs with this order for physical dependence to exist, percent, and 6.5 percent, respectively. scheduling recommendation. Marijuana evidence of a withdrawal syndrome is Tolerance is a state of adaptation meets the three criteria for placing a needed. Physical dependence is a state where exposure to a drug induces substance in Schedule I of the CSA of adaptation, manifested by a drug- changes that result in a diminution of under 21 U.S.C. 812(b)(l): class specific withdrawal syndrome one or more of the drug’s effects over (1) Marijuana has a high potential for produced by abrupt cessation, rapid time (American Academy of Pain abuse: dose reduction, decreasing blood level Medicine, American Pain Society and A number of factors indicate of the drug, and/or administration of an American Society of Addiction marijuana’s high abuse potential, antagonist (ibid). Many medications not Medicine consensus document, 2001). including the large number of associated with abuse or addiction can Tolerance can develop to some, but not produce physical dependence and individuals regularly using marijuana, all, of marijuana’s effects. Specifically, withdrawal symptoms after chronic use. marijuana’s widespread use, and the tolerance does not seem to develop in Discontinuation of heavy, chronic vast amount of marijuana available for response to many of marijuana’s marijuana use has been shown to lead illicit use. Approximately 18.9 million psychoactive effects. This lack of to physical dependence and withdrawal individuals in the United States (7.3 tolerance may relate to symptoms (American Psychiatric percent of the U.S. population) used electrophysiological data demonstrating marijuana monthly in 2012. 9 Association DSM–V, 2013; Budney and that chronic delta -THC administration Hughes, 2006; Haney et al., 1999). In Additionally, approximately 4.3 million does not affect increased neuronal firing heavy, chronic marijuana users, the individuals met diagnostic criteria for in the ventral tegmental area, a region most commonly reported withdrawal marijuana dependence or abuse in the known to play a critical role in drug symptoms are sleep difficulties, year prior to the 2012 NSDUH survey. reinforcement and reward (Wu and decreased appetite or weight loss, A 2013 survey indicates that by 12th French, 2000). In the absence of other irritability, anger, anxiety or grade, 36.4 percent of students report abuse indicators, such as rewarding nervousness, and restlessness. Some using marijuana within the past year, properties, the presence of tolerance or less commonly reported withdrawal and 22.7 percent report using marijuana physical dependence does not symptoms are depressed mood, monthly. In 2011, 455,668 ED visits determine whether a drug has abuse sweating, shakiness, physical were marijuana-related, representing potential. discomfort, and chills (Budney and 36.4 percent of all illicit drug-related However, humans can develop Hughes, 2006; Haney et al., 1999). The episodes. Primary marijuana use tolerance to marijuana’s cardiovascular, occurrence of marijuana withdrawal accounted for 18.1 percent of autonomic, and behavioral effects (Jones symptoms in light or non-daily admissions to drug treatment programs et al., 1981). Tolerance to some of marijuana users has not been in 2011. Additionally, marijuana has marijuana’s behavioral effects seems to established. The American Psychiatric dose-dependent reinforcing effects, as develop after heavy marijuana use, but Association’s DSM–V (2013) includes a demonstrated by data showing that not after occasional marijuana use. For list of symptoms of ‘‘cannabis humans prefer relatively higher doses to instance, following acute administration withdrawal.’’ Most marijuana lower doses. Furthermore, marijuana of marijuana, heavy marijuana users did withdrawal symptoms begin within 24– use can result in psychological not exhibit impairments in tracking and 48 hours of discontinuation, peak dependence. attention tasks, as were seen in within 4–6 days, and last for 1–3 weeks. (2) Marijuana has no currently occasional marijuana users (Ramaekers Marijuana withdrawal syndrome has accepted medical use in treatment in the et al., 2009). Furthermore, a been reported in adolescents and adults United States: neurophysiological assessment admitted for substance abuse treatment. FDA has not approved a marketing administered through an Based on clinical descriptions, this application for a marijuana drug electroencephalograph (EEG) which syndrome appears to be mild compared product for any indication. The measures event-related potentials (ERP) to classical alcohol and barbiturate opportunity for scientists to conduct conducted in the same subjects as the withdrawal syndromes, which can clinical research with marijuana exists, previous study, found a corresponding include more serious symptoms such as and there are active INDs for marijuana; effect in the P100 26 component of ERPs. agitation, paranoia, and seizures. however, marijuana does not have a Specifically, corresponding to Multiple studies comparing marijuana currently accepted medical use for performance on tracking and attention and tobacco withdrawal symptoms in treatment in the United States, nor does tasks, heavy marijuana users showed no humans demonstrate that the magnitude marijuana have an accepted medical use changes in P100 amplitudes following and time course of the two withdrawal with severe restrictions. acute marijuana administration, syndromes are similar (Budney et al., A drug has a ‘‘currently accepted although occasional users showed a 2008; Vandrey et al., 2005, 2008). medical use’’ if all of the following five elements have been satisfied: decrease in P100 amplitudes 8. Whether the Substance Is an (Theunissen et al., 2012). A possible a. the drug’s chemistry is known and Immediate Precursor of a Substance reproducible; mechanism underlying tolerance to Already Controlled Under This Article marijuana’s effects may be the down- b. there are adequate safety studies; regulation of cannabinoid receptors Under the eight factor analysis, the c. there are adequate and well- (Hirvonen et al., 2012; Gonzalez et al., Secretary must consider whether controlled studies proving efficacy; marijuana is an immediate precursor of d. the drug is accepted by qualified 26 The P100 component of ERPs is thought to a controlled substance. Marijuana is not experts; and relate to the visual processing of stimuli and can be an immediate precursor of another e. the scientific evidence is widely modulated by attention. controlled substance. available.

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[57 FR 10499, March 26, 1992] manufacturing, and specifications of Balster RL and Bigelow GE. Guidelines and Marijuana does not meet any of the marijuana. Additionally, a procedure for methodological reviews concerning drug abuse liability assessment. Drug and elements for having a ‘‘currently delivering a consistent dose of marijuana should also be developed. Alcohol Dependence. 2003; 70: S13–S40. accepted medical use.’’ Barnett, G.; Licko, V.; and Thompson, T. First, FDA broadly evaluated Therefore, FDA concludes marijuana Behavioral pharmacokinetics of marijuana, and did not focus its does not currently have an accepted marijuana. Psychopharmacology 1985, evaluation on particular strains of level of safety for use under medical 85(1), 51–56. marijuana or components or derivatives supervision. Battista N, Di TM, Bari M, Maccarrone M. of marijuana. Since different strains may The endocannabinoid system: an References overview. 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TABLE OF CONTENTS 1. Introduction ...... 71 2. Methods ...... 73 2.1 Define the Objective of the Review ...... 73 2.2 Define ‘‘Marijuana’’ ...... 73 2.3 Define ‘‘Adequate and Well-Controlled Clinical Studies’’ ...... 74 2.4 Search Medical Literature Databases and Identify Relevant Studies ...... 74 2.5 Review and Analyze Qualifying Clinical Studies ...... 77 3. Results and Discussion ...... 77 3.1 Neuropathic Pain ...... 77 3.1.1 Neuropathic Pain Associated with HIV-Sensory Neuropathy ...... 77 3.1.2 Central and Peripheral Neuropathic Pain ...... 81 3.2 Appetite Stimulation in HIV ...... 85 3.3 Spasticity in Multiple Sclerosis ...... 88 3.4 Asthma ...... 89 3.5 Glaucoma ...... 91 3.6 Conclusions ...... 91 3.6.1 Conclusions for Chronic Neuropathic Pain ...... 91 3.6.2 Conclusions for Appetite Stimulation in HIV ...... 92 3.6.3 Conclusions for Spasticity in MS ...... 92 3.6.4 Conclusions for Asthma ...... 92 3.6.5 Conclusions for Glaucoma ...... 93 3.7 Design Challenges for Future Studies ...... 93 3.7.1 Sample Size ...... 93 3.7.2 Marijuana Dose Standardization ...... 94 3.7.3 Acute vs. Chronic Therapeutic Marijuana Use ...... 95 3.7.4 Smoking as a Route of Administration ...... 96 3.7.5 Difficulty in Blinding of Drug Conditions ...... 96 3.7.6 Prior Marijuana Experience ...... 97 3.7.7 Inclusion and Exclusion Criteria ...... 98 3.7.8 Number of Female Subjects ...... 98 Appendix (Tables) ...... 103 List of Figure: Figure 1: Identification of Studies from PubMed Search ...... 76 List of Tables: Table 1: Randomized, controlled, double-blind trials examining smoked marijuana in treatment of neuropathic pain ...... 103 Table 2: Randomized, controlled, double-blind trials examining smoked marijuana in treatment of appetite stimulation in HIV/AIDS ...... 108 Table 3: Randomized, controlled, double-blind trails examining smoked marijuana in treatment of spasticity in Multiple Sclerosis ...... 111 Table 4: Randomized, controlled, double-blind trails examining smoked marijuana in treatment of intraocular pressure in Glaucoma ...... 112 Table 5: Randomized, controlled, double-blind trails examining smoked marijuana in treatment of asthma ...... 114

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Executive Summary and observed adverse events. The • The low number of female subjects, Marijuana is a Schedule I substance conclusions drawn by the investigators which makes it difficult to generalize under the Controlled Substances Act are then described, along with potential the study findings to subjects of both (CSA). Schedule I indicates a high limitations of these conclusions based genders. potential for abuse, no currently on the study design. A brief summary of Thus, this review discusses the accepted medical use in the United each study’s findings and limitations is following methodological changes that States, and a lack of accepted safety for provided at the end of the section. may be made in order to resolve these use under medical supervision. To date, The eleven clinical studies that met limitations and improve the design of marijuana has not been subject to an the criteria and were evaluated in this future studies which examine the safety approved new drug application (NDA) review showed positive signals that and efficacy of marijuana for specific that demonstrates its safety and efficacy marijuana may produce a desirable therapeutic indications: • Determine the appropriate number for a specific indication under the Food therapeutic outcome, under the specific of subjects studied based on Drug and Cosmetic Act (FDCA). experimental conditions tested. Notably, Nevertheless, as of October 2014, it is beyond the scope of this review to recommendations in various FDA twenty-three states and the District of determine whether these data Guidances for Industry regarding the Columbia have passed state-level demonstrate that marijuana has a conduct of clinical trials for specific medical marijuana laws that allow for currently accepted medical use in the medical indications. • Administer consistent and marijuana use within that state; similar United States. However, this review reproducible doses of marijuana based bills are pending in other states. concludes that these eleven clinical The present review was undertaken studies serve as proof-of-concept on recommendations in the FDA studies, based on the limitations of their Guidance for Industry: Botanical Drug by the Food and Drug Administration 27 (FDA) to analyze the clinical studies study designs, as described in the study Products (2004). • Evaluate the effects of marijuana published in the medical literature summaries. Proof-of-concept studies under therapeutic conditions following investigating the use of marijuana in any provide preliminary evidence on a both acute and chronic administration. therapeutic areas. First, we discuss the proposed hypothesis regarding a drug’s • Consider alternatives to smoked context for this scientific review. Next, effect. For drugs under development, marijuana (e.g., vaporization). we describe the methods used in this the effect often relates to a short-term • Address and improve whenever review to identify adequate and well- clinical outcome being investigated. possible the difficulty in blinding of controlled studies evaluating the safety Proof-of-concept studies serve as the marijuana and placebo treatments in and efficacy of marijuana for particular link between preclinical studies and clinical studies. therapeutic uses. dose ranging clinical studies. Therefore, • Evaluate the effect of prior The FDA conducted a systematic proof-of-concept studies are not experience with marijuana with regard search for published studies in the sufficient to demonstrate efficacy of a to the safety and tolerability of medical literature that meet the drug because they provide only marijuana. described criteria for study design and preliminary information about the • Strive for gender balance in the outcome measures prior to February effects of a drug. However, the studies subjects used in studies. 2013. While not part of our systematic reviewed produced positive results, In conclusion, the eleven clinical review, we have continued to routinely suggesting marijuana should be further studies conducted to date do not meet follow the literature beyond that date for evaluated as an adjunct treatment for the criteria required by the FDA to subsequent studies. Studies were neuropathic pain, appetite stimulation determine if marijuana is safe and considered to be relevant to this review in HIV patients, and spasticity in MS effective in specific therapeutic areas. if the investigators administered patients. However, the studies can serve as proof- marijuana to patients with a diagnosed The main limitations identified in the of-concept studies and support further medical condition in a well-controlled, eleven studies testing the medical research into the use of marijuana in double-blind, placebo-controlled applications of marijuana are listed these therapeutic indications. clinical trial. Of the eleven studies that below: • Additionally, the clinical outcome data met the criteria for review, five different The small numbers of subjects and adverse event profiles reported in therapeutic areas were investigated: enrolled in the studies, which limits the these published studies can beneficially • Five studies examined chronic statistical analyses of safety and inform how future research in this area neuropathic pain efficacy. is conducted. Finally, application of the • Two studies examined appetite • The evaluation of marijuana only recommendations listed above by stimulation in human after acute administration in the studies, investigators when designing future immunodeficiency virus (HIV) which limits the ability to determine studies could greatly improve the patients efficacy following chronic available clinical data that can be used • Two studies examined glaucoma administration. to determine if marijuana has validated • One study examined spasticity and • The administration of marijuana and reliable medical applications. pain in multiple sclerosis (MS) typically through smoking, which • One study examined asthma. exposes ill patients to combusted 1. Introduction For each of these eleven clinical material and introduces problems with In response to citizen petitions studies, information is provided determining the doses delivered. submitted to the Drug Enforcement regarding the subjects studied, the drug • The potential for subjects to Administration (DEA) requesting DEA conditions tested (including dose and identify whether they received to reschedule marijuana, the DEA method of administration), other drugs marijuana or placebo, which breaks the Administrator requested that the U.S. used by subjects during the study, the blind of the studies. Department of Health and Human physiological and subjective measures • The small number of cannabinoid naı¨ve subjects, which limits the ability collected, the outcome of these 27 This Guidance is available on the internet at measures comparing treatment with to determine safety and tolerability in http://www.fda.gov/Drugs/default.htm under marijuana to placebo, and the reported these subjects. Guidance (Drugs).

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Services (HHS) provide a scientific and section 201(j) of the Food, Drug and ‘‘currently accepted medical use’’. medical evaluation of the available Cosmetic Act, 21 U.S.C. 321(j), is Specifically, the present review assesses information and a scheduling sufficient to meet this requirement.’’ the 3rd criterion that addresses whether recommendation for marijuana, in ii. there must be adequate safety marijuana has ‘‘adequate and well- accordance with 21 U.S.C. 811(b). The studies. controlled studies proving efficacy’’. Secretary of HHS is required to consider ‘‘There must be adequate Thus, this review evaluates published in a scientific and medical evaluation pharmacological and toxicological clinical studies that have been eight factors determinative of control studies, done by all methods reasonably conducted using marijuana in subjects under the Controlled Substance Act applicable, on the basis of which it who have a variety of medical (CSA). Administrative responsibilities could fairly and responsibly be conditions by assessing the adequacy of for evaluating a substance for control concluded, by experts qualified by the summarized study designs and the under the CSA are performed by the scientific training and experience to study data. The methodology for Food and Drug Administration (FDA), evaluate the safety and effectiveness of selecting the studies that were evaluated with the concurrence of the National drugs, that the substance is safe for is delineated below. Institute on Drug Abuse (NIDA). Part of treating a specific, recognized disorder.’’ FDA’s evaluation and conclusions this evaluation includes an assessment iii. there must be adequate and well- regarding the remaining four criteria for of whether marijuana has a currently controlled studies proving efficacy. whether marijuana has a ‘‘currently accepted medical use in the United ‘‘There must be adequate, well- accepted medical use,’’ as well as the States. This assessment necessitated a controlled, well-designed, well- eight factors pertaining to the review of the available data from conducted, and well-documented scheduling of marijuana, are outside the published clinical studies to determine studies, including clinical scope of this review. A detailed whether there is adequate scientific investigations, by experts qualified by discussion of these factors is contained evidence of marijuana’s effectiveness. scientific training and experience to in FDA’s scientific and medical Under Section 202 of the CSA, evaluate the safety and effectiveness of evaluation of marijuana. marijuana is currently controlled as a drugs, on the basis of which it could be Schedule I substance (21 U.S.C. 812). fairly and responsibly concluded by 2. Methods Schedule I includes those substances such experts that the substance will The methods for selecting the studies that have a high potential for abuse, have the intended effect in treating a to include in this review involved the have no currently accepted medical use specific, recognized disorder.’’ following steps, which are described in in treatment in the United States, and iv. the drug must be accepted by detail in the subsections below: lack accepted safety for use under qualified experts. 1. Define the objective of the review. medical supervision (21 U.S.C. ‘‘The drug has a New Drug 2. Define ‘‘marijuana’’ in order to § 812(b)(1)(A)–(C)). Application (NDA) approved by the facilitate the medical literature search A drug product which has been Food and Drug Administration, for studies that administered the approved by FDA for marketing in the pursuant to the Food, Drug and substance, United States is considered to have a Cosmetic Act, 21 U.S.C. 355. Or, a 3. Define ‘‘adequate and well- ‘‘currently accepted medical use.’’ consensus of the national community of controlled studies’’ in order to facilitate Marijuana is not an FDA-approved drug experts, qualified by scientific training the search for relevant data and product, as a New Drug Application and experience to evaluate the safety literature, (NDA) or Biologics License application and effectiveness of drugs, accepts the 4. Search medical literature databases (BLA) for marijuana has not been safety and effectiveness of the substance and identify relevant adequate and well- approved by FDA. However, FDA for use in treating a specific, recognized controlled studies, and approval of an NDA is not the only disorder. A material conflict of opinion 5. Review and analyze the adequate means through which a drug can have among experts precludes a finding of and well-controlled clinical studies to a currently accepted medical use in the consensus.’’ and determine if they demonstrate efficacy United States. v. the scientific evidence must be of marijuana for any therapeutic In general, a drug may have a widely available. indication. ‘‘currently accepted medical use’’ in the ‘‘In the absence of NDA approval, United States if the drug meets a five- information concerning the chemistry, 2.1 Define the Objective of the Review part test. Established case law (Alliance pharmacology, toxicology, and The objective of this review is to for Cannabis Therapeutics v. DEA, 15 effectiveness of the substance must be assess the study designs and resulting F.3d 1131, 1135 (D.C. Cir. 1994)) upheld reported, published, or otherwise data from clinical studies published in the Administrator of DEA’s application widely available, in sufficient detail to the medical literature that were of the five-part test to determine permit experts, qualified by scientific conducted with marijuana (as defined whether a drug has a ‘‘currently training and experience to evaluate the below) as a treatment for any accepted medical use.’’ The following safety and effectiveness of drugs, to therapeutic indication, in order to describes the five elements that fairly and responsibly conclude the determine if they meet the criteria of characterize ‘‘currently accepted substance is safe and effective for use in ‘‘adequate and well-controlled studies medical use’’ for a drug: 28 treating a specific, recognized disorder.’’ proving efficacy’’. i. the drug’s chemistry must be known One way to pass the five-part test for and reproducible. having ‘‘currently accepted medical 2.2 Define ‘‘Marijuana’’ ‘‘The substance’s chemistry must be use’’ is through submission of an NDA In this review, the term ‘‘marijuana’’ scientifically established to permit it to or BLA which is approved by FDA. refers to the flowering tops or leaves of be reproduced into dosages which can However, FDA approval of an NDA or the Cannabis plant. There were no be standardized. The listing of the BLA is not required for a drug to pass restrictions on the route of substance in a current edition of one of the five-part test. administration used for marijuana in the the official compendia, as defined by This review focuses on FDA’s analysis studies. of one element of the five-part test for Studies which administered 28 57 FR 10499, 10504–06 (March 26, 1992). determining whether a drug has individual cannabinoids (whether

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experimental substances or marketed While the majority of the elements when the studies begin, and is updated drug products) or marijuana extracts defining an adequate and well- throughout the study. In some cases, were excluded from this review. controlled study can be satisfied results of the study or resulting Additionally, studies of administered through a published paper (elements publication citations are submitted to neutral plant material or placebo #1–6), there are two elements that the Web site after the study ends marijuana (marijuana with all cannot be met by a study published in (https://clinicaltrials.gov/ct2/about-site/ cannabinoids extracted) that had the medical literature: element #7 background). subsequently been supplemented by the (availability of a study report with full ClinicalTrials.gov was searched for all addition of specific amounts of THC or protocol and primary data) and element studies administering marijuana. The other cannabinoids were also excluded #8 (a determination of whether the data results of this search were used to (Chang et al., 1979). analysis was appropriate). Thus, for confirm that no completed studies with purposes of this review, only elements published data were missed in the 2.3 Define ‘‘Adequate and Well- #1–6 will be used to qualify a study as literature search. During the literature Controlled Clinical Studies’’ being adequate and well-controlled. search, references found in relevant The criteria for an ‘‘adequate and studies and systematic reviews were 2.4 Search Medical Literature well-controlled study’’ for purposes of evaluated for additional relevant Databases and Identify Relevant Studies determining the safety and efficacy of a citations. All languages were included human drug is defined under the Code We identified randomized, double- in the search. The PubMed search of Federal Regulations (CFR) in 21 CFR blind, placebo-controlled clinical yielded a total of 566 abstracts.30 Of 314.126. The elements of an adequate studies conducted with marijuana to these abstracts, a full-text review was and well-controlled study as described assess marijuana’s efficacy in any conducted with 85 papers to assess in 21 CFR 314.126 can be summarized therapeutic indication. Two primary eligibility. From this evaluation, only as follows: medical literature databases were eleven of 85 studies met the 6 CFR 1. The main objective must be to searched for all studies posted to the elements for inclusion as adequate and assess a therapeutically relevant databases prior to February 2013: 29 well-controlled studies. outcome. • PubMed: PubMed is a database of Figure 1 (below) provides an overview 2. The study must be placebo- published medical and scientific studies of the process used to identify studies controlled. that is maintained by the U.S. National from the PubMed search. The eleven 3. The subjects must qualify as having Library of Medicine (NLM) at NIH as a studies reviewed were published the medical condition being studied. part of the Entrez system of information between 1974 and 2013. Ten of these 4. The study design permits a valid retrieval. PubMed comprises more than studies were conducted in the United comparison with an appropriate control 24 million citations for biomedical States and one study was conducted in condition. literature from MEDLINE, life science Canada. These eleven studies examined 5. The assignment of subjects to journals, and online books (http:// the effects of smoked and vaporized treatment and control groups must be www.ncbi.nlm.nih.gov/pubmed). marijuana for the indications of chronic randomized. • ClinicalTrials.gov: neuropathic pain, spasticity related to 6. There is minimization of bias ClinicalTrials.gov is a database of multiple sclerosis (MS), appetite through the use of a double-blind study publicly and privately supported stimulation in patients with human design. clinical studies that is maintained by immunodeficiency virus (HIV), 7. The study report contains a full the NLM. Information about the clinical glaucoma, and asthma. All included protocol and primary data. studies is provided by the Sponsor or studies used adult patients as subjects. 8. Analysis of the study data is Principal Investigator of the study. All studies conducted in the United appropriately conducted. Information about the studies is States were conducted under an IND as As noted above, the current review submitted to the Web site (‘‘registered’’) Phase 2 investigations. examines only those data available in the public domain and thus relies on 29 While not a systematic review, we have 30 The following search strategy was used, clinical studies published in the followed the recent published literature on ‘‘(cannabis OR marijuana) AND (therapeutic use OR medical literature. Published studies by marijuana use for possible therapeutic purposes therapy) AND (RCT OR randomized controlled trial and, as of January 2015, we found only one new OR ‘‘systematic review’’ OR clinical trial OR their nature are summaries that do not study that would meet our criteria (Naftali et al., clinical trials) NOT (‘‘marijuana abuse’’ [Mesh] OR include the level of detail required by 2013). This study examined the effects of smoked addictive behavior OR substance related studies submitted to FDA in an NDA. marijuana on Crohn’s disease. disorders)’’.

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Two qualifying studies, which Clinical Studies), a number of clinical measures and methods of analysis used assessed marijuana for glaucoma, were studies that investigated marijuana, as in the studies to assess the treatment previously reviewed in the 1999 defined in this review, were excluded effect were examined. Institute of Medicine (IOM) report from this review. Studies that examined 3. Results and Discussion entitled ‘‘Marijuana and Medicine: the effects of marijuana in healthy Assessing the Science Base’’.31 We did subjects were excluded because they did The eleven qualifying studies in this our own analysis of these two studies not test a patient population with a review assessed a variety of therapeutic and concurred with the conclusions in medical condition (Flom et al., 1975; indications. In order to better facilitate the IOM report. Thus, a detailed Foltin et al., 1986; Foltin et al., 1988; analysis and discussion of the studies, discussion of the two glaucoma studies Hill et al., 1974; Milstein et al., 1974; the following sections group the studies is not included in the present review. Milstein et al., 1975; Soderpalm et al., by therapeutic area. Within each The present review only discusses 9 of 2001; Wallace et al., 2007; Greenwald section, each individual study is the identified 11 studies. For a summary and Stitzer, 2000). A 1975 study by summarized in terms of its design, of the study design for all eleven Tashkin et al. was excluded because it outcome data and important limitations. qualifying studies, see Tables 1–5 had a single-blind, rather than double- This information is also provided in the (located in the Appendix). blind, study design. Two other studies Appendix in tabular form for each Based on the selection criteria for were excluded because the primary study. relevant studies described in Section 2.3 outcome measure assessed safety rather 3.1 Neuropathic Pain (Define Adequate and Well-Controlled than a therapeutic outcome (Greenberg et al., 1994; Abrams et al., 2003). Five randomized, double-blind, 31 In January 1997, the White House Office of placebo-controlled Phase 2 clinical National Drug Control Policy (ONDCP) requested 2.5 Review and Analyze Qualifying studies have been conducted to examine that the IOM conduct a review of the scientific Clinical Studies the effects of inhaled marijuana smoke evidence to assess the potential health benefits and risks of marijuana and its constituent cannabinoids. Qualified clinical studies that on neuropathic pain associated with Information for this study was gathered through evaluated marijuana for therapeutic HIV-sensory neuropathy (Abrams et al., scientific workshops, site visits to cannabis buyers’ purposes were examined in terms of 2007; Ellis et al., 2009) and chronic clubs and HIV/Acquired Immunodeficiency adequacy of study design including neuropathic pain from multiple causes Syndrome (AIDS) clinics, analysis of the relevant scientific literature, and extensive consultation with method of drug administration, study (Wilsey et al., 2008; Ware et al., 2010; biomedical and social scientists. The report was size, and subject inclusion and Wilsey et al., 2013). Table 1 of the finalized and published in 1999. exclusion criteria. Additionally, the Appendix summarizes these studies.

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3.1.1 Neuropathic Pain Associated questionnaire, as well as subjective VAS Previous experience with marijuana was with HIV-Sensory Neuropathy measures of anxiety, sedation, not required for participation in the Two studies examined the effect of disorientation, paranoia, confusion, study, but 27 of 28 subjects (96%) marijuana to reduce the pain induced by dizziness, and nausea. reported previous experience with HIV-sensory neuropathy. As a result, the median daily pain was marijuana. However, of these 27 Abrams et al. (2007) conducted the reduced 34% by smoked marijuana experienced subjects, 63% (n = 18) first study entitled, ‘‘Cannabis in painful compared to 17% by placebo (p = 0.03). reported no marijuana use within the HIV-associated sensory neuropathy: A Fifty-two percent of subjects who past year. randomized placebo-controlled trial’’. smoked marijuana reported a >30% The study procedures compared the The subjects were 50 adult patients with reduction in pain compared to 24% in effects of the target dose of marijuana uncontrolled HIV-associated sensory the placebo group (p = 0.04). Although and placebo during two treatment marijuana reduced experimentally- periods lasting 5 days, with 2 weeks neuropathy, who had at least 6 ≤ experiences with smoking marijuana. induced hyperalgesia (p 0.05) during washout periods. The marijuana The subjects were split into two parallel the first smoking sessions, marijuana strengths available were 1%, 2%, 4%, groups of 25 subjects each. More than did not alter responses to acutely 6%, or 8% THC concentration by 68% of subjects were current marijuana painful stimuli. weight. Subjects smoked marijuana or users, but all individuals were required There were no serious AEs and no placebo cigarettes four times per day, to discontinue using marijuana prior to episodes of hypertension, hypotension, approximately 90–120 minutes apart, the study. Most subjects were taking or tachycardia requiring medical using a standardized cued smoking medication for pain during the study, intervention. No subjects withdrew from procedure: (1) 5 second smoke with the most common medications the study for drug related reasons. inhalation, (2) 10 second hold of smoke being opioids and gabapentin. Upon Subjects in the marijuana group in lungs, (3) 40 second exhale and entry into the study, subjects had an reported higher ratings on the subjective normal breathing between puffs. The average daily pain score of at least 30 on measures of anxiety, sedation, investigators did not provide a a 0–100 visual analog scale (VAS). disorientation, confusion, and dizziness description of the number of puffs taken Subjects were randomized to receive compared to the placebo group. There at any smoking session. All subjects either smoked marijuana (3.56% was one case of severe dizziness in a practiced the smoking procedures using THC 32) or smoked placebo cigarettes marijuana-treated subject. By the end of placebo marijuana prior to test sessions. three times per day for 5 days, using a the study, subjects treated with On the first day of each test period, standardized cued smoking procedure: marijuana and placebo reported a dose titration occurred throughout the (1) 5 second inhale, (2) 10 second reduction in total mood disturbance as four smoking sessions scheduled for holding smoke in the lungs, (3) 40 measured by POMS. that day, with a starting strength of 4% second exhale and breathing normally The authors conclude that smoked THC concentration. Subjects were between puffs. The authors did not marijuana effectively reduced chronic allowed to titrate to a personalized specify how many puffs the subjects neuropathic pain from HIV-associated ‘‘target dose’’, which was defined as the smoked at each smoking session, but sensory neuropathy with tolerable side dose that provided the best pain relief they stated that one cigarette was effects. However, limitations of this without intolerable adverse effects. This smoked per smoking session. study include: maintenance of subjects dose titration was accomplished by Primary outcome measures included on other analgesic medication while allowing subjects to either increase the daily VAS ratings of chronic pain and being tested with marijuana and a lack dose incrementally (to 6% or 8% THC) the percentage of subjects who reported of information about the number of to improve analgesia, or to decrease the a result of more than 30% reduction in puffs during each inhalation of smoke. dose incrementally (to 1% or 2% THC) pain intensity. The ability of smoked These limitations make it difficult to if AEs were intolerable. For the next 4 marijuana to induce acute analgesia was conclude that marijuana has analgesic days of each test period, the subjects assessed using both thermal heat model properties on its own and that the actual smoked their target dose during each of and capsaicin sensitization model, AEs experienced during the study in the four daily smoking sessions. To while anti-hyperalgesia was assessed response to marijuana are tolerable. maintain the blind, placebo marijuana with brush and von Frey hair stimuli. However, the study produced positive was represented as containing 1%-8% The immediate analgesic effects of results suggesting that marijuana should THC, even though it did not contain any smoked marijuana was assessed using a be studied further as an adjunct cannabinoids. 0–100 point VAS at 40-minute intervals treatment for uncontrolled HIV- The primary outcome measure was three times before and three times after associated sensory neuropathy. the change in pain magnitude on the the first and last smoking sessions, Ellis et al. (2009) conducted a more DDS at the end of each test period which was done to correspond to the recent study entitled ‘‘Smoked compared to baseline, with a clinically time of peak plasma cannabinoid levels. medicinal cannabis for neuropathic pain significant level of analgesia considered Notably, not all subjects completed the in HIV: A randomized, crossover to be a reduction in pain of at least 30%. induced pain portion of the study (n = clinical trial’’. The subjects were 28 Additional measures included the 11 in marijuana group, 9 in placebo HIV-positive adult male patients with POMS, the Sickness Impact Profile group) because of their inability to intractable neuropathic pain that was (SIP), the Brief Symptom Inventory tolerate the stimuli. Throughout the refractory to the effects of at least two (BSI) and the UKU Side Effect Rating study, subjects also completed the drugs taken for analgesic purposes. Scale and a subjective highness/ Profile of Mood States (POMS) Upon entry into the study, subjects had sedation VAS. a mean score of >5 on the Pain Intensity During the marijuana treatment week, 32 The drug dose is reported as percentage of THC subscale of the Descriptor Differential 19 subjects titrated to the 2%–4% THC present in the marijuana rather than milligrams of Scale (DDS). Subjects were allowed to dose while the 6%–8% dose was THC present in each cigarette because of the continue taking their current routine of preferred by 8 subjects and 1 subject difficulty in determining the amount of THC pain medications, which included chose the 1% dose. In contrast, during delivered by inhalation (see discussion in the section entitled ‘‘3.7.2 Marijuana Dose opioids, non-narcotic analgesics, the placebo treatment week, all 28 Standardization’’). antidepressants, and anticonvulsants. subjects titrated to the highest possible

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dose of ‘‘8% THC’’ that contained no to marijuana exposure at analgesic point VAS for allodynia, and changes in actual cannabinoids, suggesting that doses. However, the study produced thermal pain threshold. Subjective placebo treatment provided little positive results suggesting that measures were also evaluated with analgesic relief. marijuana should be studied further as unipolar 0–100 point VAS for any drug The degree of pain reduction was an adjunct treatment for uncontrolled effect, good drug effect, bad drug effect, significantly greater after administration HIV-associated sensory neuropathy. high, drunk, impaired, stoned, like the of marijuana compared to placebo drug effect, sedated, confused, 3.1.2 Central and Peripheral (median change of 3.3 points on DDS, nauseated, desire more of the drug, Neuropathic Pain p = 0.016). The median change from anxious, down, hungry, and bipolar 0– baseline in VAS pain scores was ¥17 Three studies examined the effect of 100 point VAS for sad/happy, anxious/ for marijuana treatment compared to ¥4 marijuana on chronic neuropathic pain. relaxed, jittery/calm, bad/good, for placebo treatment (p < 0.001). A Wilsey et al. (2008) examined chronic paranoid/self-assured, fearful/unafraid. larger proportion of subjects who were neuropathic pain from multiple causes Neurocognitive assessments measured treated with marijuana (0.46) reported a in the study entitled, ‘‘A Randomized, attention and concentration, learning >30% reduction in pain, compared to Placebo-Controlled, Crossover Trial of and memory, and fine motor speed. placebo (0.18). Additionally, the authors Cannabis Cigarettes in Neuropathic Marijuana produced a reduction in report improvements in total mood Pain’’. The subjects were 32 patients pain compared to placebo, as measured disturbance, physical disability, and with a variety of neuropathic pain by the pain VAS, the PGIC and on pain quality of life as measured on POMS, conditions, including 22 with complex descriptors in the NPS, including sharp SIP, and BSI scales after both placebo regional pain syndrome, 6 with spinal (P < .001), burning (P < .001), aching (P and marijuana treatment (data not cord injury, 4 with multiple sclerosis, 3 < .001), sensitive (P = .03), superficial (P provided in paper). with diabetic neuropathy, 2 with < .01) and deep pain (P < .001). Notably, In terms of safety, there were no ilioinguinal neuralgia, and 1with there were no additional benefits from alterations in HIV disease parameters in lumbosacral plexopathy. All subjects the 7% THC strength of marijuana response to marijuana or placebo. The reported a pain intensity of at least 30 compared to the 3.5% THC strength, authors report that marijuana led to a on a 0–100 VAS and were allowed to seemingly because of cumulative drug greater degree of UKU responses as well continue taking their regular effects over time. There were no changes as AEs such as difficulty in medications during the study period, in allodynia or thermal pain concentration, fatigue, sleepiness or which included opioids, responsivity following administration of sedation, increased duration of sleep, antidepressants, anticonvulsants, and either dose of marijuana. reduced salivation and thirst compared NSAIDs. All subjects were required to Marijuana at both strengths produced to placebo (data not provided in paper). have experience with marijuana but increases on measures of any drug Two subjects withdrew from the study could not use any cannabinoids for 30 effect, good drug effect, high, stoned, because of marijuana-related AEs: one days before study sessions. impairment, sedation, confusion, and subject developed an intractable The study consisted of three test hunger. The 7% THC marijuana smoking-related cough during marijuana sessions with an interval of 3–21 days increased anxiety scores and bad drug administration and the sole marijuana- between sessions. Treatment conditions effect (later in session) compared to naı¨ve subject in the study experienced were high-strength marijuana (7% delta- placebo. Neither strength of marijuana an incident of acute cannabis-induced 9–THC), low-strength marijuana (3.5% affected the measures of mood. On psychosis.33 delta-9–THC), and placebo cigarettes, neurocognitive measures, both the 3.5% The authors conclude that smoked administered through a standardized THC and 7% THC marijuana produced marijuana effectively reduced chronic cued-puff procedure: (1) ‘‘light the impairment in learning and memory, neuropathic pain from HIV-associated cigarette’’ (30 seconds), (2) ‘‘get ready’’ while only the 7% THC marijuana sensory neuropathy. The limitations of (5 seconds), (3) ‘‘inhale’’ (5 seconds), (4) impaired attention and psychomotor this study include: a lack of information ‘‘hold smoke in lungs’’ (10 seconds), (5) speed, compared to placebo. There were about the number of puffs during each ‘‘exhale,’’ and (6) wait before repeating no adverse cardiovascular side effects inhalation of smoke; a lack of the puff cycle (40 seconds). Participants and no subjects dropped out because of information about the specific timing of took 2 puffs after baseline an adverse event related to marijuana. the subjective assessments and measurements, 3 puffs an hour later, The authors conclude that marijuana collection of AEs relative to initiation of and 4 puffs an hour after that, for a may be effective at ameliorating the smoking sessions; and the inclusion cumulative dose of 9 puffs per test neuropathic pain at doses that induce of only one marijuana-naı¨ve subject. session. mild cognitive effects, but that smoking These limitations make it difficult to Hourly assessment periods were is not an optimum route of conclude that the actual AEs scheduled before and after each set of administration. The limitations of this experienced during the study in puffs and for 2 additional hours during study include: inclusion of subjects response to marijuana are tolerable. It is the recovery period. Plasma with many forms of neuropathic pain especially concerning that the only cannabinoids were measured at and maintenance of subjects on other marijuana-naı¨ve subject left the study baseline, 5 minutes after the first puff analgesic medication while being tested because of serious psychiatric responses and again at 3 hours after the last puff with marijuana. These limitations make cycle. it difficult to conclude that marijuana 33 At the time of the study, the following criteria The primary outcome measure was has analgesic properties on its own and from the Diagnostic and Statistical Manual of spontaneous pain relief, as measured by that the actual AEs experienced during Mental Disorders (DSM–IV–TR, 2000) were used to diagnose substance-induced psychotic disorders: a 0–100 point VAS for current pain. the study in response to marijuana are Prominent hallucinations or delusions; Pain unpleasantness was measured on a tolerable. The authors compared pain Hallucinations and/or delusions that develop 0–100 point VAS, and degree of pain score results by the type of pain during, or within one month of, intoxication or relief was measured on a 7-point Patient condition, with no significant withdrawal; The disturbance is not better accounted for by a psychotic disorder that is not substance Global Impression of Change (PGIC) differences found; however, the sample induced. The disturbance does not occur scale. Secondary measures included the size of this study was small thus a type exclusively during the course of a delirium. Neuropathic Pain Scale (NPS), a 0–100 II error may have been present. Thus, it

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is difficult to determine if any particular questionnaires on pain intensity, sleep, required to have a history of marijuana subset of neuropathic pain conditions medication and AEs. Subjects returned use, they refrained from use of would benefit specifically from on the fifth day to complete cannabinoids for 30 days before study marijuana administration. However, the questionnaires on pain quality, mood, sessions. study produced positive results quality of life and assessments of Subjects participated in three sessions suggesting that marijuana should be potency. At the end of the study, in which they received 1.29% or 3.53% studied further as an adjunct treatment participants completed final adverse THC marijuana or placebo marijuana. for uncontrolled neuropathic pain. event reports and potency assessments. The marijuana was vaporized using the The second study, conducted by Ware The average daily pain intensity was Volcano vaporizer and a standardized et al. (2010) in Canada is entitled, significantly lower on 9.4% THC cued-puff procedure: (1) ‘‘hold the ‘‘Smoked cannabis for chronic marijuana (5.4) than on placebo vaporizer bag with one hand and put the neuropathic pain: a randomized marijuana (6.1) (p = 0.023). The 9.4% vaporizer mouthpiece in their mouth’’ controlled trial’’. The subjects were 21 THC strength also produced more (30 seconds), (2) ‘‘get ready’’ (5 adult patients with neuropathic pain drowsiness, better sleep, with less seconds), (3) ‘‘inhale’’ (5 seconds), (4) caused by trauma or surgery anxiety and depression, compared to ‘‘hold vapor in lungs’’ (10 seconds), (5) compounded with allodynia or placebo (all p < 0.05). However, there ‘‘exhale and wait’’ before repeating puff hyperalgesia, and a pain intensity score were no significant differences on cycle (40 seconds). Subjects inhaled 4 greater than 4 on a 10 point VAS. All POMS scores or on VAS scores for high, puffs at 60 minutes. At 180 minutes, the subjects maintained their current happy, relaxed or stressed between THC vaporizer was refilled with marijuana analgesic medication and they were doses. vapor and subjects were allowed to allowed to use acetaminophen for The most frequent drug-related inhale 4 to 8 puffs using the cued breakthrough pain. Eighteen subjects adverse events reported in the group procedure. Thus, cumulative dosing had previous experience with marijuana receiving 9.4% THC marijuana were allowed for a range of 8 to12 puffs in but none of them had used marijuana headache, dry eyes, burning sensation, total for each session, depending on the within a year before the study. dizziness, numbness and cough. Reports subjects desired response and tolerance. The study design used a four-period of high and euphoria occurred on only The washout time between each session crossover design, testing marijuana three occasions, once in each dose of ranged from 3–14 days. (2.5%, 6.0% and 9.4% THC) and THC. There were no significant changes The primary outcome variable was placebo marijuana. The 2.5% and 6.0% in vital signs, heart-rate variability, or spontaneous pain relief, as assessed doses of marijuana were included to renal function. One subject withdrew using a 0–100 point VAS for current increase successful blinding. Each from the study due to increased pain pain. Secondary measures included the period was 14 days in duration, during administration of 6% THC Patient Global Impression of Change beginning with 5 days on the study drug marijuana. (PGIC), the Neuropathic Pain Scale followed by a 9-day washout period. The authors conclude that smoked (NPS), a 0–100 point VAS for allodynia. Doses were delivered as 25 mg of marijuana reduces neuropathic pain, Acute pain threshold was measured marijuana that was smoked in a single improves mood and aids in sleep, but with a thermal pain model. Subjective inhalation using a titanium pipe. The that smoking marijuana is not a measures included 0–100 point unipolar first dose of each period was self- preferable route of administration. The VAS for any drug effect, good drug administered using a standardized puff limitations of this study include: The effect, bad drug effect, high, drunk, procedure: (1) Inhale for 5 seconds, (2) lack of information on timing of impaired, stoned, drug liking, sedated, hold the smoke in their lungs for 10 assessments during the outpatient confused, nauseated, desire more drug, seconds, and (3) exhale. Subsequent portion of the study and maintenance of anxious, down and hungry. Bipolar 0– doses were self-administered in the subjects on other analgesic medication 100 point VAS included sad/happy, same manner for a total of three times while being tested with marijuana. anxious/relaxed, jittery/calm, bad/good, daily at home on an outpatient basis for These limitations make it difficult to paranoid/self-assured, and fearful/ the first five days of each period. conclude that marijuana has analgesic unafraid. Neurocognitive assessments The primary measure was an 11-point properties on its own and that the actual assessed attention and concentration, pain intensity scale, averaged over the 5 AEs experienced during the study in learning and memory, and fine motor day treatment period, which was response to marijuana are tolerable. speed. administered once daily for present, However, the study produced positive A 30% reduction in pain was worst, least and average pain intensity results suggesting that marijuana should achieved in 61% of subjects who during the previous 24 hours. be studied further as an adjunct received the 3.53% THC marijuana, in Secondary measures included an acute treatment for uncontrolled neuropathic 57% of subjects who received the 1.29% pain 0–100 point VAS, pain quality pain. THC marijuana and in 26% of subjects assessed with the McGill Pain Wilsey et al. (2013) conducted the who received the placebo marijuana (p Questionnaire, sleep assessed with the most recent study entitled, ‘‘Low-Dose = 0.002 for placebo vs. 3.53% THC, p = Leeds Sleep Evaluation Questionnaire, Vaporized Cannabis Significantly 0.007 for placebo vs 1.29% THC; p > mood assessed with the POMS, quality Improves Neuropathic Pain’’. This study 0.05 1.29% THC vs. 3.53% THC). Both of life assessed using the EQ–5D health is the only one in this review that strengths of marijuana significantly outcome instrument. Subjective utilized vaporization as a method of decreased pain intensity, measures included 0–100 point VAS marijuana administration. The subjects unpleasantness, sharpness, and scales for high, relaxed, stressed and were 36 patients with a neuropathic deepness on the NPS, as well as pain happy. pain disorder (CRPS, thalamic pain, ratings on the PGIC, compared to Over the first three hours after spinal cord injury, peripheral placebo. These effects on pain were smoking marijuana, ratings of pain, neuropathy, radiculopathy, or nerve maximal with cumulative dosing over high, relaxation, stress, happiness and injury) who were maintained on their the course of the study session, with heart rate were recorded. During the five current medications (opioids, maximal effects at 180 minutes. There days of each study period, participants anticonvulsants, antidepressants, and were no effects of marijuana compared were contacted daily to administer NSAIDs). Although subjects were to placebo on measures of allodynia or

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thermal pain. Subjects correctly positive patients who were maintained dose of dronabinol. The 3.9% THC identified the study treatment 63% of on two antiretroviral medications and marijuana increased ratings of good the time for placebo, 61% of the time for either had clinically significant drug effect, drug liking and desire to 1.29% THC, and 89% of the time for decreases in lean muscle mass 34 (low- smoke again compared with placebo. 3.53% THC. BIA group, n = 15) or normal lean Ratings of sedation were increased in On subjective measures, marijuana muscle mass (normal-BIA group, n = both groups by 10 and 30 mg produced dose-dependent increases 15). All subjects had a history of dronabinol, and in the normal BIA compared to placebo on ratings for: any smoking marijuana at least twice weekly group by the 2.8% THC marijuana. drug effect, good drug effect, drug for 4 weeks prior to entry into the study. Ratings of stimulation were increased in liking, high, stoned, sedated, confused, On average, individuals had smoked 3 the normal BIA group by 2.8% and and hungry. Both strengths of marijuana marijuana cigarettes per day, 5–6 times 3.9% THC marijuana and by 20 mg produced similar increases in drunk or per week for 10–12 years. dronabinol. Increases in ratings of impaired compared to placebo. In Subjects participated in 8 sessions forgetfulness, withdrawn, dreaming, contrast, desire for drug was rated as that tested the acute effects of 0, 10, 20, clumsy, heavy limbs, heart pounding, higher for the 1.29% THC marijuana and 30 mg dronabinol oral capsules and jittery, and decreases in ratings of compared to the 3.53% THC marijuana. marijuana cigarettes with 0%, 1.8%, energetic, social, and talkative were There were no changes compared to 2.8%, and 3.9% THC concentration by reported in the normal BIA group with placebo for bad effect, nauseous, weight, using a double-dummy design 30 mg dronabinol. There were no anxiety, feeling down or any of the (with only one active drug per session). significant changes in vital signs or bipolar mood assessments. There was The doses of dronabinol are higher than performance on neurocognitive dose-dependent impairment on learning those doses typically prescribed for measures in response to marijuana. and memory from marijuana compared appetite stimulation in order to help Notably, the time course of subjective to placebo, but similar effects between preserve the blinding. There was a one- effects peaked quickly and declined the two strengths of marijuana on day washout period between test thereafter for smoked marijuana, while attention. sessions. oral dronabinol responses took longer to The authors conclude that Marijuana was administered using a peak and persisted longer. Additionally, vaporization of relatively low doses of standardized cued procedure: (1) ‘‘light marijuana but not dronabinol produced marijuana can produce improvements in the cigarette’’ (30 seconds), (2) dry mouth and thirst. analgesia in neuropathic pain patients, ‘‘prepare’’ (5 seconds), (3) ‘‘inhale’’ (5 In general, AEs reported in this study especially when patients are allowed to seconds), (4) ‘‘hold smoke in lungs’’ (10 were low in both drug conditions for titrate their exposure. However, this seconds), and (5) ‘‘exhale.’’ Each subject both subject groups. In the low BIA individualization of doses may account smoked three puffs in this manner, with group, nausea was reported by one for the general lack of difference a 40-second interval between each puff. subject in both the 10 and 20 mg between the two strengths of marijuana. Caloric intake was used as a surrogate dronabinol conditions, while an No data were presented regarding the measure for weight gain. Subjects uncomfortable level of intoxication was total amount of THC consumed by each received a box containing a variety of produced by the 30 mg dose in two subject, so it is difficult to determine a food and beverage items and were told subjects. There were no AEs reported in proper dose-response evaluation. to record consumption of these items this group following marijuana at any Additional limitations of this study are following that day’s administration of dose. In the normal BIA group, the 30 the inclusion of subjects with many the test drug. Subjective measures mg dose of dronabinol produced an forms of neuropathic pain and included 0–100 point VAS for feel drug uncomfortable level of intoxication in maintenance of subjects on other effect, good effect, bad effect, take drug three subjects and headache in one analgesic medication while being tested again, drug liking, hungry, full, subject, while the 3.9% marijuana with marijuana. These limitations make nauseated, thirsty, desire to eat. produced diarrhea in one subject. it difficult to conclude that marijuana Neurocognitive measures and vital signs The authors conclude that smoked has analgesic properties on its own. It is were monitored. marijuana can acutely increase caloric also difficult to determine if any The low BIA group consumed intake in low BIA subjects without particular subset of neuropathic pain significantly more calories in the 1.8% significant cognitive impairment. conditions would benefit specifically and 3.9% THC marijuana conditions (p However, it is possible that the low from marijuana administration. < 0.01) and the 10, 20, and 30 mg degree of cognitive impairment reported However, the study produced positive dronabinol conditions (p < 0.01) in this study may reflect the results suggesting that marijuana should compared with the placebo condition. development of tolerance to be studied further as an adjunct In contrast, in the normal BIA group, cannabinoids in this patient population, treatment for uncontrolled neuropathic neither marijuana nor dronabinol since all individuals had current pain. significantly affected caloric intake. histories of chronic marijuana use. This lack of effect may be accountable, Additional limitations in this study 3.2 Appetite Stimulation in HIV however, by the fact that this group include not utilizing actual weight gain Two randomized, double-blind, consumed approximately 200 calories as a primary measure. However, the placebo-controlled Phase 2 studies more than the low BIA group under study produced positive results examined the effects of smoked baseline conditions. suggesting that marijuana should be marijuana on appetite in HIV-positive Ratings of high and good drug effect studied further as a treatment for subjects (Haney et al., 2005; Haney et were increased by all drug treatments in appetite stimulation in HIV patients. al., 2007). Table 2 of the Appendix both the low-BIA and normal-BIA A second study conducted by Haney summarizes both studies. groups, except in response to the 10 mg et al. (2007) is entitled, ‘‘Dronabinol and The first study, conducted by Haney marijuana in HIV-positive marijuana et al. (2005) is entitled, ‘‘Dronabinol and 34 Lean muscle mass was assessed using smokers: Caloric intake, mood, and bioelectrical impedance analysis (BIA). The low- marijuana in HIV+ marijuana smokers: BIA group was classified with having <90% BIA, sleep’’. The design of this study was acute effects on caloric intake and and the normal-BIA group was classified with nearly identical to the one conducted by mood’’. The subjects were 30 HIV- having >90% BIA. this laboratory in 2005 (see above), but

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there was no stratification of subjects by increased the desire to eat and ratings of The primary outcome measure was BIA. The subjects were 10 HIV-positive hunger. change in spasticity on the modified patients who were maintained on two Ratings of good drug effect, high, drug Ashworth scale. Additionally, subjects antiretroviral medications and had a liking, and desire to smoke again were were assessed using a VAS for pain, a history of smoking marijuana at least significantly increased by 10 mg timed walk, and cognitive tests (Paced twice weekly for 4 weeks prior to entry dronabinol and 2.0% and 3.9% THC Auditory Serial Addition Test) and AEs. into the study. On average, individuals marijuana doses compared to placebo. Treatment with 4.0% THC marijuana had smoked 3 marijuana cigarettes per Both marijuana doses increased ratings reduced subject scores on the modified day, 5 times per week for 19 years. of stimulated, friendly, and self- Ashworth scale by an average of 2.74 Subjects participated in 8 sessions confident. The 10 mg dose of dronabinol points more than placebo (p < 0.0001) that tested the acute effects of 0, 5 and increased ratings of concentration and reduced VAS pain scores compared 10 mg dronabinol oral capsules and impairment, and the 2.0% THC to placebo (p = 0.008). Scores on the marijuana cigarettes with 0, 2.0% and marijuana dose increased ratings of cognitive measure decreased by 8.7 3.9% THC concentration by weight, anxious. Dry mouth was induced by 10 points more than placebo (p = 0.003). using a double-dummy design (with 4 mg dronabinol (10 mg) and 2.0% THC However, marijuana did not affect sessions involving only one active drug marijuana. There were no changes in scores for the timed walk compared to and 4 interspersed placebo sessions). neurocognitive performance or objective placebo. Marijuana increased rating of Both drug and placebo sessions lasted sleep measures from administration of feeling high compared to placebo. for 4 days each, with active drug either cannabinoid. However, 3.9% THC 7 subjects did not complete the study administration occurring 4 times per marijuana increased subjective ratings due to adverse events (two subjects felt day (every 4 hours). Testing occurred in of sleep. uncomfortably ‘‘high’’, two had two 16-day inpatient stays. In the The authors conclude that both dizziness and one had fatigue). Of those intervening outpatient period, subjects dronabinol and smoked marijuana 7 subjects who withdrew, 5 had little or were allowed to smoke marijuana prior increase caloric intake and produce no previous experience with marijuana. to re-entry to the study unit for the weight gain in HIV-positive patients. When the data were re-analyzed to second inpatient stay. However, it is possible that the low include these drop-out subjects, with degree of cognitive impairment reported the presumption they did not have a Marijuana was administered using a in this study may reflect the positive response to treatment, the effect standardized cued procedure: (1) ‘‘light development of tolerance to of marijuana was still significant on the cigarette’’ (30 seconds), (2) cannabinoids in this subject population, spasticity. ‘‘prepare’’ (5 seconds), (3) ‘‘inhale’’ (5 since all individuals had current The authors conclude that smoked seconds), (4) ‘‘hold smoke in lungs’’ (10 histories of chronic marijuana use. This marijuana had usefulness in reducing seconds), and (5) ‘‘exhale.’’ Each subject study produced positive results pain and spasticity associated with MS. smoked three puffs in this manner, with suggesting that marijuana should be It is concerning that marijuana-naı¨ve a 40-second interval between each puff. studied further as a treatment for subjects dropped out of the study Caloric intake was used as a surrogate appetite stimulation in HIV patients. because they were unable to tolerate the measure for weight gain, but subjects psychiatric AEs induced by marijuana. were also weighed throughout the study 3.3 Spasticity in Multiple Sclerosis The authors suggest that future studies (a measure which was not collected in Only one randomized, double-blind, should examine whether different doses the 2005 study by this group). Subjects placebo-controlled Phase 2 study can result in similar beneficial effects received a box containing a variety of examined the effects of smoked with less cognitive impact. However, food and beverage items and were told marijuana on spasticity in MS. the current study produced positive to record consumption of these items This study was conducted by Corey- results suggesting that marijuana should following that day’s administration of Bloom et al. (2012) and is entitled, be studied further as an adjunct the test drug. Subjective measures ‘‘Smoked cannabis for spasticity in treatment for spasticity in MS patients. included 0–100 point VAS for drug multiple sclerosis: A randomized, effect, good effect, bad effect, take drug placebo-controlled trial’’. The subjects 3.4 Asthma again, drug liking, hungry, full, were 30 patients with MS-associated Tashkin et al. (1974) examined nauseated, thirsty, desire to eat. spasticity and had moderate increase in bronchodilation in 10 subjects with Neurocognitive measures and vital signs tone (score ≥ 3 points on the modified bronchial asthma in the study entitled, were monitored. Sleep was assessed Ashworth scale). Participants were ‘‘Acute Effects of Smoked Marijuana using both the Nightcap sleep allowed to continue other MS and Oral D9-Tetrahydrocannabinol on monitoring system and selected VAS medications, with the exception of Specific Airway Conductance in measures related to sleep. benzodiazepines. Eighty percent of Asthmatic Subjects’’. The study was a Both 5 and 10 mg dronabinol (p < subjects had a history of marijuana use double-blind, placebo-controlled, 0.008) and 2.0% and 3.9% THC and 33% had used marijuana within the crossover design. All subjects were marijuana (p < 0.01) dose-dependently previous year. clinically stable at the time of the study; increased caloric intake compared with Subjects participated in two 3-day test four subjects were symptom free, and placebo. This increase was generally sessions, with an 11 day washout six subjects had chronic symptoms of accomplished through increases in period. During each test session they mild to moderate severity. Subjects were incidents of eating, rather than an smoked a 4.0% THC marijuana cigarette tested with 0.25ml of isoproterenol HCl increase in the calories consumed in once per day or a placebo cigarette once prior to the study to ensure they each incident. Subjects also gained per day. Smoking occurred through a responded to bronchodilator similar amounts of weight after the standardized cued-puff procedure: (1) medications. Subjects were not allowed highest dose of each cannabinoid Inhalation for 5 seconds, (2) breath-hold to take bronchodilator medication treatment: 1.2 kg (2.6 lbs) after 4 days and exhalation for 10 seconds, (3) pause within 8 hours prior to the study. of 10 mg dronabinol, and 1.1 kg (2.4 lbs) between puffs for 45 seconds. Subjects Previous experience with marijuana was after 4 days of 3.9% THC marijuana. completed an average of four puffs per not required for participation in the The 3.9% THC marijuana dose also cigarette. study, but 7 of the 10 subjects reported

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previous use of marijuana at a rate of however, since the FEV1 method was under development, the effect often less than 1 marijuana cigarette per not utilized, it is unclear whether these relates to a short-term clinical outcome month. No subjects reported marijuana results would correlate if the FEV1 being investigated. Proof-of-concept use within 7 days of the study. method had been employed. studies serve as the link between The study consisted of four test 3.5 Glaucoma preclinical studies and dose ranging sessions with an interval of at least 48 clinical studies. Therefore, proof-of- hours between sessions. On two test Two randomized, double-blind, concept studies are not sufficient to sessions subjects smoked 7 mg/kg of placebo-controlled Phase 2 clinical demonstrate efficacy of a drug because body weight of either marijuana, with studies examined smoked marijuana in they provide only preliminary 2% THC concentration by weight, or glaucoma (Crawford and Merritt, 1979; information about the effects of a drug. placebo marijuana. During the other two Merritt et al., 1980). In both studies, Although these studies do not provide test sessions, subjects ingested capsules intraocular pressure (IOP) was evidence that marijuana is effective in with either 15mg of synthetic THC or significantly reduced 30 minutes after treating a specific, recognized disorder, placebo. Marijuana was administered smoking marijuana. Maximal effects these studies do support future larger using a uniform smoking technique: occurred 60–90 minutes after smoking, well-controlled studies to assess the with IOP returning to baseline within 3– subjects inhaled deeply for 2–4 seconds, safety and efficacy of marijuana for a 4 hours. These two studies were held smoke in lungs for 15 seconds, and specific medical indication. Overall, the included in the 1999 IOM report on the resumed normal breathing for conclusions below are preliminary, medical uses of marijuana. Because our approximately 5 seconds. The author based on very limited evidence. did not provide a description of the independent analysis of these studies number of puffs taken at any smoking concurred with the conclusions from 3.6.1 Conclusions for Chronic session. The authors state that the the 1999 IOM report, these studies will Neuropathic Pain smoking procedure was repeated until not be discussed in further detail in this the cigarette was consumed, which took review. No recent studies have been In subjects with chronic neuropathic approximately 10 minutes. conducted examining the effect of pain who are refractory to other pain The outcome measure used was inhaled marijuana on IOP in glaucoma treatments, five proof-of-concept studies specific airway conductance (SGaw), as patients. This lack of recent studies may produced positive results regarding the calculated using measurements of be attributed to the conclusions made in use of smoked marijuana for analgesia. thoracic gas volume (TGV) and airway the 1999 IOM report that while However, the subjects in these studies resistance (Raw) using a variable- cannabinoids can reduce intraocular continued to use their current analgesic pressure body plethysmograph. pressure (IOP), the therapeutic effects drug regime, and thus no conclusions Additionally, an assessment of degree of require high doses that produce short- can be made regarding the potential intoxication was administered only to lasting responses, with a high degree of efficacy of marijuana for neuropathic those subjects reporting previous AEs. This high degree of AEs means that pain in patients not taking other marijuana use. This assessment the potential harmful effects of chronic analgesic drugs. Subjects also had consisted of subjects rating ‘‘how ‘high’ marijuana smoking may outweigh its numerous forms of neuropathic pain, they felt’’ on a scale of 0–7, 7 modest benefits in the treatment of making it difficult to identify whether a representing ‘‘the ‘highest’ they had ever glaucoma. specific set of symptoms might be more felt after smoking marijuana’’. 3.6 Conclusions responsive to the effects of marijuana. It Marijuana produced a significant is especially concerning that some increase of 33–48% in average SGaw Of the eleven randomized, double- marijuana-naı¨ve subjects had intolerable compared to both baseline and placebo blind, placebo-controlled Phase 2 psychiatric responses to marijuana (P < 0.05). This significant increase in clinical studies that met the criteria for exposure at analgesic doses. SGaw lasted for at least 2 hours after review (see Sections 2.2 and 2.3), ten administration. The average TGV studies administered marijuana through 3.6.2 Conclusions for Appetite significantly decreased by 4–13% smoking, while one study utilized Stimulation in HIV compared to baseline and placebo (P < marijuana vaporization. In these eleven 0.05). The author stated that all subjects studies, there were five different In subjects who were HIV-positive, reported feelings of intoxication after therapeutic indications: Five examined two proof-of-concept studies produced marijuana administration. chronic neuropathic pain, two positive results with the use of both The authors conclude that marijuana examined appetite stimulation in HIV dronabinol and smoked marijuana to produced bronchodilation in clinically patients, two examined glaucoma, one increase caloric intake and produce stable asthmatic subjects with minimal examined spasticity in MS, and one weight gain in HIV-positive patients. to moderate bronchospasms. Study examined asthma. However, the amount of THC in the limitations include: inclusion of There are limited conclusions that can marijuana tested in these studies is four subjects with varying severity of be drawn from the data in these times greater than the dose of asthmatic symptoms, use of SGaw to published studies evaluating marijuana dronabinol typically tested for appetite measure lung responses to marijuana for the treatment of different therapeutic stimulation (10 mg vs. 2.5 mg; Haney et administration, and administration of indications. The analysis relied on al., 2005). Thus, it is possible that the smoke to asthmatic subjects. Smoke published studies, thus information low degree of AEs reported in this study delivers a number of harmful substances available about protocols, procedures, may reflect the development of and is not an optimal delivery symptom, and results were limited to documents tolerance to cannabinoids in this patient especially for asthmatic patients. FEV1 published and widely available in the population, since all individuals had via spirometry is the gold standard to public domain. The published studies current histories of chronic marijuana assess changes in lung function, pre and on medical marijuana are effectively use. Thus, individuals with little prior post asthma treatment, by proof-of-concept studies. Proof-of- exposure to marijuana may not respond pharmacotherapy. SGaw has been concept studies provide preliminary similarly and may not be able to tolerate shown to be a valid tool in evidence on a proposed hypothesis sufficient marijuana to produce appetite bronchoconstriction lung assessment; regarding a drug’s effect. For drugs stimulation.

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3.6.3 Conclusions for Spasticity in MS and efficacy for a particular therapeutic dosing. Specifically for marijuana In subjects with MS, a proof of use. studies, dose standardization is important because if marijuana leads to concept study produced positive results 3.7.1 Sample Size plasma levels of cannabinoids that are using smoked marijuana as a treatment The ability for results from a clinical for pain and symptoms associated with significantly different between subjects, study to be generalized to a broader this variation may lead to differences in treatment-resistant spasticity. The population is reliant on having a subjects in this study continued to take therapeutic responsivity or in the sufficiently large study sample size. prevalence of psychiatric AEs. their current medication regiment, and However, as noted above, all of the 11 thus no conclusions can be made In most marijuana studies discussed studies reviewed in this document were in this review, investigators use a regarding the potential efficacy of early Phase 2 proof of concept studies marijuana when taken on its own. It is standardized cued smoking procedure. for efficacy and safety. Thus, the sample In this procedure, a subject is instructed also concerning that marijuana-naı¨ve sizes used in these studies were subjects dropped out of the study to inhale marijuana smoke for 5 inherently small, ranging from 10 seconds, hold the smoke in the lungs for because they were unable to tolerate the subjects per treatment group (Tashkin et psychiatric AEs induced by marijuana. 10 seconds, exhale and breathe al., 1974; Haney et al., 2007) to 25 normally for 40 seconds. This process is The authors suggest that future studies subjects per treatment group (Abrams et should examine whether different doses repeated to obtain the desired dose of al., 2007). These sample sizes are the drug. However, this procedure may can result in similar beneficial effects statistically inadequate to support a with less cognitive impact. not lead to equivalent exposure to showing of safety or efficacy. FDA’s marijuana and its constituent 3.6.4 Conclusions for Asthma recommendations about sample sizes for cannabinoids, based on several factors: clinical trials can be found in the • In subjects with clinically stable Intentional or unintentional Guidance for Industry: E9 Statistical asthma, a proof of concept study differences in the depth of inhalation Principles for Clinical Trials (1998).35 produced positive results of smoked may change the amount of smoke in the For example, ‘‘the number of subjects in marijuana producing bronchodilation. subject’s lungs. a clinical trial should always be large • However, in this study marijuana was Smoking results in loss from side enough to provide a reliable answer to administered at rest and not while stream smoke, such that the entire dose the questions addressed. This number is experiencing bronchospasms. is not delivered to the subject. usually determined by the primary • Additionally, the administration of There may be differences in THC objective of the trial. The method by marijuana through smoking introduces concentration along the length of a which the sample size is calculated harmful and irritating substances to the marijuana cigarette. According to should be given in the protocol, together subject, which is undesirable especially Tashkin et al. (1991), the area of the with the estimates of any quantities in asthmatic patients. Thus the results cigarette closest to the mouth tends to used in the calculations (such as suggest marijuana may have accumulate a higher concentration of variances, mean values, response rates, bronchodilator effects, but it may also THC, but this section of the cigarette is event rates, difference to be detected).’’ have undesirable adverse effects in not smoked during a study. (pg. 21). Other clinical FDA Guidance For example, Wilsey et al. (2008) used subjects with asthma. 36 for Industry may also contain this standardized smoking procedure. 3.6.5 Conclusions for Glaucoma recommendations regarding the The reported mean (range) of marijuana appropriate number of subjects that As noted in Sections 3.5, the two cigarettes consumed was 550 mg (200– should be investigated for a specific studies that evaluated smoked 830mg) for the low strength marijuana medical indication. marijuana for glaucoma were conducted (3.5% THC) and 490 mg (270–870mg) decades ago, and they have been 3.7.2 Marijuana Dose Standardization for the high strength marijuana (7% THC). This wide range of amounts of thoroughly evaluated in the 1999 IOM Dose standardization is critical for marijuana cigarette smoked by the report. The 1999 IOM report concludes any clinical study in order to ensure individual subjects, even with that while the studies with marijuana that each subject receives a consistent standardized smoking procedure and showed positive results for reduction in exposure to the test drug. The Guidance controlled number of puffs, supports the IOP, the effect is short-lasting, requires for Industry: Botanical Drug Products issues with delivering consistent doses a high dose, and is associated with (2004) 37 provides specific information with smoke marijuana. many AEs. Thus, the potential harmful on the development of botanical drug In other marijuana studies that do not effects may outweigh any modest products. Specifically, this guidance use a cued smoking procedure, subjects benefit of marijuana for this condition. includes information about the need for are simply told to smoke the marijuana We agree with the conclusions drawn in well-characterized and consistent cigarette over a specific amount of time the 1999 IOM report. chemistry for the botanical plant (usually 10 minutes) without further product and for consistent and reliable 3.7 Design Challenges for Future instruction (Crawford and Merritt, 1979; Studies Merritt et al., 1980; Ellis et al., 2009). 35 The Guidance for Industry: E9 Statistical The positive results reported by the Principles for Clinical Trials can be found at: The use of a nonstandardized procedure studies discussed in this review support www.fda.gov/downloads/Drugs/ may lead to non-equivalent exposures to the conduct of more rigorous studies in GuidanceComplianceRegulatoryInformation/ marijuana and its constituent the future. This section discusses Guidances/ucm073137.pdf. cannabinoids between subjects because 36 Other Guidances for Industry can be found at: methodological challenges that have www.fda.gov/Drugs/ of additional factors that are not listed occurred in clinical studies with GuidanceComplianceRegulatoryInformation/ above, such as: smoked marijuana. These design issues Guidances/ucm064981.htm. • Differences in absorption and drug should be addressed when larger-scale 37 The Guidance for Industry: Botanical Drug response if subjects (especially Products can be found at: http://www.fda.gov/ ¨ clinical studies are conducted to ensure downloads/Drugs/ marijuana-naıve ones) are not instructed that valid scientific data are generated GuidanceComplianceRegulatoryInformation/ to hold marijuana smoke in their lungs in studies evaluating marijuana’s safety Guidances/ucm070491.pdf. for a certain period of time.

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• Prolonged periods between puffs physical dependence, or specific Marijuana on the other hand, has a may increase loss to side stream smoke. adverse events develop over the course unique set of psychoactive effects which • Subjects may attempt to smoke the of time with continuing use of makes the use of appropriate positive marijuana cigarette in the way they therapeutic marijuana. controls difficult (Barrett et al., 1995). would smoke a tobacco cigarette, which However, two studies did use 3.7.4 Smoking as a Route of relies primarily on short, shallow puffs. Dronabinol as a positive control drug to Administration In both standardized and non- help maintain blinding (Haney et al., standardized smoking procedures, As has been pointed out by the IOM 2005; Haney et al., 2007). subjects may seek to control the dose of and other groups, smoking is not an When blinding is done using only THC through self-titration (Crawford optimum route of administration for placebo marijuana, the ability to and Merritt, 1979; Merritt et al., 1980; marijuana-derived therapeutic drug distinguish active from placebo Tashkin et al., 1974; Abrams et al., 2007; products, primarily because introducing marijuana may lead to expectation bias Ellis et al., 2009). Self-titration involves the smoke from a burnt botanical and an alteration in perceived an individual moderating the amount of substance into the lungs of individuals responsivity to the therapeutic outcome marijuana smoke inhaled over time in with a disease state is not recommended measures. With marijuana-experienced order to obtain a preferred level of when their bodies may be physically subjects, for example, there may be an psychoactive or clinical response. The compromised. The 1999 IOM report on early recognition of the more subtle ability of an individual to self-titrate by medicinal uses of marijuana noted that cannabinoid effects that can serve as a smoking is one reason given by alternative delivery methods offering harbinger of stronger effects, which is advocates of ‘‘medical marijuana’’ in the same ability of dose titration as less likely to occur with marijuana- support of smoking of marijuana rather smoking marijuana will be beneficial naı¨ve subjects. To reduce this than through its ingestion via edibles. and may limit some of the possible long- possibility, investigators have tested However, for research purposes, self- term health consequences of smoking doses of marijuana other than the one titration interferes with the ability to marijuana. The primary alternative to they were interested in experimentally maintain consistent dosing levels smoked marijuana is vaporization, to maintain the blind (Ware et al., 2010). between subjects, and thus, valid which can reduce exposure to Blinding can also be compromised by comparisons between study groups. combusted plant material containing differences in the appearance of All of these factors can make the exact cannabinoids. The only study to use marijuana plant material based on THC dose of cannabinoids received by a vaporization as the delivery method was concentration. Marijuana with higher subject in a marijuana study difficult to Wilsey et al. (2013). The results from concentrations of THC tends to be determine with accuracy. Testing Wilsey et al. (2013) showed a similar heavier and seemingly darker, with whether plasma levels of THC or other effect of decreased pain as seen in the more ‘‘tar-like’’ substance. Subjects who cannabinoids are similar between other studies using smoking as the have experience with marijuana have subjects following the smoking delivery method (Ware et al., 2010; reported being able to identify procedure would establish whether the Wilsey et al., 2008). This similar effect marijuana from placebo cigarettes by procedure is producing appropriate of decrease pain supports vaporization sight alone when the plant material in results. Additionally, studies could be as a possibly viable route to administer a cigarette was visible (Tashkin et al., conducted to determine if vaporization marijuana in research, while potentially 1974; Ware et al., 2010). Thus, to can be used to deliver consistent doses limiting the risks associated with maintain a double-blind design, many of cannabinoids from marijuana plant smoking. studies obscure the appearance of plant material. Specifically, vaporization material by closing both ends of the devices that involve the collection of 3.7.5 Difficulty in Blinding of Drug Conditions marijuana cigarette and placing it in in vapors in an enclosed bag or chamber an opaque plastic tube. may help with delivery of consistent An adequate and well-controlled While none of these methods to doses of marijuana. Thus, more clinical study involves double-blinding, secure blinding may be completely information could be collected on where both the subjects and the effective, it is important to reduce bias whether vaporization is comparable to investigators are unable to tell the as much as possible to produce or different than smoking in terms of difference between the test treatments consistent results between subjects producing similar plasma levels of THC (typically consisting of at least a test under the same experimental in subjects using identical marijuana drug and placebo) when they are conditions. plant material. administered. All of the studies reviewed in this document administered 3.7.6 Prior Marijuana Experience 3.7.3 Acute vs. Chronic Therapeutic study treatments under double-blind Marijuana use histories in test Marijuana Use conditions and thus were considered to subjects may influence outcomes, The studies that were reviewed have an appropriate study design. related to both therapeutic responsivity administered the drug for short However, even under the most and psychiatric AEs. Marijuana-naı¨ve durations lasting no longer than 5 days rigorous experimental conditions, subjects may also experience a (Abrams et al., 2007; Ellis et al., 2009; blinding can be difficult in studies with marijuana drug product as so aversive Ware et al., 2010). Thus all studies smoked marijuana because the rapid that they would not want to use the examined the short-term effect of onset of psychoactive effects readily drug product. Thus, subjects’ prior marijuana administration for distinguishes active from placebo experience with marijuana may affect therapeutic purposes. However, many of marijuana. The presence of the conduct and results of studies. the medical conditions that have been psychoactive effects also occurs with Most of the studies reviewed in this studied are persistent or expected to last other drugs. However, most other drugs document required that subjects have a the rest of a patient’s life. Therefore, have a similar psychoactive effect with history of marijuana use (see tables in data on chronic exposure to smoked substances with similar mechanisms of Appendix that describe specific marijuana in clinical studies is needed. actions. These substances can be used as requirements for each study). However, In this way, more information will be positive controls to help maintain in studies published in the scientific available regarding whether tolerance, blinding to the active drug being tested. literature, the full inclusion criteria with

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regard to specific amount of experience tolerability of and responses to a variety 4. References with marijuana may not be provided. of THC concentrations in marijuana. For those studies that do provide 1999. Marijuana and Medicine: Assessing the 3.7.7 Inclusion and Exclusion Criteria inclusion criteria, acceptable experience Science Base. Washington, DC: National with marijuana can range from once in For safety reasons, all clinical studies Academy Press. have inclusion and exclusion criteria Abrams DI, Hilton JF, Leiser RJ, Shade SB, a lifetime to use multiple times a day. Elbeik TA, Aweeka FT, Benowitz NL, The varying histories of use might that restrict the participation of Bredt BM, Kosel B, Aberg JA, Deeks SG, affect everything from scores on adverse individuals with certain medical Mitchell TF, Mulligan K, Bacchetti P, event measures, safety measures, or conditions. For studies that test McCune JM, and Schambelan M. 2003. efficacy measures. Additionally, varying marijuana, these criteria may be based Short-term effects of cannabinoids in amounts of experience can impact on risks associated with exposure to patients with HIV–1 infection: a smoked material and the effects of THC. randomized, placebo-controlled clinical cognitive effect measures assessed trial. Annals of Internal Medicine 139 during acute administration studies. For Thus, most studies investigating marijuana require that subjects qualify (4): 258–266. instance, Schreiner and Dunn (2012) Abrams DI, Jay CA, Shade SB, Vizoso H, contend cognitive deficits in heavy for the study based on restrictive Reda H, Press S, Kelly ME, Rowbotham marijuana users continue for symptom criteria such that individuals MC, and Petersen KL. 2007. Cannabis in approximately 28 days after cessation of do not have other symptoms that may be painful HIV-associated sensory smoking. Studies requiring less than a known to interact poorly with neuropathy: a randomized placebo- month of abstinence prior to the study cannabinoids. controlled trial. Neurology 68 (7): 515– Similarly, clinical studies with 521. may still see residual effects of heavy marijuana typically exclude individuals Appendino G, Chianese G, Taglialatela- use at baseline and after placebo with cardiac or pulmonary problems, as Scafati O. 2011. Cannabinoids: marijuana administration, thus showing well as psychiatric disorders. These occurrence and medicinal chemistry. no significant effects on cognitive Curr Med Chem. 18(7):1085–99. exclusion criteria are based on the well- measures. However, these same Barrett RL, Wiley JL, Balster RL, and Martin known effects of marijuana smoke to measurements in occasional or naı¨ve BR. 1995. Pharmacological specificity of produce increases in heart rate and 9 marijuana users may demonstrate a D -tetrahydrocannabinol discrimination blood pressure, lung irritation, and the in rats. Psychopharmacology 118(4): significant effect after acute marijuana exacerbation of psychiatric disturbances 419–424. administration. Therefore, the amount in vulnerable individuals. Although Chait LD, and Pierri J. 1989. Some physical of experience and the duration of these criteria are medically reasonable characteristics of NIDA marijuana abstinence of marijuana use are cigarettes. Addictive Behaviors 14 (1): for research protocols, it is likely that important to keep in mind when 61–67. future marijuana products will be used analyzing results for cognitive and other Chang AE, Shiling DJ, Stillman RC, Godlberg in patients who have cardiac, adverse event measures. Lastly, a study NH, Seipp CA, Barofsky I, Simon RM, pulmonary or psychiatric conditions. and Rosenberg SA. 1979. Delta-9- population with previous experience Thus, individuals with these conditions tetrahydrocannabinol as an antiemetic in with marijuana may underreport the should be evaluated, whenever possible. cancer patients receiving high-dose incidence and severity of adverse Additionally, all studies reviewed in methotrexate. Annals of Internal events. Because most studies used this document allowed the subjects to Medicine 91: 819–824. Corey-Bloom J, Wolfson T, Gamst A, Jin S, subjects with prior marijuana continue taking their current regimen of experience, we are limited in our ability Marcotte TD, Bentley H, and Gouaux B. medications. Thus all results evaluated 2012. Smoked cannabis for spasticity in to generalize the results, especially for marijuana as an adjunct treatment for safety measures, to marijuana naı¨ve multiple sclerosis: a randomized, each therapeutic indication. placebo-controlled trial. Canadian populations. Medical Association Journal 184 (10): Five of 11 studies reviewed in this 3.7.8 Number of Female Subjects 1143–1150. document included both marijuana- A common problem in clinical Crane NA, Schuster RM, Fusar-Poli P, and naı¨ve and marijuana-experienced research is the limited number of Gonzalez R. 2012. Effects of Cannabis on subjects (Corey-Bloom et al., 2012; Ellis females who participate in the studies. Neurocognitive Functioning: Recent et al., 2009; Ware et al., 2010; Merritt et This problem is present in the 11 Advances, Neurodevelopmental al., 1980; Tashkin et al., 1974). Since the Influences, and Sex Differences. studies reviewed in this document, in Neuropsychology Review. number of marijuana-naı¨ve subjects in which one study did not include any Crawford WJ, and Merritt JC. 1979. Effects of these studies was low, it was not female subjects (Ellis et al., 2009), and tetrahydrocannabinol on arterial and possible to conduct a separate analysis three studies had a low percentage of intraocular hypertension. International compared to experienced users. female subjects (Abrams et al., 2007; Journal of Clinical Pharmacology and However, systematically evaluating the Haney et al., 2005; Haney et al., 2007). biopharmacy 17 (5): 191–196. effect of marijuana experience on study However, each of these four studies Ellis RJ, Toperoff W, Vaida F, Van Den outcomes is important, since many investigated an HIV-positive patient Brande G, Gonzales J, Gouaux B, Bentley patients who might use a marijuana H, and Atkinson JH. 2009. Smoked population, where there may have been medicinal cannabis for neuropathic pain product for a therapeutic use will be a larger male population pool from in HIV: a randomized, crossover clinical marijuana-naı¨ve. which to recruit compared to females. trial. Neuropsychopharmacology 34 (3): Research shows that marijuana- Since there is some evidence that the 672–680. experienced subjects have a higher density of CB1 receptors in the brain Flom MC, Adams AJ, and Jones RT. 1975. ability to tolerate stronger doses of oral may vary between males and females Marijuana smoking and reduced pressure dronabinol than marijuana-naı¨ve (Crane et al., 2012), there may be in human eyes: drug action or subjects (Haney et al., 2005). Possibly, differing therapeutic or subjective epiphenomenon? Investigative this increased tolerance is also the case responsivity to marijuana. Studies using Opthalmology 14(1): 52–55. Foltin RW, Brady JV, and Fischamn MW. when subjects smoke or vaporize a study population that is equal parts 1986. Behavioral analysis of marijuana marijuana. Thus, studies could be male and female may show whether and effects on food intake in humans. conducted that investigate the role of how the effects of marijuana differ Pharmacology Biochemistry and marijuana experience in determining between male and female subjects. Behavior 25: 577–582.

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Foltin RW, Fischman MW, and Byrne MF. Merritt JC, Crawford WJ, Alexander PC, Tashkin DP, Gliederer F, Rose J, Chang P, Hui 1988. Effects of smoked marijuana on Anduze AL, and Gelbart SS. 1980. Effect KK, Yu JL, and Wu TC. 1991. Tar, CO food intake and body weight of humans of marihuana on intraocular and blood and delta 9THC delivery from the 1st living in a residential laboratory. pressure in glaucoma. Ophthalmology 87 and 2nd halves of a marijuana cigarette. Appetite 11: 1–14. (3): 222–228. Pharmacology Biochemistry and Greenberg HS, Werness SA, Pugh JE, Andrus Milstein SL, MacCannell KL, Karr GW, and Behavior 40 (3): 657–661. RO, Anderson DJ, and Domino EF. 1994. Clark S. 1974. Marijuana produced Tashkin DP, Shapiro BJ, Lee YE, Harper CE. Short-term effects of smoking marijuana changes in cutaneous sensitivity and 1975. Effects of smoked marijuana in on balance in patients with multiple affect: users and non-users. experimentally induced asthma. sclerosis and normal volunteers. Clinical Pharmacology Biochemistry and Pharmacology and Therapeutics 55 (3): Behavior 2:367–374. American Review of Respiratory Disease 324–328. Milstein SL, MacCannell K, Karr G, and Clark 112: 377–386. Greenwald MK and Stitzer ML. 2000. S. 1975. Marijuana-produced changes in Wallace M, Schulteis G, Atkinson JH, Antinociceptive, subjective, and pain tolerance: Experiences and non- Wolfson T, Lazzaretto D, Bentley H, behavioral effects of smoked marijuana experienced subjects. Int. Gouaux B, and Abramson I. 2007. Dose- in humans. Drug and Alcohol Pharmacopsychiat 10: 177–182. dependent effects of smoked cannabis on Dependence 59: 261–275. Naftali T, Schleider LB, Dotan I, Lansky EP, capsaicin-induced pain and hyperalgesia Haney M, Gunderson EW, Rabkin J, Hart CL, Benjaminov FS, and Konikoff FM. 2013. in healthy volunteers. Anesthesiology Vosburg SK, Comer SD, and Foltin RW. Cannabis induces a clinical response in 107 (5): 785–796. 2007. Dronabinol and marijuana in HIV- patients with Crohn’s disease: A Ware MA, Wang T, Shapiro S, Robinson A, positive marijuana smokers. Caloric prospective placebo-controlled study. Ducruet T, Huynh T, Gamsa A, Bennett intake, mood, and sleep. Journal of Clinical Gastroenterology and GJ, and Collet JP. 2010. Smoked cannabis Acquired Immune Deficiency Syndromes Hepatology 11: 1276–1280. for chronic neuropathic pain: a Russo E, Mathre ML, Byrne A, Velin R, Bach (1999) 45 (5): 545–554. randomized controlled trial. Canadian Haney M, Rabkin J, Gunderson E, and Foltin PJ, Sanchez-Ramos J, and Kirlin KA. Medical Association Journal 182 (14): RW. 2005. Dronabinol and marijuana in 2002. Chronic Cannabis Use in the E694–E701. HIV(+) marijuana smokers: acute effects Compassionate Investigational New Drug on caloric intake and mood. Program: An Examination of Benefits Wilsey B, Marcotte T, Tsodikov A, Millman Psychopharmacology 181 (1): 170–178. and Adverse Effects of Legal Clinical J, Bentley H, Gouaux B, and Fishman S. Hill SY, Schwin R, Goodwin DW, and Powell Cannabis. Journal of Cannabis 2008. A randomized, placebo-controlled, BJ. 1974. Marihuana and pain. Journal of Therapeutics 2 (1): 3–57. crossover trial of cannabis cigarettes in Pharmacology and Experimental Soderpalm AHV, Schuster A, and de Wit H. neuropathic pain. J. Pain 9 (6): 506–521. Therapeutics 188(2): 415–418. 2001. Antiemetic efficacy of smoked Wilsey B, Marcotte T, Deutsch R, Gouaux B, Jampel H. 2010. American glaucoma society marijuana subjective and behavioral Sakai S, and Donaghe H. 2013. Low-dose position statement: marijuana and the effects on nausea induced by syrup of vaporized cannabis significantly treatment of glaucoma. Journal of ipecac. Pharmacology Biochemistry and improves neuropathic pain. J. Pain Glaucoma 19 (2): 75–76. Behavior 69: 343–350. 14(2):136–48.

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U.S. Department of Justice—Drug DEA submitted the petition and be studied and elucidated. Marijuana Enforcement Administration necessary data to the Department of produces various pharmacological Schedule of Controlled Substances: Health and Human Services (HHS) on effects, including subjective (e.g., Maintaining Marijuana in Schedule I of June 11, 2013, and requested that HHS euphoria, dizziness, disinhibition), the Controlled Substances Act provide a scientific and medical cardiovascular, acute and chronic evaluation and scheduling respiratory, immune system, and Background, Data, and Analysis: Eight recommendation for marijuana. In prenatal exposure effects, as well as Factors Determinative of Control and documents dated June 3 and June 25, behavioral and cognitive impairment. Findings Pursuant to 21 U.S.C. 812(b) 2015, the acting Assistant Secretary for 3. Current scientific knowledge. There Prepared by: Office of Diversion Health of the HHS 40 recommended to is no currently accepted medical use for Control, Drug and Chemical Evaluation the DEA that marijuana continue to be marijuana in the United States. Section, Washington, DC 20537 controlled in Schedule I of the CSA, and Marijuana sources are derived from provided to the DEA its scientific and numerous cultivated strains and may July 2016 medical evaluation titled ‘‘Basis for the have different levels of D9-THC and Background Recommendation for Maintaining other cannabinoids. Under the five- On November 30, 2011, Governors Marijuana in Schedule I of the element test for currently accepted medical use discussed in more detail Lincoln D. Chafee of Rhode Island and Controlled Substances Act.’’ The HHS’s below and upheld by the Court of Christine O. Gregoire of Washington recommendations are binding on the Appeals for the District of Columbia in submitted a petition to the Drug DEA as to scientific and medical Alliance for Cannabis Therapeutics v. Enforcement Administration (DEA) to matters. 21 U.S.C. 811(b). Before initiating proceedings to DEA, 15 F.3d 1131, 1135 (D.C. Cir. initiate proceedings for a repeal of the reschedule a substance, the CSA 1994) (hereinafter ‘‘ACT’’), there is no rules or regulations that place requires the Acting Administrator to complete scientific analysis of marijuana 38 in schedule I of the determine whether the HHS scheduling marijuana’s chemical components; there Controlled Substances Act (CSA). The recommendation, scientific and medical are not adequate safety studies; there are petition requests that marijuana 39 and evaluation, and ‘‘all other relevant data’’ not adequate and well-controlled ‘‘related items’’ be rescheduled in constitute substantial evidence that the efficacy studies; there is not a consensus schedule II of the CSA. The petitioners drug should be rescheduled as of medical opinion concerning medical claim that: proposed. 21 U.S.C. 811(b). The Acting applications of marijuana; and the 1. Cannabis has accepted medical use Administrator must determine whether scientific evidence regarding in the United States; 2. Cannabis is safe for use under there is substantial evidence to marijuana’s safety and efficacy is not medical supervision; conclude that the drug meets the criteria widely available. To date, scientific and 3. Cannabis for medical purposes has for placement in another schedule based medical research has not progressed to a relatively low potential for abuse, on the criteria set forth in 21 U.S.C. the point that marijuana has a currently especially in comparison with other 812(b). The CSA requires that both the accepted medical use, even under schedule II drugs. DEA and the HHS consider the eight conditions where its use is severely The DEA accepted this petition for factors specified by Congress in 21 restricted. filing on January 30, 2012. U.S.C. 811(c). This document lays out 4. History and current pattern of The Attorney General may by rule those considerations and is organized abuse. Marijuana continues to be the transfer a drug or other substance according to the eight factors. As DEA most widely used illicit drug. In 2014, between schedules of the CSA if she sets forth in detail below, the evidence there were 22.2 million current users. finds that such drug or other substance shows: There were also 2.6 million new users, has a potential for abuse, and makes the 1. Actual or relative potential for most of whom were less than 18 years findings prescribed by 21 U.S.C. 812(b) abuse. Marijuana has a high potential of age. During the same period, for the schedule in which such drug is for abuse. Preclinical and clinical data marijuana was the most frequently to be placed. 21 U.S.C. 811(a)(1). The show that it has reinforcing effects identified drug exhibit in federal, state, Attorney General has delegated this characteristic of drugs of abuse. and local forensic laboratories. 5. Scope, duration, and significance responsibility to the Acting National databases on actual abuse of abuse. Abuse of marijuana is Administrator of the DEA. 28 CFR show marijuana is the most widely abused drug, including significant widespread and significant. In 2014, for 0.100(b). example, an estimated 6.5 million In accordance with 21 U.S.C. 811(b), numbers of substance abuse treatment people aged 12 or older used marijuana after gathering the necessary data, the admissions. Data on marijuana seizures show widespread availability and on a daily or almost daily basis over a 12-month period. In addition, a 38 The Controlled Substances Act (CSA) defines trafficking. marijuana as: ‘‘All parts of the plant Cannabis 2. Scientific evidence of its significant proportion of all admissions sativa L., whether growing or not; the seeds thereof; pharmacological effect. The scientific for substance abuse treatment are for the resin extracted from any part of such plant; and understanding of marijuana, marijuana/hashish as their primary drug every compound, manufacture, salt, derivative, cannabinoid receptors, and the of abuse. In 2013, 16.8% of all such mixture, or preparation of such plant, its seeds or resin. Such term does not include the mature stalks endocannabinoid system continues to admissions—281,991 over the course of of such plant, fiber produced from such stalks, oil the year—were for primary marijuana/ or cake made from the seeds of such plant, any 40 As set forth in a memorandum of hashish abuse. other compound, manufacture, salt, derivative, understanding entered into by the HHS, the Food 6. Risk, if any, to public health. mixture, or preparation of such mature stalks and Drug Administration (FDA), and the National (except the resin extracted there from), fiber, oil, or Institute on Drug Abuse (NIDA), the FDA acts as the Together with the health risks outlined cake, or the sterilized seed of such plant which is lead agency within the HHS in carrying out the in terms of pharmacological effects incapable of germination.’’ 21 U.S.C. 802(16). Note Secretary’s scheduling responsibilities under the above, public health risks from acute that ‘‘marihuana’’ is the spelling used in the CSA. CSA, with the concurrence of the NIDA. 50 FR use of marijuana include impaired This document uses the spelling that is more 9518, Mar. 8, 1985. The Secretary of the HHS has common in current usage, ‘‘marijuana.’’ delegated to the Assistant Secretary for Health of psychomotor performance, impaired 39 Petitioners defined marijuana as all cultivated the HHS the authority to make domestic drug driving, and impaired performance on strains of cannabis. scheduling recommendations. tests of learning and associative

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processes. Chronic use of marijuana medical use only if the following five that marijuana produces reinforcing poses a number of other risks to the elements are satisfied: effects in humans. Such reinforcing public health including physical as well 1. The drug’s chemistry is known and effects can account for the repeated as psychological dependence. reproducible; abuse of marijuana. 2. There are adequate safety studies; 7. Psychic or physiological A. Indicators of Abuse Potential dependence liability. Long-term, heavy 3. There are adequate and well- use of marijuana can lead to physical controlled studies proving efficacy; The HHS has concluded in its dependence and withdrawal following 4. The drug is accepted by qualified document, ‘‘Basis for the discontinuation, as well as psychic or experts; and Recommendation for Maintaining psychological dependence. In addition, 5. The scientific evidence is widely Marijuana in Schedule I of the a significant proportion of all available. Controlled Substances Act,’’ that admissions for treatment for substance (57 FR 10499, 10506 (March 26, 1992)). marijuana has a high potential for abuse. abuse are for primary marijuana abuse; See also ACT, 15 F.3d at 1135. The finding of ‘‘abuse potential’’ is in 2013, 16.8% of all admissions were As discussed in Factor 3, below, HHS critical for control under the Controlled for primary marijuana/hashish abuse, concluded, and DEA agrees, that the Substances Act (CSA). Although the representing 281,991 individuals. scientific evidence is insufficient to term is not defined in the CSA, 8. Immediate precursor. Marijuana is demonstrate that marijuana has a guidance in determining abuse potential not an immediate precursor of any currently accepted medical use under is provided in the legislative history of controlled substance. the five-element test. The evidence was the Act (Comprehensive Drug Abuse As specified in 21 U.S.C. 812(b)(1), in insufficient in this regard also when the Prevention and Control Act of 1970, order for a substance to be placed in DEA considered petitions to reschedule H.R. Rep. No. 91–1444, 91st Cong., Sess. schedule I, the Acting Administrator marijuana in 1992 (57 FR 10499),41 in 2 (1970), reprinted in 1970 U.S.C.C.A.N. must find that: 2001 (66 FR 20038), and in 2011 (76 FR 4566, 4603). Accordingly, the following A. The drug or other substance has a 40552).42 Little has changed since 2011 items are indicators that a drug or other high potential for abuse. with respect to the lack of clinical substance has potential for abuse: • There is evidence that individuals B. The drug or other substance has no evidence necessary to establish that are taking the drug or drugs containing currently accepted medical use in marijuana has a currently accepted such a substance in amounts sufficient treatment in the United States. medical use. No studies have to create a hazard to their health or to C. There is a lack of accepted safety scientifically assessed the efficacy and the safety of other individuals or of the for use of the drug or other substance full safety profile of marijuana for any community; or under medical supervision. specific medical condition. • There is significant diversion of the To be classified in another schedule The limited existing clinical evidence drug or drugs containing such a under the CSA (e.g., II, III, IV, or V), a is not adequate to warrant rescheduling substance from legitimate drug substance must have a ‘‘currently of marijuana under the CSA. To the channels; or accepted medical use in treatment in the contrary, the data in this scheduling • Individuals are taking the drug or United States.’’ 21 U.S.C. 812(b)(2)–(5). review document show that marijuana drugs containing such a substance on A substance also may be placed in continues to meet the criteria for their own initiative rather than on the schedule II if it is found to have ‘‘a schedule I control under the CSA for the basis of medical advice from a currently accepted medical use with following reasons: practitioner licensed by law to severe restrictions.’’ 21 U.S.C. 812(b)(2). 1. Marijuana has a high potential for administer such drugs in the course of If a controlled substance has no such abuse. his professional practice; or currently accepted medical use, it must 2. Marijuana has no currently • The drug or drugs containing such be placed in schedule I. See Notice of accepted medical use in treatment in the a substance are new drugs so related in Denial of Petition, 66 FR 20038 (Apr. 18, United States. their action to a drug or drugs already 2001) (‘‘Congress established only one 3. Marijuana lacks accepted safety for listed as having a potential for abuse to schedule—schedule I—for drugs of use under medical supervision. make it likely that the drug will have the abuse with ‘no currently accepted Factor 1: The Drug’s Actual or Relative same potentiality for abuse as such medical use in treatment in the United Potential for Abuse drugs, thus making it reasonable to States’ and ‘lack of accepted safety for assume that there may be significant use . . . under medical supervision.’ ’’). Marijuana is the most commonly diversions from legitimate channels, A drug that is the subject of an abused illegal drug in the United States. significant use contrary to or without approved new drug application (NDA) It is also the most commonly used illicit medical advice, or that it has a or abbreviated new drug application drug by high school students in the substantial capability of creating (ANDA) under Federal Food, Drug, and United States. Further, marijuana is the hazards to the health of the user or to Cosmetic Act (21 U.S.C. 355), is most frequently identified drug by state, the safety of the community. considered to have a currently accepted local and federal forensic laboratories. Of course, evidence of actual abuse of medical use in treatment in the United Marijuana’s main psychoactive a substance is indicative that a drug has States for purposes of the CSA. The ingredient, D9-tetrahydrocannabinol a potential for abuse. HHS stated in its review, however, that (D9-THC),43 is an effective reinforcer in In its recommendation, the HHS FDA has not approved any NDA for laboratory animals, including primates analyzed and evaluated data on marijuana for any indication. and rodents. These animal studies both marijuana as applied to each of the In the absence of NDA or ANDA predict and support the observations above four criteria. The analysis approval, DEA has established a five- presented in the recommendation (HHS, element test for determining whether 41 See Alliance for Cannabis Therapeutics v. DEA, 2015) is discussed below: the drug has a currently accepted 15 F.3d 1131 (D.C. Cir. 1994). 1. There is evidence that individuals 42 See Americans for Safe Access v. DEA, 706 medical use in treatment in the United F.3d 438 (D.C. Cir. 2013) (rhg den. 2013). are taking the drug or drugs containing States. Under this test, a drug will be 43 The terms D9-THC and THC are used such a substance in amounts sufficient considered to have a currently accepted interchangeably though out this document. to create a hazard to their health or to

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the safety of other individuals or of the In accordance with the CSA, the only take marijuana based on medical advice community. lawful source of marijuana in the United from a practitioner only by participating The HHS stated that some individuals States is that produced and distributed in research that is being conducted are taking marijuana in amounts for research purposes under the under an Investigational New Drug sufficient to create a hazard to their oversight of NIDA and in conformity (IND) application. The HHS noted that health and to the safety of other with United States obligations under the there are several states as well as the individuals and the community. Data Single Convention on Narcotic Drugs.44 District of Columbia which have passed from national databases on actual abuse The HHS stated that there is a lack of laws allowing for individuals to use of marijuana support the idea that a significant diversion from legitimate marijuana for purported ‘‘medical’’ use large number of individuals use drug sources, but that this is likely due under certain circumstances, but data marijuana. In its recommendation (HHS, to high availability of marijuana from are not available yet to determine the 2015), the HHS presented data from the illicit sources. Marijuana is not an FDA- number of individuals using marijuana National Survey on Drug and Health approved drug product. Neither a New under these state laws. Nonetheless, (NSDUH) of the Substance Abuse and Drug Application (NDA) nor a Biologics according to 2014 NSDUH data, 22.2 Mental Health Services Administration License Application (BLA) has been million American adults currently use (SAMHSA) and the Monitoring the approved for marketing in the United marijuana (SAMHSA, 2015a). Based on Future (MTF) survey of the National States. However, the marijuana used for the large number of individuals who use Institute on Drug Abuse (NIDA), and the nonclinical and clinical research marijuana and the lack of an FDA- DEA has since updated this information. represents a very small amount of the approved drug product, the HHS The most recent data from SAMHSA’s total amount of marijuana available in concluded that the majority of NSDUH in 2014 reported that marijuana the United States and therefore individuals using marijuana do so on was the most used illicit drug. Among information about marijuana diversion their own initiative rather than by Americans aged 12 years and older, an from legitimate sources is limited or not following medical advice from a estimated 22.2 million Americans used available. licensed practitioner. marijuana within the past month The DEA notes that the magnitude of 4. The drug or drugs containing such according to the 2014 NSDUH. In 2004, the demand for illicit marijuana is a substance are new drugs so related in an estimated 14.6 million individuals evidenced by information from a their action to a drug or drugs already reported using marijuana within the number of databases presented under listed as having a potential for abuse to month prior to the study. The estimated Factor 4. Briefly, marijuana is the most make it likely that the drug will have the rates in 2014 thus reflect an increase of commonly used illegal drug in the same potentiality for abuse as such approximately 7.6 million individuals United States. It is also the most drugs, thus making it reasonable to over a 10-year period. According to the commonly used illicit drug by American assume that there may be significant 2013 NSDUH report, an estimated 19.8 high schoolers. Marijuana is the most diversions from legitimate channels, million individuals reported using frequently identified drug in state, local, significant use contrary to or without marijuana. Thus, over a period of one and federal forensic laboratories, with medical advice, or that it has a year (2013 NSDUH–2014 NSDUH), there increasing amounts of both domestically substantial capability of creating was an estimated increase of 2.4 million grown and of illicitly smuggled hazards to the health of the user or to individuals in the United States using marijuana. the safety of the community. marijuana. Given that marijuana has long been The results from the 2015 Monitoring Marijuana and its primary the most widely trafficked and abused 9 the Future survey of 8th, 10th, and 12th psychoactive ingredient, D -THC, are controlled substance in the United controlled substances in schedule I grade students indicate that marijuana States, and that all aspects of such illicit was the most widely used illicit drug in under the CSA. activity are entirely outside of the The HHS stated that one approved, these age groups. Current monthly use closed system of distribution mandated was 6.5% of 8th graders, 14.8% of 10th marketed drug product contains by the CSA, it may well be the case that synthetic D9-THC, also known as graders, and 21.3% of 12th graders. The there is little thought given to diverting Treatment Episode Data Set (TEDS) in dronabinol, and another approved, marijuana from the small supplies marketed drug product contains a 2013 reported that marijuana abuse was produced for legitimate research the primary factor in 16.8 percent of cannabinoid-like synthetic compound purposes. Thus, the lack of data that is structurally related to D9-THC, non-private substance-abuse treatment indicating diversion of marijuana from facility admissions. In 2011, SAMHSA’s the main active component in legitimate channels to the illicit market marijuana. Both products are controlled Drug Abuse Warning Network (DAWN) is not indicative of a lack of potential for reported that marijuana was mentioned under the CSA. abuse of the drug. Marinol is a schedule III drug product in 36.4% (455,668 out of approximately 3. Individuals are taking the drug or containing synthetic D9-THC 1.25 million) of illicit drug-related drugs containing such a substance on (dronabinol) formulated in sesame oil in Emergency Department (ED) visits. their own initiative rather than on the soft gelatin capsules. Marinol was Data on the extent and scope of basis of medical advice from a approved by the FDA in 1985 for the marijuana abuse are presented under practitioner licensed by law to treatment of nausea and vomiting Factors 4 and 5 of this analysis. administer such drugs in the course of associated with cancer chemotherapy in Discussion of the health effects of his professional practice. marijuana is presented under Factor 2, The HHS stated that the FDA has not patients who did not respond to and the assessment of risk to the public evaluated or approved an NDA or BLA conventional anti-emetic treatments. In health posed by acute and chronic for marijuana for any therapeutic 1992, FDA approved Marinol for the marijuana abuse is presented under indication. Consistent with federal law, treatment of anorexia associated with Factor 6 of this analysis. therefore, an individual legitimately can weight loss in patients with acquired 2. There is significant diversion of the immunodeficiency syndrome (AIDS). drug or drugs containing such a 44 See 76 FR 51403, 51409–51410 (2011) Marinol was originally placed into substance from legitimate drug (discussing cannabis controls required under the schedule II and later rescheduled to channels. Single Convention). schedule III under the CSA due to the

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low reports of abuse relative to a. Drug Discrimination Studies and at a rate of 30 injections per one marijuana. The drug discrimination paradigm is hour session. Tanda et al. (2000) used a 9 Cesamet is a drug product containing used as an animal model of human lower dose of D -THC that was rapidly the schedule II substance nabilone, a subjective effects (Solinas et al., 2006) delivered (0.2 ml injection over 200 ms) synthetic substance structurally related and is a method where animals are able than in previous self-administration to D9-THC. Cesamet was approved for to indicate whether a test drug is able studies such that analgesic activity of D9 marketing by the FDA in 1985 for the to produce physical or psychological -THC was not a confounding factor. treatment of nausea and vomiting changes similar to a known drug of The authors also stated that the doses associated with cancer chemotherapy. abuse. Animals are trained to press one were comparable to those doses used by humans who smoke marijuana. A CB1 All other naturally occurring bar (in an operant chamber) when they receptor antagonist (SR141716) blocked cannabinoids in marijuana and their receive a known drug of abuse and this rewarding effect of THC. synthetic equivalents with similar another bar when they receive a chemical structure and pharmacological Justinova et al. (2003) were able to placebo. When a trained animal receives demonstrate self-administration of D9- activity are already included as a test drug, if the drug is similar to the schedule I drugs under the CSA. THC in drug-naı¨ve squirrel monkeys (no known drug of abuse, it will press the previous exposure to other drugs). The B. Abuse Liability Studies bar associated with the drug. 9 authors tested the monkeys with several Discriminative stimulus effects of D - doses of D9-THC (1, 2, 4, 8, and 16 mg/ In addition to the indicators suggested THC have specificity for the by the CSA’s legislative history, data as kg, i.v.) and found that the maximal pharmacological effects of cannabinoids rates of self-administration were to preclinical and clinical abuse liability found in marijuana (Balster and studies, as well as actual abuse, observed with the 4 mg/kg/infusion. Prescott, 1992; Browne and Weissman, Subsequently, Braida et al. (2004) including clandestine manufacture, 1981; Wiley et al., 1993; Wiley et al., trafficking, and diversion from reported that rats will self-administer 1995). As mentioned by the HHS, the D9-THC when delivered legitimate sources, are considered in discriminative stimulus effects of this factor. intracerebroventricularly (i.c.v.), but cannabinoids appear to be unique only at the lowest doses tested (0.01– Abuse liability evaluations are because abused drugs of other classes obtained from studies in the scientific 0.02 mg/infusion, i.c.v.). including stimulants, hallucinogens, Self-administration behavior with D9- and medical literature. There are many opioids, benzodiazepines, barbiturates, THC was found to be antagonized in rats preclinical measures of a drug’s effects NMDA antagonists, and antipsychotics and squirrel monkeys by rimonabant that when taken together provide an 9 do not fully substitute for D -THC. (SR141716A, CB1 antagonist) and the accurate prediction of the human abuse Laboratory animals including opioid antagonists (naloxone and liability. Clinical studies of the monkeys (McMahon et al., 2009), mice naltrexone) (Tanda et al., 2000; Braida et subjective and reinforcing effects in (McMahon et al., 2008), and rats (Gold al., 2004; Justinova et al., 2004). humans and epidemiological studies et al., 1992) are able to discriminate provide quantitative data on abuse cannabinoids from other drugs and c. Conditioned Place Preference Studies liability in humans and some indication placebo. The major active metabolite of Conditioned place preference (CPP) is of actual abuse trends. Both preclinical D9-THC, 11-hydroxy-D9-THC, a behavioral assay where animals are and clinical studies have clearly generalizes to D9-THC (Browne and given the opportunity to spend time in 9 demonstrated that marijuana and D - Weissman, 1981). In addition, according two distinct environments: one where THC possess the attributes associated to the HHS, twenty-two other they previously received a drug and one with drugs of abuse: They function as a cannabinoids found in marijuana also where they received a placebo. If the positive reinforcer to maintain drug- substitute for D9-THC. At least one drug is reinforcing, animals in a drug- seeking behavior, they function as a cannabinoid, CBD, does not substitute free state will choose to spend more discriminative stimulus, and they have for D9-THC in rats (Vann et al., 2008). time in the environment paired with the dependence potential. b. Self-Administration Studies drug when both environments are Preclinical and most clinical abuse presented simultaneously. liability studies have been conducted Animal self-administration behavior CPP has been demonstrated with D9- with the psychoactive constituents of associated with a drug is a commonly THC in rats but only at low doses marijuana, primarily D9-THC and its used method for evaluating if the drug (0.075–1.0 mg/kg, i.p.; Braida et al., metabolite, 11-hydroxy-D9-THC. D9- produces rewarding effects and for 2004). Rimonabant (0.25–1.0 mg/kg, i.p.) THC’s subjective effects are considered predicting abuse potential (Balster, and naloxone (0.5–2.0 mg/kg, i.p.) to be the basis for marijuana’s abuse 1991; Balster and Bigelow, 2003). Drugs antagonized D9-THC-mediated CPP liability. The following studies provide that are self-administered by animals are (Braida et al., 2004). However, in a summary of that data. likely to produce rewarding effects in another study with rats, rimonabant was humans. As mentioned in the HHS 1. Preclinical Studies demonstrated to induce CPP at doses review document, earlier attempts to ranging from 0.25–3.0 mg/kg (Cheer et D9-THC, the primary psychoactive demonstrate self-administration of D9- al., 2000). Mice without m-opioid component in marijuana, is an effective THC were unsuccessful and confounded receptors did not exhibit CPP to D9-THC reinforcer in laboratory animals, by diet restrictions, animal restraint, (paired with 1 mg/kg D9-THC, i.p.) including primates and rodents, as these and known analgesic activity of D9-THC (Ghozland et al., 2002). animals will self-administer D9-THC. at testing doses (Tanda and Goldberg, These animal studies both predict and 2003; Justinova et al., 2003). Self- 2. Clinical Studies support the observations that D9-THC, administration of D9-THC was first In its scientific review (HHS, 2015), whether smoked as marijuana or demonstrated by Tanda et al. (2000). the HHS provided a list of common administered by other routes, produces Tanda et al. (2000) showed that squirrel subjective psychoactive responses to reinforcing effects in humans. Such monkeys that were initially trained to cannabinoids based on information from reinforcing effects can account for the self-administer cocaine (30 mg/kg, i.v.) several references (Adams and Martin, repeated abuse of marijuana. self-administered 2 mg/kg D9-THC (i.v.) 1996; Gonzalez, 2007; Hollister, 1986;

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Hollister, 1988; Institute of Medicine, following moderate and heavy use. As According to the 2014 NSDUH report, 1982). Furthermore, Maldonado (2002) discussed further in Factor 7, the DEA marijuana was the most commonly used characterized these subjective responses notes that the American Psychiatric and abused illicit drug. That data as pleasurable to most humans and are Association’s (APA) Diagnostic and showed that there were 22.2 million generally associated with drug-seeking Statistical Manual of Mental Disorders, people who were past month users and/or drug-taking. Later studies Fifth Edition (DSM–5) included a list of (8.4%) among those aged 12 and older (Scherrer et al., 2009; Zeiger et al., 2010) withdrawal symptoms following in the United States. (Note: NSDUH reported that high levels of positive marijuana [cannabis] use (DSM–5, figures on marijuana use include psychoactive effects correlate with 2013). hashish use; the relative proportion of increased marijuana use, abuse, and hashish use to marijuana use is very C. Actual Abuse of Marijuana— dependence. The list of the common low.) Marijuana had the highest rate of National Databases Related to subjective psychoactive effects provided past-year dependence or abuse in 2014. Marijuana Abuse and Trafficking by the HHS (HHS, 2015) is presented The NSDUH report estimates that 3.0 below: Marijuana continues to be the most million people aged 12 or older used an (1) Disinhibition, relaxation, widely used illicit drug. Evidence of illicit drug for the first time in 2014; a increased sociability, and talkativeness. actual abuse can be defined by majority (70.3%) of these past year (2) Increased merriment and appetite, episodes/mentions in databases initiates reported that their first drug and even exhilaration at high doses. indicative of abuse/dependence. The used was marijuana. Among those who (3) Enhanced sensory perception, HHS provided in its recommendation began using illicit drugs in the past year, which can generate an increased (HHS, 2015) information relevant to 65.6%, 70.3%, and 67.6% reported appreciation of music, art, and touch. actual abuse of marijuana including data marijuana as the first illicit drug (4) Heightened imagination, which results from the National Survey on initiated in 2012, 2013, and 2014 can lead to a subjective sense of Drug Use and Health (NSDUH), a respectively. In 2014, the average age of increased creativity. Monitoring the Future (MTF) survey, marijuana initiates among 12- to 49- (5) Initial dizziness, nausea, the Drug Abuse Warning Network year-olds was 18.5 years. These usage tachycardia, facial flushing, dry mouth, (DAWN), and the Treatment Episode rates and demographics are relevant in and tremor. light of the risks presented. (6) Disorganized thinking, inability to Data Set (TEDS). These data sources provide quantitative information on Marijuana had the highest rate of past converse logically, time distortions, and year dependence or abuse of any illicit many factors related to abuse of a short-term memory impairment. drug in 2014. The 2014 NSDUH report particular substance, including (7) Ataxia and impaired judgment, stated that 4.2 million persons were incidence and patterns of use, and which can impede driving ability or lead classified with substance dependence or profile of the abuser of specific to an increase in risk-taking behavior. abuse of marijuana in the past year substances. The DEA is providing (8) Illusions, delusions, and (representing 1.6% of the total updated information from these hallucinations that intensify with higher population aged 12 or older, and 59.0% databases in this discussion. The DEA doses. of those classified with illicit drug also includes data on trafficking and (9) Emotional lability, incongruity of dependence or abuse) based on criteria illicit availability of marijuana from affect, dysphoria, agitation, paranoia, specified in the Diagnostic and confusion, drowsiness, and panic DEA databases including the National Statistical Manual of Mental Disorders, attacks, which are more common in Forensic Laboratory Information System 4th edition (DSM–IV). inexperienced or high-dosed users. (NFLIS) and the National Seizure Among past year marijuana users age The HHS mentioned that marijuana System (NSS), formerly the Federal- 12 or older, 18.5% used marijuana on users prefer higher concentrations of the wide Drug Seizure System (FDSS), as 300 or more days within the previous 12 principal psychoactive component (D9- well as other sources of data specific to months in 2014. This translates into 6.5 THC) over lower concentrations. In a marijuana, including the Potency million people using marijuana on a clinical study with marijuana users (n = Monitoring Project and the Domestic daily or almost daily basis over a 12- 12, usage ranged from once a month to Cannabis Eradication and Suppression month period, significantly more than 4 times a week), subjects were given a Program (DCE/SP). the estimated 5.7 million daily or almost 9 choice of 1.95% D -THC marijuana or 1. National Survey on Drug Use and daily users in just the year before. 9 0.63% D -THC marijuana after sampling Health (NSDUH) Among past month marijuana users, both marijuana cigarettes in two choice 41.6% (9.2 million) used the drug on 20 sessions. The marijuana cigarette with The National Survey on Drug Use and or more days in the past month, a high THC was chosen in 21 out of 24 Health (NSDUH) is conducted annually significant increase from the 8.1 million choice sessions or 87.5% of the time by the Department of Health and Human who used marijuana 20 days or more in (Chait and Burke, 1994). Furthermore, Service’s Substance Abuse and Mental 2013. in a double-blind study, frequent Health Services Administration marijuana users (n = 11, usage at least (SAMHSA). SAMHSA is the primary 2. Monitoring the Future (MTF) 2 times per month with at least 100 source of estimates of the prevalence Monitoring the Future (MTF) is an occasions) when given a low-dose of and incidence of pharmaceutical drugs, ongoing study which is funded under a oral D9-THC (7.5 mg) were able to illicit drugs, alcohol, and tobacco use in series of investigator-initiated distinguish the psychoactive effects the United States. The survey is based competing research grants from the better than occasional users (n = 10, no on a nationally representative sample of National Institute on Drug Abuse use within the past 4 years with 10 or the civilian, non-institutionalized (NIDA). MTF tracks drug use trends fewer lifetime uses) and also population 12 years of age and older. among American adolescents in the 8th, experienced fewer sedative effects (Kirk The survey excludes homeless people 10th, and 12th grades. According to its and de Wit, 1999). who do not use shelters, active military 2015 survey results, marijuana was the Marijuana has also been recognized personnel, and residents of institutional most commonly used illicit drug, as was by scientific experts to have withdrawal group quarters such as jails and the case in previous years. symptoms (negative reinforcement) hospitals. Approximately 6.5% of 8th graders,

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14.8% of 10th graders, and 21.3% of ED visits involving all abuse or misuse abuse for 18.3% (352,397) of admissions 12th graders surveyed in 2015 reported in the United States and out of 1.25 in 2011; 17.5% (315,200) in 2012; and marijuana use during the past month million visits involving abuse or misuse 16.8% (281,991) in 2013. Of the 281,991 prior to the survey. A number of high of illicit drugs (excluding alcohol- admissions for marijuana/hashish school students in 2015 also reported related visits), as estimated by DAWN. treatment in 2013, 24.3% used daily use in the past month, including This is lower than the number of ED marijuana/hashish daily. Among those 1.1%, 3.0%, and 6.0% of 8th, 10th, and visits involving cocaine (505,224) and treated for marijuana/hashish as the 12th graders, respectively. higher than the number of ED visits primary substance in 2013, 27.4% were involving heroin (258,482) and 3. Drug Abuse Warning Network ages 12 to 17 years and 29.7% were ages stimulants (e.g., amphetamine, (DAWN), Emergency Department (ED) 18 to 24 years. Those admitted for methamphetamine) (159,840). Visits Visits marijuana/hashish were mostly male involving the other major illicit drugs, (72.6%) and non-Hispanic (82.2%). The Drug Abuse Warning Network such as MDMA, GHB, LSD and other Non-hispanic whites (43.2%) (DAWN) is a public health surveillance hallucinogens, PCP, and inhalants, were system that monitors drug-related represented the largest ethnic group of much less frequent, comparatively. marijuana admissions. hospital emergency department (ED) In young patients, marijuana is the visits to track the impact of drug use, illicit drug most frequently involved in 5. Forensic Laboratory Data misuse, and abuse in the United States. ED visits, according to DAWN estimates, For the purposes of DAWN, the term with 240.2 marijuana-related ED visits Data on marijuana seizures from ‘‘drug abuse’’ applies if the following per 100,000 population ages 12 to 17, federal, state, and local forensic conditions are met: (1) The case 443.8 per 100,000 population ages 18 to laboratories have indicated that there is involved at least one of the following: 20, and 446.9 per 100,000 population significant trafficking of marijuana. The use of an illegal drug, use of a legal drug ages 21 to 24. National Forensic Laboratory System contrary to directions, or inhalation of a (NFLIS) is a program sponsored by the 4. Treatment Episode Data Set (TEDS) non-pharmaceutical substance; and (2) Drug Enforcement Administration’s System the substance was used for one of the Office of Diversion Control. NFLIS following reasons: Because of drug The Treatment Episode Data Set systematically collects drug dependence, to commit suicide (or (TEDS) system is part of the SAMHSA identification results and associated attempt to commit suicide), for Drug and Alcohol Services Information information from drug exhibits recreational purposes, or to achieve System and is a national census of encountered by law enforcement and other psychic effects. Importantly, many annual admissions to state licensed or analyzed in federal, state, and local factors can influence the estimates of ED certified, or administratively tracked, forensic laboratories. NFLIS is a visits, including trends in overall use of substance abuse treatment facilities. The comprehensive information system that a substance as well as trends in the TEDS system contains information on includes data from 278 individual reasons for ED usage. For instance, some patient demographics and substance forensic laboratories that report more abuse problems of admissions to drug users may visit EDs for life- than 91% of the drug caseload in the treatment for abuse of alcohol and/or threatening issues while others may U.S. NFLIS captures data for all drugs drugs in facilities that report to state visit to seek care for detoxification and chemicals identified and reported administrative data systems. For this because they needed certification before by forensic laboratories. More than entering treatment. Additionally, database, the primary substance of 1,700 unique substances are represented DAWN data do not distinguish the drug abuse is defined as the main substance in the NFLIS database. responsible for the ED visit from other of abuse reported at the time of drugs that may have been used admission. TEDS also allows for the Data from NFLIS showed that concomitantly. As stated in a DAWN recording of two other substances of marijuana was the most frequently report, ‘‘Since marijuana/hashish is abuse (secondary and tertiary). identified drug in federal, state, and frequently present in combination with In 2011, the TEDS system included local laboratories from January 2004 other drugs, the reason for the ED visit 1,928,792 admissions to substance through December 2014. Marijuana may be more relevant to the other abuse treatment; in 2012 there were accounted for between 29.47% and drug(s) involved in the episode.’’ 1,801,385 admissions; and in 2013 there 34.84% of all drug exhibits analyzed In 2011, marijuana was involved in were 1,683,451 admissions. Marijuana/ annually during that time frame 455,668 ED visits out of 2,462,948 total hashish was the primary substance of (Table 1).

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Since 2004, the total number of Federal Bureau of Investigation, United clandestine laboratory and contraband reports of marijuana and the amount of States Customs and Border Protection, (chemicals and precursors, currency, marijuana encountered federally has and United States Immigration and drugs, equipment and weapons). FDSS remained high (see data from Federal- Customs Enforcement. It also records reports total federal drug seizures [in wide Drug Seizure System and Domestic maritime seizures made by the United kilograms (kg)] of substances such as Cannabis Eradication and Suppression States Coast Guard. Drug seizures made cocaine, heroin, MDMA, Program below). by other Federal agencies are included methamphetamine, and cannabis 6. Federal-Wide Drug Seizure System in the FDSS database when drug (marijuana and hashish). The yearly The Federal-wide Drug Seizure evidence custody is transferred to one of volume of cannabis seized (Table 2), System (FDSS) contains information the agencies identified above. FDSS is consistently exceeding a thousand about drug seizures made within the now incorporated into the National metric tons per year, shows that jurisdiction of the United States by the Seizure System (NSS), which is a cannabis is very widely trafficked in the Drug Enforcement Administration, the repository for information on United States.

7. Potency Monitoring Project THC concentrations of marijuana, the percentage of D9-THC increased hashish and hash oil samples provided from 1995 to 2010 with an average THC The University of Mississippi’s by DEA regional laboratories and by content of 3.75% in 1995 and 9.53% in Potency Monitoring Project (PMP), state and local police agencies. After 2010. In examining marijuana samples through a contract with the National 2010, PMP has analyzed only marijuana only provided by DEA laboratories, the Institute on Drug Abuse (NIDA), samples provided by DEA regional average D9-THC content was 3.96% in analyzes and compiles data on the D9- laboratories. As indicated in Figure 1, 1995 in comparison to 11.16% in 2015.

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8. The Domestic Cannabis Eradication agencies. Only California and Hawaii that in the United States in 2014, there and Suppression Program were active participants in the program were 3,904,213 plants eradicated in The Domestic Cannabis Eradication at its inception. However, by 1982 the outdoor cannabis cultivation areas and Suppression Program (DCE/SP) was program had expanded to 25 states and compared to 2,597,798 plants in 2000. established in 1979 to reduce the supply by 1985 all 50 states were participants. Significant quantities of marijuana were of domestically cultivated marijuana in Cannabis is cultivated in remote also eradicated from indoor cultivation the United States. The program was locations and frequently on public lands operations. There were 396,620 indoor designed to serve as a partnership and illicitly grown in all states. Data plants eradicated in 2014 compared to between federal, state, and local provided by the DCE/SP (Table 3) show 217,105 eradicated in 2000.

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The recent statistics from these Furthermore, as noted by the HHS, medical use in treatment in the United various surveys and databases show that many substances scheduled under the States. marijuana continues to be the most CSA are evaluated within the context of Moreover, the petitioners failed to commonly used illicit drug, with drug development using data submitted review the indicators of abuse potential, considerable rates of heavy abuse and under a New Drug Application (NDA). as discussed in the legislative history of dependence. They also show that However, the petitioners have not the CSA. The petitioners did not use marijuana is the most readily available identified a specific indication for use of data on marijuana usage, diversion, illicit drug in the United States. marijuana and therefore the HHS notes psychoactive properties, and dependence in their evaluation of Petitioners’ Major Comments in Relation that an appropriate comparator based on indication cannot be identified. marijuana abuse potential. The HHS and to Factor 1 and the Government’s the DEA discuss those indicators above Responses (2) The petitioners indicated that the in this factor. HHS’s evaluation of the actual or relative potential of abuse of (1) In Exhibit B, the petitioners full range of data led HHS and DEA to marijuana is low. The petitioners state, conclude that marijuana has a high compared the effects of marijuana to ‘‘Some researchers claim that cannabis currently controlled schedule II potential for abuse. is not particularly addictive. Experts The petitioners, based on their review substances and made repeated claims assert that cannabis’s addictive of a survey by Gore and Earleywine about the comparative effects. potential parallels caffeine’s.’’ (Exhibit (2007), concluded that marijuana has a The HHS noted that comparisons B, page 19, lines 20–21). Furthermore, low abuse potential. Gore and between marijuana and schedule II petitioners stated that, ‘‘Cannabis use Earleywine surveyed 746 mental health substances are difficult because of indicates a lower likelihood of addiction professionals and asked them to rate the differences in the actions of different and abuse potential as compared to addictiveness (based on a seven-point pharmacological classes of schedule II other substances.’’ (Exhibit B, page 22, scale) of several drugs (heroin, nicotine, drugs in the CSA. The HHS notes that lines 12–13). cocaine/crack, oxycodone, schedule II substances include methamphetamine, amphetamine, Under the CSA, for a substance to be stimulant-like drugs (e.g., cocaine, caffeine, alcohol, and marijuana). The placed in schedule II, III, IV, or V, it amphetamine), opioids (e.g., fentanyl, petitioners stated that the health oxycodone), depressant drugs (e.g., must have a currently accepted medical 45 professionals rated marijuana as least pentobarbital), dissociative anesthetics use in treatment in the United States. addictive of the drugs surveyed. The (e.g., phencyclidine), and naturally As DEA has previously stated, Congress DEA notes that the survey cited by the occurring plant components (e.g., coca established only one schedule, schedule petitioners is based on subjective leaves and poppy straw). The I, for drugs of abuse with ‘‘no currently opinions from health professionals. mechanism of action of D9-THC and accepted medical use in treatment in the (3) The petitioners mentioned that marijuana, which act primarily through United States.’’ 76 FR 40552 (2011). many of the cannabinoids in marijuana the cannabinoid receptors (discussed Thus, any attempt to compare the decrease the psychoactive effects of D9- further in Factor 2) are completely relative abuse potential of schedule I THC, and therefore marijuana lacks different from the above-mentioned substance to that of a substance in sufficient abuse potential for placement classes of schedule II substances. The another schedule is inconsequential into schedule I. Further, the petitioners HHS concludes that the differences in since a schedule I substance must mentioned on page 4 in Exhibit B (lines the mechanisms of action in the various remain in schedule I until it has been 11–15), ‘‘While the DEA considers classes of schedule II substances make found to have a currently accepted cannabis a schedule I drug, it classifies it inappropriate to compare the range of dronabinol (Marinol) as schedule III. those substances with marijuana. 45 See Americans for Safe Access, 706 F.3d at 440. Dronabinol is 100 percent THC and is

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potentially very psychoactive. Natural use for Marinol in the United States and underlie the antinociceptive and cannabis typically would be no more allowing for Marinol to be rescheduled psychoactive effects of cannabinoids. than 15 percent THC by weight. Thus it into schedule II and subsequently into D9-THC acts as an agonist at is inconsistent that cannabis, with 15 schedule III of the CSA. The HHS cannabinoid receptors. percent weight THC, remains a mentioned that marijuana and Marinol CB1 receptors are primarily found in [s]chedule I drug, while dronabinol, at differ on a wide variety of factors and the central nervous system and are 100 percent THC, is schedule III.’’ these differences are major reasons for The HHS addressed this issue by differential scheduling of marijuana and located mainly in the basal ganglia, indicating that the modulating effects of Marinol. Marijuana, as discussed more hippocampus and cerebellum of the the other cannabinoids in marijuana on fully in Factors 3 and 6, does not have brain (Howlett et al., 2004). CB1 D9-THC have not been demonstrated in a currently accepted medical use in the receptors are also located in peripheral controlled studies. The HHS and the United States, is highly abused, and has tissues such as the immune system (De DEA also note that the determination of a lack of accepted safety. Petrocellis and Di Marzo, 2009), but the the abuse potential of a substance concentration of CB1 receptors there is considers not only psychoactive effects Factor 2: Scientific Evidence of the considerably lower than in the central Drug Pharmcological Effects, if Known but also chemistry, pharmacology, nervous system (Herkenham et al., 1990; pharmacokinetics, usage patterns, and The HHS stated that there are large 1992). CB2 receptors are found diversion history among other measures. amounts of scientific data on the primarily in the immune system and Marinol (dronabinol in sesame oil) neurochemistry, mechanistic effects, predominantly in B lymphocytes and was rescheduled from schedule II to toxicology, and pharmacology of natural killer cells (Bouaboula et al., schedule III on July 2, 1999 (64 FR marijuana. A scientific evaluation, as 1993). CB2 receptors are also found in conducted by the HHS and the DEA, of 35928, DEA 1999). In assessing Marinol, the central nervous system, primarily in HHS compared Marinol to marijuana on marijuana’s neurochemistry, human and the cerebellum and hippocampus (Gong several aspects of abuse potential and animal behavioral pharmacology, et al., 2006). found that major differences between central nervous system effects, and the two, such as formulation, other pharmacological effects (e.g., Two endogenous ligands to the availability, and usage, contribute to cardiovascular, immunological effects) cannabinoid receptors, anandamide and differences in abuse potential. The is presented below. arachidonyl glycerol (2–AG), were psychoactive effects from smoking are identified in 1992 (Devane et al., 1992) Neurochemistry generally more rapid and intense than and 1995 (Mechoulam et al., 1995), those that occur through oral Marijuana contains numerous respectively. Anandamide is a low- administration (HHS, 2015; Wesson and constituents such as cannabinoids that efficacy agonist (Brievogel and Childers, Washburn, 1990; Hollister and have a variety of pharmacological 2000) and 2–AG is a high efficacy Gillespie, 1973). Therefore, as actions. The petition defined marijuana agonist (Gonsiorek et al., 2000) to the concluded by both the HHS and the as including all cannabis cultivated cannabinoid receptors. These DEA, the delayed onset of action and strains. The HHS stated that different endogenous ligands are present in both marijuana samples derived from various longer duration of action from an oral the central nervous system and in the cultivated strains may differ in their dose of Marinol may contribute in periphery (HHS, 2015). limiting the abuse potential of Marinol chemical constituents including D9-THC 9 relative to marijuana, which is most and other cannabinoids. Therefore D -THC and cannabidiol (CBD) are often smoked. The HHS also stated that marijuana products from different two of the major cannabinoids in the extraction and purification of strains will have different biological and marijuana. D9-THC is the major dronabinol from the encapsulated pharmacological effects. The chemical psychoactive cannabinoid (Wachtel et sesame oil mixture of Marinol is highly constituents of marijuana are discussed al., 2002). D9-THC has similar affinity complex and difficult, and that the further in Factor 3. for CB1 and CB2 receptors and acts as presence of sesame oil mixture may The primary site of action for a weak agonist at CB2 receptors. The preclude the smoking of Marinol-laced cannabinoids such as D9-THC is at the HHS indicated that activation of CB1 cigarettes. cannabinoid receptor. Two cannabinoid receptors mediates psychotropic effects Furthermore, marijuana and Marinol receptors, CB1 and CB2, have been of cannabinoids. CBD has low affinity show significant differences in actual identified and characterized (Battista et for both CB1 and CB2 receptors. CBD abuse and illicit trafficking. There have al., 2012; Piomelli, 2005) and are G- has antagonistic effects at CB1 receptors, been no reports of abuse, diversion, or protein-coupled receptors. Activation of and some inverse agonistic properties at public health risks due to Marinol. In these inhibitory G-protein-coupled CB2 receptors. contrast, 22.2 million American adults receptors inhibits adenylate cyclase report currently using marijuana activity, which prevents conversion of Animal Behavioral Effects (SAMHSA, 2015a). The DEA database, ATP to cyclic AMP. Cannabinoid NFLIS, showed that marijuana was the receptor activation also results in Animal abuse potential studies (drug most frequently identified drug in state inhibition of N- and P/Q-type calcium discrimination, self-administration, and local forensic laboratories from channels and activates inwardly conditioned place preference) are January 2001 to December 2014 and rectifying potassium channels (Mackie discussed more fully in Factor 1. indicates the high availability of et al., 1995; Twitchell et al., 1997). The Briefly, it was consistently marijuana. The differences in HHS mentioned that inhibition of N- demonstrated that D9-THC, the primary composition, actual abuse, and type calcium channels decreases psychoactive component in marijuana, diversion contribute to the differences neurotransmitter release and this may and other cannabinoids in marijuana in scheduling between marijuana and be the underlying mechanism in the have a distinct drug discriminative Marinol. ability of cannabinoids to inhibit profile. In addition, animals self- Additionally, the FDA approved a acetylcholine, norepinephrine and administer D9-THC, and D9-THC in low New Drug Application (NDA) for glutamate from specific areas of the doses produces conditioned place Marinol, indicating a legitimate medical brain. These cellular actions may preference.

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Central Nervous System Effects weight) and high D9-THC (3.6% by and accuracy. Furthermore, weight) groups. Subjective psychoactive administration of 3.95% D9-THC in a Psychoactive Effects effects were significantly greater for all smoked marijuana cigarette increased The clinical psychoactive effects of groups in comparison to placebo and the latency in a task of simulated marijuana are discussed more fully in there were no significant differences in braking in a vehicle (Liguori et al., Factor 1. Briefly, the psychoactive effects among the treatments (Ilan et al., 1998). The HHS noted that the motor effects from marijuana use are 2005). impairments reported in these studies considered pleasurable and associated The HHS also referred to a study with (Kurzthaler et al., 1999; Liguori et al., with drug-seeking or drug-taking (HHS, D9-THC and cannabinol (CBN) (Karniol 1998) are critical skills needed for 2015; Maldonado, 2002). Further, it was et al., 1975). In this study, oral operating a vehicle. noted by HHS that marijuana users administration of either 12.5, 25, or 50 As mentioned in the HHS document, prefer higher concentrations of the mg CBN combined with 25 mg D9-THC some studies examined the persistence principal psychoactive component (D9- (ratio of at least 1:2 CBN to D9-THC) of the behavioral impairments THC) over lower concentrations (HHS, significantly increased subjective immediately after marijuana 2015). psychoactive ratings of D9-THC administration. Some of marijuana’s Studies have evaluated psychoactive compared to D9-THC alone (Karniol et acute effects may still be present for at effects of THC in the presence of high al., 1975). least 24 hours after the acute CBD, CBC, or CBN ratios. Even though psychoactive effects have subsided. In a Behavioral Impairment some studies suggest that CBD may brief communication, Heishmann et al. decrease some of D9-THC’s psychoactive Several factors may influence (1990) reported that there were effects, the HHS found that the ratios of marijuana’s behavioral effects including cognitive impairments (digit recall and CBD to D9-THC administered in the the duration (chronic or short term), arithmetic tasks) in two out of three studies were not comparable to the frequency (daily, weekly, or experienced marijuana smokers for 24 amounts found in marijuana used by occasionally), and amount of use (heavy hours after smoking marijuana cigarettes most people (Dalton et al., 1976; Karniol or moderate). Researchers have containing 2.57% D9-THC. However, et al., 1974; Zwardi et al., 1982). In fact, examined how long behavioral Fant et al. (1998) evaluated subjective the CBD ratios in these studies are impairments persist following chronic effects and performance measures for up significantly higher than the CBD found marijuana use. These studies used self- to 25 hours in 10 healthy males after in most marijuana currently found on reported histories of exposure duration, exposure to either 1.8% or 3.6% D9-THC the streets (Mehmedic et al., 2010). HHS frequency, and amount of marijuana in marijuana cigarettes. Peak indicated that most of the marijuana use, and administered several decrements in subjective and available on the street has a high THC performance and cognitive tests at performance measures were noted and low CBD content and therefore any different time points following within 2 hours of marijuana exposure lessening of THC’s psychoactive effects marijuana abstinence. According to but there were minimal residual by CBD will not occur for most HHS, behavioral impairments may alterations in subjective or performance marijuana users (HHS, 2015). Dalton et persist for up to 28 days of abstinence measures at 23–25 hours after exposure. al. (1976) reported that when volunteers in chronic marijuana users. Persistence of behavioral impairments smoked cigarettes with a ratio of 7 CBD Psychoactive effects of marijuana can following repeated and chronic use of to 1 D9-THC (0.15 mg/kg CBD and 0.025 lead to behavioral impairment including marijuana has also been investigated mg/kg D9-THC), there was a significant cognitive decrements and decreased and was reviewed in the HHS document decrease in ratings of acute subjective ability to operate motor vehicles (HHS, (HHS, 2015). In particular, researchers effects and achieving a ‘‘high’’ in 2015). Block et al. (1992) evaluated examined how long behavioral comparison to smoking D9-THC alone. cognitive measures in 48 healthy male impairments last following chronic In oral administration studies, the subjects following smoking a marijuana marijuana use. In studies examining subjective effects and anxiety produced cigarette that contained 2.57% or 19 mg persistence of effects in chronic and by combination of CBD and THC in a D9-THC by weight or placebo. Each heavy marijuana users, there were ratio of at least 1:2 CBD to D9-THC (15, subject participated in eight sessions significant decrements in cognitive and 30, 60 mg CBD to 30 mg D9-THC; (four sessions with marijuana; four motor function tasks in all studies of up Karniol et al., 1974) or a ratio of 2:1 CBD sessions with placebo) and several to 27 days, and in most studies at 28 to D9-THC (1 mg/kg CBD to 0.5 mg/kg cognitive and psychomotor tests were days (Solowij et al., 2002; Messinis et D9-THC; Zuardi et al., 1982) are less administered (e.g. verbal recall, facial al., 2006; Lisdahl and Price, 2012; Pope than those produced by D9-THC recognition, text learning, reaction et al., 2002; Bolla et al., 2002; Bolla et administered alone. time). Marijuana significantly impaired al., 2005). In studies that followed heavy In one study (Ilan et al., 2005), the performances in most of these cognitive marijuana users for longer than 28 days authors calculated the naturally and psychomotor tests (Block et al., and up to 20 years of marijuana occurring concentrations of CBC and 1992). abstinence, cognitive and psychomotor CBD in marijuana cigarettes with either Ramaekers et al. (2006) reported that impairments were no longer detected 1.8 or 3.6% D9-THC by weight. The in 20 recreational users of marijuana, (Fried et al., 2005; Lyons et al., 2004; authors varied the concentrations of acute administration of 250 mg/kg and Tait et al., 2011). For example, Fried et CBC and CBD for each concentration of 500 mg/kg D9-THC in smoked marijuana al. (2005) reported that after 3 months D9-THC in the marijuana cigarettes. resulted in dose-dependent impairments of abstinence from marijuana, any Administrations in healthy marijuana in cognition, motor impulsivity, motor deficits in intelligence (IQ), memory, users (n=23) consisted of either: (1) Low control (tracking impairments), and risk and processing speeds following heavy CBC (0.1% by weight) and low CBD taking. In another study (Kurzthaler et marijuana use were no longer observed (0.2% by weight); (2) high CBC (0.5% by al., 1999), when 290 mg/kg D9-THC was (Fried et al., 2005). In a meta-analysis weight) and low CBD; (3) low CBC and administered via a smoked marijuana that examined non-acute and long- high CBD (1.0% by weight); or (4) high cigarette in 30 healthy volunteers with lasting effects of marijuana, any deficits CBC and high CBD and the users were no history of substance abuse there were in neurocognitive performance that divided into low D9-THC (1.8% by significant impairments of motor speed were observed within the first month

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were no longer apparent after exposed to marijuana from birth until Classification of Diseases (ICD–10) and approximately one month of abstinence adulthood: The Ottawa Prenatal would not be appropriate for use in (Schreiner and Dunn, 2012). HHS Prospective Study (OPPS; Fried et al., evaluating the association between further notes that in moderate marijuana 1980), and the Maternal Health Practices marijuana use and psychosis. For users deficits in decision-making skills and Child Development Project example, researchers characterized were not observed after 25 days of (MHPCD; Day et al., 1985). Both psychosis as ‘‘schizophrenic cluster’’ abstinence and additionally IQ, longitudinal studies report that heavy (Maremmani et al., 2004), ‘‘subclinical immediate memory and delayed prenatal marijuana use is associated psychotic symptoms’’ (van Gastel et al., memory skills were not significantly with decreased performance on tasks 2012), ‘‘pre-psychotic clinical high risk’’ impacted as observed with heavy and assessing memory, verbal and (van der Meer et al., 2012), and chronic marijuana users (Fried et al., quantitative reasoning in 4-year-olds symptoms related to ‘‘psychosis 2005; HHS, 2015). (Fried and Watkinson, 1990) and in 6 vulnerability’’ (Griffith-Lendering et al., As mentioned in the HHS document year olds (Goldschmidt et al., 2008). In 2012). (HHS, 2015), the intensity and subsequent studies with the OPPS The HHS discussed an early persistence of neurological impairment cohort, deficits in sustained attention epidemiological study conducted by from chronic marijuana use also may be were reported in children ages 6 and Andreasson et al. (1987), which dependent on the age of first use. In two 13–16 years (Fried et al., 1992; Fried, examined the link between psychosis separate smaller scale studies (less than 2002) and deficits in executive and marijuana use. In this study, about 100 participants per exposure group), neurological function were observed in 45,000 18- and 19-year-old male Fontes et al. (2011) and Gruber et al. 9- and 12-year-old children (Fried et al., Swedish subjects provided detailed (2012) compared neurological function 1998). DEA further notes that with the information on their drug-taking history in early onset (chronic marijuana use MHPCD cohort, follow-up studies and 274 of these subjects were prior to age 15 or 16) and late onset reported an increased rate of delinquent diagnosed with schizophrenia over a 14- (chronic marijuana use after age 15 or behavior (Day et al., 2011) and year period (1969–1983). Out of the 274 16) heavy marijuana users and found decreased achievement test scores subjects diagnosed with psychosis, 21 that there were significant deficits in (Goldschmidt et al., 2012) at age 14. individuals (7.7%) had used marijuana executive neurological function in early When the MHPCD cohort was followed more than 50 times, while 197 onset users which were not observed or to age 22, there was a marginal (p = individuals (72%) never used were less apparent in late onset users. 0.06) increase in psychosis with marijuana. As presented by the authors In a prospective longitudinal birth prenatal marijuana exposure and early (Andreasson et al., 1987), individuals cohort study following 1,037 onset of marijuana use (Day et al., 2015). who claimed to take marijuana on more individuals (Meier et al., 2012), a than 50 occasions were 6 times more significant decrease in IQ and Association of Marijuana Use With likely to be diagnosed with neuropsychological performance was Psychosis schizophrenia than those who had never observed in adolescent-onset users and There has been extensive research to consumed the drug. The authors persisted even after abstinence from determine whether marijuana usage is concluded that marijuana users who are marijuana for at least one year. associated with development of vulnerable to developing psychoses are However, Meier et al. (2012) reported in schizophrenia or other psychoses, and at the greatest risk for schizophrenia. In there was no significant change in IQ in the HHS indicated that the available adult-onset users. data do not suggest a causative link a 35 year follow up to the subjects The HHS noted that there is some between marijuana and the evaluated in Andreasson et al. (1987), evidence that the severity of the development of psychosis (HHS, 2015; Manrique-Garcia et al. (2012) reported persistent neurological impairments Minozzi et al., 2010). As mentioned in similar findings. In the follow up study, may also be due in part to the amount the HHS review (HHS, 2015), numerous 354 individuals developed of marijuana usage. In the study large scale longitudinal studies schizophrenia. Of those, 32 individuals mentioned above, Gruber et al. (2012) demonstrated that subjects who used (9%) had used marijuana more than 50 found that the early onset users marijuana do not have a greater times and were 6.3 times more likely to consumed three times as much incidence of psychotic diagnoses develop schizophrenia. 255 of the 354 marijuana per week and used it twice as compared to non-marijuana users (van individuals (72%) never used often as late onset users. Meier et al. Os et al., 2002; Fergusson et al., 2005; marijuana. (2012) reported in their study, Kuepper et al., 2011). Further, the HHS The HHS also noted that many studies mentioned above, that there was a commented that when analyzing the support the assertion that psychosis correlation between IQ deficits in available data examining the association from marijuana usage may manifest only adolescent onset users and the increased between marijuana and psychosis, it is in individuals already predisposed to amount of marijuana used. critical to differentiate whether the development of psychotic disorders. patients in a study are already Marijuana use may precede diagnosis of Behavioral Effects of Prenatal Exposure diagnosed with psychosis or if the psychosis (Schimmelmann et al., 2011), In studies that examined effects of individuals have a limited number of but most reports indicate that prodromal prenatal marijuana exposure, many of symptoms associated with psychosis symptoms of schizophrenia are the pregnant women also used alcohol without qualifying for a diagnosis of the observed prior to marijuana use and tobacco in addition to marijuana. disorder. (Schiffman et al., 2005). In a review Even though other drugs were used in As mentioned by the HHS, some of examining gene-environmental conjunction with marijuana, there is the studies examining the association interaction between marijuana exposure evidence of an association between between marijuana and psychosis and the development of psychosis, it heavy prenatal marijuana exposure and utilized non-standard methods to was concluded that there is some deficits in some cognitive function. categorize psychosis and these methods evidence to support that marijuana use There have been two prospective did not conform to the criteria in the may influence the development of longitudinal birth cohort studies Diagnostic and Statistical Manual psychosis but only for susceptible following individuals prenatally (DSM–5) or the International individuals (Pelayo-Teran et al., 2012).

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Degenhardt et al. (2003) modeled the Hackam, 2015). Panayiotides (2015) smokers (age range 31–37 years) with no prevalence of schizophrenia against reported that approximately 25.6% of history of tobacco smoking (Fung et al., marijuana use across eight birth cohorts the cardiovascular cases from marijuana 1999). Furthermore, in a case-control in individuals born during 1940 to 1979 use resulted in death from data study (n = 173 individuals with in Australia. Even though there was an provided by the French squamous cell carcinoma of the head increase in marijuana use in the adult Addictovigilance Network during the and neck; n = 176 controls; Zhang et al., subjects over this time period, there was period of 2006–2010. Several case 1999), prevalence of marijuana use was not an increase in diagnoses of studies on marijuana usage and 9.7% in controls and 13.9% in cases psychosis for these same subjects. The cardiovascular events were discussed and the authors reported that marijuana authors concluded that use of marijuana and it was concluded that although a use may dose-dependently interact with may increase schizophrenia only in causal link cannot be established due to mutagenic sensitivity, cigarette persons vulnerable to developing not knowing exact amounts of smoking, and alcohol use to increase psychosis. marijuana used in the cases and risk associated with head and neck confounding variables, the available Cardiovascular and Autonomic Effects cancers (Zhang et al., 1999). However, evidence supports a link between in a large clinical study with 1,650 The HHS stated that acute use of marijuana and cardiotoxicity. Hackham subjects, no positive correlation was marijuana causes an increase in heart (2015) reviewed 34 case reports or case found between marijuana use and lung rate (tachycardia) and may increase series reports of marijuana and stroke/ cancer (Tashkin et al., 2006). This blood pressure (Capriotti et al., 1988; ischemia in 64 stroke patients and finding held true regardless of the extent Benowitz and Jones, 1975). There is reported that in 81% of the cases there of marijuana use when both tobacco use some evidence that associates the was a temporal relationship between and other potential confounding factors 9 increased heart rate from D -THC marijuana usage and stroke or ischemic were controlled. The HHS concluded exposure with excitation of the event. The author concluded that that new evidence suggests that the sympathetic and depression of the collective analysis of the case reports effects of smoking marijuana on parasympathetic nervous systems supports a causal link between respiratory function and cancer are (Malinowska et al., 2012). Tolerance to marijuana use and stroke. different from the effects of smoking tachycardia develops with chronic tobacco (Lee and Hancox, 2011). exposure to marijuana (Jones, 2002; Respiratory Effects Sidney, 2002). The HHS stated that transient The DEA further notes the publication Prolonged exposure to D9-THC results bronchodilation is the most typical of recent review articles critically in a decrease in heart rate (bradycardia) respiratory effect of acute exposure to evaluating the association between and hypotension (Benowitz and Jones, marijuana (Gong et al., 1984). In a recent marijuana and lung cancer. Most of the 1975). These effects are thought to be longitudinal study, information on reviews agree that the association is mediated through peripherally located, marijuana use and pulmonary data weak or inconsistent (Huang et al., 2015; presynaptic CB1 receptor inhibition of function were collected from 5,115 Zhang et al., 2015; Gates et al., 2014; norepinephrine release with possible individuals over 20 years from 4 Hall and Degenhardt, 2014). Huang et al. direct activation of vascular communities in the United States (2015) identified and reviewed six cannabinoid receptors (Wagner et al., (Oakland, CA; Chicago, IL; Minneapolis, studies evaluating the association 1998; Pacher et al., 2006). MN; Birmingham, AL) (Pletcher et al., between marijuana use and lung cancer As stated in the HHS recommendation 2012). Of the 5,115 individuals, 795 and the authors concluded that an (HHS, 2015), marijuana exposure causes individuals reported use of only association is not supported most likely orthostatic hypotension (fainting-like marijuana (without tobacco). The due to the small amounts of marijuana feeling; sudden drop in blood pressure authors reported that occasional use of smoked in comparison to tobacco. upon standing up) and tolerance can marijuana (7 joint-years for lifetime or 1 Zhang et al. (2015) examined six case develop to this effect upon repeated, joint/day for 7 years or 1 joint/week for control studies from the US, UK, New chronic exposure (Jones, 2002). 49 years) does not adversely affect Zealand, and Canada within the Tolerance to orthostatic hypotension is pulmonary function. Pletcher et al. International Lung Cancer Consortium potentially related to plasma volume (2012) further concluded that there is and found that there was a weak expansion, but tolerance does not some preliminary evidence suggesting association between smoking marijuana develop to supine hypotensive effects that heavy marijuana use may have a and lung cancer in individuals who (Benowitz and Jones, 1975). detrimental effect on pulmonary never smoked tobacco, but precision of Marijuana smoking, particularly by function, but the sample size of heavy the association was low at high those with some degree of coronary marijuana users in the study was too marijuana exposure levels. Hall and artery or cerebrovascular disease, poses small. Further, as mentioned in the HHS Degenhardt (2014) noted that even risks such as increased cardiac work, recommendation document (HHS, though marijuana smoke contains increased catecholamines and 2015), long-term use of marijuana may several of the same carcinogens and co- carboxyhemoglobin, myocardial lead to chronic cough, increased carcinogens as tobacco smoke (Roth et infarction and postural hypotension sputum, as well as increased frequency al., 1998) and has been found to be (Benowitz and Jones, 1981; Hollister, of chronic bronchitis and pharyngitis mutagenic and carcinogenic in the 1988; Mittleman et al., 2001; (Adams and Martin, 1996; Hollister, mouse skin test, epidemiological studies Malinowska et al., 2012). However, 1986). have been inconsistent, but more electrocardiographic changes were The HHS stated that the evidence that consistent positive associations have minimal after administration of large marijuana may lead to cancer of the been reported in case control studies. cumulative doses of D9-THC (Benowitz respiratory system is inconsistent, with Finally Gates et al. (2014), reviewed the and Jones, 1975). some studies suggesting a positive studies evaluating marijuana use and The DEA notes two recent reports that correlation while others do not (Lee and lung cancer and concluded that there is reviewed several case studies on Hancox, 2011; Tashkin, 2005). The HHS evidence that marijuana produces marijuana and cardiovascular noted a case series that reported lung changes in the respiratory system complications (Panayiotides, 2015; cancer occurrences in three marijuana (precursors to cancer) that could lead to

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lung cancer, but overall association is Reproductive Cancers may interact with the glucocorticoid weak between marijuana use and lung receptor system. The HHS stated that recent studies cancer especially when controlling for support a possible association between Immune System tobacco use. frequent, long-term marijuana use and The HHS stated that cannabinoids Endocrine System increased risk of testicular germ cell alter immune function but that there can tumors. In a hospital-based case-control Reproductive Hormones be differences between the effects of study, the frequency of marijuana use synthetic, natural, and endogenous The HHS stated that administration of was compared between testicular germ cannabinoids (Croxford and Yamamura, cell tumor (TGCT) patients (n = 187) marijuana to humans does not 2005; Tanasescu and Constantinescu, and controls (n = 148) (Trabert et al., consistently alter the endocrine system. 2010). 2011). In a controlled human exposure study The HHS noted that there are (n = 4 males), subjects were acutely TGCT patients were more likely to be conflicting results in animal and human administered smoked marijuana frequent marijuana users than controls studies with respect to cannabinoid with an odds ratio (OR) of 2.2 (95% containing 2.8% D9-THC or placebo and effects on immune functioning in confidence limits of 1.0–5.1) and were an immediate significant decrease in subjects with compromised immune less likely to be infrequent or short-term luteinizing hormone and an increase in systems. Abrams et al. (2003) examined users with odds ratios of 0.5 and 0.6, the effects of marijuana and D9-THC in cortisol was reported in the subjects that respectively in comparison to controls smoked marijuana (Cone et al., 1986). 62 HIV–1-infected patients. Subjects (Trabert et al., 2011). The DEA further received one of three treatments, three Furthermore, as cited by the HHS, two notes that in two population-based case- later studies (Dax et al., 1989; Block et times a day: smoked marijuana cigarette control studies (Daling et al., 2009; containing 3.95% D9-THC, oral tablet al., 1991) reported no changes in Lacson et al., 2012), marijuana use was containing D9-THC (2.5 mg oral hormone levels. Dax et al. (1989) compared between patients diagnosed dronabinol), or oral placebo. There were recruited male volunteers (n = 17) that with TGCT and matched controls in no changes in CD4+ and CD8+ cell were occasional or heavy users of Washington State or Los Angeles counts, HIV RNA levels, or protease marijuana. Following exposure to County. In both studies, it was reported inhibitor levels in any of the treatment 9 smoked D -THC (18 mg/cigarette) or oral that TCGT patients were twice as likely groups (Abrams et al., 2003). Therefore, 9 D -THC (10 mg three times per day for as controls to use marijuana. Authors of use of cannabinoids showed no short- three days and on the morning of the both studies concluded that marijuana term adverse virologic effects in fourth day), the subjects in that study use is associated with an elevated risk individuals with compromised immune showed no changes in plasma of TGCT (Daling et al., 2009; Lacson et systems. Conversely, Roth et al. (2005) adrenocorticotropic hormone (ACTH), al., 2012). reported that in immunodeficient mice cortisol, prolactin, luteinizing hormone, The HHS cited a study (Sarfaraz et al., implanted with human blood cells or testosterone levels. Additionally, 2005) demonstrating that WIN 55,212–2 infected with HIV, exposure to D9-THC Block et al. (1991) compared plasma (a mixed CB1/CB2 agonist) induces in vivo suppresses immune function, hormone levels amongst non-users as apoptosis (one form of cell death) in increases HIV co-receptor expression, well as infrequent, moderate, and prostate cancer cells and decreases and acts as a cofactor to enhance HIV frequent users of marijuana (n = 93 men expression of androgen receptors and replication. and 56 women) and found that chronic prostate specific antigens, suggesting a The DEA notes two recent clinical use of marijuana (infrequent, moderate, potential therapeutic value for studies reporting a decrease in cytokine and frequent users) did not significantly cannabinoid agonists in the treatment of and interleukin levels following alter concentrations of testosterone, prostate cancer, an androgen-stimulated marijuana use. Keen et al. (2014) luteinizing hormone, follicle stimulating type of carcinoma. compared the differences in the levels of hormone, prolactin, or cortisol. Other Hormones (e.g. Thyroid, Appetite) IL–6 (interleukin-6), a proinflammatory The HHS noted that there is a cytokine, amongst non-drug users (n = In more recent studies, as cited by the 78), marijuana only users (n = 46) and discrepancy in the effect of marijuana HHS, chronic marijuana use by subjects marijuana plus other drug users (n = 45) on female reproductive system (n = 39) characterized as dependent on in a community-based sample of functionality between animals and marijuana according to the ICD–10 middle-aged African Americans (Keen humans (HHS, 2015). Female rhesus criteria did not affect serum levels of et al., 2014). After adjusting for monkeys that were administered 2.5 thyroid hormones: TSH (thyrotropin), confounders, analyses revealed that 9 mg/kg D -THC, i.m., during days 1–18 of T4 (thyroxine), and T3 lifetime marijuana only users had the menstrual cycle had reduced (triiodothyronine) (Bonnet, 2013). With significantly lower IL–6 levels than the progesterone levels and ovulation was respect to appetite hormones, in a pilot nonuser group. Further, Sexton et al. suppressed (Asch et al., 1981). However, study with HIV-positive males, smoking (2014) compared several immune women who smoked marijuana (1 gram marijuana dose-dependently increased parameters in healthy individuals and marijuana cigarette with 1.8% D9-THC) plasma levels of ghrelin and leptin and subjects with multiple sclerosis (MS) during the periovulatory period (24–36 decreased plasma levels of peptide YY and found that the chronic use of hours prior to ovulation) did not exhibit (Riggs et al., 2012). marijuana resulted in reduced monocyte changes in reproductive hormone levels The HHS stated that D9-THC reduces migration, and decreased levels of CCL2 or their menstrual cycles (Mendelson binding of the corticosteroid and IL–17 in both healthy and MS and Mello, 1984). In a review article by dexamethasone in hippocampal tissue groups. Brown and Dobs (2002), the authors from adrenalectomized rats and acute The DEA also notes a review state that endocrine changes observed D9-THC releases corticosterone, with suggesting that D9-THC suppresses the with marijuana are no longer observed tolerance developing to this effect with immune responses in experimental with chronic administration and this chronic administration (Eldridge et al., animal models and in vitro and that may be due to drug tolerance. 1991). These data suggest that D9-THC these changes may be primarily

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mediated through the CB2 cannabinoid deaths attributed to a drug is not resulted in potencies ranging from a low receptor (Eisenstein and Meissler, 2015). evidence that the drug is safe for of 1 to 2% up to a high of 17% as medical use. indicated by cannabinoid content. The Petitioners’ Major Comments in Relation concentration of D9-THC averages to Factor 2 and the Government’s Factor 3: The State of the Current approximately 12% by weight in a Responses Scientific Knowledge Regarding the typical marijuana mixture of leaves and Drug or Substance (1) The petitioners state that stems. However, some specifically ‘‘[m]edical use of cannabis is considered Chemistry grown and selected marijuana samples safe.’’ (Exhibit B, page 7); and that 9 The HHS stated that marijuana, also can contain 15% or greater D -THC ‘‘[t]here are adequate and well- known as Cannabis sativa L., is part of (Appendino et al., 2011). As a result, the controlled studies proving the medical 9 the Cannabaceae plant family and is one D -THC content in a 1 gram marijuana efficacy of cannabis.’’ (Exhibit B, page cigarette can range from as little as 3 10). The petitioners also allege that of the oldest cultivated crops. The term ‘‘marijuana’’ is generally used to refer to milligrams to 150 milligrams or more. In ‘‘Cannabis is safer than current, legal a systematic review conducted by Schedule II opiate drugs’’ and that it a mixture of the dried flowering tops and leaves from Cannabis. Marijuana Cascini et al. (2012), it was reported that presents milder side effects (Exhibit B, marijuana’s D9-THC content has page 9–10). users primarily smoke the marijuana leaves, but individuals also ingest increased significantly from 1979–2009. As detailed in the HHS review and as Since there is considerable variability marijuana through food infused with discussed later in this document (see in the cannabinoid concentrations and marijuana and its extracts. Cannabis Factor 3), there are neither adequate chemical constituency among marijuana sativa is the primary species of safety studies nor adequate, well- samples, the interpretation of clinical controlled studies proving marijuana’s Cannabis that is illegally marketed in data with marijuana is complicated. A efficacy. The DEA notes that neither the the United States. Marijuana is one of primary issue is the lack of consistent CSA nor established scheduling criteria three major derivatives sold as separate concentrations of D9-THC and other suggest that the HHS and DEA should illicit products, the other two being substances in marijuana which consider the relative safety profiles of hashish and hash oil. Hashish is complicates the interpretation of the drugs when determining the proper composed of the dried and compressed effects of different marijuana schedule. To the extent that the cannabinoid-rich resinous material of constituents. An added issue is that the petitioners were referring to abuse and Cannabis and is found as balls and non-cannabinoid components in dependence liability, this document cakes as well as other forms. Individuals marijuana may potentially modify the discusses those effects in factors 1, 4, may break off pieces and place them overall pharmacological and and 7. into a pipe to smoke. Hash oil, a viscous toxicological properties of various (2) The petitioners state that brown or amber colored liquid, is marijuana strains and products. ‘‘scientific evidence regarding the safety produced by solvent extraction of Various Cannabis strains contain and efficacy of cannabis is readily cannabinoids from Cannabis and more than 525 identified natural available directly from the National contains approximately 50% constituents including cannabinoids, 21 Library of Medicine.’’ (Exhibit B, page cannabinoids. One to two drops of hash (or 22) carbon terpenoids found in the 14). oil on a cigarette has been reported to plant, as well as their carboxylic acids, The government agrees that many produce the equivalent of a single analogues, and transformation products articles discuss marijuana and its marijuana cigarette (DEA, 2015). (Agurell et al., 1984; 1986; Mechoulam, constituents. Yet, these articles in no The HHS indicated in its evaluation 1973; Appendino et al., 2011). To date, way demonstrate that marijuana is safe that the petitioners defined marijuana as more than 100 cannabinoids have been and effective for the treatment of any including all Cannabis cultivated characterized (ElSohly and Slade, 2005; disease or condition. As mentioned in strains. However, different marijuana Radwan et al., 2009; Appendino et al., the HHS review and as discussed later samples are derived from numerous 2011), and most major cannabinoid in this document (see Factor 3), the cultivated strains and may have compounds occurring naturally have current research does not provide different chemical compositions been identified. There are still new and adequate detailed scientific evidence including levels of D9-THC and other comparably more minor cannabinoids regarding chemistry, pharmacology, cannabinoids (Appendino et al., 2011). being characterized (Pollastro et al., toxicology, and effectiveness derived A consequence of having different 2011). The majority of the cannabinoids from well-controlled clinical chemical compositions in the various are found in Cannabis. One study investigations to permit a conclusion marijuana samples is that there will be reported accumulation of two that marijuana is safe and effective for significant differences in safety, cannabinoids, cannabigerol and its treating a specific, recognized disorder. biological, pharmacological, and corresponding acid, in Helichrysum (H. (3) The petitioners mentioned on page toxicological profiles and therefore, umbraculigerum) which is a non- 9 of exhibit B that ‘‘[t]here has never according to the HHS, all Cannabis Cannabis source (Appendino et al., been a lethal overdose of marijuana strains cannot be considered 2011). reported in humans’’ and that ‘‘[t]here is collectively because of the variations in Of the cannabinoids found in no known LD50 for any form of chemical composition. Furthermore, the marijuana, D9-THC (previously known cannabis.’’ concentration of D9-THC and other as D1-THC) and delta-8- As more fully discussed in Factor 3 cannabinoids present in marijuana may tetrahydrocannabinol (D8-THC, D6-THC) below, the HHS and DEA conclude that vary due to growing conditions and have been demonstrated to produce there are not adequate studies to processing of the plant after harvesting. marijuana’s psychoactive effects. determine the safety of marijuana. As For example, the plant parts collected Psychoactive effects from marijuana discussed in the HHS document and such as flowers, leaves and stems can usage have been mainly attributed to D9- below, the determination of safety is influence marijuana’s potency, quality, THC because D9-THC is present in more complex than a mere and purity (Adams and Martin, 1996; significantly more quantities than D8- determination of the rate or likelihood Agurell et al., 1984; Mechoulam, 1973). THC in most marijuana varieties. There of death. Moreover, the lack of overdose Variations in marijuana harvesting have are only a few marijuana strains that

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contain D8-THC in significant amounts (weighing between 0.5 and 1 gram) or in Absorption and Distribution of Orally (Hively et al., 1966). D9-THC is an a pipe. More recently, vaporizers have Administered Marijuana optically active resinous substance that been used as another means for Following oral administration of D9- is extremely lipophilic. The chemical individuals to inhale marijuana. 9 THC or marijuana, onset of effects start name for D -THC is (6aR-trans)- Marijuana may also be ingested orally in within 30 to 90 minutes, peak after 2 to 6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3- foods or as an extract in ethanol or other 3 hours and effects remain for 4 to 12 pentyl-6H-dibenzo-[b,d]pyran-1-ol, or solvents. Pharmacokinetic studies with hours (Grotenhermen, 2003; Adams and (–)-delta9-(trans)-tetrahydrocannabinol. marijuana focused on evaluating the Martin, 1996; Agurell et al., 1984; D9 The (–)-trans -THC isomer is absorption, metabolism, and elimination Agurell et al., 1986). Dose titration of D9- pharmacologically 6 to 100 times more profile of D9-THC and other THC from orally ingested marijuana is potent than the (+)-trans isomer (Dewey cannabinoids (Adams and Martin, 1996; difficult for users in comparison to et al., 1984). Agurell et al., 1984; Agurell et al., 1986). smoked or inhaled marijuana due to the Other relatively well-characterized delay in the onset of effects. Oral cannabinoids present in marijuana Absorption and Distribution of Inhaled bioavailability of D9-THC, either in its include cannabidiol (CBD), Marijuana Smoke cannabichromene (CBC), and pure form or in marijuana, is low and cannabinol (CBN). CBD and CBC are There is high variability in the variable with a range from 5% to 20% major cannabinoids in marijuana and pharmacokinetics of D9-THC and other (Agurell et al., 1984; Agurell et al., are both lipophilic. The chemical name cannabinoids from smoked marijuana 1986). There is also inter- and intra- for CBD is 2-[(1R,6R)-3-methyl-6-prop-1- due to differences in individual subject variability of orally administered 9 en-2-ylcyclohex-2-en-1-yl]-5- smoking behavior even under controlled D -THC under experimental conditions pentylbenzene-1,3-diol and the experimental conditions (Agurell et al., and even under repeated dosing experiments (HHS, 2015). The HHS chemical name for CBC is 2-methyl-2-(4- 1986; Herning et al., 1986; Huestis et al., noted that in bioavailability studies methylpent-3-enyl)-7-pentyl-5- 1992a). Experienced marijuana users using radiolabeled D9-THC, D9-THC chromenol. CBN is a minor naturally- can titrate and regulate the dose by occurring cannabinoid with weak plasma levels following oral holding marijuana smoke in their lungs administration of D9-THC were low psychoactivity and is also a major for an extended period of time resulting metabolite of D9-THC. The chemical relative to plasma levels after inhaled or in increased psychoactive effects by intravenously administered D9-THC. name for CBN is 6,6,9-trimethyl-3- prolonging absorption of the smoke. pentyl-benzo[c]chromen-1-ol. The low and variable bioavailability of This property may also help explain orally administered D9-THC is due to In summary, marijuana has several why there is a poor correlation between strains with high variability in the first pass hepatic elimination from venous levels of D9-THC and the concentrations of D9-THC, the main blood and erratic absorption from intensity of effects and intoxication psychoactive component, as well as stomach and bowel (HHS, 2015). (Agurell et al., 1986; Barnett et al., 1985; other cannabinoids and compounds. Huestis et al., 1992a). The HHS Metabolism and Excretion of Marijuana is not a single chemical and Cannabinoids From Marijuana does not have a consistent and recommended that puff and inhalation reproducible chemical profile with volumes should be tracked in Studies evaluating cannabinoid experimental studies because the metabolism and excretion focused on predictable or consistent clinical effects. 9 In the HHS recommendation for concentration of cannabinoids can vary D -THC because it is the primary marijuana scheduling (HHS, 2015), it at different stages of smoking. psychoactive component in marijuana. D9 was recommended that investigators D9-THC from smoked marijuana is -THC is metabolized via microsomal hydroxylation and oxidation to both consult a guidance for industry entitled, rapidly absorbed within seconds. active and inactive metabolites Botanical Drug Products,46 which Psychoactive effects are observed (Lemberger et al., 1970; Lemberger et al., provides information on the approval of immediately following absorption with 1972a; Lemberger et al., 1972b; Agurell botanical drug products. Specifically, in measurable neurological and behavioral et al., 1986; Hollister, 1988). Metabolism order to investigate marijuana in changes for up to 6 hours 9 support of a New Drug Application of D -THC is consistent among frequent (Grotenhermen, 2003; Hollister, 1986; and infrequent marijuana users (Agurell (NDA), clinical studies under an Hollister, 1988). D9-THC is distributed Investigational New Drug (IND) et al., 1986). The primary active to the brain in a rapid and efficient metabolite of D9-THC following oral application should include ‘‘consistent 9 manner. Bioavailability of D -THC from ingestion is 11-hydroxy-D9-THC which batches of a particular marijuana marijuana (from a cigarette or pipe) 9 product for [a] particular disease.’’ is equipotent to D -THC in producing ranges from 1 to 24% with the fraction marijuana-like subjective effects (HHS, 2015). Furthermore, the HHS absorbed rarely exceeding 10 to 20% noted that investigators must provide (Agurell et al., 1986; Lemberger and (Agurell et al., 1986; Hollister, 1988). Rubin, 1975). Metabolite levels data meeting the requirements for new The low and variable bioavailability of drug approval as stipulated in 21 CFR following oral administration may be D9-THC is due to loss in side-stream 9 314.50 (HHS, 2015). greater than that of D -THC and may smoke, variation in individual smoking contribute greatly to the Human Pharmacokinetics behaviors and experience, incomplete pharmacological effects of oral D9-THC Pharmacokinetics of marijuana in absorption of inhaled smoke, and or marijuana. humans is dependent on the route of metabolism in lungs (Herning et al., Plasma clearance of D9-THC administration and formulation (Adams 1986; Johansson et al., 1989). After approximates hepatic blood flow at a 9 and Martin, 1996; Agurell et al., 1984; cessation of smoking, D -THC venous rate of approximately 950 ml/min or Agurell et al., 1986). Individuals levels decline within minutes and greater. Rapid clearance of D9-THC from primarily smoke marijuana as a cigarette continue to decline to about 5% to 10% blood is primarily due to redistribution of the peak level within an hour to other tissues in the body rather than 46 Available at http://www.fda.gov/Drugs/ (Agurell et al., 1986; Huestis et al., to metabolism (Agurell et al., 1984; default.htm under Guidance (Drugs). 1992a; Huestis et al., 1992b). Agurell et al., 1986). Outside of the

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liver, metabolism in most tissues is 5. Scientific evidence must be widely enough to derive reproducible and considerably slow or does not occur. available. standardized doses. The elimination half-life of D9-THC In its review (HHS, 2015), the HHS Element #2: There must be adequate ranges from 20 hours to between 10 and evaluated the five elements with respect safety studies. 13 days (Hunt and Jones, 1980). to the currently available research for ‘‘There must be adequate Lemberger et al. (1970) reported that the marijuana. The HHS concluded that pharmacological and toxicological half-life of D9-THC ranged from 23–28 marijuana does not meet any of the five studies, done by all methods reasonably hours in heavy marijuana users and up elements—all of which must be applicable, on the basis of which it to 60 to 70 hours in naı¨ve users. The demonstrated to find that a drug has a could fairly and responsibly be long elimination half-life of D9-THC is ‘‘currently accepted medical use.’’ A concluded, by experts qualified by due to slow release of D9-THC and other brief summary of the HHS’s evaluation scientific training and experience to cannabinoids from tissues and is provided below. evaluate the safety and effectiveness of drugs, that the substance is safe for subsequent metabolism. Inactive Element #1: The drug’s chemistry 9 treating a specific, recognized disorder.’’ carboxy metabolites of D -THC have must be known and reproducible. terminal half-lives of 50 hours to 6 days 57 FR 10499, 10506 (March 26, 1992). ‘‘The substance’s chemistry must be or more and serve as long-term markers The HHS stated that there are no scientifically established to permit it to in urine tests for marijuana use. adequate safety studies on marijuana. be reproduced into dosages which can Most of the absorbed D9-THC dose is As indicated in their evaluation of be standardized. The listing of the eliminated in the feces and about 33% Element #1, the considerable variation substance in a current edition of one of in the chemistry of marijuana in urine. The glucuronide metabolite of the official compendia, as defined by complicates the safety evaluation. The D9-THC is excreted as the major urine section 201(j) of the Food, Drug and HHS concluded that marijuana does not metabolite along with 18 non- Cosmetic Act, 21 U.S.C. 321(j), is satisfy Element #2 for having adequate conjugated metabolites (Agurell et al., sufficient generally to meet this safety studies such that medical and 1986). requirement.’’ 57 FR 10499, 10506 scientific experts may conclude that it is Research Status and Test of Currently (March 26, 1992). safe for treating a specific ailment. Accepted Medical Use for Marijuana Marijuana, as defined in the petition, Element #3: There must be adequate includes all Cannabis strains. (For and well-controlled studies of efficacy. According to the HHS, there are ‘‘There must be adequate, well- numerous human clinical studies with purposes of the CSA, marijuana includes all species of the genus controlled, well-designed, well- marijuana in the United States under conducted and well-documented FDA-regulated IND applications. Results Cannabis, including all strains therein 47). Based on the definition of studies, including clinical of small clinical exploratory studies investigations, by experts qualified by have been published in the medical marijuana in the petition, the chemistry of marijuana is not reproducible such scientific training and experience to literature. Approval of a human drug for evaluate the safety and effectiveness of marketing, however, is contingent upon that a standardized dose can be created. 9 drugs, on the basis of which it could be FDA approval of a New Drug Chemical constituents including D - THC and other cannabinoids vary fairly and responsibly concluded by Application (NDA) or a Biologics such experts that the substance will License Application (BLA). According significantly in marijuana samples derived from different strains have the intended effect in treating a to the HHS, the FDA has not approved specific, recognized disorder.’’ 57 FR any drug product containing marijuana (Appendino et al., 2011). As a result, there will be significant differences in 10499, 10506 (March 26, 1992). for marketing. As indicated in the HHS’s review of safety, biological, pharmacological, and The HHS noted that a drug may be marijuana (HHS, 2015), there are no toxicological parameters amongst the found to have a medical use in adequate or well-controlled studies that various marijuana samples. Due to the treatment in the United States for prove marijuana’s efficacy. The FDA variation of the chemical composition in purposes of the CSA if the drug meets independently reviewed (FDA, 2015) marijuana samples, it is not possible to the five elements described by the DEA publicly available clinical studies on reproduce a standardized dose when in 1992. Those five elements ‘‘are both marijuana published prior to February considering all strains together. The necessary and sufficient to establish a 2013 to determine if there were HHS does advise that if a specific prima facie case of currently accepted appropriate studies to determine Cannabis strain is cultivated and medical use’’ in treatment in the United marijuana’s efficacy (please refer to processed under controlled conditions, States.’’ (57 FR 10499, 10504 (March 26, FDA, 2015 and HHS, 2015 for more the plant chemistry may be consistent 1992)). This five-element test, which the details). After review, the FDA HHS and DEA have utilized in all such determined that out of the identified analyses for more than two decades, has 47 Although the CSA definition of marijuana refers only to the species ‘‘Cannabis sativa L.,’’ articles, including those identified been upheld by the Court of Appeals. federal courts have consistently ruled that all through a search of bibliographic ACT, 15 F.3d at 1135. The five elements species of the genus cannabis are included in this references and 566 abstracts located on that characterize ‘‘currently accepted definition. See United States v. Kelly, 527 F.2d 961, PubMed, 11 studies met the a priori medical use’’ for a drug are summarized 963–964 (9th Cir. 1976) (collecting and examining cases). The Single Convention (article 1, par. 1(c)) selection criteria, including placebo here and expanded upon in the likewise defines the ‘‘cannabis plant’’ to mean ‘‘any control and double-blinding. FDA and discussion below: plant of the genus Cannabis.’’ As explained above HHS critically reviewed each of the 11 1. The drug’s chemistry must be in the attachment titled ‘‘Preliminary Note studies to determine if the studies met known and reproducible; Regarding Treaty Considerations,’’ 21 U.S.C. 811(d)(1) provides that, where a drug is subject to accepted scientific standards. FDA and 2. There must be adequate safety control under the Single Convention, the DEA HHS concluded that these studies do studies; Administrator must control the drug under the not ‘‘currently prove efficacy of 3. There must be adequate and well- schedule he deems most appropriate to carry out marijuana’’ for any therapeutic controlled studies proving efficacy; such treaty obligations, without regard to the findings required by 21 U.S.C. 811(a) or 812(b) and indication due to limitations in the 4. The drug must be accepted by without regard to the procedures prescribed by 21 study designs. The HHS indicated that qualified experts; and U.S.C. 811(a) and (b). these studies could be used as proof of

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concept studies, providing preliminary current, modern accepted standards for consumption, particularly in its crude evidence on a proposed hypothesis what constitutes medicine.’’ (Exhibit B, smoked form’’ (ACP, 2008). The IOM, involving a drug’s effect. page 13). On page 3 of the cover letter consistent with others in the medical Element #4: The drug must be of the petition, the petitioners stated, community, endorses further studies accepted by qualified experts. ‘‘The American medical community into the potential therapeutic uses of ‘‘[A] consensus of the national supports rescheduling, and there are marijuana, but did not advocate for community of experts, qualified by safe pharmacy-based methods to medicinal use without further testing scientific training and experience to dispense medical cannabis.’’ (IOM, 2009). evaluate the safety and effectiveness of Furthermore, they stated that ‘‘[i]n As detailed in the HHS review, in drugs, accepts the safety and 2009, the American Medical Association order for a drug to be found to have a effectiveness of the substance for use in (AMA) reversed its earlier position that ‘‘currently accepted medical use,’’ it treating a specific, recognized disorder. supported [s]chedule I classification of must be accepted by qualified experts. A material conflict of opinion among cannabis. The AMA now supports There is no evidence that there is a experts precludes a finding of investigation and clinical research of consensus among qualified experts that consensus.’’ 57 FR 10499, 10506 (March cannabis for medicinal use, and urged marijuana is safe and effective for use in 26, 1992). the federal government to reassess the treating a specific, recognized disorder. The HHS concluded that there is [s]chedule I classification. The (2) The petitioners claim that, ‘‘The currently no evidence of a consensus American College of Physicians [ACP] chemistry of cannabis is known and among qualified experts that marijuana recently expressed similar support.’’ In reproducible’’ (Exhibit B, page 6) and is safe and effective in treating a specific addition, they note that the Institute of ‘‘newer medicinal strains of cannabis and recognized disorder. The HHS Medicine (IOM) also documented the are lower in THC and higher in the non- indicated that medical practitioners scientific basis and therapeutic effects of psychoactive, more therapeutic who are not experts in evaluating drugs cannabis (Exhibit B, page 13). cannabinoids, such as CBD, and CBN. cannot be considered qualified experts The DEA notes that the statements by These compounds further improved the (HHS, 2015; 57 FR 10499, 10505). the cited organizations (AMA, ACP, efficacy of cannabis.’’ (Exhibit B, page Further, the HHS noted that the 2009 IOM) support more research into the 10). American Medical Association (AMA) potential medical properties associated As indicated by the HHS, the report entitled, ‘‘Use of Cannabis for with marijuana. The HHS did not find petitioners defined marijuana to include Medicinal Purposes’’ does not conclude that the statements by these all Cannabis strains. As such, the that there is a currently accepted organizations provide evidence chemistry of marijuana is not medical use for marijuana. HHS also supporting a conclusion that adequate reproducible such that a standardized pointed out that state-level ‘‘medical safety studies and adequate, well- dose can be created. Chemical marijuana’’ laws do not provide controlled efficacy studies demonstrate constituents including D9-THC and evidence of such a consensus among the safety and efficacy of marijuana other cannabinoids vary significantly in qualified experts. (HHS, 2015). The AMA’s official policy different marijuana samples (Appendino Element #5: The scientific evidence on medicinal use of marijuana is as et al., 2011). Furthermore, the HHS cited must be widely available. follows: ‘‘Our AMA urges that a published report that indicates that ‘‘In the absence of NDA approval, marijuana’s status as a federal new substances in marijuana are information concerning the chemistry, [s]chedule I controlled substance be continually being characterized pharmacology, toxicology, and reviewed with the goal of facilitating the (Pollastro et al., 2011). If there is effectiveness of the substance must be conduct of clinical research and significant variance in the chemical reported, published, or otherwise widely development of cannabinoid-based composition of marijuana between available, in sufficient detail to permit medicines, and alternative delivery samples, it is not possible for the experts, qualified by scientific training methods. This should not be viewed as chemistry to be reproducible. and experience to evaluate the safety an endorsement of state-based medical Because the petition defines and effectiveness of drugs, to fairly and cannabis programs, the legalization of marijuana as including all cultivated responsibly conclude the substance is marijuana, or that scientific evidence on strains, the DEA believes that the THC safe and effective for use in treating a the therapeutic use of cannabis meets and CBD level of specific strains is not specific, recognized disorder.’’ 57 FR the current standards for a prescription relevant to this consideration. In fact, 10499, 10506 (March 26, 1992). drug product.’’ (AMA, 2009). the average D9-THC content in The HHS concluded that the currently The DEA further notes that the 2013 marijuana has steadily risen from 1995 available data and information on AMA House of Delegates report states to 2014 as reported by the University of marijuana is not sufficient to allow that, ‘‘cannabis is a dangerous drug and Mississippi Potency Monitoring Project, scientific scrutiny of the chemistry, as such is a public health concern.’’ as presented in Factor 1. In 1995, the D9- pharmacology, toxicology, and (AMA, 2013). In 2008, the ACP THC content was 4% on average and by effectiveness. In particular, scientific indicated that ‘‘further research is 2015, the average content of THC had evidence demonstrating the chemistry needed to compare cannabinoids’ risen to 11.2% over a 20 year period. In of a specific Cannabis strain that could efficacy and safety with current the same time period, CBD and CBN provide standardized and reproducible treatments.’’ (ACP, 2008). The ACP percentages have ranged from 0.15% to doses is not available. stated that, ‘‘ACP urges an evidence- 0.60% on average. based review of marijuana’s status as a The DEA also notes statements in the Petitioners’ Major Comments in Relation [s]chedule I controlled substance to petitioners’ document that support the to Factor 3 and the Government’s determine whether it should be conclusion reached by DEA and HHS Responses reclassified to a different schedule. This that the chemistry of marijuana as (1) The petitioners indicate that there review should consider the scientific broadly defined by the petitioners is not is medical support and acceptance for findings regarding marijuana’s safety reproducible or well-defined. For the medical use of marijuana and stated and efficacy in some clinical conditions example, the petitioners acknowledge that ‘‘[c]annabis has been accepted by as well as evidence on the health risks that ‘‘Cannabis is a complex plant, with the medical community as meeting the associated with marijuana several subtypes of cannabis.’’ (Exhibit

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B, page 6). The petitioners also period, of which one patient died. graders, respectively, reported using acknowledge that ‘‘the ratios of the While the findings cited by the marijuana in the past year. A number of various cannabinoids differ according to petitioners and authors (e.g. no adverse high school students reported daily use the plant strain, and, to some extent, outcomes with long term marijuana use) in the past month, including 1.1%, how the plant is grown.’’ (Exhibit B, are informative, conclusions on long- 3.0%, and 6.0% of 8th, 10th, and 12th page 12). term use of marijuana cannot be applied graders, respectively. (3) The petitioners stated in Exhibit B, to the general population. The prevalence of marijuana use and page 8, that ‘‘[o]verall, the 33 completed abuse is also indicated by criminal and published American controlled Factor 4: Its History and Current investigations for which drug evidence clinical trials with cannabis have Pattern of Abuse was analyzed in federal, state, and local studied its safety, routes of Marijuana continues to be the most forensic laboratories, as discussed above administration, and use in comparison widely used illicit drug. In 2013, an in Factor 1. The National Forensic with placebos, standard drugs, and in estimated 24.6 million Americans age Laboratory System (NFLIS), a DEA some cases dronabinol ...,’’ and 12 or older were current (past month) program, systematically collects drug further cited a systematic review by illicit drug users. Of those, 19.8 million identification results and associated Wang et al. (2008), that evaluated 23 were current (past month) marijuana information from drug cases submitted randomized controlled trials and 8 users. As of 2013, an estimated 114.7 to and analyzed by federal, state, and observational studies, stating that, ‘‘[o]f million Americans age 12 and older had local forensic laboratories. NFLIS data all the adverse events reported, 97 used marijuana or hashish in their shows that marijuana was the most percent were considered ‘not serious,’ lifetime and 33.0 million had used it in frequently identified drug from January with the most commonly reported the past year. 2001 through December 2014. In 2014, ‘dizziness.’ ’’ According to the NSDUH estimates, marijuana accounted for 29.3% The petitioners also cited in Exhibit 3.0 million people age 12 or older used (432,989) of all drug exhibits in NFLIS. B, page 8, ‘‘There has been a long-term, an illicit drug for the first time in 2014. The high consumption of marijuana is prospective, federally funded cannabis Marijuana initiates totaled 2.6 million in being fueled by increasing amounts of clinical study jointly administered by 2014. Nearly half (46.8%) of the 2.6 domestically grown marijuana as well as National Institute on Drug Abuse million new users were less than 18 increased amounts of foreign source (NIDA) and FDA. This study has been years of age. In 2014, marijuana was marijuana being illicitly smuggled into running for over 30 years without any used by 82.2% of current (past month) the United States. In 2014, the Domestic demonstrable adverse outcomes related illicit drug users. In 2014, among past Cannabis Eradication and Suppression to chronic medicinal cannabis use.’’ year marijuana users age 12 or older, Program (DCE/SP) reported that As cited in the HHS recommendation 18.5% used marijuana on 300 or more 3,904,213 plants were eradicated in document (HHS, 2015), the FDA days within the previous 12 months. outdoor cannabis cultivation areas conducted its own evaluation of the This translates into 6.5 million people compared to 2,597,798 in 2000, as published clinical studies on the using marijuana on a daily or almost shown above in Table 3. Significant medical application of marijuana prior daily basis over a 12-month period, a quantities of marijuana were also to February 2013 (FDA, 2015). Further significant increase from the 3.1 million eradicated from indoor cultivation details on the FDA review can be found daily or almost daily users in 2006 and operations. There were 396,620 indoor in the published report (FDA, 2015). from the 5.7 million in just the previous plants eradicated in 2014 compared to Based on the analysis, 11 studies were year. In 2014, among past month 217,105 eradicated in 2000. As shown evaluated further and the FDA marijuana users, 41.6% (9.2 million in Table 2 above, in 2014, the National concluded that none of these studies people) used the drug on 20 or more Seizure System (NSS) reported seizures ‘‘meet the criteria required by the FDA days in the past month, a significant of 1,767,741 kg of marijuana. to determine if marijuana is safe and increase from the 8.1 million in 2013. effective in specific therapeutic areas.’’ Marijuana is also the illicit drug with Petitioners’ Major Comments in Relation (page 6; FDA, 2015). the highest numbers of past year to Factor 4 and the Government’s The DEA has reviewed the systematic dependence or abuse in the U.S. Responses review by Wang et al. (2008) and notes population. According to the 2014 (1) The petitioners indicated that the that most of the studies included in the NSDUH report, of the 7.1 million history and current pattern of abuse is review were synthetic cannabinoid persons aged 12 or older who were difficult to estimate since ‘‘a large medicines (e.g. dronabinol) or classified with illicit drug dependence percentage of United States citizens’’ cannabinoid extracts (e.g. Sativex®); or abuse, 4.2 million of them abused or have used marijuana at least once in these types of studies were excluded in were dependent on marijuana their lifetime and some estimates have the FDA review as the analysis focused (representing 59.0% of all those indicated that ‘‘over 40 percent of the solely on natural forms of marijuana classified with illicit drug dependence nation has tried the plant.’’ Further, the (FDA, 2015). Wang et al. (2008) or abuse and 1.6% of the total U.S. non- petitioners stated that ‘‘trying marijuana concluded that ‘‘good safety and institutionalized population aged 12 or once should not be confused with a efficacy data on smoked cannabis are older). health problem, let alone a diagnosis of urgently needed.’’ According to the 2015 Monitoring the dependence or abuse.’’ (Exhibit B, page With respect to the 30-year study Future (MTF) survey, marijuana is used 26). cited by the petitioners (Russo et al., by a large percentage of American Marijuana usage numbers mentioned 2001) on page 8 of Exhibit B, it should youths, and is the most commonly used in both the HHS Recommendation and be clarified that the referenced study illicit drug among American youth. this DEA document include surveys was not jointly administered by NIDA Among students surveyed in 2015, from NSDUH and MTF. These surveys and the FDA. As with other clinical 15.5% of 8th graders, 31.1% of 10th measure extent of use of marijuana. As studies, an IND application was graders, and 44.7% of 12th graders mentioned in this Factor, according to approved by the FDA and marijuana reported that they had used marijuana the results of the 2013 NSDUH survey, was supplied by NIDA. The authors in their lifetime. In addition, 11.8%, 17.4% of past year marijuana users age evaluated only 8 patients over this 25.4%, and 34.9% of 8th, 10th, and 12th 12 or older used marijuana on 300 or

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more days within the previous 12 adolescence and it increases to 25 to dependence in teenagers and young months. This indicates that 5.7 million 50% of those who are daily users. adults. people used marijuana on a daily or Factor 5: The Scope, Duration, and Petitioners’ Major Comment in Relation almost daily basis over this 12-month Significance of Abuse to Factor 5 and DEA’s Response period, which is a 1.8-fold increase from the 3.1 million daily or almost daily Abuse of marijuana is widespread and (1) Petitioners’ contend that, ‘‘The users in 2006. Furthermore, 6% of all significant. As previously noted, prevalence and significance of potential twelfth graders in the United States according to the NSDUH, in 2014, an abuse are limited for cannabis, reported daily use of marijuana in the estimated 117.2 million Americans especially in relation to other [s]chedule 2015 MTF survey. These data strongly (44.2%) age 12 or older had used II substances.’’ The petitioners cited indicate that there is a significant marijuana or hashish in their lifetime, results from the 1990 NIDA Household portion of the U.S. population using 35.1 million (13.2%) had used it in the Survey on Drug Abuse and indicated marijuana on a daily basis. past year, and 22.2 million (8.4%) had that, ‘‘more than four out of five people (2) As stated in Exhibit B on page 26, used it in the past month. Past year and who had used cannabis in the previous subpart A, ‘‘Rates of dependence or past month marijuana use has increased year reported no problems related to the abuse are remarkably low’’ and further significantly since 2013. Past month drug.’’ (Exhibit B, page 28). suggest that ‘‘[i]nterviews for the marijuana use is highest among 18–21 The prevalence of marijuana usage National Longitudinal Alcohol year olds and it declines among those 22 and marijuana dependence is significant Epidemiological Survey ([NLAES] [sic] years of age and older. In 2014, an in the United States. The 2014 NSDUH and National Epidemiological Survey estimated 18.5% of past year marijuana findings indicate that there are on Alcohol and Related Conditions users age 12 or older used marijuana on approximately 6.5 million Americans ([NESARC] [sic] each confirm that rates 300 or more days within the past 12 using marijuana on a daily or almost of dependence or abuse of cannabis months. This translates into 6.5 million daily basis. Further, Volkow et al. (2014) have never exceed (sic) two percent in persons using marijuana on a daily or reported that in long-term or heavy a given year.’’ almost daily basis over a 12-month marijuana users, 9% of users become The authors of study cited by the period. In 2014, an estimated 41.6% (9.2 addicted to marijuana. Among those petitioners (Compton et al., 2004) million) of past month marijuana users who began using marijuana in concluded that a higher percentage of age 12 or older used the drug on 20 or adolescence, marijuana dependence American adults had a marijuana use more days in the past month (SAMHSA, increases to 17%, and it further disorder in 2001–2002 (1.5%) than in NSDUH). Chronic use of marijuana is increases to 25 to 50% of daily users 1991–1992 (1.2%). Compton et al. associated with a number of health risks that started using marijuana during (2004) noted that the marijuana use (see Factors 2 and 6). adolescence. These collective findings disorder increase of 0.3% over the 10 Furthermore, the average percentage indicate that there is considerable year period would equate to an increase of D9-THC in seized marijuana has significance associated with marijuana from 2.2 million people to 3 million increased over the past two decades use and abuse since 9% of users become people in the United States. The (The University of Mississippi Potency addicted to marijuana, 25 to 50% of petitioners failed to explain the impact Monitoring Project). Additional studies daily marijuana users started during of 1.5% (or less than 2 percent) of the are needed to clarify the impact of adolescence, and prevalence of usage is U.S. population having a marijuana use greater potency, but one study shows significantly high based on the data disorder. In order to put these numbers that higher levels of D9-THC in the body presented from Volkow et al (2014) and into perspective, the DEA reviewed the are associated with greater psychoactive the 2014 NSDUH survey. literature and found that non-medical effects (Harder and Rietbrock, 1997), prescription drug use and abuse rates which can be correlated with higher Factor 6: What, if any, Risk There is to were examined in the same NLAES and abuse potential (Chait and Burke, 1994). the Public Health NESARC (1991–1992 and 2001–2002) TEDS data show that in 2013, In its recommendation, the HHS populations (Blanco et al., 2007). Blanco marijuana/hashish was the primary discussed public health risks associated et al (2007) examined non-medical substance of abuse in 16.8% of all with acute and chronic marijuana use in prescription drug use and abuse rates admissions to substance abuse treatment Factor 6. Public health risks as from the periods of 1991–1992 and among patients age 12 and older. TEDS measured by emergency department 2001–2002. In 1991 through 1992, the data also show that marijuana/hashish visits and drug treatment admissions are prevalence of non-medical prescription was the primary substance of abuse for discussed by HHS and DEA in Factors drug (opioid, stimulant, and 77.0% of all 12- to 14-year-olds 1, 4, and 5. Similarly, Factor 2 discusses tranquilizer) abuse and dependence was admitted for drug treatment and 75.5% marijuana’s pharmacology and presents 0.1%. Non-medical prescription drug of all 15- to 17-year-olds admitted for some of the adverse health effects (primarily opioid-based drugs) abuse drug treatment in 2013. Among the associated with use. Marijuana use may and dependence increased to 0.3% in 281,991 admissions to drug treatment in affect the physical and/or psychological 2001 through 2002. Therefore, in the 2013 in which marijuana/hashish was functioning of an individual user, but same 2001–2002 NLAES and NESARC the primary drug, the average age at may also have broader public impacts populations, the percentage of people admission was 25 years and the peak including driving impairments and with a marijuana use disorder was age cohort was 15 to 17 years (22.5%). fatalities from car accidents. approximately five-fold higher (1.5% Thirty-nine percent of the 281,991 versus 0.3%) than those with opioid primary marijuana/hashish admissions Risks From Acute Use of Marijuana abuse and dependence resulting from (35.9%) were under the age of 20. As discussed in the HHS review non-medical prescription drug use. In summary, the recent statistics from document (HHS, 2015), acute usage of Further, Volkow et al. (2014) reported these various surveys and databases (see marijuana impairs psychomotor that in long-term or heavy marijuana Factor 1 for more details) demonstrate performance including motor control users, 9% of users become addicted to that marijuana continues to be the most and impulsivity, risk taking and marijuana. This percentage increases to commonly used illicit drug, with large executive function (Ramaekers et al., 17% when marijuana use starts in incidences of heavy use and 2004; Ramaekers et al., 2006). In a

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minority of individuals using marijuana, (Wang et al., 2013). The DEA also notes pulmonary consequences, including dysphoria, prolonged anxiety, and a larger scale evaluation of pediatric chronic cough and increased sputum psychological distress may be observed exposures using the National Poison (Adams and Martin, 1996), and (Haney et al., 1999). The DEA further Data System (Wang et al., 2014). That histopathologic abnormalities in notes a recent review of acute marijuana study reported that there were 985 bronchial epithelium (Adams and effects (Wilkinson et al., 2014) that unintentional marijuana exposures in Martin, 1996). reported impaired neurological function children (9 years and younger) between including altered perception, paranoia, January 1, 2005 to December 31, 2011. Marijuana as a ‘‘Gateway Drug’’ delayed response time, and memory The authors stratified the ED visits by The HHS reviewed the clinical deficits. states with laws allowing medical use of studies evaluating the gateway In its recommendation, HHS marijuana, states transitioning to references a meta-analysis conducted by legalization for medical use, and states hypothesis in marijuana and found Li et al (2012) where the authors with no such laws. Out of the 985 them to be limited. The primary reasons concluded that psychomotor exposures, 495 were in non-legal states were: (1) Recruited participants were impairments associated with acute (n = 33 states), 93 in transitional states influenced by social, biological, and marijuana usage have also been (n = 8 states), and 396 in ‘‘legal’’ states economic factors that contribute to associated with increased risk of car (n = 9 states). The authors reported that extensive drug abuse (Hall and Lynskey, accidents with individuals experiencing there was a twofold increase (OR = 2.1) 2005), and (2) most studies testing the acute marijuana intoxication (Li et al., in moderate or major effects in children gateway drug hypothesis for marijuana 2012; HHS, 2015). The DEA further with unintentional marijuana use and a use the determinative measure any use notes more recent studies examining the threefold increase (OR = 3.4) in of an illicit drug rather than applying risk associated with marijuana use and admissions to critical care units in states DSM–5 criteria for drug abuse or driving. Younger drivers (under 21) allowing medical use of marijuana, in dependence (DSM–5, 2013). have been characterized as the highest comparison to non-legal states. risk group associated with marijuana The HHS cited several studies where use and driving (Whitehill et al., 2014). Risks Associated With Chronic Use of marijuana use did not lead to other Furthermore, in 2013, marijuana was Marijuana illicit drug use (Kandel and Chen, 2000; found in 13% of the drivers involved in The HHS noted that a major risk from von Sydow et al., 2002; Nace et al., automobile-related fatal accidents chronic marijuana use is a distinctive 1975). Two separate longitudinal (McCartt, 2015). The potential risk of withdrawal syndrome, as described in studies with adolescents using automobile accidents associated with the 2013 DSM–5. The HHS analysis also marijuana did not demonstrate an marijuana use appears to be increasing quoted the following description of risks association with use of other illicit since there has been a steady increase in associated with marijuana [cannabis] drugs (Kandel and Chen, 2000; von individuals intoxicated with marijuana abuse from the DSM–5: Sydow et al., 2002). over the past 20 years (Wilson et al., Individuals with cannabis use disorder It was noted by the HHS that, when 2014). However, a recent study may use cannabis throughout the day over a evaluating the gateway hypothesis, commissioned by the National Highway period of months or years, and thus may differences appear when examining use Traffic Safety Administration (NHTSA) spend many hours a day under the influence. versus abuse or dependence of other reported that when adjusted for Others may use less frequently, but their use confounders (e.g., alcohol use, age, causes recurrent problems related to family, illicit drugs. Van Gundy and Rebellon gender, ethnicity), there was not a school, work, or other important activities (2010) reported that there was a significant increase in crash risk (fatal (e.g., repeated absences at work; neglect of correlation between marijuana use in and nonfatal, n = 2,682) associated with family obligations). Periodic cannabis use adolescence and other illicit drug use in marijuana use (Compton and Berning, and intoxication can negatively affect early adulthood, but when examined in behavioral and cognitive functioning and terms of drug abuse of other illicit 2015). thus interfere with optimal performance at The DEA also notes recent studies work or school, or place the individual at drugs, age-linked stressors and social examining unintentional exposures of increased physical risk when performing roles were confounders in the children to marijuana (Wang et al., activities that could be physically hazardous association. Degenhardt et al. (2009) 2013; 2014). Wang et al. (2013) reviewed (e.g. driving a car; playing certain sports; reported that marijuana use often emergency department (ED) visits at a performing manual work activities, including precedes use of other illicit drugs, but children’s hospital in Colorado from operating machinery). Arguments with dependence involving drugs other than January 1, 2005 to December 31, 2011. spouses or parents over the use of cannabis in the home, or its use in the presence of marijuana frequently correlated with As stated by the authors, in 2000 higher levels of illicit drug abuse. Colorado passed Amendment 20 which children, can adversely impact family functioning and are common features of Furthermore, Degenhardt et al. (2010) allowed for the use of marijuana. those with cannabis use disorder. Last, reported that in countries with lower Following the passage of ‘‘a new Justice individuals with cannabis use disorder may prevalence of marijuana usage, use of Department policy’’ instructing ‘‘federal continue using marijuana despite knowledge other illicit drugs before marijuana was prosecutors not to seek arrest of medical of physical problems (e.g. chronic cough marijuana users and suppliers as long as related to smoking) or psychological often documented. they conform to state laws’’ (as stated in problems (e.g. excessive sedation or Based on these studies among others, Wang et al., 2013), 14 patients in exacerbation of other mental health the HHS concluded that although many Colorado under the age of 12 were problems) associated with its use. (HHS 2015, individuals with a drug abuse disorder page 34). admitted to the ED for the unintended may have used marijuana as one of their use of marijuana over a 27 month The HHS stated that chronic first illicit drugs, this does not mean period. Prior to the passage of this marijuana use produces acute and that individuals initiated with policy, from January 1, 2005 to chronic adverse effects on the marijuana inherently will go on to September 30, 2009 (57 months), there respiratory system, memory and become regular users of other illicit were no pediatric ED visits due to learning. Regular marijuana smoking drugs. unintentional marijuana exposure can produce a number of long-term

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Petitioners’ Major Comment in Relation It is believed that lack of tolerance to previously included in DSM–IV) to Factor 6 and the Government’s psychoactive effects may relate to because marijuana withdrawal has now Responses electrophysiological data demonstrating been reliably presented in several 9 (1) The petitioners commented that that chronic D -THC administration studies (Hasin et al., 2013). In short, marijuana does not significantly impact does not affect increased neuronal firing marijuana withdrawal signs are reported social behavior in domains such as in the ventral tegmental area, a brain in up to one-third of regular users and motivation, driving, aggression, or region that plays a critical role in drug between 50% and 90% of heavy users hostility (Exhibit B, pages 30–41). reinforcement and reward (Wu and (Hasin et al., 2013). According to DSM– The HHS concluded that ‘‘Marijuana’s French, 2000). Humans can develop 5 criteria, in order to be characterized as acute effects can significantly interfere tolerance to marijuana’s cardiovascular, having marijuana withdrawal, an with a person’s ability . . . to operate autonomic, and behavioral effects (Jones individual must develop at least three of motor vehicles.’’ (HHS, 2015) As et al., 1981). Tolerance to some the seven symptoms within one week of mentioned in this factor, there is a behavioral effects appears to develop decreasing or stopping the heavy and significant risk with marijuana use and with heavy and chronic use, but not prolonged use (DSM–5, 2013). These driving. Marijuana was found in 13% of with occasional usage. Ramaekers et al. seven symptoms are: (1) Irritability; drivers involved in automobile fatal (2009) reported that following acute anger or aggression, (2) nervousness or accidents (McCartt, 2015). Furthermore, administration of marijuana, occasional anxiety, (3) sleep difficulty, (4) in a meta-analysis conducted by Li et al. marijuana users still exhibited decreased appetite or weight loss, (5) (2011), an association was identified impairments in tracking and attention restlessness, (6) decreased mood, (7) between marijuana use by the driver tasks whereas performance of heavy somatic symptoms causing significant and an increased risk of getting into a users on the these tasks was not discomfort (DSM–5, 2013). car accident. affected. In a follow-up study with the The DEA notes that the petitioners same subjects that participated in the Psychological (Psychic) Dependence in only considered whether marijuana study by Ramaekers et al. (2009), a Humans creates social problems, and did not neurophysiological assessment was High levels of psychoactive effects consider physiological changes and conducted where event-related such as positive reinforcement correlate impacts that also should be evaluated in potentials (ERPs) were measured using with increased marijuana abuse and determining the risk to public health. electroencephalography (EEG) dependence (Scherrer et al., 2009; The HHS and DEA considered the (Theunissen et al., 2012). Similar to the Zeiger et al., 2010). Epidemiological public health impacts of such earlier results, the heavy marijuana physiological effects, as discussed in users (n = 11; average of 340 marijuana marijuana use data reported by NSDUH, this factor and others above. Marijuana uses per year) had no changes in their MTF, and TEDS support this assertion may result in acute cardiovascular ERPs with the acute marijuana as presented in the HHS 2015 review of toxicity as indicated by recent reviews exposure. However, occasional users (n marijuana and updated by the DEA. examining these associations (Hackham, = 10; average of 55 marijuana uses per According to the findings in the 2014 2015; Panayiotides, 2015). There is a year) had significant decreases in the NSDUH survey, an estimated 9.2 possible association between frequent, amplitude of an ERP component million individuals 12 years and older long-term marijuana use and increased (categorized as P100) on tracking and used marijuana daily or almost daily (20 risk of testicular germ cell cancers and attention tasks and ERP amplitude or more days within the past month). In some evidence that chronic marijuana change is indicative of a change in brain the 2015 MTF report, daily marijuana use may lead to lung cancer although activity (Theunissen et al., 2012). use (20 or more days within the past 30 The HHS indicated that down- the evidence is inconsistent. days) in 8th, 10th, and 12th graders is regulation of cannabinoid receptors may Furthermore, a more recent risk is the 1.1%, 3.0%, and 6.0%, respectively. be a possible mechanism for tolerance to increase in ED visits of children The 2014 NSDUH report stated that marijuana’s effects (Hirvonen et al., unintentionally exposed to marijuana 4.2 million persons were classified with 2012; Gonzalez et al., 2005; Rodriguez with increased risk factors for major dependence on or abuse of marijuana in de Fonseca et al., 1994; Oviedo et al., adverse effects or admission to critical 1993). the past year (representing 1.6% of the care units in states that have legalized As indicated by the HHS, the most total population age 12 or older, and marijuana for medical purposes (Wang common withdrawal symptoms in 59.0% of those classified with illicit et al., 2014). heavy, chronic marijuana users are sleep drug dependence or abuse) based on Factor 7: Its Psychic or Physiological difficulties, decreased appetite or criteria specified in the Diagnostic and Dependence Liability weight loss, irritability, anger, anxiety or Statistical Manual of Mental Disorders, nervousness, and restlessness (Budney 4th edition (DSM–IV). Furthermore, of Physiological (Physical) Dependence in and Hughes, 2006; Haney et al., 1999). the admissions to licensed substance Humans As reported by HHS, most marijuana abuse facilities, as presented in TEDS, The HHS stated that heavy and withdrawal symptoms begin within 24– marijuana/hashish was the primary chronic use of marijuana can lead to 48 hours of discontinuation, peak substance of abuse for; 18.3% (352,297) physical dependence (DSM–5, 2013; within 4–6 days, and last for 1–3 weeks. of 2011 admissions; 17.5% (315,200) of Budney and Hughes, 2006; Haney et al., The HHS pointed out that the 2012 admissions; and 16.8% (281,991) 1999). Tolerance is developed following American Psychiatric Association’s of 2013 admissions. Of the 281,991 repeated administration of marijuana (APA’s) Diagnostic and Statistical admissions in 2013 for marijuana/ and withdrawal symptoms are observed Manual of Mental Disorders-5 (DSM–5) hashish as the primary substance, as following discontinuation of included a list of withdrawal symptoms 24.3% used marijuana/hashish daily. marijuana usage (HHS, 2015). following marijuana [cannabis] use Among admissions to treatment for The HHS mentioned that tolerance (DSM–5, 2013). The DEA notes that a marijuana/hashish as the primary can develop to some of marijuana’s DSM–5 working group report indicated substance in 2013, 27.4% were ages 12 effects, but does not appear to develop that marijuana withdrawal symptoms to 17 years and 29.7% were ages 20 to with respect to the psychoactive effects. were added to DSM–5 (they were not 24 years.

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Petitioners’ Major Comment in Relation The HHS concluded that marijuana Chemical constituents including D9- to Factor 7 and the Government’s has a high potential for abuse based on THC and other cannabinoids in Response a large number of people regularly using marijuana vary significantly in different (1) The petitioners stated, ‘‘There is marijuana, its widespread use, and the marijuana strains. In addition, the no severe physical withdrawal vast amount of marijuana that is concentration of D9-THC and other syndrome associated with cannabis. available through illicit channels. cannabinoids may vary between strains. Cannabis addiction is amenable to Marijuana is the most abused and Therefore the chemical composition treatment.’’ (Exhibit B, page 10). The trafficked illicit substance in the United among different marijuana samples is petitioners further indicated that States. Approximately 22.2 million not reproducible. Due to the variation of marijuana ‘‘may be psychologically individuals in the United States (8.4% the chemical composition in marijuana addictive, but much less so than other of the United States population) were strains, it is not possible to derive a Scheduled [sic] II drugs,’’ (Exhibit B, past month users of marijuana according standardized dose. The HHS does page 10) and that there is a low risk of to the 2014 NSDUH survey. A 2015 advise that if a specific Cannabis strain dependence associated with marijuana national survey (Monitoring the Future) is cultivated and processed under use. Petitioners further stated in Exhibit that tracks drug use trends among high controlled conditions, the plant B, page 23, ‘‘Cannabis has low relative school students showed that by 12th chemistry may be consistent enough to dependence risk and does not reach the grade, 21.3% of students reported using derive standardized doses. severity associated with other drugs.’’ marijuana in the past month, and 6.0% ii. There must be adequate safety The HHS states that marijuana reported having used it daily in the past studies. withdrawal syndrome ‘‘appears to be month. In 2011, SAMHSA’s Drug Abuse There are not adequate safety studies mild compared to classical alcohol and Warning Network (DAWN) reported that on marijuana for use in any specific, barbiturate withdrawal syndromes’’ and marijuana was mentioned in 36.4% of recognized medical condition. The is similar in magnitude and time course illicit drug-related emergency considerable variation in the chemistry to tobacco withdrawal syndrome. department (ED) visits, corresponding to of marijuana results in differences in DSM–5 now recognizes and describes 455,668 out of approximately 1.25 safety, biological, pharmacological, and a marijuana [cannabis] withdrawal million visits. The Treatment Episode toxicological parameters amongst the syndrome. The lifetime risk of Data Set (TEDS) showed that 16.8% of various marijuana samples. dependence to marijuana is non-private substance-abuse treatment iii. There must be adequate and well- approximately 9% among heavy or long- facility admissions in 2013 were for controlled studies proving efficacy. term users (Volkow et al., 2014). marijuana as the primary drug. There are no adequate and well- Marijuana results in tolerance and Marijuana has dose-dependent controlled studies that determine withdrawal as described earlier in this reinforcing effects that encourage its marijuana’s efficacy. In an independent Factor 7. The data from NSDUH indicate abuse. Both clinical and preclinical review performed by the FDA of that there is constant desire for studies have demonstrated that publicly available clinical studies on marijuana as noted by the consistently marijuana and its principle marijuana (FDA, 2015), FDA concluded 9 high numbers of current daily users in psychoactive constituent, D -THC, that these studies do not have enough adults and adolescents. Marijuana use possess the pharmacological attributes information to ‘‘currently prove efficacy also persists despite problems associated with drugs of abuse. They of marijuana’’ for any therapeutic associated with the drug. Changes in IQ function as discriminative stimuli and indication. have been noted in adolescent-onset, as positive reinforcers to maintain drug iv. The drug must be accepted by chronic or dependent marijuana users, use and drug-seeking behavior. qualified experts. in addition to withdrawal symptoms. Additionally, use of marijuana can At this time, there is no consensus of However, marijuana use has not result in psychological dependence. opinion among experts concerning the declined in the time that usage of this 2. Marijuana has no currently medical utility of marijuana for use in drug has been monitored. Additionally, accepted medical use in treatment in the treating specific recognized disorders. there has been an increase in content of United States. v. The scientific evidence must be the primary psychoactive chemical, D9- The HHS stated that the FDA has not widely available. THC, in marijuana samples analyzed by approved an NDA for marijuana. The The currently available data and the University of Mississippi’s Potency HHS noted that there are opportunities information on marijuana is not Monitoring Project, suggesting for scientists to conduct clinical sufficient to address the chemistry, preference for marijuana strains with research with marijuana and there are pharmacology, toxicology, and higher levels of D9-THC. active INDs for marijuana, but marijuana effectiveness. The scientific evidence does not have a currently accepted regarding marijuana’s chemistry with Factor 8: Whether the Substance is an medical use in the United States, nor regard to a specific cannabis strain that Immediate Precursor of a Substance does it have an accepted medical use could be formulated into standardized Already Controlled Under the CSA with severe restrictions. and reproducible doses is not currently Marijuana is not an immediate FDA approval of an NDA is not the available. precursor of another controlled sole means through which a drug can be 3. There is a lack of accepted safety substance. determined to have a ‘‘currently for use of marijuana under medical accepted medical use’’ under the CSA. supervision. Determination Applying the five-part test summarized Currently, there are no FDA-approved After consideration of the eight factors below, a drug has a currently accepted marijuana products. The HHS also discussed above and of the HHS’s medical use if all of the following five concluded that marijuana does not have Recommendation, the DEA finds that elements have been satisfied. As a currently accepted medical use in marijuana meets the three criteria for detailed in the HHS evaluation and as treatment in the United States or a placing a substance in schedule I of the set forth below, none of these elements currently accepted medical use with CSA under 21 U.S.C. 812(b)(1): has been fulfilled for marijuana: severe restrictions. According to the 1. Marijuana has a high potential for i. The drug’s chemistry must be HHS, the FDA is unable to conclude abuse. known and reproducible. that marijuana has an acceptable level of

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