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1 BENJAMIN B. WAGNER United States Attorney 2 RICHARD BENDER SAMUEL WONG 3 GREGORY T. BRODERICK Assistant United States Attorneys 4 501 I Street, Suite 10-100 Sacramento, CA 95814 5 Telephone: (916) 554-2991 Facsimile: (916) 554-2900 6 Attorneys for Plaintiff 7 United States of America 8 IN THE UNITED STATES DISTRICT COURT 9 EASTERN DISTRICT OF CALIFORNIA

10 UNITED STATES OF AMERICA CASE NO. 2:11-CR-00449-KJM-16 11 Plaintiff, DECLARATION OF BERTHA 12 MADRAS, PH.D v. 13 BRIAN SCHWEDER, et. al. 14 Defendant, 15

16 I, Bertha K. Madras, Ph.D, declare as follows: 17 1. I am a Professor of Psychobiology at Harvard Medical School, Department of 18 Psychiatry. My office is located in the Alcohol and Drug Abuse Program at McLean Hospital, an 19 affiliate hospital of Harvard. I have been retained to offer opinions in United States v. Schweder, et. al., 20 Case No. 2:11-CR-0449-KJM (E.D. Cal.). I am not employed by the Department of Justice, the Drug 21 Enforcement Administration (DEA), or any other federal office or agency. I neither speak for, nor set 22 policy for, these agencies. Nor can I speculate about, or predict the outcome of, the rescheduling 23 petition currently pending before DEA. Rather, my opinions are my own, are based in science, and 24 reflect my 50 years of education, research, and experience in the relevant area. 25 I. SUMMARY OF QUALIFICATIONS 26 2. I have dedicated a significant portion of my career to researching and working in the 27 areas of abuse and addiction. During my career, I have engaged in significant study of how 28 psychoactive and therapeutic drugs affect the brain (including cocaine, ecstasy or MDMA, 1 Declaration of Bertha Madras, Ph.D

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1 methamphetamine, marijuana’s active constituent THC, other cannabinoids, anti-psychotic, anti- 2 epileptic, anti-hyperactivity, and anti-narcoleptic drugs) and in development of medications and brain 3 imaging probes. My recent research focuses on contrasting molecular and behavioral effects of THC 4 and psychostimulant drugs on adolescent and adult brain. A brain imaging drug I invented with 5 collaborators was evaluated through the FDA process. I am familiar with the literature showing 6 marijuana’s effects, the potential (or lack thereof) of isolated cannabinoids as medicine, and the adverse 7 effects of marijuana use. I submit this declaration as my direct testimony on the rationality of 8 marijuana’s “continued inclusion” as a Schedule I Controlled Substance. 9 3. I graduated with honors from McGill University in 1963, earning a Bachelor’s of Science 10 in Honours Biochemistry. As a J.B. Collip Fellow of the Faculty of Medicine, I was awarded a Doctor of 11 Philosophy in Biochemistry (metabolism and pharmacology, including hallucinogens such as LSD, 12 psilocybin) from McGill University in 1967. Following my Ph.D, I completed two post-doctoral 13 fellowships from 1967-69. The first was in the Department of Biochemistry at Tufts University, 14 continued in the Department of Biochemistry at Cornell University Medical College when my mentor 15 relocated as Chair of Biochemistry at Cornell University Medical College mid-training. During this 16 period, I laid the groundwork for future development of a widely used anti-cancer (lymphoblastic 17 leukemia) drug, asparaginase. My other post-doctoral fellowship was in the Department of Biology at the 18 Massachusetts Institute of Technology. Thereafter, I was appointed Research Associate at the 19 Massachusetts Institute of Technology from 1972-1974, and an Assistant Professor in the Departments of 20 Pharmacology and Psychiatry at the University of Toronto. In 1986, I was appointed Assistant Professor 21 at Harvard Medical School. Subsequently, I was promoted to Associate Professor and then to the rank of 22 Professor, with a cross-appointment to the Department of Psychiatry, the Massachusetts General 23 Hospital. I also founded and chaired the Division of Neurochemistry at Harvard Medical School’s New 24 England Primate Research Center, a multidisciplinary, translational research program which spanned 25 chemical design, molecular and cellular biology, behavioral biology, and brain imaging approaches. 26 4. As an educator, I developed and served as Course Director of the Advanced Biomedical 27 Sciences: Substance abuse and addictive processes since 1991, a course on addictions offered to fourth 28 year medical students at Harvard Medical School. I was a founding member of Harvard Medical 2 Declaration of Bertha Madras, Ph.D

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1 School’s Division on Addictions and served as Associate Director for Public Education from 1998- 2 2006 at Harvard Medical School’s Division on Addictions. I have delivered numerous Continuing 3 Medical Education Courses on the Biology of Addiction, with a recent emphasis on marijuana. In 2001, 4 I founded, directed, and delivered lectures in an international Cold Spring Harbor Course on the Cell 5 Biology of Addiction, which included a section on marijuana. 6 5. I have served on a number of academic and medical committees. At Harvard Medical 7 School, I was a member of the Subcommittee of Professors, which recommends promotions and 8 appointments to the rank of full Professor. I was also a member of the Department of Psychiatry’s 9 Research Committee, and the Steering Committee for the Division on Addictions. Prior to Harvard, I 10 founded and chaired the University of Toronto, Faculty of Medicine’s Neuroscience course and 11 program committee. Additionally, from 1980-82, I served on both the Research and Educational 12 Advisory Committees at the Clarke Institute of Psychiatry and was Chair of the Ontario Mental Health 13 Foundation (Ontario Ministry of Health), Fellowships and Awards Committee (1988‐1990). 14 Through the course of my career, I have been asked to serve on more than 50 National Institutes of 15 Health (NIH) committees and other government and private sector advisory boards, a reflection of my 16 expertise in neurobiology, brain imaging, addictions, analysis of study design, and the validity of 17 scientific data. These include the National Institute on Drug Abuse (NIDA) Medications Development 18 Scientific Advisory Board, the NIDA Council work group on mechanisms of transferring NIDA- 19 sponsored addiction treatment research to community treatment centers, numerous grant review panels 20 for NIDA and other NIH institutes, Advisory Board of the Addiction Studies Institute for Journalists, 21 the Science and Technology Advisory Committee of Brookhaven National Laboratory. I also served 22 on the Special Review Committee for the Office of National Drug Control Policy and the U.S. 23 Department of Education’s Safe and Drug-free School Advisory Committee (2007-2008). 24 6. In addition to my academic and professional work, I have served in public policy 25 positions. In 2005, I was nominated by the President of the United States to be the Deputy Director for 26 Demand Reduction (prevention, intervention, treatment) for the White House Office of National Drug 27 Control Policy (“ONDCP”). My nomination was confirmed by the United States Senate with 28 unanimous consent, and I served in that capacity until fall of 2008. Among other initiatives, I 3 Declaration of Bertha Madras, Ph.D

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1 spearheaded expansion of alcohol and drug screening, brief intervention and referral to treatment 2 (SBIRT) services, and led the successful effort to obtain Medicare, Medicaid, and CPT billing codes to 3 reimburse for these services. I also generated the first publication of official SBIRT effectiveness data, 4 gleaned from more than 450,000 subjects. 5 7. I am a member of numerous professional societies: American College of Neuropsycho- 6 pharmacology (1994-present), DANA Alliance for Brain Initiatives (1994-present), College on 7 Problems of Drug Dependence (1989-present), and the Society for Neuroscience (1987-2014). I also 8 served on committees for these professional societies: Public Information Committee, Society for 9 Neuroscience, 1992-95; College on Problems of Drug Dependence (Board member; Membership 10 Committee, 1994-2001; Media Committee, 1994-97 & 2009-present, Chair 2013-present); Bowman 11 Grey School of Medicine, External Advisory Board for the Center for the Neurobiological Investigation 12 of Drug Abuse (1998-2006). 13 8. In a continuing effort to translate scientific discoveries for the public good, I have given 14 more than 100 public lectures on the science of addiction, including more than 30 recent presentations 15 on the subject of marijuana. I have also distributed an array of slide presentations on marijuana and 16 written summaries of marijuana science, upon request. I testified twice in sessions of the Maryland 17 Legislature on medical marijuana bills in 2008. In 1998, I presented at a NIDA Town Meeting on the 18 neuroscience of drug abuse and addiction. In 2000 and in 2009, I spoke in South Africa on shaping 19 drug policy to emerging scientific data, have delivered a number of drug policy presentations to the 20 Organization of American States, and other government agencies internationally. My audiences have 21 included judges, lawyers, policy-makers, legislators, law enforcement agents, educators, parents, and 22 high school students, both in the United States and on four other continents. I have spoken at the 23 Department of Public Health and Massachusetts Judicial Institute on “The science of substance abuse 24 and the brain.” Recently, in 2011, I presented the case against medical marijuana to the Albany State 25 Governor’s Office on medical marijuana. I directed a NIDA-sponsored exhibit titled “Changing your 26 Mind: Drugs in the Brain,” at the Museum of Science in Boston (1994-2006), which included a CD 27 (licensed by Disney in 2006), and a play, and was a major contributor to the story board of a joint 28 NIDA/DEA-sponsored exhibit in Times Square, New York. 4 Declaration of Bertha Madras, Ph.D

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1 9. I have published more than 140 scientific articles and book chapters in my area of 2 research. Several are specific to marijuana, including studies of cannabinoid and dopamine receptor 3 agonists and their synergistic sedative effects in nonhuman primates, and cannabinoid receptor agonist 4 and antagonist effects on motor function in a nonhuman primate model of Parkinson’s disease. My 5 most recent preclinical research, presented at 2013 and 2014 annual meetings, documents the effects of 6 THC, the main psychoactive constituent of marijuana, on genes in the adolescent brain implicated in 7 brain development. I am also the co-editor of a number of scientific textbooks, including “Imaging of 8 the Human Brain in Health and Disease (2013),” with a chapter on imaging marijuana signaling 9 systems in human brain. I am the principal editor of “The Cell Biology of Addiction,” and principal 10 editor of a book on the impact of drug abuse on the brain, titled “The Effects of Drug Abuse on the 11 Human Nervous System,” which includes two comprehensive chapters on marijuana (2013). I hold 19 12 patents, for novel medications, and for a class of agents that image dopamine brain cells affected by 13 addictive drugs. This invention was recently highlighted in the Better World Report as one of 25 14 technology transfer innovations that changed the world. 15 10. I am honored to be the recipient of the Marion W. Fischman lectureship award by the 16 College on Problems of Drug Dependence for “outstanding woman scientist in drug abuse research,” 17 the Founders Award of the American Association of Addiction Psychiatry, a NIDA Public Service 18 Award, a MERIT award from NIDA-NIH, and others. 19 11. Further information, including research grants I have been awarded, as well as other 20 research, academic duties and a bibliography of my significant publications (including peer-reviewed 21 scientific publications (142), book chapters, reviews/editorials (22), published books/monographs (4), 22 and numerous others), are listed in my Curriculum Vitae, attached hereto as Exhibit A. My most recent 23 commentary, for the Proceedings of the National Academy of Science, 2014, in press, is titled 24 “Dopamine Challenge Reveals Neuroadaptive Changes in Marijuana Abusers.” A non-exhaustive 25 bibliography of materials I considered is attached hereto as Exhibit B. 26 II. SUMMARY OF OPINIONS 27 12. “Marihuana” was listed as a Schedule I Controlled Substance with the adoption of the original 28 Controlled Substances Act in the 1970s. Although the Controlled Substances Act gives the Attorney General 5 Declaration of Bertha Madras, Ph.D

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1 the authority to reschedule or de-schedule controlled substances, the Attorney General has delegated this 2 authority to DEA, which periodically works with the Food and Drug Administration (“FDA”) and NIDA in 3 determining whether to amend the Controlled Substance schedules. Despite several petitions over the past 40 4 years, neither DEA, the Attorney General, nor the Congress have decided to alter marijuana’s placement on 5 Schedule I. It is my understanding that this Court has ordered a hearing “to probe the scientific and medical 6 information” regarding “the continued inclusion of marijuana as a Schedule I controlled substance.” For the 7 reasons set forth below, it is my opinion that the current classification of marijuana on Schedule I is strongly 8 supported by valid scientific research and medical evidence. 9 13. As set forth in 21 U.S.C. § 812(b)(1), three factors determine whether a substance 10 belongs on Schedule I: 11 a. The drug or other substance has a high potential for abuse;

12 b. The drug or other substance has no currently accepted medical use in treatment in the United States; 13 c. There is a lack of accepted safety for use of the drug or other substance under 14 medical supervision. 15 As further explained below, it is my opinion that the science strongly supports a conclusion that 16 marijuana has a high potential for abuse, has no currently accepted medical use in the United States, and 17 that sufficient assurances of safety for use of marijuana under medical supervision are lacking. Based 18 on my training, experience, and research in the field, the science strongly supports the conclusion that 19 marijuana has met, and continues to meet, the criteria for inclusion in Schedule I of the Controlled 20 Substances Act. 21 III. THE SCIENTIFIC PROCESS FOR DETERMINING MEDICAL USE 22 14. It is important to understand that the United States has long adhered to a scientifically 23 driven process for reviewing and approving medicines to ensure that they are both safe and effective 24 before they are released to the public. It is this process—which includes large teams of chemists, 25 pharmacologists, physicians, microbiologists, veterinarians and even lawyers—and not individual 26 physicians or anecdotal information from users, that determines whether a product has accepted 27 medical uses, and may be safely used as a medicine by the general public. 28 15. In the past 100 years, the United States developed a scientific process to ensure that 6 Declaration of Bertha Madras, Ph.D

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th 1 proposed medicines are both safe and effective. Starting in the 19 century, chemists began to isolate 2 pure chemicals from medicinal plants, study them, and make safer variants: the active drugs morphine 3 from the opium poppy, cocaine from the coca bush, digitalis from the foxglove plant, salicylic acid 4 (converted to aspirin) from willow bark, ephedrine from the Ma Huang plant, and quinine from 5 cinchona bark were isolated (or, at times, further modified). Behind this new science was the dawn of 6 rational development of medications. Chemists and physicians reasoned that it was wiser to isolate a 7 pure compound from a plant, remove it from other chemicals and contaminants that may be toxic or 8 interfere with its actions, and administer a pure drug of known quantity, in a safe dosage range. 9 Another advantage of isolating the active constituents of botanical plants was to enable discovery of 10 their mechanisms of action, thereby placing each botanically-derived compound on a firm scientific 11 base. Isolated compounds led to the discovery of receptors (targets) and signaling systems of opiates, 12 cannabinoids, hallucinogens, nicotine, cocaine, methamphetamine and a host of other psychoactive 13 drugs, which resulted in an explosion of information on disease processes, mechanisms of brain 14 reward, hallucinations, and therapeutic benefit, and enabled rational design of improved medications. 15 A relevant example is the isolation of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) 16 from the marijuana plant in the 1960’s. It is now known that mechanisms of action of intoxicant THC 17 and the non-psychoactive CBD are distinct; CBD can oppose some of the memory and behavioral 18 impairment of THC, CBD does not impair memory as does THC, and their therapeutic indications 19 may differ. This compelling evidence supports the need to continue the process and methodology of 20 modern medicine with respect to the marijuana plant. The evolution of marijuana research is 21 following the same principles as drug therapies in general, following the discovery of its active 22 chemicals in the early 1960’s. Science should continue to isolate pure cannabinoids in the marijuana 23 plant and evaluate them separately to determine whether they have medicinal value, all through an 24 evidence-based process designed to protect patients and the general public. 25 16. Although more than 30% of current therapeutic drugs are plant-derived, no one 26 currently eats or smokes foxglove plants to treat a heart condition, chews cinchona bark to alleviate 27 malaria symptoms, or eats opium poppies to relieve post-surgical pain. Instead, scientists have 28 isolated compounds, identified safe and effective dose ranges, and developed medicines from these 7 Declaration of Bertha Madras, Ph.D

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1 plants to treat these conditions. It is as irrational to smoke marijuana for medicinal purposes in the st th 2 21 century as it was to chew bark to relieve a headache or smoke opium for pain in the 20 century. 3 17. In 1938, our safe drug supply system advanced once again, as the newly formed FDA 4 required strong scientific evidence of both effectiveness and safety for drug approval. The creation of 5 the FDA was in response to numerous examples of illness or death resulting from entrepreneurs who 6 marketed dangerous drugs, tinctures, or other concoctions with unsubstantiated claims for medical 7 benefit or safety. The FDA currently has a well-developed and rigorous evaluation and approval 8 process for determining whether scientific evidence is adequate to support claims that a specific drug 9 is effective and safe for use in diagnosing, mitigating, treating, or curing disease. When such claims 10 are made about a substance, it is considered a drug under section 201(g)(1)(B) of the Act and is subject 11 to regulation as such. 12 18. The Federal Food, Drug, and Cosmetic Act requires that new drugs be shown to be 13 safe and effective for their intended use before being marketed in this country. FDA’s drug approval 14 process begins after a producer identifies a handful of compounds that may be effective and safe in 15 cells, in an animal model of disease and in toxicity studies. When this phase is over, the drug 16 developers apply to the FDA for permission to study the drug in humans. 17 19. Before conducting testing in humans of a drug that has not been approved by the 18 FDA, an investigator submits an investigational new drug (IND) application, which is reviewed by 19 the FDA. An IND includes protocols describing proposed studies, the qualifications of the 20 investigators who will conduct the clinical studies, and assurances of informed consent and 21 protection of the rights, safety, and welfare of the human subjects. The FDA reviews the IND to 22 ensure that the proposed studies, generally referred to as clinical trials, do not place human subjects 23 at unreasonable risk of harm. The FDA also verifies that there are adequate assurances of informed 24 consent and human subject protection. 25 20. Well-controlled human trials are performed in at least three phases, the first to 26 measure the safety of a range of doses, usually in less than 100 healthy volunteers or subjects. These 27 Phase I studies carefully assess how to safely administer and dose the drug with an emphasis on 28 evaluating the toxic manifestations of therapy, how the body distributes and degrades the drug, and 8 Declaration of Bertha Madras, Ph.D

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1 how side-effects relate to dose. Phase II clinical studies monitor the effectiveness of the drug at a 2 range of doses for a particular indication and to determine common, short-term side-effects. Phase II 3 usually involves a few hundred subjects. Once Phase II is complete, Phase III trials assess the safety 4 and effectiveness of the drug in randomly assigned, larger patient populations (usually from several 5 hundred to several thousand). The testing is conducted consistent with the protocol and is usually 1 6 double blinded, in which case neither the person administering the drug nor the patient know 7 whether they are given the investigational drug or a control (which could be a placebo or another 8 already-approved product). 9 21. These studies establish efficacy for a specific medical indication, examine additional 10 uses, may provide further safety data including long-term experience, and consider additional 11 population subsets, dose response and other factors. Once Phase III trials are completed, the sponsor 12 submits the results of all the relevant testing to FDA in the form of a New Drug Application (NDA). 13 FDA’s medical officers, chemists, statisticians, and pharmacologists review the application to 14 determine if the sponsor’s data in fact show that the drug is both safe and effective. The drug’s 15 manufacturing process is evaluated to confirm that the product can be produced consistently with 16 high quality. It is common to allow subjects in Phase II and III studies to continue on a therapy if it 17 seems to be providing benefit. This practice provides long-term safety information at an early stage 18 in this process. 19 22. The FDA insists on a vast array of information on the drug from the manufacturer that 20 shows all the pre-human research, the scientific evidence that drug is effective at a fixed dose range in 21 humans, proof that the drug is pure, that it can be manufactured indefinitely to produce the same 22 chemical in pure form with inert fillers and uncontaminated with microbes, that the tested shelf life is 23 known, what percent enters the blood stream, what percent gets to its target, how it is metabolized and 24 cleared by the body, how long it takes for the body to clear, how often it should be taken, how long it 25 can be safely taken, whether side effects are acceptable, and a myriad of other criteria to ensure patient 26 safety. With this scientific documentation at hand, the FDA then decides whether to approve the drug 27 for a specific condition, what information should be included in the package insert, and other labeling

28 1 Double-blinded studies are preferred, except where doing so is either impossible or unethical. 9 Declaration of Bertha Madras, Ph.D

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1 decisions. If a drug product is to be marketed, these disciplined, systematic, scientifically conducted 2 trials are the best means to obtain data to ensure that drug is safe and effective when used as indicated. 3 Efforts to bypass the FDA drug approval process are adverse to public health because they are likely to 4 expose patients to unsafe and ineffective drug products. Results of controlled clinical trials are 5 determined by evidence-based medicine, allowing physicians and patients to use therapies with a clear 6 understanding of their benefits and risks and, in some cases, a basis for strong public health 7 recommendations for treatments. 8 23. An example that illustrates the importance of conducting clinical trials are the results of 9 an NIH Women’s Health Initiative (WHI) study of estrogen and progesterone in treating post- 10 menopausal women (more than 16,000 women). As extracted from testimony by Dr. Robert J. Meyer, 11 M.D. Director, Office of Drug Evaluation II, Center for Drug Evaluation and Research Food and Drug 12 Administration in 2004: “this rigorous clinical trial was done to confirm the widely held belief that 13 estrogen/progesterone therapy in post-menopausal women would significantly reduce the risk of 14 cardiovascular events, such as heart attacks and strokes, with some hope that this post-menopausal 15 therapy might lessen the onset of Alzheimer’s disease. These widely held beliefs were based on 16 scientific evidence that was not from clinical trials, such as epidemiology. On the strengths of these 17 beliefs, post-menopausal hormone therapy was very widely used and growing in popularity. The WHI 18 trial of post-menopausal estrogen/progesterone preceded but was stopped early due to an excess of harm 19 in women taking these drugs compared to placebo…women given the active drugs were more likely to 20 suffer heart attacks and strokes and appeared to be more likely to develop dementia. This study not only 21 failed to prove the widely held notion that this therapy was good for preventing these types of 22 occurrences, but actually confirmed harm. These important results have led to significant changes in the 23 use of post-menopausal hormones.” Similarly, laetrile was approved via ballot initiatives in over 15 24 states during the 1970’s, until it was shown in carefully controlled clinical trials, spearheaded by NIH 25 and FDA, to be ineffective and to carry considerable risk from cyanide poisoning (Milazzo et al, 2011). 26 24. The FDA also protects patients after it has approved a drug. If there is evidence of 27 newly emerging unacceptable side effects, the FDA can modify prescribing practices, issue a “Black 28 Box” warning, or withdraw the drug. If a pharmaceutical company makes an unsupported claim that its 10 Declaration of Bertha Madras, Ph.D

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1 approved drug can treat a different disease, the FDA can and has fined companies (more than $10 2 billion in past few years). 3 25. The FDA process has protected the American public from ineffective or even 4 dangerous drugs for more than 75 years. Drugs that do not meet this standard do not have accepted 5 medical uses in my opinion. 6 26. The marijuana plant, like other plants, is not reasonably amenable to analysis by the 7 current, established FDA approval process. While many of our medicines have their origin in plant- 8 derived compounds, I am unaware of any whole plant that has been approved for medical use in recent 9 times. A medicine is something of known and reproducible chemistry, and which can be provided in 10 pure form(s) and precise dosage amounts. Marijuana does not meet any of the FDA criteria for a safe 11 drug: It is made up of more than 400 chemical compounds, of which over 80 are cannabinoids, the 12 majority of which have unknown effects or side effects. Nor have there been systematic or reliable 13 studies of marijuana’s side-effects or adverse effects (e.g. addiction) over extended periods of use for 14 chronic medical conditions, a critical factor in determining whether a drug may be safely used under a 15 doctor’s supervision. 16 IV. DEA’s SCHEDULING PROCESS 17 27. My opinion is that, from a scientific perspective, there is a strong basis for concluding that 18 marijuana appropriately remains a Schedule I substance at this time. Before evaluating the specific 19 reasons for this opinion, it is important to understand the Controlled Substances Act’s Scheduling process. 20 28. The Controlled Substances Act delegates to the Attorney General the authority to 21 schedule, de-schedule, or reschedule controlled substances. The Attorney General has, in turn, 22 delegated the review process to the Drug Enforcement Administration (DEA), which must work 23 closely with the FDA and NIDA in making its determination on scheduling. Although the Attorney 24 General or DEA may undertake this Scheduling inquiry at any time, it is most typically done through 25 a Scheduling petition. It is my understanding that a Scheduling petition is currently pending before 26 DEA and FDA, and was filed by the Governors of Washington and Rhode Island. 27 29. Marijuana was placed on Schedule I by Congress in 1970, and DEA has periodically 28 reviewed that decision, including as recently as 2011. Its decision, after consultation with FDA and 11 Declaration of Bertha Madras, Ph.D

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1 others, has always been to maintain marijuana on Schedule I. See Denial of Petition To Initiate 2 Proceedings To Reschedule Marijuana, 76 F.R. 40552 (July 8, 2011), attached hereto as Exhibit C. 3 It is my understanding that this decision was upheld by the United States Court of Appeals for the 4 District of Columbia Circuit in 2013 against a challenge that it was “arbitrary and capricious.” 5 Americans for Safe Access v. Drug Enforcement Admin., 706 F.3d 438 (D.C. Cir. 2013). 6 30. DEA’s process, which is described in further detail in the Federal Register notice 7 announcing its 2011 decision not to reschedule, is scientifically-driven and evidence-based. It is my 8 opinion that DEA, in conjunction with FDA and NIDA, was well-justified in reaching the conclusion 9 that the safety assurances required for medicines were lacking when they denied the most recent petition 10 to reschedule marijuana in 2011. Under the factors set forth below for evaluating whether to schedule a 11 substance, as well as the factors for whether a substance meets Schedule I criteria, the DEA’s decisions 12 to maintain marijuana on Schedule I (including in 2011) are strongly supported by the science. 13 31. The Attorney General (or his delegate) may, after recommendation from HHS, decide 14 to add a substance to a schedule or to transfer a scheduled substance to another schedule if it is found 15 that such drug or other substance has a potential for abuse. A substance may also be removed from 16 the schedule if it is determined that the substance does not meet the requirements for inclusion in any 17 schedule. The recommendation to schedule a substance (as opposed to the decision of where to 18 schedule a substance) is made on the basis of the following criteria:

19 (1) Its actual or relative potential for abuse2 20 (2) Scientific evidence of its pharmacological effects; 21 (3) The state of current scientific knowledge regarding the drug or other substance; 22 (4) Its history and current pattern of abuse; 23 (5) The scope, duration, and significance of abuse; 24 (6) What, if any, risk there is to the public health; 25 (7) Its psychic or physiological dependence liability; and 26 (8) Whether the substance is an immediate precursor of a substance already controlled.

27 2 Any drug having a stimulant, depressant, or hallucinogenic effect on the central nervous system, is considered to have 28 abuse potential. 12 Declaration of Bertha Madras, Ph.D

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1 21 U.S.C. § 811(c). In addition, the United States has obligations to control marijuana’s use under 2 international treaties, conventions, and protocols. 3 32. With regard to the specific question of whether a non-FDA-approved controlled substance 4 has a currently accepted medical use in treatment in the United States, DEA has set forth a five-part test: 5 (1) The drug’s chemistry must be known and reproducible; 6 (2) There must be adequate safety studies; 7 (3) There must be adequate and well-controlled studies proving efficacy; 8 (4) The drug must be accepted by qualified experts; and 9 (5) The scientific evidence must be widely available. 10 57 Fed. Reg. 10499, 10504-10506 (1992). Failure to meet any of these five prongs precludes a finding 11 that the drug has a currently accepted medical use in treatment in the United States for purposes of the 12 Controlled Substances Act. Id.; see also Alliance for Cannabis Therapeutics v. DEA, 15 F.3d 1131, 13 1135 (D.C. Cir. 1994); Americans for Safe Access v. DEA, 706 F.3d 438, 449-450 (D.C. Cir. 2013). 14 This five-part test is consistent with the core criteria of the FDA drug approval process. 15 33. FDA engages in a rigorous process in evaluating the eight factors set forth in 21 U.S.C. 16 § 811(c), the factors for particular schedules set forth in 21 U.S.C. § 812(b), and, where appropriate, the 17 five-part test for determining whether a substance has a currently accepted medical use in treatment in 18 the United States. In so doing, FDA focuses exclusively on science. It then makes a recommendation 19 to DEA. 20 34. By following this rigorous scientific process, for which judicial review is available, the 21 scientific community can be confident, to the degree possible, that scientific decisions are being made 22 on the basis of scientific data and judgment. This is the hallmark of our system, and we should not 23 deviate from it for marijuana simply because there are anecdotal tales of success, greater social 24 acceptability for use of marijuana, or information derived from controlled clinical trials of inadequate 25 sample sizes or evaluation of adverse effects. While Congress certainly has the authority to make such 26 a political and/or policy judgment, the role of the scientists and regulators at FDA and DEA must 27 remain scientific and regulatory. There is no doubt that there is currently a rational basis for 28 maintaining marijuana on Schedule I. 13 Declaration of Bertha Madras, Ph.D

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1 V. SPECIFIC OPINIONS 2 35. Marijuana continues to meet the criteria for Schedule I under the Controlled Substances 3 Act. The basic supporting data and reasons for my opinions are set forth below. Given the wealth of 4 supporting research and scientific information, it is not reasonable to list every detail. Such details, if 5 needed, can be provided as part of my oral testimony.

6 A. There is Strong Scientific Support for Concluding that Marijuana Has High Potential for Abuse 7 8 36. The current data and scientific research strongly support the conclusion that marijuana 9 both has a high potential for abuse, and is actually abused. This is particularly true in young people. 10 The earlier one first uses marijuana, the more likely one is to abuse marijuana. As an example, the 11 prevalence of a marijuana (cannabis) use disorder among persons who initiate marijuana use at age 14 12 or younger (13.2%) is six times higher than those who initiate marijuana use at age 18 (2.2%) or older 13 (NSDUH 2013). Marijuana is addictive in approximately 9-10% of users and 25-50% of daily users 14 become addicted. It should be apparent that people who use marijuana for chronic conditions will use 15 it daily and over an extended period, and are thus at high risk for addiction. The diagnostic and 16 statistical manual of Mental Disorders (“DSM”) of the American Psychiatric Association has 17 designated that marijuana is addictive, and currently recognizes a specific Cannabis Dependence (Use) 18 Disorder. (See DSM-IV, § 304.30, and DSM-V). In the DSM-IV and -V, marijuana fulfills the criteria 19 of a full spectrum of a substance use disorder, from abuse (hazardous use, social and interpersonal 20 problems related to use, neglected major roles and responsibilities), to addiction (withdrawal, tolerance, 21 uncontrollable use, unintentional use of larger amounts and for longer periods of time than intended, 22 repeated unsuccessful attempts to quit, psychological/physical problems related to use, activities given 23 up, craving). As the DSM recognizes, individuals with this disorder have compulsive use and 24 associated problems, use of the drug often interferes with family, school, work responsibilities, 25 recreational activities, and chronic use persists despite knowledge of related physical or psychological 26 problems, such as chronic cough, excessive sedation, difficulty concentrating, and a decrease in goal- 27 oriented activities. 28 37. The DSM-V also recognizes that marijuana use occurs along a spectrum of severity of 14 Declaration of Bertha Madras, Ph.D

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1 adverse effects. Abuse occurs even if the hallmarks of addiction are not involved. A criteria count 2 (from two to eleven) is used as an overall severity indicator, such that mild (two to three criteria), 3 moderate (four to five), and severe (six or more) disorders are documented. 4 38. Marijuana is the most widely used illicit substance in the United States, and more 5 Americans (4.3 million) harbor a medical (DSM-IV) diagnosis of marijuana abuse/addiction than any 6 other illicit drug. Many more youth are DSM-IV positive for a marijuana use disorder than for an 7 alcohol use disorder, as a percentage of those in treatment. Treatment admissions for youth aged 15 to 8 17 most frequently reported marijuana (71.9 %) or alcohol (17.7%) as their primary substance of abuse. 9 About 14.3% of older adolescent admissions reported first using their primary substance of abuse at age 10 11 or younger, and over half (56.3%) reported first using their primary substance between the ages of 11 12 and 14. Marijuana treatment may require billions of dollars in treatment needs nationally. Although 12 treatment admissions for alcoholism and cocaine addiction declined between 1992 and 2007, marijuana 13 use disorder admissions climbed significantly during the same period. Similarly, emergency department 3 14 mentions have also increased significantly between 2004 and 2008. 15 39. Although addiction, habituation, and abuse do not necessarily require physiological or 16 physical symptoms during withdrawal, abstinence in heavily addicted marijuana users unmasks 17 physical and psychological neuroadaptation, manifest by a withdrawal syndrome. The validity of 18 marijuana withdrawal has been demonstrated in preclinical, clinical, and epidemiological studies. 19 Marijuana withdrawal is reported by up to one-third of regular users in the general population and by 20 50%–95% of heavy users in treatment or research studies. The clinical significance of marijuana 21 withdrawal is demonstrated by use of marijuana or other substances to relieve it, its association with 22 difficulty quitting, and worse treatment outcomes associated with greater withdrawal severity. It is true 23 that marijuana is not as likely to cause death by overdose as other scheduled substances, but it is still a 24 dangerous substance for brain, body, and behavior. 25 40. The scientific research shows that marijuana literally changes the brain, with 26 abnormalities detected both in the short term and the long term. Marijuana also adversely affects brain 27 function over the short term and long term, and compromised brain function has shown to be correlated

28 3 See http://www.samhsa.gov/data/2k12/TEDS_061/TEDS_061_LateAdolescents_2012.htm 15 Declaration of Bertha Madras, Ph.D

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1 with the changed brain. Smoking marijuana is intoxicating in the short term, but can also produce 2 residual cognitive deficits (on learning and memory), which may persist. These deficits are readily 3 quantified, are exaggerated in certain populations, such as schizophrenics. Adolescent and long term 4 use of marijuana is also associated with a significant reduction in IQ measured at age 38, and also 5 reduced motivation and increased prevalence of psychosis later in life. 6 41. The mortality of patients with a substance use disorder was assessed in patients 7 hospitalized in California from 1990 to 2005 with medical diagnoses of methamphetamine (n = 8 74,139), alcohol (n = 582,771), opioid (n = 67,104), marijuana (n = 46,548), or cocaine use disorders (n 9 = 48,927). Groups were followed for up to 16 years and age-, sex-, and race-adjusted standardized 10 mortality rates (SMRs) were generated. The SMR is the ratio of mortality rates comparing people that 11 harbor a substance use disorder to matched controls. Although the opioid and methamphetamine 12 cohorts had the highest SMR (5.71, 4.67), marijuana was third in mortality rate (3.85), slightly higher 13 than alcohol (3.83) or cocaine (2.96). The reasons for the higher mortality rates among populations with 14 a marijuana use disorder remain unknown. 15 42. Marijuana use can compromise a student’s ability to focus in class for several days, 16 expose a construction worker to greater risk of injury, engender concentration problems, and reduce 17 motivation. There is good reason why it is unacceptable for soldiers, airline pilots, nuclear power plant 18 operators, physicians, and law enforcement officers to test positive for marijuana use at any time, rather 19 than only on the job. 20 43. A 2009 National Highway Traffic Safety Administration (NHTSA) report showed that 21 more people are driving on weekend nights under the influence of marijuana (8.3%) than alcohol 22 (2.2%). There is a significant increase nationally in traffic fatalities involving drivers that tested 23 positive for marijuana (Brady JE and Li G, Trends in Alcohol and Other Drugs Detected in Fatally 24 Injured Drivers in the United States, 1999-2010, Am J Epidemiol. 17: 692-699, 2014) and a large 25 increase in fatalities involving marijuana-positive drivers since marijuana has become more available in 26 states like Colorado. (Salomonsen-Sautel S, Min SJ(2), Sakai JT, Thurstone C, Hopfer C., Trends in 27 fatal motor vehicle crashes before and after marijuana commercialization in Colorado, Drug Alcohol 28 Depend. 2014 Apr 23). 16 Declaration of Bertha Madras, Ph.D

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1 44. Marijuana has a high potential for abuse because many users seek its euphoric effects. That 2 is, even if some people may use marijuana believing in good faith that it is helping with their symptoms, 3 many other people use marijuana to get high and not for any other purpose. As to medicinal claims, a 4 significant proportion of older cancer patients who had no previous experience with marijuana refused to 5 continue its use because the subjective psychoactive effects were too unpleasant. For such reasons, 6 there is significant doubt whether smoked marijuana will find widespread clinical application, except 7 among those who have previously used it for nonmedical purposes (Kalant, 2008). 8 45. In brief, there is no question that extensive data and practical experience support the 9 conclusion that marijuana has a high potential for abuse, and is actually abused. This does not mean that 10 policy makers could not choose a different outcome, and determine that the risks and consequences of 11 marijuana abuse are outweighed by other factors. See, e.g., 21 U.S.C. § 802(6) (alcohol and tobacco 12 exempted from Controlled Substances Act); see also U.S. Const. Amend XXI (repealing prohibition on 13 alcohol). But there is more than adequate support to reach the conclusion that marijuana has a high 14 potential for—and high actual incidence of—abuse. Further support for, and explanation of this position 15 may be found in the Secretary of Health and Human Service’s recent conclusions on marijuana’s 16 potential for abuse. See 58 F.R. 20038, 20039 (April 18, 2001); 76 F.R. 40552 (July 8, 2011).

17 B. There is Strong Scientific Support for Concluding that there is No Currently Accepted Medical Use for Marijuana. 18 19 46. Merely because some medical practitioners support the use of marijuana as medicine, 20 or clinically controlled, but small, trials report therapeutic benefit, does not mean that there is a 21 currently accepted medical use for the drug. The FDA has not approved marijuana as a medicine. At 22 this time, there are insufficient high quality clinical studies to ensure the safe and effective use of 23 marijuana as medicine. Also, contrary to modern medications, marijuana is a complex mixture of 24 hundreds of chemicals of unknown concentrations, pharmacological effects, and side-effects, and is 25 delivered mainly by an unacceptable route of administration: smoking. It thus has no currently 26 accepted medical use. 27 47. The FDA’s role in the regulation of drugs, including marijuana and marijuana-derived 28 products, includes review of applications to market drugs to determine whether proposed drug 17 Declaration of Bertha Madras, Ph.D

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1 products are safe and effective for their intended indications. The FDA’s drug approval process 2 requires that clinical trials be designed and conducted in a way that provide the agency with the 3 necessary scientific data upon which it can make its approval decisions. Without this review, the 4 FDA cannot determine whether a drug product is safe and effective. It also cannot ensure that a drug 5 product meets appropriate quality standards. For certain drugs that have not been approved by the 6 FDA, such as marijuana, the lack of FDA approval and oversight means that the purity and potency 7 of the drug may vary considerably. 8 48. The FDA supports research into the potential medical use of marijuana and its 9 constituents through cooperation with other federal agencies involved in marijuana research. 10 Conducting clinical research using marijuana involves interactions with other federal agencies. The 11 FDA reviews the Investigational New Drug (IND) application and the research protocol submitted 12 by the applicant. The Drug Enforcement Administration (DEA) reviews the registration application 13 filed by the researcher. The National Institute on Drug Abuse (NIDA) operates pursuant to the 14 Single Convention on Narcotic Drugs. NIDA has been designated with the responsibility to supply 15 research-grade marijuana to researchers. 16 49. Conducting clinical research using marijuana involves interactions with three federal 17 agencies. This includes: obtaining the marijuana for research from NIDA within the National 18 Institutes of Health; review of an IND application and the research protocol by the FDA; and a site 19 inspection and research registration by DEA. 20 50. NIDA’s role is to obtain the marijuana for research. NIDA’s marijuana supply 21 program operates pursuant to the Single Convention on Narcotic Drugs, which imposes certain 22 obligations related to governmental oversight of marijuana cultivation. NIDA contracts with the 23 University of Mississippi to grow marijuana in a secure environment for use in research studies. The 24 FDA reviews an IND application, as noted above. This required step gives regulators and researchers 25 a path to follow that includes regular interactions with the FDA to support efficient drug 26 development while protecting the patients who are enrolled in the trials. DEA is required to 27 determine whether the researcher will have adequate controls in place to safeguard against diversion 28 of the drug. 21 U.S.C. § 823(f). For more information. See 21 C.F.R. § 1301.18 (DEA Research 18 Declaration of Bertha Madras, Ph.D

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1 Protocols). 2 51. In reality, marijuana is a botanical product in that it is composed of plant materials. 3 Because marijuana is a botanical product, there are substantial obstacles to meeting the statutory 4 standard for approval. For instance, FDA would expect an NDA for a synthetic or highly purified 5 drug to identify the active ingredient. In the context of a proposed marijuana drug product, it will be 6 particularly challenging to identify the active ingredient because marijuana is made up of more than 7 400 chemical compounds, including more than 80 are cannabinoids, the majority of which have 8 unknown effects or side effects. It is much more likely that effective compounds (if any) will be 9 identified, isolated, purified, and individually approved as medicines. 10 52. Marijuana smoke contains significant amounts of toxic chemicals, including 11 ammonia, hydrogen cyanide and nitric oxide. The doses of active ingredients are unknown to 12 patients and physicians, and there is no guarantee of product purity or absence of microbes or 13 pesticides that can produce infections and other disease. Further, the percentage of THC that enters 14 the body is unknown and can vary widely if the marijuana is smoked (10-50%) or eaten (~6%+), 15 with effects lasting for unknown times. It is virtually universally recognized among physicians and 16 researchers that smoking anything is harmful to health. Standard medicines are not smoked, but enter 17 the body in many other ways (pill, injection, topical creams, patches, inhalants, eye drops, 18 suppositories, etc.) with the amount entering the blood stream evaluated in clinical trials and doses 19 carefully chosen to account for rate of entry. When the effects of orally administered cannabis 20 extract, THC, and placebo on both appetite and quality of life were compared in a large, double- 21 blinded, controlled trial of patients with cancer-related anorexia-cachexia syndrome, no significant 22 differences in patients’ appetite or quality of life were found between cannabis extract and THC at 23 the dosages investigated. An independent data review board recommended termination of 24 recruitment because of insufficient differences between study arms. (Strasser et al, 2006). 25 53. The chemistry of marijuana is not uniform. It varies from strain to strain and even from 26 plant to plant. In other words, the term “marijuana” is virtually useless to one analyzing whether there 27 are medical applications. In controlled clinical trials with marijuana, THC and possibly CBD content 28 are the only composition of matter provided. There is too great a variance among the existence and 19 Declaration of Bertha Madras, Ph.D

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1 concentrations of compounds within the variety of plants sold in dispensaries to produce reliable 2 indications for marijuana’s use as a medicine. The precedent for modern medicine of the past 100 3 years is clear: each compound within the marijuana plant requires extraction, isolation, purification to 4 reproducible pure forms for evaluation for possible medical applications. Only by systematic 5 evaluation of pure compounds, and possibly by designing variants that are safer and more effective 6 (for example, the design of lidocaine to replace cocaine as a local anesthetic) can safe, controllable, 7 and effective doses of cannabinoids be introduced into modern medicine. Indeed, the FDA has 8 approved a product (Marinol) which contains THC (delta-9-tetrahydrocannabinol), the most active 9 constituent of marijuana, to treat nausea caused by chemotherapy and wasting disease (extreme weight 10 loss) caused by AIDS. The FDA has also approved Nabilone (Cesamet) which contains a synthetic 11 cannabinoid similar to THC and is used for the same purposes. Sativex, which contains approximately 12 equal parts THC and cannabidiol (CBD), is currently approved in the UK and several European 13 countries to treat spasticity caused by multiple sclerosis (MS), and it is now in Phase III clinical trials 14 in the U.S. and on a “fast-track” to expedite development and review of its effectiveness and safety in 15 treating cancer-related pain. Although it has not yet undergone clinical trials to establish its 16 effectiveness and safety (necessary to obtain FDA approval), a CBD-based drug called Epidiolex has 17 recently been developed to treat certain forms of childhood epilepsy. 18 54. It is possible, and perhaps probable, that science may discover medicines from the 19 compounds within the marijuana plant in the years to come. Those compounds would then be 20 evaluated by the FDA-approval process to ensure that they are effective and may be safely used. But 21 this does not mean that the marijuana plant, composed of more than 400 compounds, is itself 22 medicine. A clinical trial comparing the effects of smoked marijuana with dronabinol (THC alone) 23 suggested that, under controlled conditions, marijuana and dronabinol decreased pain, but dronabinol 24 produced longer-lasting decreases in pain sensitivity and lower ratings of abuse-related subjective 25 effects than marijuana. Another pilot study measuring daily caloric intake and body weight in HIV- 26 positive marijuana smokers compared placebo with marijuana and dronabinol. It found that marijuana 27 and dronabinol effects were comparable, and that both dronabinol and marijuana were well-tolerated 28 and produced substantial and comparable increases in food intake. All cannabinoid conditions 20 Declaration of Bertha Madras, Ph.D

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1 produced significant intoxication, except for low-dose dronabinol. To the best of my knowledge, no 2 other clinical trials have compared smoked marijuana to oral/spray THC or THC/CBD for other 3 medical conditions, leaving the issue of whether smoked marijuana confers any advantage in efficacy 4 and safety unresolved. 5 55. In reality, there is no such thing as “medical marijuana”; that is, there is not a 6 particular type of marijuana used for medicinal purposes, let alone for a specific, proven medical 7 purpose. Physician recommendations for medicinal use of smoked marijuana (obtainable in a 8 dispensary) are not grounded in systematic, evidence-based research, which is the hallmark of our 9 system. 10 56. For these and other reasons, the major medical associations do not endorse the use of 11 marijuana as medicine, including the American Medical Association, the American Society for 12 Addiction Medicine, the American Psychiatric Association, the American Cancer Society, the 13 American Glaucoma Society, the American Academy of Ophthalmology, the American Academy of 14 Pediatrics, the National Multiple Sclerosis Society, the British Medical Association, and Canadian 15 Society of Addiction Medicine. A substantial majority—perhaps the vast majority—of scientists 16 familiar with the literature and research agree that, at this time, marijuana does not have medical 17 application. Future medical applications that might be derived from marijuana, if any, will be 18 discovered through isolation of particular compounds that can be administered in pure, safe, and 19 reliable dosages. 20 57. In 2013, the AMA voted to confirm its position that “cannabis is a dangerous drug and 21 as such is a public health concern.” According to the AMA Policy on Medical Marijuana (November 22 2009), the AMA “calls for further adequate and well-controlled studies of marijuana and related 23 cannabinoids” and urges all actions, including marijuana’s scheduling, to promote study and scientific 24 research on marijuana, rather than uninformed action one way or the other. 25 58. The American Psychiatric Association policy on medical marijuana is as follows:

26 ● There is no current scientific evidence that marijuana is in any way beneficial for the treatment of any psychiatric disorder. In contrast, current evidence supports, at 27 minimum, a strong association of cannabis use with the onset of psychiatric disorders. Adolescents are particularly vulnerable to harm, given the effects of cannabis on 28 neurological development. 21 Declaration of Bertha Madras, Ph.D

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1 ● Further research on the use of cannabis-derived substances as medicine should be encouraged and facilitated by the federal government. The adverse effects of 2 marijuana, including, but not limited to, the likelihood of addiction, must be simultaneously studied. 3 ● Policy and practice surrounding cannabis-derived substances should not be altered until sufficient clinical evidence supports such changes. 4 ● If scientific evidence supports the use of cannabis-derived substances to treat specific conditions, the medication should be subject to the approval process of the FDA. 5 Regarding state initiatives to authorize the use of marijuana for medical purposes: 6 ● Medical treatment should be evidence-based and determined by professional standards of care; it should not be authorized by ballot initiatives. 7 ● No medication approved by the FDA is smoked. Marijuana that is dispensed under a state-authorized program is not a specific product with controlled dosages. The buyer 8 has no way of knowing the strength or purity of the product, as cannabis lacks the quality control of FDA-approved medicines. 9 ● Prescribers and patients should be aware that the dosage administered by smoking is 10 related to the depth and duration of the inhalation, and therefore difficult to standardize. The content and potency of various cannabinoids contained in marijuana 11 can also vary, making dose standardization a challenging task. ● Physicians who recommend use of smoked marijuana for “medical” purposes should 12 be fully aware. 13 APA, Position Statement on Marijuana as Medicine (December 2013). 14 59. Both inadequate clinical trials and anecdotal evidence reporting improvement from 15 marijuana use are insufficient to establish “currently accepted medical use.” The FDA’s rigorous 16 process for making these determinations must be followed, or there is a risk of a return to the days of 17 ineffective or dangerous elixirs. The United States’ medical system, indeed the global system, has 18 benefitted tremendously from this scientific approach and progress. Science, and a scientifically-based 19 approval process, should continue to be the central factor in evaluating and approving substances for 20 use as medicine. If safe medical applications for phytocannabinoids (cannabinoids made by marijuana 21 plants) or synthetic cannabinoids (created by chemists) or novel drugs that alter cannabinoid signaling 22 systems in the body, are revealed, then this scientific process will prove no barrier to their approval. 23 60. As noted above, DEA also uses a five-part test to evaluate whether a drug that is not 24 approved by FDA has a “currently accepted medical use.” All five factors must be met:

25 (1) The drug’s chemistry must be known and reproducible; 26 (2) There must be adequate safety studies; (3) There must be adequate and well-controlled studies proving efficacy; 27 (4) The drug must be accepted by qualified experts; and 28 (5) The scientific evidence must be widely available. 22 Declaration of Bertha Madras, Ph.D

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1 These factors are consistent with the core requirements for FDA approval, and the agency recognized as 2 much in adopting the five-factor test. See 57 FR 104504. It is my opinion that the marijuana plant fails 3 to meet any of these requirements. As noted above and below, there are no adequate safety studies for 4 daily functioning (e.g. driving, working, attentiveness at school, learning and memory) or long-term use, 5 nor are there adequate and well-controlled randomized double-blinded trials (RCT) demonstrating 6 efficacy in general (drug-naïve) populations. The majority of studies recruit experienced marijuana 7 users as subjects for a number of reasons, including concerns of unacceptability and drop-out rates th 8 among marijuana-naïve subjects. Considering the concerted effort during the 20 century to minimize 9 or eliminate psychoactive effects of any medication, clinical trials evaluating marijuana should include 10 side-by-side comparisons with isolated cannabinoids or alternative drugs (e.g. for chemotherapy-induced 11 nausea or glaucoma). The most that can be said for marijuana in this regard is that the safety studies 12 (particularly for long-term uses) are lacking, and that the efficacy studies are insufficient to meet FDA 13 standards. Even assuming that there were adequate efficacy studies, marijuana poses significant 14 challenges. Smoking is not an appropriate drug delivery system. Approval of a complex plant with 15 hundreds of chemicals is not a progressive step in the evolution of modern medicine, but rather 16 regressive. Marijuana would also need several studies comparing it to alternatives. 17 61. Moreover, marijuana’s chemistry is a major hurdle if regulatory agencies adhere to 18 consistent criteria in the drug approval process and standards for medications: the plant (other than 19 specific suppliers, e.g. NIDA) is simply too variable to meet this standard at this time. For these and 20 other reasons, marijuana is not an accepted medicine among qualified experts at this time; at best, 21 there is sharp dispute as to marijuana’s utility and safety. This is not to say that isolated compounds 22 within marijuana have not been accepted as medicine—they have (e.g., Marinol). But there is no 23 agreement among qualified experts that marijuana itself is an acceptable medicine. Finally, the 24 scientific data supposedly supporting marijuana’s use as medicine is not widely available. For the 25 most part, it is lacking. Further, most studies used to support marijuana’s treatment as medicine are 26 inadequate (not RCT, small number of subjects, side effect evaluation inadequate) or are described 27 only in abstract form or summarized together with data from isolated cannabinoids. Raw data and 28 data transparency are critical, and would permit the scientific community to evaluate the information 23 Declaration of Bertha Madras, Ph.D

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1 first hand. Thus, it is my opinion that marijuana fails each of the five criteria. It does not have a 2 currently accepted medical use for FDA purposes, nor does it have a currently accepted medical use 3 under DEA’s five-part test meant to approximate the FDA standards. 4 62. While some physicians may believe that marijuana does have medical uses, the 5 current, reliable scientific research does not support this view. Based on my own research and my 6 familiarity with the research of others, and the stringent FDA process, it is my view that, although 7 the research is ongoing, the marijuana plant itself has no place in modern medicine, and no medical 8 indications that fulfill current safety and efficacy standards.

9 C. There is Strong Scientific Support for Concluding that Adequate Assurances that Marijuana Can be Safely Used under Medical Supervision is Lacking. 10 11 63. The issue of safe use of marijuana under medical supervision is largely subsumed within 12 the prior discussion about marijuana’s supposed medical uses. Indeed, part of the FDA process is to 13 determine that drugs can be safely used in this manner. With no reliable information about the 14 composition of the varying strains of marijuana, and even the variations from plant to plant, safe use 15 simply cannot be established. In other words, a substance cannot be used safely, even under medical 16 supervision, if one does not have an adequate understanding of the composition of the substance. 17 Levels of the psychoactive substance within marijuana (delta-9 THC) can vary from below 1% to above 18 30%. Other compounds in marijuana botanicals (e.g. cannabidiol) may also vary widely, depending on 19 the breed of the plant. They are simply too many variables to assure safety to potential patients at this 20 time, and to assure that drug-drug interactions will be harmless. 21 64. The psychoactive effects of marijuana represent a significant obstacle to designing 22 double-blinded clinical trials. Recent studies suggest that between 20% and 50% of individuals report 23 paranoia, persecutory ideas, or hallucinations while under the influence of marijuana (Green et al., 24 2003; Reilly et al., 1998). Side effects of marijuana have to be viewed in the context of immediate 25 effects and after repeated long term use. Ranganathan and D’Souza (2006) examined studies that dealt 26 primarily with effects on memory, and found dose-related impairments of immediate and delayed recall 27 of information presented while the subjects were under the influence of the drug. Various phases of 28 learning and memory were affected, as were signs of depersonalization, distorted sensory perception, 24 Declaration of Bertha Madras, Ph.D

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1 and altered time perception. Crean et al. (2011) reviewed executive functions in marijuana users 2 (attention, concentration, decision-making, impulsivity, self-control, reaction time, risk taking, verbal 3 fluency and working memory) and found all of these functions impaired acutely in a dose-dependent 4 manner. In long-term users seen after periods of withdrawal of at least 21 days, some components of 5 executive function recover completely, while decision-making, concept formation and planning deficits 6 persist. Persistent deficits are more likely to be detected in those who began regular marijuana use 7 early in adolescence, or who used marijuana more heavily and for a longer time. These conclusions 8 agree with clinical impressions based on population studies (e.g., Kalant, 2004, Kalant, 2013, Hall and 9 Degenhardt, 2014, Degenhardt et al, 2013, Degenhardt and Hall 2008). 10 65. In addition, the only indications for medical use of marijuana offered by its proponents 11 have been for chronic conditions (e.g. AIDS neuropathy, AIDS wasting, multiple sclerosis, chronic 12 pain), but I am aware of no long term studies examining the effects of chronic marijuana use among 13 people using marijuana for medical conditions, with particular voids in long term progression to 14 addiction or cognitive impairment. 15 66. Especially in view of marijuana’s negative side-effects, one simply cannot be assured 16 that marijuana can be safely used, even under medical supervision, for long term open-ended use. 17 Current estimates are that 25-50% of daily marijuana users develop an addiction to marijuana. 18 Important information about side-effects and safety could be collected if marijuana went through the 19 normal evaluation for approval as a medicine. The FDA collects information from “adverse event 20 reports,” yet adverse event reports regarding marijuana use are extremely limited at this time because it 21 has not gone through FDA’s process. Further information on the potential adverse effects of using 22 marijuana and its constituents can come from clinical trials using marijuana that have been published 23 (if interrogated), as well as from spontaneously reported adverse events sent to the FDA. 24 67. For heavy users, other side effects can include altered brain structure and brain circuits 25 impaired short-term memory, compromised judgment and decision-making, and mood effects that can 26 range from severe anxiety manifest as paranoia or even psychosis, especially after high-doses. 27 Marijuana can reduce motor coordination alone or combined with alcohol, slow the reaction time of 28 drivers. Marijuana smoking can cause or worsen breathing problems such as bronchitis or chronic 25 Declaration of Bertha Madras, Ph.D

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1 cough and evidence is increasing that it may cause serious cardiovascular problems in some users. 2 Regular use of marijuana for asserted medical purposes is so recent that its long-term effects on 3 seriously ill people cannot be adequately predicted at this time, especially among those that harbor 4 cognitive impairment as a consequence of their the disease (e.g HIV-AIDS, multiple sclerosis, 5 Alzheimer’s, certain seizure disorders). The impact of long-term use on young people, whose frequent 6 use for asserted medical reasons is increasing rapidly, cannot be adequately predicted at this time either. 7 Young people are particularly vulnerable to the adverse effects of marijuana. Especially if used 8 regularly by adolescents, who experience a period of rapid brain development, marijuana may result in 9 long-term or irreversible decreases in cognitive ability and intelligence. Marijuana use during 10 pregnancy may also be associated with brain and behavioral deficits in babies. Further study of the 11 long-term effects on these vulnerable populations is absolutely required before one can claim that 12 marijuana has adequate safety and efficacy studies to be evaluated as a medicine. 13 68. In summary, the immediate, acute effects of marijuana may include, but are not limited to: 14 intoxication (changed perceptions, thinking, memory, judgment, impaired driving or work or school 15 performance for hours to days after last dose, risks for accidents, injuries, falls); psychological effects 16 (anxiety, panic, paranoia, increased appetite); cardiovascular effects (increased heart rate, blood pressure, 17 increased risk of heart attack, increased risk of stroke, injury to brain blood vessels) and worsening of 18 symptoms of asthma, other lung conditions. The long term effects of smoking marijuana are associated 19 with, may include, but are not limited to: addiction, withdrawal symptoms, problems with academics, 20 work, social interactions; Impaired cognition (learning, memory, executive function, lowering of IQ); 21 psychosis (schizophrenia other psychiatric disorders); bronchitis, asthma symptoms, heart attack, 22 testicular cancer; unborn children may develop behavioral, developmental, cognitive impairment. 23 69. I am aware of no recent study with a large cohort of marijuana-naïve subjects that would 24 compel the conclusion that there is an acceptable level of safety for use of marijuana under medical 25 supervision. Without long-term studies and an assurance of consistent composition of the substance, 26 and without proof that the substance is free of contamination or adulteration, one cannot conclude that 27 there is an acceptable level of safety for marijuana’s use under medical supervision. Marijuana’s 28 chemistry, manufacturing, and specifications must be further studied, developed, and chemical isolation 26 Declaration of Bertha Madras, Ph.D

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1 of its cannabinoids should be encouraged. 2 70. Simply put, further information about the safety and effectiveness of marijuana and its 3 constituents is needed. Clinical trials of marijuana (and especially its isolated constituents) conducted 4 under an IND application, and adequately powered (sufficiently large number of subjects) could collect 5 this important information as a part of the drug development process. 6 71. Under these circumstances, exposing patients to the known negative side-effects of 7 marijuana, particularly in smoked or other delivery forms, is being done without an adequate 8 understanding (by the user or physicians) of the long-term negative effects. DEA, in conjunction with 9 FDA, were well-justified in reaching the conclusion that the safety assurances required for medicines 10 were lacking when they denied the most recent petition to reschedule marijuana in 2011. See Denial of 11 Petition To Initiate Proceedings To Reschedule Marijuana, 76 F.R. 40552 (July 8, 2011). 12 72. Until reliable research into the long-term consequences of chronic marijuana for asserted 13 medical conditions is conducted, it is too soon to know what users are being exposed to. Many 14 potential users are vulnerable, uninformed about the lack of safety and safeguards, in a poor position to 15 objectively judge and weigh the potential risks, and may harbor psychiatric conditions, cognitive 16 impairment, motor incoordination, or latent cardiovascular disease that can be exacerbated by 17 marijuana use. Thus, at this time, there is a strong basis for concluding that adequate safety assurances 18 for the use of marijuana, even under medical supervision, are lacking. 19 VI. REBUTTAL TO OPINIONS OF THE DEFENSE EXPERTS 20 73. I have reviewed the declarations filed by the defense in this matter, and disagree with a 21 number of the statements made therein. Below, I set forth specific points of disagreement and rebuttal, 22 which I can expand upon if called to testify orally. 23 74. In general, the declarations offered by the defense are flawed because they ask the wrong 24 question. There is anecdotal evidence that marijuana use by some people appears to make them feel better 25 or to cope with their conditions, and very limited, quality clinical evidence. And, as stated above, there is 26 promising medical research into some of the compounds found in marijuana. But this does not mean that 27 marijuana should be available to the general public as medicine, nor that it has an accepted medical use. 28 At a minimum, further reliable studies are required to test the efficacy and safety of marijuana. 27 Declaration of Bertha Madras, Ph.D

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1 A. Rebuttal to Declaration of Dr. Carter 2 75. Dr. Carter is incorrect in claiming that the chemistry of marijuana is well known and 3 highly reproducible. While it is true that the chemical composition of smoked marijuana has been 4 analyzed and is known in general terms (e.g., Moir et al, A Comparison of Mainstream and Sidestream 5 Marijuana and Tobacco Cigarette Smoke Produced under Two Machine Smoking Conditions. Chem. 6 Res. Toxicol., 2008, 21 (2), pp 494–502), there is no standard “marijuana” chemistry. The chemical 7 composition of marijuana depends on too many conditions, including soil quality, light quality, 8 microbiological environment, water supply, mineral content of the soil, fertilizer and pesticide use, and 9 other environmental factors which are not controlled or regulated. Moreover, marijuana growers have 10 manipulated the germ seeds of marijuana to raise the THC content dramatically over the past decade 11 and reduce CBD content (to increase the “high”). No assumptions can be made on the content of the 12 other 80+ cannabinoids in the plant when the major constituents have been so significantly altered. 13 76. Dr. Carter also claims that adequate efficacy and safety studies exist for using marijuana 14 as a medicine. It is my opinion that he is in error for the reasons stated above. 15 77. Dr. Carter’s claim that a large body of randomized, double-blinded, placebo-controlled 16 clinical trials documenting the efficacy of marijuana as treatment is incorrect. While there are a 17 number of large, controlled double-blinded clinical trials with isolated cannabinoids, those for smoked 18 marijuana are scarce. Smoked or ingested marijuana is not equivalent to oral or sprayed THC, CBD, 19 Marinol, Nabilone, or any other combination of isolated cannabinoids. In addition, most of the early 20 research on therapeutic benefit of marijuana is unacceptable by modern standards because these were 21 survey, open or case studies, in which participants were not randomized to placebo or drug, nor blinded 22 to whether they were receiving placebo or drug, but asked to self-report marijuana benefits. In 23 carefully controlled clinical trials, subjects are randomly assigned to control or experimental groups (or 24 crossed-over to the other group), other medications are either withdrawn or their doses are reported, and 25 investigators make every effort to devise methods to objectively quantify outcomes. Without these 26 methods, the results of such studies are of little scientific utility. 27 78. In addition, Dr. Carter’s citation of 20,000 + peer-reviewed articles on marijuana 28 benefits offers no support for his claim because many of these articles describe the adverse 28 Declaration of Bertha Madras, Ph.D

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1 consequences of marijuana use, the neurobiology of the endocannabinoids and their receptors, 2 cannabinoid drug discovery, analytical methods, epidemiological and psychological studies, and others 3 irrelevant to clinical trials. 4 79. Dr. Carter also cites to a paper by Dr. Nora Volkow for support of his opinion that 5 marijuana has medical benefits. In reality, the point of Dr. Volkow’s article is to voice concern that the 6 spread of marijuana through the medical or legalization route is troublesome in view of the growing 7 evidence of the adverse health effects of marijuana, including addiction, poor school performance, 8 memory impairment, compromised lifetime achievement, relationship to mental illness, gateway drug 9 effects, risks during brain development, risks of cancer, motor vehicle accidents, and other conditions 10 set forth above. Dr. Volkow concludes, and I agree, that there is a need to improve our understanding 11 of how to harness the potential medical benefits of the compounds within the marijuana plant without 12 exposing people who are sick to its intrinsic risks. The same is true of the cited Institute of Medicine 13 (IOM) report Marijuana and Medicine, which acknowledges the potential benefits of marijuana- 14 derived compounds but stresses the importance of focusing research efforts on the therapeutic potential 15 of synthetic or pharmaceutically pure cannabinoids, and states that there is no future in smoked 16 marijuana. The IOM report emphasized that smoked marijuana is a crude drug delivery system that 17 exposes patients to a significant number of harmful substances, and concludes that “if there is any 18 future in marijuana as a medicine, it lies in its isolated components, the cannabinoids and their synthetic 19 derivatives.” There are particular concerns with regard to long-term smoking of marijuana by 20 vulnerable populations, including some evidence to suggest that use of marijuana by patients with 21 HIV/AIDS symptoms may actually exacerbate HIV-associated cognitive deficits. 22 80. Dr. Carter also claims that cannabis, if metabolized, will not become another controlled 23 substance. This claim is without support. It is not possible to conclude this without knowing the 24 content, metabolism and pharmacology of each of the 80+ cannabinoids in the marijuana plant, which 25 is presently unknown. 26 81. Dr. Carter’s opinions on the abuse potential for marijuana are also mistaken, and largely 27 premised on avoiding a definition of abuse or addiction. As noted above, the DSM-IV and DSM-V 28 criteria provide the appropriate definition, are founded on solid scientific evidence, and widely used by 29 Declaration of Bertha Madras, Ph.D

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1 psychiatrists, other physicians and treatment specialists to define abuse or addiction. In both the earlier 2 and current version of DSM, and deliberated by a panel of experts in psychiatry, addiction treatment, 3 and psychology, the evidence that marijuana is an abusable and addictive drug is abundant. 4 Furthermore, comparisons with other drugs are immaterial to determining whether marijuana has a high 5 abuse potential. First, each addictive drug can produce a unique set of adverse consequences, in 6 addition to addiction. Second, the prevalence of addiction for early onset marijuana users is as high as 7 other addictive drugs such as cocaine. Finally, the Institute of Medicine Report is now considered 8 obsolete regarding its conclusion on “less severe, less likely” marijuana addiction. More recent studies 9 and higher potency marijuana have altered this view considerably, and strongly support the views I 10 have expressed above. 11 82. In addition, Dr. Carter claims that cannabis is widely used, but that its “negative 12 consequences remain rare” and that THC-impaired driving is not a problem. This view is not 13 sustainable, as evidence mounts on marijuana-associated driving fatalities (see references in earlier 14 sections), amotivational syndrome, impairment of judgment, association with psychosis, reduction of 15 IQ, cognitive and memory impairment, neurodevelopmental problems, and pulmonary and 16 cardiovascular problems. (See, e.g., Thomas G, Kloner RA, Rezkalla S. Adverse cardiovascular, 17 cerebrovascular, and peripheral vascular effects of marijuana inhalation: what cardiologists need to 18 know. Am J Cardiol. 2014 Jan 1;113(1):187-90). 19 83. Dr. Carter’s testimony about marijuana’s use as a medicine is largely based on a 20 paper submitted to DEA as an attachment to the pending petition to remove marijuana from 21 Schedule I. Neither Dr. Carter’s conclusions in his declaration, nor the conclusions of his paper, are 22 well-founded. In brief, his conclusions largely rely on outdated information, studies of inadequate 23 size or quality, or that conflate the medicinal value of compounds within marijuana, or synthetic 24 cannabinoids, with marijuana itself. While there is growing evidence that isolated THC-CBD 25 mixtures, CBD alone, other phytocannabinoids, and synthetic cannabinoids have promise as 26 medicine, that does not make the marijuana plant (of unknown quality, composition, and side- 27 effects) into medicine. If anything, it means that the traditional process of isolating and 28 standardizing these compounds, now routine for other plant-based medications, will obviate the 30 Declaration of Bertha Madras, Ph.D

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1 disputes about the use of marijuana (and especially smoked marijuana) as medicine. For example, 2 non-psychoactive cannabidiol, if proven effective in clinical trials for certain forms of epilepsy, will 3 obviate this therapeutic claim for the intoxicating marijuana plant. There is, at present, insufficient 4 support for the claim that the marijuana plant is medically effective or safe for use in treating these 5 chronic conditions. 6 84. The data does not currently support the conclusion that the marijuana plant itself is an 7 effective treatment. In neurological diseases, no reliable conclusions can be drawn (Koppel et al, 8 2014). For patients with Huntington’s disease; for patients with Parkinson’s disease, cannabinoids 9 are probably ineffective for treating levodopa-induced dyskinesias; for patients with Tourette 10 syndrome: data is insufficient to support or refute efficacy of THC for reducing tic severity; for 11 patients with cervical dystonia: data is insufficient to support or refute the efficacy of dronabinol; for 12 patients with epilepsy: data is insufficient to support or refute the efficacy of cannabinoids for 13 reducing seizure frequency. Against this background, the risks and of using marijuana should be 14 weighed carefully. 15 85. None of the research by the Center for Medicinal Cannabis Research (“CMCR”) 16 establishes a currently accepted medical use. CMCR was designed to coordinate rigorous scientific 17 studies to assess the safety and efficacy of cannabis and cannabis compounds for treating medical 18 conditions, and funded by the state of California more than a decade ago. The legislation called for a 19 program overseeing medical research that was objective and of high quality, intended to “enhance 20 understanding of the efficacy and adverse effects of marijuana as a pharmacological agent.” 21 CMCR’s research focused on the potential medicinal benefits of cannabis for diseases and 22 conditions as specified by the National Academy of Sciences, Institute of Medicine Report (1999) 23 and by the Workshop on the Medical Utility of Marijuana, National Institutes of Health (1997). 24 Despite a decade of work and millions of dollars in funding, only 5 of 41 publications (excluding 25 abstracts) from the CMCR report the effects of smoked cannabis in patients for alleviating medical 26 conditions. Four are in patients with neuropathic pain, and one is in patients with multiple sclerosis. 27 Several large and critical studies were cancelled because of inability to recruit an adequate number 28 of subjects. In addition, with a slight deviation in one study, all subjects were required to be 31 Declaration of Bertha Madras, Ph.D

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1 experienced marijuana smokers. Given the small and skewed sample sizes, these results cannot be 2 translated to the general public. A San Diego Union Tribune article republished on CMCR’s own 3 web-page states that:

4 While much more is known today about the medical effectiveness of the species cannabis sativa than in 1996, scientists maintain that they can’t prove efficacy for 5 many conditions that marijuana is routinely used to treat. It’s often difficult to distinguish what’s simply promising from what has peer-reviewed scientific 6 legitimacy, researchers said. 7 B. Rebuttal to Declaration of Dr. Denney 8 86. Dr. Denney claims that “accepted and used medically to treat multiple serious 9 medical conditions, marijuana has been safely used under medical supervision for nearly sixteen 10 years in the State of California and elsewhere. Moreover, the safety and medical efficacy of 11 cannabis far exceeds that of many other prescribed and over-the-counter (OTC) medications, in that 12 it is less toxic, possesses a low abuse potential, and is incapable of causing lethal overdose.” This 13 statement contradicts critical, scientific findings made in the past decade, as set forth above. 14 Moreover, Dr. Denney implies that the safety and efficacy of drugs can be determined solely on the 15 basis of overdose deaths or physical side effects. This is incorrect. Accumulating evidence indicates 16 that frequent marijuana use is associated with significant adverse brain and behavioral consequences, 17 that can be more disruptive to normal life than side effects of, for example, antibiotics. In addition 18 to acute intoxication with potential hazards to self and others, marijuana has abuse potential, is 19 addictive and a robust marijuana withdrawal syndrome has been described by several authors and 20 demonstrated in preclinical, clinical, and epidemiological studies. It is comparable to nicotine or 21 cocaine withdrawal. Marijuana withdrawal is reported by up to one-third of regular users in the 22 general population and by 50%–95% of heavy users in treatment or research studies. The clinical 23 significance of marijuana withdrawal is demonstrated by use of marijuana or other substances to 24 relieve it, its association with difficulty quitting, and worse treatment outcomes associated with 25 greater withdrawal severity. 26 87. In addition, Dr. Denney is simply incorrect about marijuana’s use under medical 27 supervision. Marijuana differs significantly from normal, FDA-approved prescription medications, 28 and evidence supporting its use as a medication is not consistent with the standards of the FDA’s 32 Declaration of Bertha Madras, Ph.D

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1 current drug approval process. It is also often used in a manner that is inconsistent with standard 2 practice of medicine that requires maintaining patient records, objectively determining cause of 3 symptoms, follow-up care, and limiting repeat prescriptions, on a case-by-case determination. 4 Marijuana is smoked, while other medications are not smoked. Its safe dose ranges (for THC? other 5 cannabinoids? ammonia?), side-effects if taken as a medicine long term, acceptability for marijuana- 6 naïve patients, long-term effects, and ability to engender tolerance or sensitization in marijuana- 7 naïve or experienced smokers, are all unknown. And, as noted above, I am aware of no research on 8 the critical question of marijuana’s safety and effectiveness for use for medical conditions that span 9 multiple years. Without this data, and without a consistent, pure, standard, and well-understood 10 product, one cannot conclude that there are adequate assurances that marijuana can be safely used as 11 a medicine by the general public, particularly when we know of its adverse consequences as 12 summarized in the recent New England Journal of Medicine article by Volkow, et al., cited above. 13 88. Dr. Denney correctly points out that many over-the-counter drugs can be dangerous if 14 taken in the wrong quantities. But this does not mean that marijuana is safe or even safer than these drugs. 15 89. The same is true for Dr. Denney’s comparisons of over-the-counter medications, alcohol, 16 and tobacco. The same psychological effects (relaxation, etc.) he reports for marijuana are also 17 frequently reported for alcohol and tobacco products. But a diligent physician would not prescribe 18 alcohol or smoking cigarettes for a patient. Moreover, there is no evidence that that any of the over-the- 19 counter medications listed in his declaration produce a unique spectrum of negative side-effects of 20 marijuana, such as learning and memory impairment, loss of judgment, distorted time perception, 21 paranoia, addiction, cognitive deficits, IQ decreases, or significant brain changes, pulmonary deficits, or 22 cardiovascular events. Moreover, and as noted above, a robust marijuana withdrawal syndrome has been 23 described by several authors and demonstrated in preclinical, clinical, and epidemiological studies. It is 24 comparable to nicotine withdrawal. Marijuana withdrawal is reported by up to one-third of regular users 25 in the general population and by 50%–95% of heavy users in treatment or research studies. The clinical 26 significance of marijuana withdrawal is demonstrated by use of marijuana or other substances to relieve 27 it, its association with difficulty quitting, and worse treatment outcomes associated with greater 28 withdrawal severity. 33 Declaration of Bertha Madras, Ph.D

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1 90. Dr. Denney is incorrect to downplay the association between psychosis and cannabis 2 use. Association-based case-studies, surveys, and epidemiological studies indicate a strong 3 association between marijuana and psychosis or psychotic disorders, including schizophrenia. 4 Symptoms of schizophrenia increase with marijuana use, and the magnitude of the symptoms is 5 associated with amount used and frequency of use. In individuals with an established psychotic 6 disorder, cannabinoids can exacerbate symptoms, trigger relapse, and have negative consequences 7 on the course of the illness. At the present time, the evidence indicates that marijuana may be a 8 component cause in the emergence of psychosis, and further research is continuing. (See, e.g., 9 Radhakrishnan R, Wilkinson ST, D'Souza DC, Gone to Pot - A Review of the Association between 10 Cannabis and Psychosis, Front Psychiatry. 2014 May 22;5:54; Degenhardt et al 2013). 11 91. Dr. Denney’s declaration that he has “found cannabis has been successfully used to 12 treat psychological disorders such as anxiety, depression and PTSD in a number of patients who 13 have not found other treatments sufficiently helpful” does not establish that marijuana has a 14 currently accepted medical use for the general public. Furthermore, as quoted above, the American 15 Psychiatric Association’s position (December 2013) is that that: “There is no current scientific 16 evidence that marijuana is in any way beneficial for the treatment of any psychiatric disorder. In 17 contrast, current evidence supports, at minimum, a strong association of cannabis use with the onset 18 of psychiatric disorders. Adolescents are particularly vulnerable to harm, given the effects of 19 cannabis on neurological development.” There are no objective randomized control trials that 20 demonstrate cannabis effectiveness has been successfully used to treat psychological disorders such 21 as anxiety, depression and PTSD (e.g. Greer et al 2014). Marijuana is not a medically approved 22 method to treat these disorders. 23 92. Dr. Denney’s citation to a survey conducted by the New England Journal of Medicine 24 in 2013 for the proposition that the majority of clinicians favored of the use of marijuana for 25 medicinal purposes is misleading. The article cited a case of a terminally ill cancer patient, which is 26 not at all typical of patients requesting a recommendation for marijuana (Adler JN, Colbert JA. 27 Clinical decisions, Medicinal use of marijuana--polling results, N Engl J Med. 2013 May 28 0;368(22):e30). As such, it generated much debate, support and refutation by others, who highlighted 34 Declaration of Bertha Madras, Ph.D

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1 the unusual and morbidly ill patient with metastatic breast cancer in this presentation (Bostwick JM, 2 Reisfield GM, DuPont RL. Clinical decision, Medicinal use of marijuana. N Engl J Med. 2013 Feb 3 28;368(9):866-8). As Dr. Bostwick, et al., explained, there is no benefit to smoking marijuana, 4 though likely little risk to such an advanced cancer patient. Moreover, they explain that

5 Smoked marijuana is a nonmedical, nonspecific, and potentially hazardous method of drug delivery. The cannabis plant contains hundreds of pharmacologically active 6 compounds, most of which have not been well characterized. Each dispensed quantity of marijuana is of uncertain provenance and of variable and uncertain potency and may 7 contain unknown contaminants. There are other questions to consider in Marilyn’s case. Could marijuana’s cognitive side effects, particularly its effects on memory, promote or 8 exacerbate chemotherapy-induced cognitive dysfunction? If Marilyn’s pulmonary disease includes lymphangitic spread, could smoking cause hypoxemia? What effects 9 will marijuana’s potential immunologic hazards (e.g., chemical constituents, pyrolized gases, viable fungal spores, or pesticide residues) have on her health during periods of 10 immunocompromise? How will marijuana, alone or in combination with other medications associated with potential cognitive and psychomotor impairment, affect her 11 ability to safely operate a motor vehicle? What are the possible effects of marijuana on tumor progression? 12 13 I agree with them that there are too many open questions to sanction the use of marijuana as medicine. 14 93. In addition, Dr. Denney’s reliance on CMCR is inadequate for the reasons stated 15 above, except to refute his own claim that marijuana research has been impaired. CMCR is well- 16 funded and gained approval to conduct a number of clinical trials with marijuana for serious medical 17 conditions, but was compelled to cancel five major studies due to lack of volunteers. 18 94. Dr. Denney also points to the use of THC and CBD as medicine to treat seizures and 19 other conditions. He has inadvertently refuted his central claim: that marijuana is medicine. In 20 reality, THC and CBD, isolated and administered at known doses, are approved as medicine. The 21 marijuana plant, which contains CBD, THC, and 400+ other chemicals, is not. Modern medicine is 22 based on pure compounds, known doses, known benefits and side effects and long term outcomes. 23 Conflating marijuana with isolated cannabinoids misunderstands the scientific literature, and 24 confuses physicians, policy makers and patients. In the 21st century, patients deserve evidence- 25 based medicines that are safe, effective, and of known composition for proven indications. 26 C. Rebuttal to Declaration of Carl Hart. 27 95. I also disagree with the conclusions of Carl Hart for the reasons already set forth 28 above, and thus will not restate those same reasons here. 35 Declaration of Bertha Madras, Ph.D

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1 VII. CONCLUSION 2 96. There is a strong scientific foundation for continuing to include marijuana on Schedule I 3 of the Controlled Substances Act. There was strong support for DEA’s prior decisions, including in 4 2001 and 2011, and the evidence remains strong today. Nothing in the scientific record compels the 5 conclusion that marijuana can no longer be on Schedule I.

6 I swear that the foregoing is true and correct to the best of my knowledge. Executed this 29th 7 day of July, 2014, at Belmont, Massachusetts.

8 By: 9 ______10 Bertha Madras, Ph.D

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Exhibit A

Case 2:11-cr-00449-KJM Document 324-1 Filed 07/29/14 Page 2 of 66 Curriculum Vitae Bertha K. Madras

July 2014 (Harvard Medical School format)

CURRICULUM VITAE

Bertha K. Madras, PhD (the Honorable)

I. General Information

Office Address McLean Hospital Harvard Medical School Alcohol and Drug Abuse p[rogram Oaks Building, Room 342 115 Mill Street Belmont MA 02478 Phone: (617)-855-2406

Recent Office Harvard Medical School New England Primate Research Center One Pine Hill Drive Southborough, MA 01772-9102 Phone: (508) 624-8073

Home Address Newton, MA 02458

Work e-mail [email protected]

Country of origin Montreal, Canada Citizenship U.S. citizen

Education

09/59-06/63 BSc McGill University, Montreal, Canada; Honours Biochemistry 09/63-08/66 PhD McGill University, Montreal, Canada; metabolism, pharmacology; thesis and orals completed 1966; degree conferred June 1967 J.B. Collip Fellow of the Faculty of Medicine

Postdoctoral Training

09/66-08/67 Post-doctoral fellow: Dept of Biochemistry, Tufts University, Boston, MA and Cornell University Medical College, New York, NY 09/67-06/69 Post-doctoral fellow: Dept of Biology, Massachusetts Institute of Technology, Cambridge, MA

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06/69-06/72 Maternity leave 09/72-06/74 Research Associate: Dept of Endocrine Regulation, Massachusetts Institute of Technology, Cambridge, MA 1974-1978 Maternity leave

Academic Appointments

Current

2014 - Professor of Psychobiology, Dept. of Psychiatry, Harvard Medical School, Psychobiology, McLean Hospital 1999-2014 Professor of Psychobiology, Dept. of Psychiatry, Harvard Medical School Core scientist, New England Primate Research Center, Southborough campus of Harvard Medical School 01.05-04.14 Department of Psychiatry, Massachusetts General Hospital

Recent

06/96-7/08 Chair, Division of Neurochemistry, New England Primate Research Center, Southborough campus of Harvard Medical School 1990-1999 Associate Professor of Psychobiology, Dept. of Psychiatry, Harvard Medical School 1986-1990 Assistant Professor of Psychobiology, Dept. of Psychiatry, Harvard Medical School 1991-1997 Department of Psychiatry, Massachusetts General Hospital, Boston 1992-1995 Center Faculty, Norman E. Zinberg Center for Addiction Studies 1979-1984 Assistant Professor, Department of Pharmacology, University of Toronto 1980-1984 Assistant Professor, Department of Psychiatry, University of Toronto 1980-1984 Graduate Faculty, Department of Pharmacology, University of Toronto 1979-1984 Research Scientist, Clarke Institute of Psychiatry 1978-1979 Lecturer, Department of Pharmacology University of Toronto, Canada

Other/Visiting Appointments

2006-2008 Deputy Director for Demand Reduction White House Office of National Control Policy (ONDCP) Executive Office of the President

Administrative Responsibilities: Harvard University, Medical School (partial list)

2013- Chair, Radiation Safety Committee, Harvard University 2012- Chair, Quality Assurance, Quality Control Committee, NEPRC 1996-2006 Chair, Division of Neurochemistry, NEPRC, Harvard Medical School (until leave of absence) 2003-2004 Chair, Faculty Partners Committee, Harvard Medical School 1998-2006 Associate Director for Public Education, Division on Addictions, HMS

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1991- Course Director, Harvard Medical School, Advanced Biomedical Sciences: Substance abuse: addictive processes (not 2005-2009); catalogued but not offered since 2005. 1998-1999 Acting Director, New England Primate Research Center 1995-1999 Chair, Radiation Safety Committee, Harvard University 1987-1999 Chair, Radiation Safety Committee, New England Primate Research Center

Committee Assignments: Harvard Medical School

2012-2014 Member, IACUC, HMS 2009-2012 Member, Subcommittee of Professors, Harvard Medical School: promotions committee for appointments to rank of Professor 2002-2012 Chair and/or committee member: ad hoc committees for individual candidate promotions to rank of Professor 2013 Ad hoc Committee for promotions at NEPRC ’09,-’12 NEPRC, pilot project review committee ’10-‘13 NEPRC Awards Committee, selection of best manuscript (post-doctoral fellows) 2009-2010 Member, Search Committee to appoint Chair, Department of Psychiatry, Beth-Israel Deaconess Medical Center 2005 -2006 Member, HMS Research Compliance Advisory Committee 2005 Organizer, NEPRC Research Symposium 2004 - 2006 Member, Subcommittee of Professors, Harvard Medical School: promotions committee to appoint faculty to rank of Professor 2000 - 2003 Member, Appointments and Promotions Committee, Harvard Medical School, promotions committee to appoint faculty to rank of Assistant, Associate Professor 1992 -1994 Steering Committee, Division on Addictions, Harvard Medical School 1994- 2006 Research Committee, Dept. of Psychiatry, Harvard Medical School 1997 HST Task Force, Development of Experimental PET Center, HMS 1996-1999 Animal Use Committee, New England Regional Primate Research Center 1990-1991 Planning Committee for Substance Abuse, Harvard Medical School 1987-1999 Member, Radiation Safety Committee, Harvard University 1989 Faculty representative (NEPRC); initial HMS- Harvard Union dialog

Committee Assignments: Other Universities (partial list, majority not recorded)

1980-1982 Research Advisory Committee, Clarke Institute of Psychiatry 1980-1982 Educational Advisory Committee, Clarke Institute of Psychiatry 1979 Founder and Chair, Neuroscience course and program committee, Faculty of Medicine, University of Toronto

Committee Assignments: Government Service

2012 Member, CDC Panel: Insights from the Demand Side: What Makes the Case for Alcohol Screening and Brief Intervention? 2012 Member, FDA panel: “Role of Naloxone in Opioid Overdose Fatality Prevention”. Washington, DC

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2011-2012 Member, NIDA Council Work Group: Transfer of NIDA-sponsored treatment research to Community Treatment Centers 2011 Ad hoc member, Board of Scientific Counselors, NIAAA National Institute on Alcohol Abuse and Alcoholism (Sept 2011) 2006-‘08 Member, Office of Juvenile Justice Delinquency Prevention Committee, US Dept of Justice 2007-‘08 Member, Safe and Drug-free School Advisory Committee, US Dept of Education 2005-‘06 Member, Medications Development Scientific Advisory Board, NIDA-NIH 2004 Member, Medications Development Subcommittee of NIDA, Advisory Council on Drug Abuse, NIH 2004 Advisor and story-board writer, NIDA-DEA Exhibit, 1 Times Square, NY, NY. 2002 Member, Search Committee for Director, Brookhaven National Laboratory 1999-2005 Member, Science and Technology Advisory Committee, Brookhaven National Laboratory 1997 Office of National Drug Control Policy, Special Review Committee, ONDCP 1997 Review Committee, Chemistry and Medical Departments, Brookhaven National Laboratory, U.S. Dept. of Energy. 1992-1996 NIDA Medications Development Division; Expert panel; Dopamine transporter review committee, dopamine receptor review committee, NIH 1991-1996 Visiting Review Committee, Chemistry and Medical Departments, Brookhaven National Laboratory, for A.U.I. and Dept. of Energy 1988-1990 Chair, Ontario Mental Health Foundation (Ontario Ministry of Health), Fellowships and Awards Committee 1984-1990 Ontario Mental Health Foundation, Fellowships and Awards Committee 1990-1992 Trillium Award Selection Panel, Ontario Ministry of Health 1991-1998 Scientific Reviewer, Brookhaven National Laboratory, (for DOE, AUI, other)

Committee Assignments: Government Grant Review Panels

2014 Special emphasis panel, 2014/05 ZDK1 GRB-G (M4), NINDDK RFA-DK-13-507, “Limited Competition of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network” and RFA-DK-13-025, “Expansion of the MAPP Research Network”. 2014 Special emphasis panel NIDA 2014/05 ZDA1 MXL-F (10) S Imaging- I/START 2013 Special emphasis panel, ZMH1 ERB-C (01) S - National Cooperative Drug Discovery Groups (NCDDG) 2013 Special emphasis panel ZRG1 BBBP-J 02M 2013 Special Emphasis Panel/Scientific Review Group 2013/10 ZDA1 GXM-A (03) 2012 ZDA1 GXM-A 11 for RFA DA13-004; Synthesis & Preclinical Evaluation of Medications to Treat Substance Use Disorder (SUDS); 11/01/2012 2012 ZDA1 GXM-A (03) NIDA Imaging (I/START; 11/06/2012-11/07/2012 2011 ZRG1 BBBP-J 04 M, Biobehavioral regulation, learning, and ethology; Special emphasis panel

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2011 ZDA1-JXR-D(06), “New Molecular Entities to Treat Substance Use Disorders, (May) 2011 BBBP-T (03) Biobehavioral and Behavioral Processes Across the Lifespan, (Jan) 2010 ZRG1 BBBP-R (05) M, Child Psychopathology, Special emphasis panel 2008 ZRG1 ETTN-H (13)B, Mol, Cellular and Developmental Neurobiological Small Business App. NIH grant reviews 2005 Review of NIMH center grant applications on the pharmacologic, developmental, metabolic, cognitive of ADHD and schizophrenia (declined) Nov 3,4 2005 Reviewer, Nov 2005 Ad hoc reviewer, Board of Scientific Counselors, NIDA (declined) 2003-2005 Member, Molecular Neuropharmacology Signaling Study Section (MNPS), NIH 2002 MDCN Special emphasis panel ZRG1 SSS-P 05, NIH grant reviews 2002 NINDS Special emphasis panel ZNS1 SRB-E (02), NIH grant reviews 2002 Chair, Special emphasis panel MDCN-5 April 4, NIH grant reviews 2002 NINDS Special Emphasis Panel ZNS1 SRB-A01; 3/21/2002, NIH grant reviews 1998-2003 Member, Molecular, Developmental, Cellular Neuroscience-5 Study Section, (MDCN-5); NIH grant reviews 2001 Special emphasis panel ZDA MXG-S 01 R:The transition from drug abuse to addiction, NIH grant reviews 2001 Special emphasis panel, ZDA1 SRC(99), NIH grant reviews 2000 Special emphasis panel, NICDH, RFA HD-00-001, Developmental Pharmacology, NIH grant reviews 2000 Special emphasis panel, NIMH, Neuroinformatics, ZMH1 BRB-P 3/22/00, NIH grant reviews 1998 Ad Hoc reviewer, NIMH, NIH grant reviews 1997-1998 Chair, NIDA/B Study Section, NIH grant reviews 1998 Ad hoc member, Board of Scientific Counselors, Intramural Research Program, NIDA 1993-1998 Member, NIDA/B Study Section Review Committee, NIH grant reviews 1998 Member, NIDA Special Emphasis Panel review (February), NIH grant reviews 1998 Member, NIDA Special Review Committee (March), NIH grant reviews 1998 NIDA Special Review Committee (April), NIH grant reviews 1997 NIDA Special Review Committee; UCLA imaging project, NIH grant reviews 1993-1997 Member, special review panels, NIDA (> 8 panels), NIH 1992-1993 Ad Hoc Reviewer, NIDA, DABR2, NIH 1992, 1995 Ad hoc reviewer, NIMH

Professional Societies: committees (partial list)

2013- Chair, Media Committee, College on Problems of Drug Dependence (CPDD) 2009-2013 Media Committee, College on Problems of Drug Dependence (CPDD) 2004-2006 Fellow, CPDD 1999-2003 Board member, College on Problems of Drug Dependence (CPDD) 1998-2006 External Advisory Board, Center for the Neurobiological Investigation of Drug Abuse, Wake Forest University, Bowman Grey School of Medicine

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1999-2002 Animal Use Committee, Society for Neuroscience 1998-2001 Members Committee, College on Problems of Drug Dependence 1994-1997 Media Committee, College on Problems of Drug Dependence 1994-1998 Credentials, Membership Committee, College on Problems of Drug Dependence 1992-1995 Public Information Committee, Society for Neuroscience

Professional Societies: membership

01/87-2014 Society for Neuroscience; [reinstated 2008 after required resignation 2006-2008 by White House counsel] 1989- College on Problems of Drug Dependence; [reinstated 2008 after required resignation 2006-2008, by White House] 09/94 - DANA Alliance for Brain Initiatives; [reinstated 2008 after required resignation, White House] 12/03- American College of Neuropsychopharmacology; [reinstated, after required 2006- 2008 resignation, White House] 05/97-2002 Society for Nuclear Medicine (lapsed membership) American Chemical Society (lapsed membership)

Board memberships, community service, other

2014- Advisor, Marijuana prevention film (Brad Heilman, lead) 2014- Chair, Scientific Advisory Board, Teen Safe, (Children’s Hospital) 2014- Prescription Drug Advisory Panel; NFL (National Football League) 2013- Scientific Advisory Board, Rivermend Treatment Centers 2013- Board of Advisors, MedRespond SBIRT Training Advisory Group 2012-2013 Board of Advisors/Directors, Shatterproof 2012 Ad hoc Advisor, Hilton Foundation 2011- Prexa Pharmaceuticals, Consultant 2011- Advisory Board, Institute of Behavioral Health, Washington, DC 2010-2012 Review Editorial Board; Frontiers in Molecular Psychiatry, a specialty section of Frontiers in Psychiatry (2/27/2010-present) 2010- Board, Friends of NIDA 2009- Guidepoint Global 2008 Betty Ford Institute, Graduate Medical Education for primary care physicians, Rancho Mirage, CA 2008-2009 Education Committee, American Board of Addiction Medicine Foundation (ABAM), Chevy Chase, MD 2008-2009 Advisory Board, Center for Integrated Behavioral Health Policy, George Washington University 2002-2005 Scientific Advisory Board, M.I.N.D. Institute Research (Autism), UC Davis, CA 2002-2004 Scientific Advisory Board, Clera, Inc 2002-2005 Member, Advisory Board of Canadian Statistical Assessment Service (CANSTATS) 1999-2006 Advisory Board, Addiction Studies Institute for Journalists 1992-1994 Scientific Advisory Board, Boston Life Sciences, Inc

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Community Service: Related to Professional Work (partial list)

Grant Reviewer National Institutes of Health, National Science Foundation, Fellowships, Medical Research Council (Canada), Ontario Mental Health Foundation (Canada), Veterans Health Administration, Department of Energy, International Human Science Frontier Program, Office of National Drug Control Policy, Canadian Foundation for Innovation, Hospital for Sick Children, Toronto, Canadian Psychiatric Foundation

Prize Nominator, at request of agencies: (CONFIDENTIAL) Nobel Prize, Japan Prize, Kyoto Prize, MacArthur Awards; other confidential nominations

Journals Ad hoc Reviewer The American Journal of Drug and Alcohol Abuse, Arch. Gen. Psychiatry, Biological Psychiatry, Biochemical Pharmacology, Biochemistry, Brain Research, Drug and Alcohol Dependence, European J. Pharmacology, JAMA, Journal Medicinal Chemistry, J. Neurochemistry, J. Neuroscience, J. Pharmacology Experimental Therapeutics, Life Sciences, Molecular Pharmacology, Molecular Psychiatry, Neuropsychopharmacology, Neuropharmacology, Psychopharmacology, Proceedings National Academy of Science, (USA), Science, Synapse, others

Community Service Related to Professional Work: Public Education

Examples of public lectures; community service, some redundant with invited lectures

2014 Changing your mind: drugs in the brain, Brain Awareness Week Lecture. Louisiana State University, New Orleans, LA 2014 Marijuana: is it safe? is it a medicine? Virginia Commonwealth University, Richmond, VA 2014 Marijuana: the science. Ardsley High School, Ardsley, NY 2014 Marijuana and FDA approval, Tampa Drug Summit, Tampa, FL 2013 Lecture series on marijuana for healthcare professionals, Ossining, NY 2013 Keynote speaker; European Cities Against Drugs, Moscow, Russia 2013 Lecture series on marijuana; parents, students, professionals, Mamaroneck, NY 2013 Webinar, nationally broadcast, Designer drugs: Tampa, FL 2013 Marijuana as medicine, Symposium, Tampa, FL 2012 Webinar on Prescription Medication Abuse; sponsored by Arts and Education Channel, PDFA and ONCDP; http://www.aetv.com/the-recovery-project/medicine-abuse/index- post.jsp 2011 Presentation to Albany State Governor’s Office on medical marijuana (October 4, 2011) 2011 Presentation to California Coalition for Drug-Free California 2010 CICAD (Inter-American Drug Abuse Control Commission) Meeting with Latin American Universities: “The Drug Phenomenon from the International Health Perspective”, Organization of American States, Panama City, Panama 2010 Changing your mind: drug policy and science; Marijuana research; medical marijuana, World Forum Against Drugs, Stockholm, Sweden 2010 Drug dependence: a health and social issue. Drugs Summit, European, Latin American, Caribbean Mayors and Cities, Organization of American States (OAS), Lugo, Spain

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2009 Lectures (4) on substance abuse, suicide, public policy, Taipei, Taiwan 2009 South Africa Conference on Substance Abuse (at request of US Department of State) 2009 Ireland Conference on Substance abuse 2006 Disney Corp. licensee of CD-ROM, “Changing your mind: drugs in the brain” 2005 PBS: “Bill Nye, the science guy” incorporates components of CD-ROM for TV production on drugs. 2005 RCMP training program for drug prevention, intervention, St. John’s Newfoundland 2004 Panelist, ONDCP conference on drug-related medical education, Washington, D.C. 2004 Contributed to storyboard of NIDA-DEA exhibit, Times Square (2004-2005) 2004 Project Success-Careers in science, Countway Library of Medicine (Angela Counts, a program for inner city students) 2004 Taiwan; Series of lectures on substance abuse (from basic biology to treatment approaches); consultant on drug policy 2004 Brain Science Boot Camp, Knight Science Journalism Fellowships at MIT, Cambridge, MA 2004 Learning and the Brain Conference, Boston, MA 2003 Royal Canadian Mounted Police (RCMP): The Biology of Drugs and Addiction. International Police Conference sponsored by the RCMP, Ottawa, CA 2003 New England Governor’s Summit, The biology and treatment of drug addiction; Sponsored by the Office of National Drug Control Policy (ONDCP) Boston. MA 2003 Keynote speaker, Vermont Judicial College (Vermont Supreme Court Judges and other judges). Is addiction a brain disease? 2001 Drugs, the brain, and the law, Renaissance New Year’s Weekend, SC. 2001 Prescription drugs for children: benefit and risks? World Conference on Drugs, Visby, Sweden 2001 The science of substance abuse and the brain” Dept of Public Health and Massachusetts Judicial Institute 2001 Massachusetts Department of Health, Grand Rounds, “Changing your mind: drugs in the brain”. Boston, MA 2000 Changing your mind: drugs in the brain. Flaishner Institute for Judicial Studies, MA 2000 “Shaping drug policy to the latest scientific data” (2 lectures) The threat of drugs and the need for high level action Symposium Pretoria, South Africa 2000 Changing your mind: drugs in the brain” European Cities Against Drugs; Cork, Ireland 1999 The Neurobiology of Opiates and Stimulants. 2 lectures Swedish Police, Uppsala, Sweden 1998 Facilitate Apache Nation (Cibeque, White Mountain tribe in Arizona) to create a version of a CD-ROM for instruction of tribal members on consequences of drug use 1998 Developed manual to be used in conjunction with the CD-ROM 1998 Consultation with Center for Excellence in Multi-Media, a U.S. Air Force committee to develop CD-ROM for public information on alcohol and tobacco. 1998 NIDA Town Meeting presentation “neuroscience of drug abuse, addiction”. Boston, MA ‘92-‘95 Project Director and PI (NIH grant) to develop a museum exhibit, CD-ROM, and play, for the Museum of Science, Boston. The exhibit, titled, “Changing your mind; drugs in the brain” opened in November 1994, toured the nation; exhibited at the Museum of Science, Boston for 10 years. ‘82-‘84 Developed science curriculum for Grades 2,3,4 and volunteer taught (one hour/week) for 2 years. Organized and judged Science Fairs for several years.

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Editorial Boards for Books, Journals

2011- BK Madras, MJ Kuhar, eds., “The Effects of Drug Abuse on the Human Nervous System”, Elsevier (2014) 2011- P Seeman, BK Madras, eds. “Imaging of the Human Brain in Health and Disease”, Elsevier (2014). 2010- Review Editorial Board, Frontiers in Molecular Psychiatry ‘96-‘06 Section Editor, Neuroscience-Net (Pharmacology) ‘93-‘03 Editorial Board, Synapse

Awards and Honors

2011 Marian W. Fischman Award; for an outstanding woman scientist in drug abuse research, CPDD 2008 Recognition Award, 7th Bi-National United States-Mexico Demand Reduction, Monterrey, Mexico 2006 Founder’s Award, American Association of Addiction Psychiatry (AAAP) 2006 The Better World Report 2006. Invention of Altropane selected as one of 25 technology transfer innovations that changed the world. 2005-06 Presidential nomination and appointment as Deputy Director, Demand Reduction, White House Office of National Drug Control Policy, July 2005; Appointed in 2006 2006 Unanimous Senate confirmation for ONDCP position, September 2006 2005 NIDA Public Service Award 2004- American College of Neuropsychopharmacology (ACNP) member 1999 Selected by Harvard University President Rudenstine’s office to be sole Faculty Representative of Harvard University for Science Coalition Day, presentations to United States Congressional representatives, Washington D.C. 1998-06 MERIT Award (R37), National Institute on Drug Abuse, NIH (NIDA-NIH) 1997-06 K02, K05 Senior Scientist Award, NIDA (NIH) 1994-06` Member, Dana Alliance for Brain Initiatives, membership reinstated in 2008 1996 Smithsonian Institution, Washington, D.C. Series on Neuroscience 1995 Healthy Women 2000 Conference lecture. Health and Human Services Symposium on Capitol Hill, Washington, D.C 1995 Distinguished Scientist Lecture Series; Food and Drug Administration, National Center for Toxicology Research, Jefferson, AK 1994 John H. Kendig Neuroscience Lecture, St Louis, MO 1963-66 JP Collip Fellow of the Faculty of Medicine 1961-63 Women’s editor and Women’s Sports Editor, McGill Daily 1959 Winner, Women’s Public Speaking Contest, McGill University 1961-63 Red Wing Society, McGill University (honorary society for excellence in academics, leadership, athletics, faculty selected)

Drug policy, prevention, intervention (please see section starting page 41; Non-Local Leadership

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II. Research/Teaching

Narrative report of research

1. Translational research. Translational and basic research in the Neurochemistry Division and Neurochemistry Laboratory is multidisciplinary and collaborative, and spans molecular, chemical, cellular, genetics, biochemical, behavioral and imaging methodologies. A few examples of our translational research program are outlined. a. Parkinson’s disease: novel diagnostic markers and drug therapies. In March 1, 1989, my laboratory discovered that a phenyltropane analog of cocaine, [3H]CFT (WIN 35,428) effectively detected the dopamine transporter, localized on dopamine neurons. It is currently the most widely used probe for the transporter. [3H]CFT also detected Parkinson’s disease in postmortem human brain with high specificity and selectivity, resulting in the use of CFT and its analogs to detect dopamine neuron injury in living brain of Parkinson’s diseased patients, amphetamine(s) abusers, and variants have been used to assess transporter levels and dopamine neuron status in more than 20 other applications for neuropsychiatric disorders. Development of the CFT analog altropane for SPECT and PET imaging in living brain followed. Altropane was sublicensed as an imaging agent to diagnose Parkinson’s disease, for development and commercialization in 2012. We advanced SPECT imaging by showing the feasibility of imaging the dopamine transporter in brain with a 99mtechnetium probe, contrary to predictions that its cumbersome size/charge would prevent passage across the blood- brain barrier. Behavioral research showed that dopamine transport inhibitors and D1 dopamine receptor agonists effectively alleviated specific, but not all parkinsonian symptoms in a primate model of Parkinson’s disease. b. Attention Deficit Hyperactivity Disorder: pathophysiology and genotype/phenotype associations. We showed that juvenile monkeys displayed a range of activity levels. When challenged with the antihyperactivity medication methylphenidate, the drug reduced activity of highly active, but not relatively inactive juvenile monkeys. In vitro, we showed that the 9- repeat sequence of the 3’-untranslated region of the human dopamine transporter gene expressed higher levels of a transfected reporter gene than the gene with the 10-repeat sequence. To clarify whether this genetic association translated to living human brain, our collaborative team at MGH imaged the dopamine transporter in ADHD/control subjects and detected elevated dopamine transporter (DAT) levels in ADHD adults with the PET ligand [11C]altropane, a finding corroborated by some, but not all groups. We then reported that the 9-repeat genotype correlated with elevated levels of the DAT in human brain of ADHD subjects or controls, confirming in vitro data. c. Modafinil targets in brain. Modafinil, a widely used anti-narcoleptic, had been designated an atypical drug, with conflicting theories of action. With PET imaging we showed that modafinil occupied the dopamine and norepinephrine transporters in living primate brain, a finding we and others corroborated in human subjects. The study illuminated a plausible pharmacological target of modafinil, mechanisms for abuse liability, the potential of neglected low affinity compounds as medications, and invigorated interest in this class of transport inhibitors as medications for addiction and other applications. d. Methylphenidate formulation to reduce abuse liability. A collaborative PET imaging study showed that a slow release formulation of the ADHD drug methylphenidate entered

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human brain more slowly, occupied fewer transport sites, and engendered lower “likeability” than the conventional rapid onset formulation. The findings demonstrated that pharmacokinetic properties are critical determinants of drug reward of this dopamine transporter drug. e. MDMA medications: a potential role for norepinephrine transport inhibitors. Our laboratory demonstrated that MDMA is a potent norepinephrine transporter blocker in vitro followed by demonstrating that a norepinephrine transport (NET) inhibitor blocked MDMA- induced cognitive impairment and stimulant effects in primates. Our speculation that NET inhibitors may block psychoactive effects in human MDMA users was subsequently corroborated in human studies by a drug company. The research identified the previously unrecognized role of norepinephrine in MDMA pharmacology. f. Chemotherapy. As a post-doctoral fellow, I developed an assay for, discovered asparagine synthetase in Novikoff hepatoma tumors and hypothesized that tumors that do not express this enzyme would be susceptible to asparaginase treatment. Subsequently, the laboratory showed that a wide range of tumors unable to express asparagine synthetase were susceptible to asparaginases. The findings were critical for developing asparaginase therapy, a current indispensable treatment for acute lymphoblastic leukemia in children (Seeman P. Discovery of why acute lymphoblastic leukaemia cells are killed by asparaginase: Adventures of a young post-doctoral student, Bertha K Madras. J Med Biogr. 2013 Sep 27;22(2):90-92).

2. Neurobiology of psychostimulant drugs of abuse and drug discovery a. Cocaine acute effects and neuroadaptation. We developed novel assays for cocaine binding sites/dopamine transporter in primate striatum. Collaborative behavioral studies subsequently showed that the transporter was a principal, immediate target of cocaine in the brain. Cocaine also accumulated in other cortical and subcortical structures, leading to the view, corroborated by others, that cocaine’s immediate effects extended beyond the basal ganglia. Repeated cocaine exposure in primates resulted in neuroadaptation, manifest by motor responses and correlating with induction of regionally and compartmentally specific striatal activation patterns. Based on these studies, we postulated that axonal guidance molecules (AGMs), critical for development of neural circuitry and neuroadaptive changes in the adult brain conceivably contribute to neuroadaptation. The hypothesis was corroborated by the discovery that dopamine receptor agonists directly modulated gene expression of AGMs implicated in development of mesocortical dopamine circuitry during adolescence, conceivably linking cocaine blockade of the dopamine transporter to activation of dopamine receptors and subsequent modulation of AGMs. b. Cocaine and psychostimulant addiction: medications development. In seeking novel candidate medications for cocaine addiction, in collaboration with a medicinal chemist Dr. Peter Meltzer resulted in the design of over 600 novel compounds as candidate cocaine medications, and resulting in 19 patents. Among the seminal discoveries was a counterintuitive discovery of potent compounds that contained no amine nitrogen in their structures. The finding radically revised conventional dogma of structural requirements for drugs to produce pharmacological effects. c. Novel psychostimulant targets: trace amine receptor1. Decades ago trace amines were implicated in neuropsychiatric disorders and addiction. In seeking immediate and downstream novel targets for medications development, we cloned the rhesus monkey trace amine receptor1. Phenethylamine (PEA) and amphetamines directly activated the receptor

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and the dopamine transporter enhanced its activity. Intriguingly, cocaine and therapeutic drugs that block dopamine transport via the transporter also blocked PEA transport, implicating the trace amine receptor1 and trace amines in psychostimulant or therapeutic drug response.

3. Primate models of genetically-based human neuropsychiatric disorders a. Genotyping/phenotyping of primates. In seeking to clarify whether nonhuman primates could serve as naturalistic models for genetically-based human neuropsychiatric disorders, the Division cloned and sequenced primate receptors and transporters that comprise major targets of psychotherapeutic drugs in human brain (e.g. opioid, dopamine, cannabinoid receptors, monoamine transporters). Based on the high homology of gene and protein sequences between humans and nonhuman primates, we further investigated the potential role of primates as naturalistic models of genetically-based human neuropsychiatric disorders. b. In support of a primate genetic model of ADHD, 3’-UTR polymorphisms in the nonhuman primate dopamine transporter gene corresponding to the 3’-UTR polymorphisms of the human genome, altered dopamine transporter expression levels and were modestly associated with activity levels. c. The primate may conceivably model a human mu opioid receptor single nucleotide polymorphism (SNP), associated in some studies with human heroin addiction. A functional SNP in the coding region of the primate receptor corresponded to the functional SNP in the human mu opioid receptor, detected by others. The association of this SNP with altered beta- endorphin affinity, endocrine function and behaviors, analogous to humans, provides support for developing primate models of human genetic neuropsychiatric disorders.

4. Adolescent susceptibility to addiction, cognitive impairment a. Differences in adolescent and adult response to addictive drugs: MDMA and methamphetamine. The adolescent brain is not fully developed and undergoes a continuum of changes until 25 years of age. Young adolescents are more susceptible to psychostimulant addiction and other adverse consequences than adults. As axonal guidance molecules play critical functions in neuroadaptation and in brain development, the lab is interrogating the hypothesis that psychostimulants regulate these genes/proteins differently in the adolescent and adult brain. Our accumulating data have shown distinct differences in rodent adolescent and adult gene expression profiles of guidance/cell adhesion molecules/vascular endothelial growth factors, following exposure to MDMA or methamphetamine. These differences may illuminate why addiction and cognitive impairment are more prevalent among early drug use initiators. b. Differences in adolescent and adult response to addictive drugs: marijuana. Young adolescents are more susceptible to marijuana addiction than adults. Our pilot data show that rodent adolescent and adult expression profiles of guidance/cell adhesion molecule genes differ in specific brain regions following exposure to THC, the most active constituent of the marijuana plant.

5. Report of Research, other: SBIRT effectiveness in federally funded programs

During service as deputy director for Demand Reduction in the White House Office of National

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Drug Control Policy, I developed sustainable initiatives to reduce drug demand and improve treatment quality in our nation, including new CPT® codes for alcohol/drug screening and brief interventions. I assembled a team of NIDA and SAMHSA investigators to compile the federal data and published the results of a large multi-center Federal program for screening, brief interventions, referral to treatment (SBIRT) for illicit drug use and alcohol. Our report showed that 22.7% of 459,599 patients screened positive for problematic substance use at multiple healthcare sites. Those offered a brief or more intensive intervention reported significantly reduced drug use and heavy alcohol use six months later. The manuscript has received 140 citations since its publication in 2009.

Funded Activities

Includes grants only if Madras is PI or co-PI. Excludes a number of other grants in which Madras served as a co-investigator; these were not tracked.

Years Source PI or Grant title other 1979- Medical Research Co-PI Anticonvulsant drugs and receptors 1982 Council, Canada 1979- Clarke Institute of PI C.I.P. Research Fund 1980 Psychiatry 1980 Ontario Mental PI Liquid scintillation spectrometer Health Foundation (OMHF) 1981- Banting Research PI Dopamine receptor pharmacology 1982 Foundation 821-111 1981- OMHF PI Isolation of brain dopamine receptors 1984 1981, OMHF Co-PI Major equipment grants (2) 1982 PI: Tang 1981 Bickell Foundation PI Dopamine receptors 3-353-284-90 1984- OMHF #902 PI Purification of brain dopamine receptors 1986 1987 Milton Fund, HMS PI Dopamine receptors 1988 NIH-R43 PI-subcon. Phase I High affinity probes for the cocaine receptor DA05648 1987- NIH-R43 PI-subcon. Phase I. Synthesis of fluorescent probes for 1988 NS25870 monitoring brain receptor distribution and mobility 1987- NSF PI-subcon. Phase I. Selective dopamine D-1 and D-2 fluorescent 1988 ISI-8760870 probes 1989- NIH-R43 PI-subcon. Phase II. Synthesis of fluorescent probes for 1991 NS25870 monitoring brain receptor distribution and mobility 1989- NSF PI-subcon. Phase II. Selective dopamine D-1 and D-2 fluorescent 1991 ISI-8760870 probes

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1989- NIH-R01 Co-PI Molecular probes for specific cocaine recognition sites 1992 DA06303 1990 Parkinson’s PI Imaging agents for Parkinson’s disease Disease Foundation 1992- NIH-R01 PI Molecular Probes for Specific Cocaine Recognition 1997 DA06303 Sites 1992- NIH-R25 PI Society for Neuroscience Partnership for Science 1994 DA08178 Literacy 1994- NIH-R01 PI Cocaine and Cocaine Substitutes 1999 DA09462 1992- NIH-R01 PI Novel Markers and Drug Therapies for Parkinson's 1997 NS 30556 Disease ’98 - NCE 1992- Boston Life PI Imaging agents for Parkinson’s disease 1995 Sciences, Inc (BLSI) 1994- NIH-NIMH PI Research training - biological sciences 1999 T32 14275 ‘00 - NCE 1994- NIH-N01 PI- Medicinal chemistry - synthesis of potential treatment 1997 DA4-8309 subcont. agents for cocaine addiction 1994- NIH-R29 PI- Potent and selective probes for the dopamine 1999 DA08647 subcont. transporter 1995- NIH-R43 PI- Design of a novel cocaine antagonist 1996 DA10144 subcont. 1996- BLSI PI Development of a technetium labeled SPECT imaging 1999 agent for the dopamine transporter 1997- NIH-R01 PI Molecular probes for Cocaine Recognition Sites 2002 R37 (’98-) DA06303 1997- NIH-R01 PI Evaluation of Novel Cocaine Medications 2002 DA11558 1997- NIH-K02 PI Research Scientist Award 2002 DA00304 Cocaine-Molecular targets, brain imaging and medications 1998- NIH-N01 PI- Medicinal Chemistry-Synthesis of Potential Agonists 2002 DA7-8077 subcont. DA7-8081, 8825 1998- NIH-R01 PI- Discovery of novel pharmacotherapies for cocaine 2005 DA11542 subcont. addiction 1999- BLSI PI A study of Parkinson’s disease therapeutics 2002 ‘02 - NCE 1999- NIH-R01 PI Novel Markers and Drug Therapies for Parkinson’s

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2003 NIH-NS30556 Disease

2002- BLSI PI Evaluation of inosine in primates 2003 2002- NIH-N01 PI- Medicinal chemistry – Synthesis of potential 2005 DA7-8155 subcont. treatment agents for cocaine addiction 2002- NIH-R01 PI Evaluation of Novel Cocaine Medications 2006 DA11558 2002- NIH-R37 (MERIT) PI Molecular probes for Cocaine Recognition Sites 2006 DA06303 2002- NIH-K05 PI Senior Research Scientist Award 2009 DA15305 Cocaine-Molecular Targets/Brain Imaging and LOA: Medications 2006- 2008 2010- NIH-DA029790 PI Methamphetamine and neurodevelopment in 2012 adolescent and adult mice

Harvard Medical School Courses 1992-2005 Course director, developer, lecturer, tutor, Advanced Biomedical Sciences (ABS) elective course; Substance Abuse; Addictive processes; (not offered in 1994, 2005-) Harvard Medical School 4th year students. 1 month elective block course, 1 month preparation; 50 hours (approximate) contact time. Still listed 1996-1998 ABS Course; Pain; Lecturer and tutor; Harvard Medical School 4th year students (4-6/year); 2.5 hours (approximate) contact time. 1989, 1990 HST-130; Neuroscience Harvard Medical School/MIT, MD/PhD students (30- 40/year); Lecturer; 6 hours (approximate) contact time.

Graduate Medical Courses HMS

2009 Longwood Psychiatry Grand Rounds (SBIRT), BIDMC, Boston, MA 2008 Medical Grand Rounds (SBIRT), Brigham and Women’s Hospital, Boston, MA 2006 Psychiatry Grand Rounds (SBIRT), MGH, Boston, MA 2005 Neuroscience Combined Grand Rounds, Massachusetts General Hospital 2005 HMS Residents in Addiction, the Neurobiology of Addiction 2004 Grand Rounds, Translational research, Massachusetts General Hospital, Boston 2003 HMS Residents in Addiction, the Neurobiology of Addiction 2002 HMS Residents Psychiatry Day. McLean Hospital Addiction as a brain disease: What is the evidence? ‘97-‘02 Psychostimulants; Zinberg Fellowship Lectures, Harvard Medical School. 1998 Neuroscience research seminar; 30 fellows. 1998 Cocaine addiction and Parkinson’s disease; new insights with novel probes Prebaccalaureate students and fellows

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Curriculum Vitae Bertha K. Madras

1997 The Neurobiology of Drug Addiction, A Unifying Theory? Grand Rounds Longwood Medical Area, Dept. of Psychiatry.200 residents, fellows, faculty 1997 Molecular basis of drug addiction seminar, PGY III Lecture series, Cambridge Hospital 1997 Dept. Psychiatry Teaching Day seminar; HMS Psychiatry residents, 8 residents. 1997 Neurobiology of addiction, Lecture series, Cambridge Hospital; Psychiatry residents (PGY3) 1997 The dopamine transporter; a window on dopamine neurons? Seminar series, McLean

1996 Neurobiology of stimulant drugs Division on Addictions, HMS 1995 New imaging techniques; the potential for attention deficit disorder

faculty 1995 Imaging the Dopamine transporter, Massachusetts General Hospital PET Lecture Series; 30 residents, fellows, faculty 1994 Cocaine; a nefarious role for dopamine? Dept. Anesthesiology, Beth Israel Hospital, residents, fellows 1994 Dopamine and drug addiction, Dept. Anesthesiology Residents, Beth Israel Hospital 1993 Neurobiology of Drug Abuse; an overview, Massachusetts Mental Health Center, Boston, MA (PGY-3) 1994 “The Neurobiology of Substance abuse” Norman E. Zinberg post-graduate program in substance abuse, MMHC Preparation time; 3 hours; contact time; 1.25 hours 1993 Neurobiology of Substance Abuse, Psychopharmacology Lecture Series, Massachusetts Mental Health Center 1992 The Dopamine Transporter, Massachusetts Mental Health Center; Psychopharmacology series 1991 Dopamine receptors and transporters Beth Israel Hospital, Psychiatry Grand Rounds

Local Invited Presentations

2009 Medications for psychostimulant drugs of abuse: old and new targets, Center for Drug Discovery, Northeastern University, Boston, MA, May 20 2005 Current trends in drug abuse research symposium, Northeastern University Symposium, Boston, MA March 2005 Neuroscience Grand Rounds, MGH, Boston, MA, March 2003 Grand Rounds, Translational research, Massachusetts General Hospital, Boston, MA, Nov 2002 MIT, Cambridge, MA Illicit Drugs—What are the Facts?: examining the neurobiological effect of drugs on the brain and long-term effects of drug use. Jan 2002 CME Addictions. Boston, MA 2002 Addiction as a brain disease: What is the evidence? Harvard Residents Psychiatry Day. McLean Hospital, Belmont, MA, Jan 2001 Changing your mind: drugs in the brain. Winthrop House, Harvard University, Cambridge, MA, Sept 2001 Zinberg Training program in Addictions, HMS, Oct 2001 The Education Cooperative Harriet Goldin High school Neuroscience biopsychology,

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NERPRC, Jan 2000 Clinical relevance of the dopamine transporter. MIT, Cambridge, MA April 3 2000 Clinical relevance of the dopamine transporter. MIT, Cambridge, MA April 3, 2000 Psychiatry Grand Rounds, Lahey Clinic, Burlington, MA, Oct 24 2000 Zinberg Center for Addiction Studies, HMS, Oct 2000 Educational Cooperative high school students, NERPRC, Nov 1999 N. Zinberg training Program in Addictions, HMS, Boston, MA, Oct 1999 Harvard Medical Community Seminar for Science and Medical Writers, Boston, MA, Oct 1999 A.P. Biology students, Arlington, H.S., NERPRC, June 1999 Brain imaging agents. Center for Integrative Medicine and Innovative Technology (CIMIT), MGH, Boston, MA, Mar 1999 National Association of Science teachers, NERPRC, Mar 1997 The dopamine transporter; a window on dopamine neurons? McLean Hospital, Belmont, 1998 Consortium of High School Biology students, NEPRC, Oct. 1998 Cocaine addiction: Research approaches. Division on Addictions Roundtable, Boston, Apr 1997 Grand Rounds, Tewksbury Hospital; 20 - 30 residents, staff 1997 Imaging the dopamine transporter, Dept. Radiology Seminars, Brigham and Women’s Hospital. 30 residents, fellows, faculty 1996 The life of a scientist, Daughters at Work Day, HMS, 30 people parents, children, faculty, staff 1996 Brain research, the present, the future. Harvard School of Public Health summer project for minority students. NEPRC 1998 Seminar series for pre-bacclaureate summer program trainees. NEPRC 1996 Neuroscience Research in nonhuman primates. Framingham State College biology students, NEPRC. 1996 Substance abuse and Brain Imaging; the promise of research. National Society for Spinal Cord Injury. Evening at Harvard Medical School, Boston, MA 1996 Neuroscience research in primates. Tufts University graduate students. NEPRC 1996 Exploring and exploiting the dopamine transporter. Organix Inc. Woburn, MA 1996 Drugs in the brain; how research can inform us. Lincoln-Sudbury students. NEPRC 1995 Imaging the Dopamine transporter. Massachusetts General Hospital PET Lecture Series, MGH, Boston, MA 1995 Three lectures on research. Lincoln-Sudbury School biology class, NERPRC 1995 The biology of substance abuse. Massachusetts Society for Medical Research, Waltham, MA 1995 New imaging techniques; the potential for attention deficit disorder Dept. Radiology, Massachusetts General Hospital, Boston, MA 1995 Neuroscience research. Framingham State College biology students, NERPRC 1994 Non-Federal Funding Sources, Office for Academic Careers, Harvard Medical School, Grant-writing Workshop, Boston, MA; fellows, junior faculty 1994 Cocaine; a nefarious role for dopamine? Dept. Anesthesiology, Beth Israel Hospital, Boston, MA 1994 “Plant products; the Great Brain Impostors” Eastern Association of Chemistry Teachers, Framingham State College, Framingham, MA 1994 Office for Academic Careers, Harvard Medical School, “Non-Federal Funding Sources”. Grant-writing Workshop, Boston, MA

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1993 Drugs and the Brain. National Association of Biology Teachers, Southborough, MA 1992 Development of PET imaging probes for cocaine receptors on dopamine nerve terminals NERPRC seminar series 1992 Brain dopamine systems; relevance to schizophrenia, Parkinson’s disease and cocaine abuse. Framingham State College, Framingham, MA 1992 Cocaine abuse; a nefarious role for dopamine. M.I.T. Cambridge, MA 1991 Imaging probes for cocaine recognition sites associated with the dopamine transporter, Dana-Farber Cancer Institute, Boston, MA 1991 Imaging probes for cocaine recognition sites associated with the dopamine transporter. Dana-Farber Cancer Institute, Boston, MA 1991 Cocaine receptors and cocaine abuse. Tufts University, Boston, MA 1991 University of Pennsylvania, Lecture for Residents, “Cocaine Abuse” 1988 Dopamine and cocaine receptors in primate brain, McLean Hospital, Belmont

Continuing Medical Education (CME)

2014 CME, Neurobiology of Addiction, Division on Addictions, Cambridge Health Alliance, Boston, MA (to be delivered) 2013 CME, Screening, Assessing, and Treating Unhealthy Substance Use at Hospitals, Division on Addictions, Cambridge Health Alliance, Boston, MA 2011 “Update in Neuroscience for the Non-neuroscientist: Clinical Information”. CME Addictions Course, Harvard Medical School, Boston, MA. 2011 “The Science of Addiction: Drugs, Brain, and Behavior” at Harvard Medical School and Department of Psychiatry at Cambridge Health Alliance Annual “Treating the Addictions” Conference, CME, Boston, MA. 2010 CME, Toward systematic screening brief intervention and referral to treatment, in Addiction Medicine: Prescribing during the new era of SBIRT (Screening, Brief Intervention, and Referral to Treatment). HMS Division on Addictions, Boston, MA 2010 CME Conference, sponsored by McLean Hospital, Boston, MA 2008 ACCME Videotape for ACCME website - Screening, brief intervention, referral to treatment, Chicago, IL 2008 Keynote, ACCME Summit, Chicago, IL 2006 Keynote, Accreditation Council For Continuing Medical Education (ACCME) conference, Chicago, IL 2005 (2 CME invitations declined) 2005 CME: [25th Anniversary] Addiction Neuroscience in the new millennium. Boston, MA 2002 CME: Neuroscience of Addiction in the 21st century, Boston, MA 2000 CME Conference, Addiction Medicine, Boston, MA; “The Neuroscience of addiction.” 1998 CME, Addiction Medicine, Harvard Medical School, Boston, MA; “Neurobiology of addiction.” 1997 CME, Addiction Medicine, “Neuroscience of addiction.” Harvard Medical School, Boston, MA. 1996 CME, “Biological perspective on cocaine addiction.” Annual Addiction Symposium, Cambridge Hospital, Boston, MA

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1992 “Addiction medicine; Update on basic mechanisms and genetics of addiction.” 1992 CME; New Pathways in General Medical Education, Panelist 1991 CME; CNS receptors and imaging probes; 1990 Basic neuropharmacology course, American Society of Neuroradiology

Advisory/Supervisory responsibilities 22 advanced or post-doctoral students 28 pre-baccalaureate students 1 pre-baccalaureate student senior thesis (2014) Service on 14 Ph.D. or M.Sc. thesis committees

Local Teaching, Leadership Role

Course organizer, developer, director, Substance Abuse: Addictive Processes. Advanced Biomedical Sciences elective Course, for 4th year HMS students ABS 521.M.O 1991-2005. This course consistently recruited in excess of the minimal number of students and generated high student ratings. It provided medical school students with an overview of substance abuse biology, medical consequences and pathology, diagnosis and treatment. The course offered opportunities to interview patients undergoing withdrawal and treatment, and innovative presentations by (a) members of the Board of Registration in Medicine, MA to outline responsibilities of a medical license regarding substance abuse issues and other related topics, patient boundaries, (b) representatives from the Physicians’ Health Services to introduce recognition of impairment in colleagues and self, and how to respond to this, other problems, (c) representative of the Drug Enforcement Agency, (d) research scientists in site visits to research facilities at HMS hospital affiliates. The format of the course was didactic lectures, roundtable discussions, student presentations and student debates on controversial topics.

Advisees/Trainees (partial list)

Training Past Pre Period Trainees or Post Current Position 1981-1982 Alan Davis Post-doc Industry 1981-1983 Betty Chan Pre-doc MD 1981-1982 Maxine Okazaki Pre-doc PhD, Duke University faculty member current: Medical Writer 1989-1990 Donald Canfield Post-doc DVM, Faculty, UC Davis Primate Center 1989-1992 Mark Kaufman Post-doc Associate Professor, McLean Hospital, HMS 1991-1993 Michele Fahey Pre-doc DVM, Assistant Professor, HMS

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Training Past Pre Period Trainees or Post Current Position 1988-1996 Christine Pfaelzer Pre-bacc MD psychiatrist 1989-1996 Tracy Duffy students DVM Frank Vittimberga, Jr MD surgeon, TX Mikyung Kwah Physician Joanne Bilanceri Azita Hamedani MD, MPH, Asso. Pro. Chief, ER Medicine Lindsay Mains MD 1997-2013 Ann Trafton (Science writer) Jacob Bendor PhD (Rockefeller University) Ava Meyerhoff MD Tony Wei MD Soha Ahmed Heather Munro Matthew Evans Courtney Norton Martha Konar Sophia Schippers Alyssa Waite Catherine Summer Luke Hawes Anuradha Phadke (MD) Liz Calder Ashley-Kay Fryer PhD Student, HBS, Harvard University Maurine Baun Graduate student Anjali Rafsanjani Brad Constant Medical school Tim Walsh Medical school Joshua Zimmer Pre-med 1996-1997 Justine Meschler Pre-doc MD, PhD research Anesthesiologist Medical Center of Central Georgia, GA 1997 Francis A Clarkson Pre-bacc MD, Emergency Medicine, Palmetto Health Hospital, SC Summer, Christina Barr Post-doc PhD Investigator, Laboratory of Clinical and 1998 Translational Studies and Laboratory of Neurogenetics, NIAAA-NIH 1991-1993 Larry Gracz Post-doc Assistant Professor of Biochemistry Mass College of Pharmacy 1996-1999 Richard DeLa Garza II Post-doc Professor, Baylor College of Medicine 1997-2004 Gregory Miller Instructor Associate Professor, Harvard Medical School

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Training Past Pre Period Trainees or Post Current Position 1998-2000 Martin Goulet Post-doc Principle Scientist, Alnylam Pharmaceuticals 1999-1999 Ekaterina Tsaioun Post-doc President, Pharma Launcher 1999-2002 Servet Yatin Post-doc President and CEO, Tangi Learning Center Professor of Chemistry, Quincy College 2001-2002 Jeffrey Brown Post-doc Senior Research Investigator, Bristol-Myers Squibb 2003-2004 Danqing Xiao Post-doc Assistant professor, Regis College, MRI Technologist, McLean Hospital 2003-2005 Christopher Verrico Post-doc Assistant Professor, Baylor College of Medicine-Menninger Department of Psychiatry and Behavioral Sciences 2003-2005 Amy Jassen Post-doc Scientist-analyst, consultant, Alkermes 2005-2006 Zhicheng Lin Post-doc Assistant Professor Psychiatry, McLean Instructor Hospital, HMS

Non-local Invited Presentations

Partial list of invited lectures. Scheduled presentations at scientific meetings are not listed

1973 Invited Lecture Glucose regulates free and unbound tryptophan. McGill University, Montreal, Canada 1973 Invited Lecture Insulin, glucose, free fatty acids and free and unbound plasma tryptophan. Peter Bent Brigham Hospital, Boston, MA 1973 Invited Lecture Regulation of brain tryptophan. NIMH, St. Elizabeth’s Hospital, Washington, DC 1973 Invited Lecture 5-Hydroxytryptamine (Serotonin) Symposium, Cagliari, Italy 1980 Invited Lecture Epilepsy research; in search of new targets and medications Epilepsy Foundation, Toronto, Canada

1981 1981 Invited Lecture Dopamine receptors. Canadian College of Neuropsychopharmacology, Toronto, Canada 1981 Invited Lecture D2 dopamine receptors and schizophrenia, Office of Research Administration, University of Toronto, Toronto, Canada 1981 Invited Lecture D2 dopamine receptors and schizophrenia: partial purification and pharmacology. Massachusetts General Hospital, Boston, MA 1981 Invited Lecture New trends in schizophrenia research. Canadian Friends of Schizophrenics, Toronto, Canada 1981 Public lecture “Drugs in the Brain”; York University, Toronto, Canada

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1982 1982 Invited Lecture Current schizophrenia research: how do anti-psychotic drugs act? Canadian Friends of Schizophrenics, Toronto, Canada 1982 Invited Lecture D2 dopamine receptors. International Symposium of CNS Receptors, Strasbourg, France 1982 Invited Lecture Neurotransmitter and Receptor update course, Congress of Neurological Surgeons, Toronto, Ontario 1984

1984 Invited Lecture Research and brain diseases. The Winsor School, Boston, MA 1988 Jan Invited Lecture Dopamine and cocaine receptors in primate brain. McLean Hospital, Belmont, MA, Nov Invited Lecture Dopamine receptors in three regions of monkey brain. Schering Corp., Bloomfield, NJ Dec Invited Lecture Cocaine binding sites in non-human primate brain; relevance to behavioral effects of cocaine. University of Pittsburgh, Pittsburgh, PA 1989 Jan Invited Lecture Recent advances in schizophrenia research. The Winsor School, Boston, MA Jul Invited Lecture Cocaine receptors in primate brains. National Institute on Drug Abuse, Baltimore, MD 1990 Jan Invited Lecture Novel probes for cocaine receptors. National Institute of Mental Health Neurosciences Center, Washington, DC Jan Invited Lecture Cocaine receptors; from binding to behavior. Univ. of Toronto, Toronto, Canada Mar Invited Lecture Mechanisms of cocaine abuse; a nefarious role for dopamine? Addiction Research Center, Univ. of Pennsylvania, Philadelphia, PA Apr Testimony to U.S. Congress, House of Representatives Appropriations Committee on Labor, Health and Human Services, Education and related agencies, on behalf on NIH-sponsored Regional Primate Research Centers Jun Invited Lecture Cocaine receptors. Clarke Institute of Psychiatry, Toronto, Canada Jun Invited Lecture Cocaine receptors and cocaine abuse. National Institute of Mental Health, Bethesda, MD, Jun Discussant “Elevated D2 dopamine receptor concentrations in 26 schizophrenia patients “Research Scientist Development Awardees Conference, National Institute of Mental Health; Chevy Chase, MD Sep Symposium Basic Neuropharmacology Course. Annual Meeting of American Society of Neuroradiology, Chicago, IL Oct Invited Lecture High affinity probes for cocaine receptors. Northeastern Section, American Chemical Society, Boston, MA Oct Invited Lecture CNS Symposium; Dopamine receptors and transporters. Boehringer-

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Ingelheim, Burlington, Ontario 1991 Oct Invited Lecture Strategies for Schizophrenia; role of selective dopamine antagonists; the Pathophysiology of schizophrenia; the dopamine hypothesis. Astra Symposium, Toronto, Ontario Oct Invited Lecture Strategies for Schizophrenia; role of selective dopamine antagonists; the Pathophysiology of schizophrenia; the dopamine hypothesis. Astra Symposium, Montreal, Quebec Nov Invited Lecture Drugs and the Brain. The Winsor School, Boston, MA 1992 Feb Invited Lecture Novel cocaine receptor probes; applications for cocaine abuse/neurodegenerative disorders. SUNY, Stony Brook, NY Mar Invited Lecture Novel cocaine receptor probes; potential applications for cocaine abuse. National Institute on Drug Abuse (NIDA), Rockville Pike, MD Mar Invited Medicinal Chemistry Workshop. Medications Development Branch Discussant (NIDA), Rockville Pike, MD June Symposium Cocaine congeners as probes for cocaine receptors/Parkinson’s disease. speaker American Nuclear Society, Boston, MA June Symposium PET imaging probes for cocaine recognition sites. NIDA Symposium, Lecture Keystone, CO June Symposium The dopamine transporter; a target for cocaine and a marker for Lecture Parkinson’s disease. 7th International Catecholamine Symposium, Amsterdam, Holland Sept Invited Lecture Dopamine receptors and schizophrenia: The significance of D1 to D5.Symposium; New Developments in the Understanding and Treatment of Schizophrenia. London, England Oct Invited Lecture Novel PET Imaging Ligands for cocaine recognition sites. PET/SPECT in Medications Development, NIDA, Rockville, MD Nov Invited Lecture Drugs and the Brain: Where Does Cocaine Act? Drug Policy Foundation, Washington, DC. Dec Symposium Cocaine abuse; basic mechanisms and therapeutic approaches. The lecture Biochemical Society Annual Symposium, London England 1993 Feb Invited Lecture Cocaine Abuse; basic mechanisms and therapeutic approaches. Massachusetts Psychiatric Society, Committee on Addiction, Cambridge, MA May Invited Lecture Cocaine Recognition sites in primate brain; in vitro and in vivo. NIDA Technical Review, Rockville Pike, MD Oct Invited Lecture Imaging the dopamine transporter. Brookhaven National Laboratory, Upton, NY Nov Invited Lecture “How do drugs act in the brain?” American Chemical Society Symposium, Museum of Science, Boston, MA

1994

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Apr Invited Lecture Brain dopamine systems; targets for drug development. Dept. of Psychology, Neuroscience and Behavior program, U. Mass, Amherst, MA Apr Invited Lecture Novel imaging agents for the dopamine transporter. Mallinckrodt Medical, St. Louis, MO Jun Invited Lecture Novel probes for imaging the dopamine transporter Symposium; XIXth Collegium International Neuropsycho-pharmacologium (CINP) Congress, Washington, DC Jul Symposium The dopamine transporter and cocaine abuse; differences between Lecture cocaine and other dopamine transport inhibitors. Dopamine ‘94 Symposium, Quebec City, Quebec Jul Symposium Basic and clinical applications of the dopamine transporter speaker and co- International Union of Pharmacology (IUPHAR) Symposium, Montreal, chair Canada Jul Invited Lecture Cocaine research in the 1990’s. Robert Wood Johnson Foundation, Princeton, NJ Jul Invited Lecture “The brain, the mind, and the heart in chemical dependency” Allied Health Professionals, Edgewood Hospital, St. Louis, MO Jul Invited Lecture The neurobiological basis of substance abuse. John H. Kendig Neuroscience Lecture, St Louis, MO Nov Invited Plenary Imaging the dopamine transporter. Plenary lecture, International Movement Disorder Congress, Orlando, FL Nov Chair of Session Society for Neuroscience Annual Meeting, Orlando. FL Dec Invited Lecture Imaging the dopamine transporter in human brain Symposium and Panel speaker, Amer. Coll. Neuropsychopharmacol. San Juan, Puerto Rico 1995 May Invited Lecture SPECT imaging of the dopamine transporter. Symposium on dopamine transporter imaging, Copenhagen, Denmark May Invited Lectures I. The development of an exhibit. II. The molecular targets of cocaine in brain Medical College of Virginia, Richmond, VA June Co-Chair Altropane, a novel SPECT imaging agent for cocaine binding sites on the Symposium Dopamine Transporter. College on Problems of Drug Dependence, Scottsdale Session AZ June Invited Lecture Highlights of NIDA-sponsored exhibit on Changing your mind; drugs in the brain. College on Problems of Drug Dependence, Scottsdale, AZ. Jul Symposium The Dopamine Transporter. FASEB Summer Conference on Drug Abuse, Lecture Copper Mountain, CO. Sep Invited Lecture Shattering the image. Drugs in the brain. Healthy Women 2000 Conference. HHS Symposium on Capitol Hill, Washington, DC Sep Invited Lecture Distinguished Scientist Lecture Series; Food and Drug Administration, National Center for Toxicology Research, Jefferson, AK. Cocaine targets in brain. 1996 Feb Invited Lecture Exploring and exploiting the dopamine transporter. NIH, NIDDK, Bethesda,

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MD Feb Invited Lecture The making of a CD-ROM and Museum exhibit, Changing your mind; drugs in the brain. NIH, Bethesda, MD Apr Invited Lecture Novel insights with novel tropanes. NIDA workshop, Washington, DC Apr Invited Medication for drug abuse; effectiveness and challenges. tele-lecture to New Teleconference England sites. Research to Practice Series; Impact of chemical abuse on the Lecture Nervous System; implications for clinical practice, Cambridge, MA May Invited Lecture Changing your Mind; drugs in mature brain. American Association of Retired Persons (AARP), Washington, DC May Plenary The Neuroscience of Drug Abuse. Massachusetts College of Pharmacy, Lecture Boston, MA June Symposium Changing your mind; drugs in the brain. First International Conference on speaker Drug Research, Prevention, Treatment, Organized Crime, Hassela, Sweden. June Invited Lecture The dopamine transporter; novel insights with novel drugs. Karolinska Institute, Stockholm, Sweden. June Chair Novel drugs reveal that nitrogen-based drugs are not essential for dopamine Symposium transport blockade. College Problems Drug Dependence, San Juan, Puerto Session Rico Aug Invited Lecture Control of radioactive materials; the view from three perspectives. Nuclear Regulatory Commission, King of Prussia, PA Sept Invited Lecture Dopamine transporter Imaging. Satellite Symposium of European Society Nuclear Medicine, Copenhagen, Denmark Dec Invited Lecture Cocaine medications. American College of Neuropsychopharmacology Study group (ACNP). San Juan, Puerto Rico moderator 1997 Jan Symposium Neurotransmitters, drugs and function of the brain. Danish Year of Speaker Brain, Odense, Denmark Mar Symposium The Neuroscience of Drug Addiction. Brain Awareness Week, St. Louis, Speaker MO Apr Invited Lecture Imaging the dopamine transporter. Brigham and Women’s Hospital, Boston, MA Apr Invited Lecture Novel drugs for monoamine transporters. IBC International Conference, Dopaminergic Disorders, Boston, MA Apr Invited Lecture Changing your mind; drugs in the brain. European Cities Against Drugs Symposium. Hulst, Holland Jun Symposium Imaging of brain receptors; development of probes. Society of Nuclear Speaker Medicine annual meeting, Symposium, Development of receptor-based radiopharmaceuticals for nuclear medicine procedures. San Antonio, TX. June Symposium Cocaine and opiate effects in the brain; immediate and long-term Speaker consequences. Second International Conference on drug abuse. Hassela, Sweden Sept Invited Lecture The Dopamine Hypothesis of Drug Addiction; Evidence For and Against. Massachusetts Psychiatric Society, Faculty Club, Harvard

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University, Cambridge, MA Oct Symposium Cocaine Targets in Primate Brain; Liberation from prosaic views. Speaker Society for Neuroscience, Satellite Symposium, New Orleans, LA Chair of Cocaine Targets in Primate Brain; Liberation from Prosaic Views. Dec Symposium Panel. American College of Neuropsychopharmacology, Hawaii. Session 1998 Feb Invited Lecture The dopamine transporter; new insights with novel drugs Bowman- Grey School of Medicine, Winston-Salem, NC Mar Invited Lecture Imaging the dopamine transporter; a window on dopamine neurons. NIH Workshop; Recent Advances in Neurodegenerative Disorders (Alzheimer’s and Parkinson’s Disease). NINDS, San Diego, CA Mar Invited Lecture Superintendents’ Working Group on Effective Prevention Curricula. Concord, MA. Apr Invited Lecture Understanding Drug Abuse and Addiction. The Neurobiology of Cocaine Addiction, NIDA Town Meeting, Boston, MA Apr Invited Lecture The Dopamine Transporter and Cocaine Abuse. Psychiatry Grand Rounds, Univ. of Michigan, Detroit, MI May Invited Lecture Supreme Judicial Court, Massachusetts, All Court Conference on Substance Abuse, Randolph, MA May Symposium Brain Imaging Studies of Substance Abuse. Carolinas Health Care speaker System Spring Symposium, Charlotte, NC May Invited Lecture Nonamines; A new generation of reuptake inhibitors? Yerkes Primate Research Center, Emory University, Atlanta, GA June Chair of College on Problems of Drug Dependence (CPDD), 60th Annual Session Scientific Meeting; Scottsdale, AZ Jul Symposium The stimulant domain on monoamine transporters. XXIst CINP Co Congress Speaker (International College of NNNeuropsychopharmacology), Glasgow, Scotland. Aug Lecture Neuroscience research at the Primate Center. Boston University School of Medicine; Dept. of Neurobiology and Anatomy, NEPRC Nov Seminar Imaging and the Primate model of Parkinson’s disease. R.W. Johnson Research Institute, San Diego, CA Nov Invited Detection of Parkinson’s disease by imaging the dopamine transporter. NEN Poster Session on Neurodegenerative diseases, Soc. For Neuroscience Annual meeting, Los Angeles, CA Dec Seminar Neurobiology of addiction, Committee for Supreme Judicial Court, Boston, MA. Dec Poster Non-amines, a new generation of monoamine reuptake inhibitors. ACNP meeting. 1999 Jan Invited The Neurobiology of Opiates and Stimulants. 2 lectures to police, speaker Uppsala, Sweden May Invited Dopamine transporters as a target of Drug development. The VIII speaker Symposium on Medical Applications of Cyclotrons Brain Imaging

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Symposium, Turku, Finland. Chair of session: PET in clinical drug development-perspectives. Presenter at session Jun Speaker College on Problems Drug Dependence Sep Invited Neurobiology of addiction. Drugs in the brain. St. Vincent’s Institute speaker of Medical Research, Melbourne, Australia Sep Invited Neurobiology of addiction. Melbourne Neuromuscular Research speaker Institute, Australia Sep Sole Faculty Science Coalition, presentations to United States Congress, Representative Washington D.C. (With HU President Neil Rudenstine) Harvard University Oct Chair, Session Soc. Neuroscience Annual meeting Oct Invited Soc. Neuroscience; Neuropharmacology social Speaker Oct Invited lecture Can neuroscience inform management? Harvard Business School, Boston, MA Oct Invited The Science of Drug Addiction, Symposium, San Patrignano, Italy, speaker Dec Invited ADHD research. National Institute of Mental Health workshop on speaker Attention Deficit Hyperactivity Disorder, Bethesda, MD Dec 4 2000 Jan Invited Paradoxical effects of dopamine on activity. McLean Hospital, Belmont, speaker MA, Jan 11 Feb Invited Brain Imaging of the Dopamine Transporter in ADHD ADHD contributor Symposium, 6th Internet World Congress for Biomedical Sciences, 2000 Mar Invited New Frontiers in the Neurobiology of Addiction. Addiction Medicine speaker Conference, “CME-HMS, Boston, MA. March 3 Apr Invited speaker The dopamine transporter: a window on dopamine-related neuropsychiatric disorders? St. Louis University, St. Louis, MO. April 4 Apr Keynote Changing your mind: drugs in the brain. European Cities Against speaker Drugs Conference, Cork, Ireland; April 29 May Invited Hyperactivity: an example of translational research Massachusetts speaker Association of Science Supervisors. Boston, MA, May 4, 2000 May Invited Changing your mind: drugs in the brain. Flaishner Institute for speaker Judicial Studies, Cape Cod, MA, May 18 May Invited Biological relevance of the dopamine transporter. Millenium speaker Pharmaceuticals, Cambridge, MA, May 25 Jun Invited Receptors. American Society for Pharmacology Exp. Therapeutics speaker Boston. MA. June 4, 2000 Jul Keynote Cell Biology of Addiction. NIDA Symposium, Bethesda, MD, July 24 speaker Jul Invited The science of drug addiction; 2 lectures. Doctors For Life speaker Symposium, Pretoria, SA Oct Invited Neuroscience of Addiction. History of Addiction Symposium, Smith

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symposium College, Amherst, MA, Oct 13 Speaker Nov Invited Society for Neuroscience, press conference, Nov 6 speaker Nov Invited session Society for Neuroscience, Chair of Transporter session, Nov 6 chair Nov Invited Modeling of dopamine disorders in nonhuman primates. Tulane speaker University, new Orleans, LA Dec Speaker How drugs affect the brain. Renaissance weekend, Hilton Head SC

2001

Jan Invited speaker Modeling of dopamine disorders in nonhuman primates. Emory University, Atlanta, GA Jan 24 Feb Invited speaker The Biological Basis of Addiction. Tewksbury Hospital, Tewksbury, MA, Feb 8, 2001 Mar Invited speaker Changing your mind: drugs in the brain. Massachusetts Department of Health, Grand Rounds, Boston, MA Apr Symposium Relevance of the dopamine transporter to attention deficit speaker hyperactivity disorder. ADHD Symposium International Behavioral Neuroscience Society, Cancun, Mexico, April 27, 2001 May Invited speaker Prescription Drugs for Children. World Conference on Drugs, HNN, Visby, Sweden, June Invited chair Chair, Molecules and Genes Session, CPDD Aug Course director, Cold Spring Harbor Workshop speaker Sept Invited speaker MGH-NMR Center, Boston, MA Oct Invited speaker The science of substance abuse and the brain, An Insider’s view of addiction and treatment. Dept of Public Health, HMS Division on Addictions and the Judicial Institute, Boston, MA Oct Invited Annual substance abuse conference, Rutland, Vermont speaker Dec Keynote Renaissance weekend. Seminar: Drugs, the brain, the law speaker Charleston, SC Dec Invited NIDA Trafficking and addiction workshop, Washington, DC speaker

2002 Mar 2002 Invited speaker Changing your mind: drugs in the brain. Learning and the Brain Symposium Cambridge, MA Apr 2002 Invited speaker Primate models of dopamine-related neuropsychiatric disorders. NCRR meeting, Portland OR May 2002 Invited lecture Nonhuman primates models of drug abuse, addiction, treatment, ONDCP Scientific meeting. Boston, MA. Jun 2002 Invited chair CPDD session

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Jul 2002 Invited Dopamine 2002, Portland, OR symposium speaker Sep 2002 Invited Imaging molecular targets in the brain. Neuroimaging Symposium, symposium Athens Greece. speaker Sep 2002 Invited speaker World Forum: Drugs, Dependencies, Montreal Canada Oct 2002 Invited speaker Learning and the brain conference, Cambridge, MA Nov 2002 Invited speaker Annual Substance Abuse Conference for Physicians, Rutland Vermont Dec 2002 Invited sym Neurobiology of drug addiction. Symposium on gambling and other speaker addictions, Las Vegas, NV, Dec 2002 Invited panelist ACNP annual meeting ADHD and brain imaging, (BKM cancelled) 2003 May 2003 Invited speaker Changing your mind: drugs in the brain. Brooks School, MA Jun 2003 Invited Is addiction a brain disease? Vermont Judicial College (Vermont symposium Supreme Court Judges and other judges), VT speaker Jun 2003 Invited DAT Imaging: from SPECulative to SPECTacular, CPDD, Bal Harbor, FL symposium speaker Jun 2003 Invited The evolution of a collaboration: biologically speaking, it’s all in the symposium chemistry. CPDD, Bal Harbor, FL speaker Jul 2003 Invited keynote Changing your mind: imaging drugs in the brain. Center for Imaging speaker Processing in Education, Olympia, WA Aug 2003 Course Introduction to the Cell Biology of Addiction. Cell Biology of Addiction, director Cold Spring Harbor Laboratory Course, CSHL, NY. Speaker Sep 2003 Invited keynote Cocaine Neurobiology: from targets to treatment. Understanding the speaker Biology of Addiction. Tri-state Conference on Substance Use and Victimization (organized by the US attorney General Office in Vermont), Burlington, VT Sep 2003 Invited The Biology of Drugs and Addiction. International Police Conference speaker sponsored by the RCMP, Ottawa, Canada Sep 2003 Invited The biology and treatment of drug addiction. Office of National Drug speaker Control Policy (ONDCP). New England Governor’s Summit, Boston. MA Oct 2003 Invited Opiates session, SFN, New Orleans speaker Nov 2003 Invited The dopamine transporter and ADHD. Advancing the Neuroscience of speaker ADHD: an Educational and Scientific Conference, Boston, MA 2004 Mar Invited Changing your mind: drugs in the Brain, Brain Awareness Week, Drug speaker addiction. Pittsburgh, MA Mar 2004 Invited Monoamine transporters: relevance to neuropsychiatric disorders, U speaker Pittsburgh, Pittsburgh, PA Mar 2004 Invited 1. Parkinson’s Disease; 2. Changing your mind: drugs in the brain

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speaker Knight Science Journalism Fellowships at MIT, Cambridge, MA Mar 2004 Invited Biology of Addiction: Focus on the Adolescent. Learning and the Brain speaker Conference, Boston, MA May 2004 Invited 1. CME. Imaging the Brain in ADHD and Parkinson’s Disease 2. speaker Changing your Mind: Drugs in the Brain. Montana Prevention Association Annual Conference. Billings, MT May 2004 Invited The dopamine transporter: functional consequences and therapeutic speaker target. Genomics of Reward Symposium, Vanderbilt University, TN May 2004 Invited National Conference on Drugs of Abuse 1. Changing your mind: drugs speaker in the Brain. 2. Medications for Drug Addiction. 3. Neuroadaptation and drug addiction. 4. ADHD and three other presentations. Taipei, Taiwan, other cities. Jun 2004 Invited Changing your mind: drugs in the brain. Addiction Institute for speaker Journalists, San Juan, Puerto Rico Jun 2004 Invited Project Success; Careers in science, Countway Library of Medicine speaker (Angela Counts, a program for inner city students) Aug 2004 Invited Neurotransmitter transporters, Benzon Symposium, Copenhagen, symposium Denmark speaker Nov 2004 Invited The renaissance of trace amines/trace amine receptors. Temple speaker University, Philadelphia, PA Dec 2004 Invited ONDCP symposium, Washington, D.C. panelist 2005 Jan Invited NIDA-IRP Seminar, Addiction Research Center, NIDA, Baltimore, MD speaker Mar 2005 Invited Opiates and Neuroadaptation, American Pain Society, Boston, MA symposium speaker Mar 2005 Invited Poly-substance abuse in the workplace, Montreal, Canada symposium (required to decline) speaker Apr 2005 Invited Non-amines: are we too aminated? ASPET Symposium. San Diego, CA symposium speaker Apr 2005 Invited RCMP training in substance abuse, St. John’s Newfoundland speaker Apr 2005 Invited An overview of neuroscience research, Learning and the Brain speaker Conference, Boston, MA Jun 2005 Invited NIDA medications development workshop Orlando, FL (required to speaker cancel) Jun 2005 Invited chair CPDD Orlando, FL: 2 presentations Jul 2005 Invited BIDMC meeting (required to cancel) Jul 2005 Invited Monoamine transporter drugs: liberation from prosaic views. FASEB speaker summer conference. Saxtons River, VT (required to cancel) Jul 2005 Invited July 26-27 Medications Development Advisory Board (required to

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presenter cancel) Aug 2005 Invited mentor NIDA- K award mentoring meeting in DC (required to cancel) Aug 2005 Course Introduction and speaker Cold Spring Harbor Laboratory, Cell Biology director and of Addiction, (required to cancel) speaker Sep 2005 Speaker National Foundation for Women Legislators Annual Conference Sept 8-12; OTC pseudoephedrine (required to decline) Sept 8 Sep 2005 Speaker American Psychiatric Association Counsel on Addictions (required to decline) Sep 2005 NEPRC Moderator and speaker Oct 2005 Symposium The DAT gene: functional variation. World Congress of Psychiatric speaker Genetics workshop: genes and function (required to decline) Oct 14 Oct 2005 Keynote CME, Addictions Division on Addictions (required to decline) speaker Oct 2005 Keynote ASAM Course on State of the Art in Addiction Medicine Challenges in speaker translating science to services (required to decline) Oct 9 Nov 2005 Chair, session SFN: New perspectives on neurotransmitter transporter biology (required to cancel) Nov 2005 Presenter Integrity Gala, Introduction to recipient Theresa Branchek (required to cancel) Nov 19 Nov 2005 Symposium Great Issues in Medicine and Global Health, Addiction, sponsored by speaker Dartmouth Medical School (Community; Grand Rounds) (required to decline)Nov 17, 18 2006 Feb Grand rounds U Mass Medical Center (required to decline) Mar 2006 Grand rounds Boston University Medical Center (required to decline) Mar 2006 Invited CME on Addictions, Boston, MA (required to decline) speaker May 2006 Invited SBIRT, MGH Grand rounds speaker May 2006 Invited ADHD Symposium, American Psychiatric Association (required to speaker decline) Jun 2006 Invited plenary New England Institute of Addiction Studies Summer Program speaker U Conn. (required to decline June 6) June 2006 Invited Neuroscience of substance abuse (required to decline) MGH, June 9 speaker May 2006 Speaker Swearing-in ceremony, Eisenhower Executive Office Building, DC, May 16 May 2006 keynote National Association of State Alcohol/Drug Abuse Directors (NASADAD), Albuquerque, NM June 2006 Keynote Parents Corps, Washington, DC June 2006 Keynote National Association of Drug Court Professionals (NADCP), Seattle, WA June 2006 Invited Congressional testimony on methamphetamine, Rayburn Office Building June 2006 Hill Briefing on Student Drug Testing, Rayburn Office Building

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July 2006 Invited Congressional testimony on prescription drug abuse, Capitol Hill July 2006 Science of Addiction, ONDCP (2 X) July 2006 Symposium Fentanyl Forum, Philadelphia, PA speaker, chair, moderator Aug 2006 Farewell For Charlie Curie, Director of SAMHSA, EEOB, Washington, DC. Aug 3 Speech Aug 2006 Keynote Substance Abuse Programs Administrators Association (SAPAA), San Antonio, TX, Aug 16 Aug 2006 Keynote Annual Arizona Drug Court Conference, Scottsdale, AZ, Aug 23 Aug 2006 Speaker National Prevention Network, Lexington, KY, Aug 27 Aug 2006 Speaker Steroid testimony; major professional sports leagues (MLB, NBA, NFL, NHL), Zero Tolerance Roundtable, Rayburn Office Building, Washington, DC, Aug 30 Sept 2006 Speaker Hill briefing on SBIRT, Sept 6 Screening, brief intervention referral to treatment briefing, Rayburn Office Building, Washington, DC Sept 2006 Speaker Town Hall Meeting , NBC interview, Hazards of Internet, Chicago, IL, Sept 6 evening Sept 2006 Speaker Recovery Month Luncheon, Al-Anon Washington. DC, Sept 7 Sept 2006 Speaker Board meeting, American Association for Treatment of Opioid Dependence (AATOD), DC, Sept 15 Sept 2006 Speaker Board meeting, American Psychiatric Association (APA), DC, Sept 15 Sept 2006 Speaker Partnership for Drug-Free America, Capitol Hill, US Senate, DC, Sept 19 Sept 2006 Speaker Hill Briefing, Access to Recovery, Rayburn Office Building, DC, Sept 19 Sept 2006 Speaker National TASC, Birmingham, AL, Sept 20 Sept 2006 Speaker SBIRT celebration, Houston, TX, Sept 21 Sept 2006 Speaker Honorary Breakfast, Baylor, Houston, TX, Sept 22 Sept 2006 Speaker SBIRT grantees, DC, Sept 25 Sept 2006 Speaker SBIRT VTC to 8 cities, Sept 25 Sept 2006 Speaker Idaho Interagency Cte on Substance Abuse Prevention, treatment, Boise, ID, Sept 27 Sept 2006 Plenary National Association of Alcohol and Drug Abuse Counselors (NAADAC, Keynote NALGAP), Burbank, CA, Sept 30 Oct 2006 VTC keynote 2 videoconferences on SBIRT, DC, Oct 3 Oct 2006 Keynote National Nursing Association Centers Annual Conference, Delray Beach, FL, Oct 10 Oct 2006 Speaker AMA CPT Board presentation, DC, Oct 12 Oct 2006 Speaker Media campaign round table, Austin, TX, Oct 17 Oct 2006 Speaker Grand Rounds, MGH, Boston, MA, Oct 20 Oct 2006 Speaker DATIA, DC, Oct 26 Oct 2006 Speaker SBIRT, Emory University, Atlanta, GA, Oct 27 Nov 2006 Speaker Annual AMERSA National Conference, DC, Nov 3 Nov 2006 Speaker Los Angeles Veterans Administration SBIRT, Los Angeles, CA, Nov 8 Nov 2006 Speaker MN Hennepin County Medical Center, Minneapolis, MN, Nov 17

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Nov 2006 Speaker Meth Awareness Day SW Illinois Correctional Center, East St Louis, IL, Nov 30 Dec 2006 Speaker, Chair Medical Education Conference: Intro, Summary, DC, Dec 1 Dec 2006 Speaker State Dept Speech to Kazakhstan delegation, DC, Dec 4 Dec 2006 Speaker, chair Radio media campaign for parents: Crucial conversations, DC, Dec 6 Dec 2006 Speaker AAAP, St. Petersburg FL and Board, Dec 8 Dec 2006 Speaker SBIRT, ACCME, Chicago, IL, Dec 9 Dec 2006 Speaker National Conference High School Athletic Directors, Anaheim, CA, Dec 11 Dec 2006 Speaker Institute for Neuroscience and Behavior, DC, Dec 11 Dec 2006 Overview Deputy Mayor, City of Los Angeles, CA, Dec 12 presentation Dec 2006 Speaker American Pain Care Forum Lunch Meeting, Washington, DC, Dec 14 Dec 2006 Overview Deputy Mayor, City of Baltimore, Baltimore, MD, Dec 14 presentation Dec 2006 Presentation Baltimore Public Health Commission SBIRT, Baltimore, MD, Dec 14 2007 Jan 2007 Plenary SBIRT, ASAM Columbia SC (cancelled illness) Speaker Jan 2007 Speaker Board, NADCP, DC, Jan 27 Jan 2007 Speaker Student Drug testing Summit, Charleston, SC, Jan 24 Feb 2007 Speaker Minister of Interior meeting, People’s Republic of China, DC, Feb 5 Feb 2007 Speaker AMA CPT panel San Diego, CA, Feb 8 Feb 2007 Speaker Demand reduction Policies, Delegation from Columbia, South America, Feb 22 Feb 2007 Speaker Federal CME Partners, Bethesda, MD, Feb 23 Feb 2007 Speaker Student Drug testing Summit, Newark NJ, Feb 27 Mar 2007 Testimony Why medical marijuana is poor public health policy. Maryland State Legislature House Judiciary Cte, Annapolis, MD, Mar 6 Mar 2007 Testimony Why medical marijuana is poor public health policy. Maryland State Legislature Senate Judiciary Cte, Annapolis, MD, Mar14 Mar 2007 Speaker Inhalant Press Conference, National Press Club, Washington, DC, Mar 14 Mar 2007 Invited plenary Translational research bridge gap between basic and clinical research. pediatric bipolar disorder (decline), Mar 31 Mar 2007 Speaker SDT Summit, Honolulu HI , Mar 28 Mar 2007 Speaker Border Legislature Conference, Chihuahua, Mexico, Mar 30 Mar 2007 Speaker Archdiocese of Miami, Miami, FL, Mar 28 Apr 2007 Speaker SBIRT, Grand Rounds, Detroit Dept of Health, Detroit, MI, Apr 11 Apr 2007 Speaker SBIRT. Town Hall Meeting with DC officials, DC, Apr 17 Apr 2007 Introductory Las Vegas Student drug testing Summit, Las Vegas, NV, Apr 24 remarks Apr 2007 Luncheon CADCP Annual meeting, Sacramento, CA, Apr 26 remarks Apr 2007 Plenary ASAM Policy meeting, Miami, FL, Apr 28 speaker

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May 2007 Invited International conference on Drugs, Visby, Sweden (required to speaker decline) May 2007 Speaker SBIRT-SAMHSA Meeting, Washington, DC. May 10 May 2007 Grand Rounds SBIRT. Grand Junction, CO, May 15 May 2007 Speaker US Border Health Association, South Padre Island, TX, May 22 May 2007 Keynote DUI Court Conference of Judicial Council of Georgia, Atlanta, GA. May 30 Jun 2007 Keynote NASADAD, National Prevention Network, Burlington, VT, Jun 7 Jun 2007 Speaker Manhattan Drug Treatment Court Graduation , New York, NY, Jun 8 Jun 2007 Speaker International Narcotics Enforcement Management Center, Clearwater, FL , June 12 Jun 2007 Luncheon Substance Abuse Prevention Forum, DC, June 13 Keynote Jun 2007 Panelist NADCP 13th Annual Training Conference, Washington, DC, June 15 Jun 2007 Keynote CPDD Annual Meeting Quebec City, Quebec, June 18 Jun 2007 Dinner speaker 1st Annual Conference on SDT, Washington, DC, June 25 Jun 2007 Speaker US Capitol SDT Hill briefing, Washington, DC, June 26 Jun 2007 Speaker SBIRT, DC Department of Health, Doctor’s Luncheon, Washington, DC, June 29 July 2007 Testimony New Jersey, Dept of Education, Hearings on RSDT Trenton, NJ, Jul 18 July 2007 Speaker NIDA-SBIRT Research Meeting, Washington, DC, Jul 19 July 2007 Speaker Johnson Institute Board of Directors, Washington, DC, Jul 26 July 2007 Speaker Florida High School Sports Coaches, Gainesville, FL, Jul 21 Aug 2007 Speaker US Dept Education, Safe and Drug-free Schools, Washington, DC, Aug 4 Aug 2007 Grand Rounds SBIRT, Vanderbilt University, Nashville, TN, Aug 14 Aug 2007 Speaker Opening of new housing, Judge Seth Norman’s Drug Court, Nashville, TN, Aug 14 Aug 2007 Speaker Fentanyl Symposium, Washington, DC, Aug 28 Sept 2007 Luncheon NAADAC on Capitol Hill for Recovery Month, Washington, DC, Sept 6 Speaker Sept 2007 Speaker APA Board, Washington, DC, Sept 6 Sept 2007 Plenary NAADAC Conference, Nashville, TN, Sept 7 Speaker Sept 2007 Speaker HRSA Regional E meeting, Olympia, WA, Sept 19 Sept 2007 Speaker Detroit Summit on RSDT, Detroit, MI, Sept 25 Sept 2007 Speaker Policy Makers Drug Forum Breakfast, Danvers, MA, Sept 26 Sept 2007 Grand Rounds Miller School of Medicine Jackson Memorial Hospital, Miami, FL, Sept 28 Sept 2007 Keynote Annual American Academy of Pain Management, Las Vegas, NV, Sept 29 Oct 2007 Speaker Illinois Alcoholism and Drug Dependence Association Conference, Chicago, IL, Oct 2 Oct 2007 Keynote SAPAA Conference, San Diego, CA, Oct 10 Oct 2007 Grand Rounds SBIRT, University of MN Medical School, Minneapolis, MN, Oct 11 Oct 2007 Keynote Rhode Island Family Court Symposium, Providence, RI, Oct 19 Oct 2007 Keynote AATOD Policy Maker’s Lunch, San Diego, CA, Oct 22

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Speaker Oct 2007 Keynote International Congress on Addictions Conference, Mexico City, Mexico, Oct 25 Oct 2007 Keynote SBIRT, ASAM Course on State of the Art in Addiction Medicine, Oct 27 Nov 2007 Speaker University of Maine Conference on Prescription Drugs, Portland, ME, Nov 1 Nov 2007 Speaker SBIRT Hill Briefing, Washington, DC, Nov 1 Nov 2007 Speaker SBIRT, National Association of State Medicaid Directors, Washington, DC, Nov 14 Nov 2007 Plenary SBIRT, 2007 ACCME Summit, Chicago, IL, Nov 15 Speaker Nov 2007 Speaker DC ATR/DFC Roll-out event, Washington, DC, Nov 20 Nov 2007 Speaker Legal Action Center's National HIRE Network 3rd Annual NY Policy Conference, New York, NY, Nov 28 Nov 2007 Plenary SECAD, Atlanta, GA, Nov 29 address Dec 2007 Grand Rounds SBIRT, UCLA, Los Angeles, CA, Dec 11 Dec 2007 Speaker SDT Summit Philadelphia Charter Schools, Philadelphia, PA, Dec 19 2008 Jan 2008 Grand Rounds SBIRT, Cleveland Clinic, Cleveland, OH, Jan 3 Jan 2008 Grand Rounds SBIRT, Cornell University Medical School, Westchester Campus, Westchester, NY, Jan 8 Jan 2008 Grand Rounds SBIRT, Cornell University Medical School Manhattan Campus, New York, NY, Jan 9 Jan 2008 Grand Rounds SBIRT, New York Psychiatric Institute, Columbia U, New York, NY, Jan 11 Jan 2008 Keynotes, host ONDCP Medical Education Conference, Washington DC, Jan 15 Jan 2008 Speaker SDT Summit Des Moines, WA, Jan 16 Jan 2008 Speaker SDT Summit, Pasco, WA, Jan 17 Jan 2008 Four keynote Eastern European Demand Reduction Symposium, Budapest, addresses Hungary, Jan 23-24 Jan 2008 Keynote ONDCP Random Student Dug Testing, Jacksonville, FL, Jan 29 Jan 2008 Speaker SBIRT Grantee Meeting, Bethesda, MD, Jan 30 Jan 2008 Keynote ONDCP Student Dug Testing Summit, Oklahoma, City, OK. Jan 31 Feb 2008 Keynote ONDCP Random Student Dug Testing, VTC (4 cities), Feb 5 Feb 2008 Keynote ONDCP Random Student Drug Testing Summit Albuquerque, NM, Feb 6 Feb 2008 Keynote Closeup Foundation, GSA Bldg, Washington, DC, Feb 11 Feb 2008 Keynote National Network for Safe and Drug Free Schools and Communities, Washington, DC, Feb 11 Feb 2008 Keynote RSDT Summit for Charter Schools, Washington DC, Feb 15 Feb 2008 Grand Rounds Stanford University Medical School, Palo Alto, CA, Feb 28 Feb 2008 Speaker SBIRT, Executive Committee, National Conference of State Legislators, DC, Feb 29 Mar 2008 Host, Opening Coordinating Council on Juvenile Justice and Delinquency Prevention, remarks Washington, DC, Mar 7

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Mar 2008 Federal The future of Drug Courts, Washington, DC, Mar 3 roundtable Mar 2008 Keynote National Organization for Youth Safety Meeting, Washington, DC, Mar 6 Mar 2008 Seminar SBIRT, Brandeis University , Waltham MA, Mar 10 speaker Mar 2008 Testimony Maryland State House; SDT Bill, Annapolis, MD, Mar 11 Apr2008 Keynote Lonnie Mitchell Conference, Atlanta, GA, Apr 3 Apr 2008 Keynote American Society Addiction Medicine Annual meeting, Toronto, Canada , Apr 11 Apr 2008 Speaker RSDT Summit, Pagosa Springs, CO, Apr 24 Apr 2008 Keynote Arizona Substance Abuse Conference, Phoenix, AZ, Apr 29 Apr 2008 Speaker Indian Health Services Meeting, Albuquerque, NM, Apr 30 May 2008 Speaker 42nd General Session of Inter-American drug abuse control commission CICAD meeting at OAS, Washington, DC, May 1 May 2008 Speaker NY State Lion’s Club Meeting, Niagara Fall, NY, May 2 May 2008 Presentation American Psychiatric Association, Board Council on Addiction, May 5 May 2008 Speaker APA Annual Meeting, Washington, DC. May 5 May 2008 Speaker, Chair RSDT Summit, ONDCP, Washington, DC, May 7 May 2008 Webinar SBIRT, Health Resources Services Administration (HRSA), ONDCP, DC, speaker May 9 May 2008 Webinar SBIRT, Federation of State Medical Boards, Washington, DC, May 15 speaker May 2008 Speaker NIDA screening, brief interventions meeting, MD, May 12 May 2008 Speaker ONDCP-NIDA Prescription drug abuse conference, MD, May 19 May 2008 Speaker Interagency coordinating Cte on Prevention of Underage drinking, hosted by Surgeon General, Washington, DC, May 27 May 2008 Opening National Assoc Drug Court Professionals, St Louis, MO, May 30 remarks June 2008 Keynote NIDA Blending Conference, Cincinnati, OH, June 3 June 2008 Speaker Transforming the American Workplace, Dept of Labor Summit on Disability Employment Policy, Washington, DC, June 3 June 2008 Speaker RSDT Summit, ONDCP, Washington, DC, June 4 June 2008 Keynote Dallas Independent School District Student Services Academy, Dallas, TX, June 4 June 2008 Video SBIRT, Accreditation Council Continuing Medical Education, (ACCME) interview Chicago, IL, June 16 June 2008 Speaker Independent Advisory Cte on Prescription Stimulant Abuse, Washington, DC, June 24 June 2008 Speaker and White House Faith-based meeting ATR, Washington, DC, June 26 Panel Chair July 2008 Keynote SBIRT, National Association of School Nurses, Albuquerque, NM, July 1 July 2008 Keynote National Conference on Indian Education, Rapid City, SD, July 8 July 2008 Keynote 4 presentations, Bi-national meeting Mexico-US, Monterrey, Mexico, speaker, host July 22-24 July 2008 Speaker 2nd Annual Public Health Care Congress, Washington, DC, July 25

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Aug 2008 Speaker Small Business Administration Drug-free workplace, DC, Aug 5 Aug 2008 Plenary Access to Recovery Grantee Conference, Milwaukee, WI, Aug 6 speaker Aug 2008 Opening SAMHSA Drug testing Advisory Board meeting, Chevy Chase, MD, Aug remarks 19 Aug 2008 Opening Indian Health Services and SAMHSA National Behavioral Health plenary and Conference, Billings, MT, Aug 20 lunch time speaker Aug 2008 Speaker Ryan White HIV/AIDS HRSA Meeting, Washington, DC, Aug 27 Aug 2008 Plenary NAADAC annual Meeting and Kansas Association of Addiction Professionals, Kansas City, KA, Aug 30 Sept 2008 Plenary Recovery Month Annual Luncheon, Washington, DC, Sept 4 Sept 2008 Chair and 4 presentations, White House SBIRT Summit, EEOB, Washington, DC, Plenary Sept 5 Sept 2008 Remarks APA, Council on Substance Abuse, Washington, DC, Sept 5 Sept 2008 Remarks SBIRT, American Hospital Association Governing Council, DC, Sept 9 Sept 2008 Grand Rounds SBIRT, Drexel University, Philadelphia, PA, Sept 11 Oct 2008 Keynote Illinois - American Society Addiction Medicine, Chicago, IL, Oct 25 Nov 2008 Invited The Frederick Corneel Lecture, McLean Hospital, Belmont, MA, Nov speaker 24 Dec 2008 Invited Betty Ford Institute Medical Education Residency Programs, Dec 4-6 participant 2009 Feb 2009 Invited Prevention and Intervention: The Response of Cities; World Mayors’ symposium Conference on Drugs Goteborg, Sweden, Feb 6 speaker Feb 2009 Invited Longwood Psychiatry Grand Rounds, BIDMC, Boston, MA, Feb 26 speaker May 2009 Invited Medications for psychostimulant drugs of abuse: old and new targets, speaker in Current trends in drug abuse research the Center for Drug Discovery, Northeastern University, Boston, MA, May 20 June 2009 Symposium CPDD Drug policy, June 24 speaker Aug 2009 Invited Cold Spring Harbor Course Cell Biology of Addiction, Introductory speaker lecture, Long Island, NY, Aug 6 Oct 2009 Invited National Conference on Substance Abuse and Alcohol Misuse; Getting speaker a Grip 2009, Killarney, Ireland, Oct 1 Oct 2009 Plenary “Drug Policy, Public Health and Science” in Forging Active speaker Partnerships Towards a Drug-free Society: Best practices Conference, Cape Town South Africa, Oct 19 Oct 2009 Chair and Evidence-based prevention practices in “Forging Active Partnerships Moderator Towards a Drug-free Society: Best practices Conference”, Cape Town Plenary session South Africa, Oct 20 Oct 2009 Invited “Biology of Addiction” National Yang-Ming University, Institute of speaker Brain Science and Institute of Neuroscience lecture, Taipei, Taiwan,

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Oct 28 Oct 2009 Invited “Drug Policy, Public health and Science”. National Health Research speaker Institute, Taiwan, Taipei, Oct 29 Oct 2009 Invited “The fundamentals of a national Drug Control Policy: a balanced speaker approach to demand and supply reduction”. Dept of Justice, Taiwan, Taipei, Oct 30 Oct 2009 Keynote “Substance abuse, suicide and overdose deaths in adolescents: policy and practical perspectives”, Oct 31 Oct 2009 TVGH anniversary; Taiwan, Taipei, Oct 31 2010 Apr 2010 Keynote Drug dependence: a health and social issue. Drugs Summit, European, Panel Latin American, Caribbean Mayors and Cities, Organization of discussant American States (OAS), Lugo, Spain. April 22 Apr 2010 Invited Addictions in 2010. Screening, brief intervention, and referral to speaker treatment: an idea whose time has come. McLean Hospital & Harvard Medical School CME, Boston, MA, April 30 May 2010 Keynote (1) Changing your mind: drug policy and science; (2) Marijuana and 3 Research; (3) Medical Marijuana, World Forum Against Drugs, presentations Stockholm, Sweden; May 22-24 June 2010 Invited Screening, brief interventions for abuse of opioid medications; Tufts speaker Program on Opioid Risk Management, Boston, MA, June 4 June 2010 CPDD Screening, brief intervention symposium, Scottsdale, AZ Symposium Sept 2010 Symposium OAS/CICAD Latin American Universities On The Drug Phenomenon speaker From The International Health Perspective Organization of American States. Panama City, Panama Oct 2010 Keynote Toward systematic screening brief intervention and referral to treatment, in Addiction Medicine: Prescribing during the new era of SBIRT (Screening, Brief Intervention, and Referral to Treatment). HMS Division on Addictions, CME, Boston, MA Nov 2010 Neuroscience Durban, South Africa (cancelled) course lecture Nov 2010 Speaker Marijuana and Youth, Special Lecture, San Diego Prevention Community, San Diego, CA, Nov 15 Dec 2010 Invited Do axonal guidance molecules respond differently in the adolescent speaker and and adult brain? NIDA-Sponsored Brain Development Web chair Symposium: Neurodevelopment and Drugs of Abuse Dec 16 2011 Mar 2011 Invited “The Science of Addiction: Drugs, Brain, and Behavior” at the Harvard speaker Medical School and Department of Psychiatry at Cambridge Health Alliance Annual “Treating the Addictions”, Boston, MA, Mar 4 Mar 2011 Invited US State Department meeting, Lima Peru (cancelled), Mar 20 speaker Mar 2011 Invited MIT Neuroscience Symposium, Mar 22 symposium speaker

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Jun 2011 Invited Marian Fischman Award Lecture, CPDD Annual meeting, Hollywood, speaker FL June 2011 Invited Southern California Anti-drug Coalition, CA speaker Sept 2011 Invited Marijuana as Medicine – A Fresh Look, Washington, DC Speaker Sept 2011 Invited Successful Implementation of SBIRT in Primary Care Settings in “The speaker Evidence for Integrated Care: Substance Use Disorders, Mental Health, and Primary Care.” Conference California Department of Alcohol and Drug Programs and the Pacific Southwest Addiction Technology Transfer Center. Sacramento, CA, Sept 16 Oct 2011 Invited “Update in Neuroscience for the Non-neuroscientist: Clinical speaker Information”. CME Addictions Course, Boston, MA 2012 Mar 2012 Invited Workshop speaker, Imaging Studies of Drug Transport and Response, speaker ASCPT annual meeting, National Harbor, MD. March 23 Invited “Drug Policy, Public Health, and Translational Research”, Research speaker Psychiatry Seminar Series, McGill University, Montreal, Canada April 2 Invited Marijuana and the adolescent brain, Middlesex County, Middlesex symposium Partnerships for Youth, Inc. Lowell, MA speaker April 12 Invited Role of Naloxone in Opioid Overdose Fatality Prevention, NIDA-FDA- panelist DEA Symposium, Silver Spring. MD April 16 Invited “A Scientist in the White House Office of National Drug Control speaker Policy: Reducing Youth Drug Use as a National Imperative”. Dartmouth College May 11 Invited “Marijuana as Medicine: History, biology, liability, and acceptability, symposium Marijuana symposium”, Dartmouth College. speaker,panelis t May 22 Invited plenary (1) “Drugs and the developing adolescent brain”. (2) and “Preventing youth drug use is a global imperative"; World Forum symposium Against Drugs. Stockholm, Sweden speaker June 12 Symposium MDMA and methamphetamine elicit contrasting behavioral and speaker and molecular responses in the adolescent and adult brain, in Drug effects chair in the developing adolescent brain, CPDD Annual meeting symposium, Palm Springs, CA June 13 Invited A scientist in the media spotlight: converging and conflicting symposium missions. 2. Making sense of science with sound bites. CPDD Annual speaker Meeting, Palm Springs, CA June 28 Invited Screening, brief intervention referral to treatment in general hospital commentator settings, Massachusetts General Hospital, Boston, MA Aug 14 Invited CDC round-table on preventing substance use in pregnant women, panelist and in primary care settings, Atlanta, GA Aug 16 Invited Marijuana as medicine: history, biology, acceptability. Training

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speaker program for substance use prevention, Tarrytown,. NY Sept 27 Invited Invited speaker webinar on Medicine Abuse and SBIRT; PDFA, A&E panelist Channel, ONDCP; Newseum, Washington, DC Oct 26 Invited Marijuana and the adolescent brain, Fall River, MA speaker Nov 28 Invited Opioid misuse and diversion: the role of SBIRT, District Attorney of webinar Middlesex County (BKM cancelled) speaker 2013 Feb 18 Symposium FDA process and modern medicine, Marijuana Summit, U Tampa, FL. speaker Feb 26 Panelist Drug Policy Meeting, Heritage Foundation, Washington DC April Invited Marijuana biology and the adolescent brain. 4 lectures. Larchmont- speaker Mamaroneck, NY May 13, Invited Mayors Conference; European Cities Against Drugs, Moscow, Russia 14 keynote May 23 Invited Designer drugs, nationally broadcast webinar, Tampa, FL speaker June 18 Symposium Media training, CPDD annual meeting, San Diego, CA speaker July 26 Symposium “Stimulant Designer Drugs and Transporters: Predictors of Abuse speaker Liability and Drug Scheduling”, in NIDA-symposium, Emerging trends in the Abuse of Designer Drugs and Their Catastrophic Health Effects: Update on Chemistry, Toxicology, Drug Development and Treatment; Rockville, MD Sept 23 Invited “The science of marijuana” National Marijuana Policy and Strategy speaker Conference, Rancho Cucamonga, CA Oct 12 Invited CME, Substance Abuse Screening, Harvard Medical School, Boston, MA speaker Oct 16 Invited “The Science of marijuana” Two lectures. Ossining, NY speaker Nov 15 Invited Translational Neuroscience, Nanjing, China speaker

2014

Feb 24 Symposium Marijuana as a medicine, as a psychoactive drug, Drug Summit, speaker U Tampa, FL. Mar 13 Invited speaker Marijuana as Medicine, Virginia Commonwealth University, Richmond, Virginia Mar 24 Invited Changing your mind: drugs in the brain, Brain Awareness Week, keynote Louisiana State University, New Orleans, LA Mar 25 Invited speaker Changing your mind: drugs in the brain, Ardsley High School, Ardsley, NY Apr 18 Invited speaker Prescription drug abuse forum., Cape Cod Coalition, Cape Cod Community College, Hyannis, MA

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May 2 Invited panelist Marijuana and public policy, American Pain Society, Tampa, FL May 14 Keynote SBIRT: screening brief intervention and referral to treatment Organization of American States OAS/CICAD expert group on Demand Reduction, Washington, DC May 19 Invited speaker World Federation Against Drugs (WFAD); European Cities Against 2 talks Drugs (ECAD) Stockholm, Sweden Jun 11 Invited speaker Gaps and Opportunities For Device Development in Neuroscience, Medical Development Group, Boston, MA Jun 16 Workshop Knowledge Translation in Addiction Sciences: Why and how to share speaker research knowledge beyond the academic community. CPDD, San Juan, Puerto Rico Jun 17 Symposium Media press conference and symposium, Chair, CPDD, San Juan, chair Puerto Rico Sep 9 Invited speaker Florida Drug Summit, Haines City, FL Sep 11 Invited speaker Grand Rounds, "Transitions In Life: From Science to the White House and Back”; Women in Medicine month, McLean Hospital, Belmont, MA Oct 10 Invited speaker CME, Neurobiology of Addiction, Harvard Medical School, Boston, MA

Non-Local Teaching: Leadership Role

2001-2005 Course creator, director, curriculum developer, syllabus, instructor. Cold Spring Harbor Laboratory Course: “Cell Biology of Addiction” The course has been offered biannually since 2001 (Spain, 2012). It has trained an average of 20-25 professionals during each session, for a career in addiction research. Attendees were graduate students, post-doctoral fellows, assistant, associate, full professors, government officials and other qualified applicants. Enrollment was competitive, with an average of 20% selected from applicants. Scholarships were provided for those in need and a limited number of spaces were given to foreign scientists. Ratings for the course were consistently high, as the quality of the instructors recruited were excellent.

Public education: translation of research into instruments of public education

1. Designer Drug Webinar broadcast throughout US, 2013. 2. NIDA YouTube commentator on Designer Drugs, 2013 3. Invited speaker for webinar: “Medicine Abuse and SBIRT”; sponsors: PDFA, A&E Channel, ONDCP; Newseum, Washington, DC, 2012 4. Slide sets (over 50 sets) on science of drugs and addiction sent in response to requests. 5. A recipient of a NIDA grant and project director and in collaboration with the Museum of Science, Boston, developed an exhibit for display at Museum of Science, Boston “Changing your Mind; Drugs in the Brain”, a CD-ROM, and a two-actor play. (on Exhibit, 1994-2006) 6. During the period of exhibition at the Museum of Science, Boston, it completed a national tour. 7. An abbreviated version was created for and toured Denmark. 8. Several thousand copies of the CD-ROM were distributed nationally and internationally.

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9. The Disney Corp licensed the CD in 2006. 10. Assisted NIDA in developing the storyboard for a NIDA-DEA exhibit in Times Square, NY. 11. Components of this storyboard were incorporated into the NIDA monograph on “Drugs, Brain, Behavior: the Science of Addiction”.

Non-Local Teaching (partial list, majority listed in invited talks, excludes Grand Rounds)

2013 Media training for CPDD attendees of annual meeting, San Diego, CA 2012 Media training for CPDD attendees of annual meeting, Palm Springs, CA 2002 Illicit Drugs-What are the Facts? Examining the neurobiological effect of drugs on the brain and long-term effects of drug use. MIT, Cambridge, MA 2000 “Receptors” American Society for Pharmacology Exp. Therapeutics Boston. MA 1994 Office for Academic Careers, Harvard Medical School, Grant-writing Workshop, Boston, MA “Non-Federal Funding Sources”. 1992, 1995 Framingham State College, Guest Lecturer, “Brain dopamine systems, substance abuse” 1991 University of Pennsylvania, Lecture for Residents, “Cocaine Abuse” 1989, 1991 Tufts University, Guest Lecturer in Graduate Courses 1982 Neurotransmitter and Receptor update course, Congress of Neurological Surgeons, Toronto, Ontario 1979-1981 Chair, committee to develop Neuroscience training program, Univ. of Toronto 1961-1963 McGill University Teaching Assistant, Comparative Anatomy

Non-Local Leadership Roles

Dec ‘10 Chair, organizer, invited speaker, Do axonal guidance molecules respond differently to drugs in the adolescent and adult brain? NIDA-Sponsored Brain Development Web Symposium: Neurodevelopment and Drugs of Abuse, Dec 16 Sep ‘08 Chair, White House National Leadership Conference, Medical Education in Substance Abuse; Organized and chaired White House Conference on Medical Education with a focus on substance abuse screening, interventions and prescription drug abuse. In attendance were representatives from major medical organizations in the United States (including leadership of AMA, ACCME, AAMC, APA, AAAP), representatives from major Federal agencies, Director of NIDA, NIAA, and others. Meeting resulted in recommendations and a full report. A number of recommendations were acted on by attendees. Mar ‘08 Chair, Coordinating Council on Juvenile Justice and Delinquency Prevention Meeting. Please see narrative above. Jan ‘08 Chair, White House National Leadership Conference, Medical Education in Substance Abuse. Please see narrative above. Apr-Jun ‘08 Host and chair 3 White House mini-summits on RSDT Jul ‘08 American host, Bi-National US-Mexico Conference on Demand Reduction. Monterrey, Mexico Jan 2007 Host and Chair: Eastern European Conference on “What Works to Reduce Drug Use? Budapest, Hungary Dec ‘06 Chair, White House National Leadership Conference, Medical Education in

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Substance Abuse. Please see narrative above. 2006-08 Chair and speaker, RSDT Summits throughout United States

Non-local leadership roles: Office of National Drug Control Policy (ONDCP) narrative

As Deputy Director for the Office of Demand Reduction (ODR) at the White House Office of National Drug Control Policy, ODR accomplished a number of priorities, a representation of which is listed below. In 2007-2008, the Office of Demand Reduction developed 104 operational priorities and 15 quantifiable measures to achieve by August 31, 2008. All were accomplished, the majority ahead of deadlines. Screening, brief intervention and referral to treatment (SBIRT) was a major initiative during my tenure, but other programs and projects were supported and sustained. ODR had oversight of ~$4 billion annual federal demand reduction budget, with responsibility to lead and coordinate relevant initiatives within certain Federal agencies (Dept. Education, NIDA, SAMHSA, Dept Justice, Dept Labor, Dept Commerce, Dept Veterans Affairs, HRSA, CMS) and within the private sector. For overview, see Madras, 2010.

ACHIEVEMENTS New CPT®, Medicare and Medicaid billing codes for SBIRT 1. A critical leader-participant in the petition to the American Medical Association CPT® Board to adopt new billing codes for screening and brief interventions in healthcare settings. Codes were adopted January 2008, as well as “H” and “G” Medicaid, Medicare codes. 2. Petitioned 50 state Medicaid directors to adopt new CMS Medicaid codes. Before leaving office, 10 states had adopted the codes and seven additional ones in 2009. Now incorporated into routine service by the ACA. 3. Successfully petitioned the Office of Personnel and Management (OPM) in the federal government to include the new billing codes in the annual “call” letter which guides healthcare insurers on new government policies and initiatives. OPM oversees healthcare insurance for all Federal employees, their families and guides health care insurance companies on government priorities. As of 2008, over 70% of Federally employees healthcare services will be covered for SBIRT services. (5.6 million). 4. Successfully petitioned health insurance providers to disseminate value of screening, brief interventions to healthcare providers and insurance companies. Based on evalue8 survey, 86 healthcare insurance companies to reimburse for the new codes. 5. As of January 2012, Medicare will cover an annual alcohol misuse screening by a beneficiary’s primary care provider and include four behavioral counseling sessions/year if a beneficiary screens positive for alcohol misuse. 6. As of July, 2011, the Joint Commission for Accreditation of Health Care Organizations submitted two sets of inpatient public health measures for NQF review: Tobacco screening, treatment and follow-up, and alcohol and drug screening, brief intervention, treatment and follow-up. 7. The Joint Commission published the eight SBIRT measures in their official standards manual for use by hospitals starting January 2012.

Screening, Brief Interventions Services 8. CMS: successfully petitioned CMS to set aside $250 million for reimbursement of SBIRT

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services via Medicaid. 9. VA: successfully petitioned VA to mandate alcohol SBI. VA system mandated SBI for alcohol in all their health care systems, June 2008. 10. SAMHSA: successfully petitioned SAMHSA for: (1) Expansion of screening, brief interventions services to over 14 locations in SAMHSA program; (2) Expansion screening, brief interventions services for prescription drug abuse to 93% of federally funded SBIRT sites; (3) Expansion of screening brief interventions for prescription drug abuse to over 50% of College Campus SBIRT sites; (4) develop a medical residency training program in screening, brief interventions; (5) promote publications of effective programs and outcome measures; (6) develop a screening, brief interventions program for juvenile justice system. RFA was issued. 11. American College of Surgeons, Committee on Trauma: successfully petitioned ACS- COT to expand screening, brief interventions services in 21 Level I trauma Centers to include screening for prescription drug abuse. 12. Federation of State Medical Boards. successfully petitioned Federation of State Medical Boards to adopt new policies for medical education on screening, brief interventions and prescription drug abuse. 13. Accreditation Council for Continuing Medical Education (ACCME). The Accreditation Council for Continuing Medical Education features screening, brief interventions as their representative CME course and video of SBI on their website. 14. Health Resources Services Administration (HRSA). successfully petitioned HRSA to incorporate screening, brief interventions modules into new grant system for the Health Resources and Services Administration. 15. NIDA. successfully petitioned NIDA to (1) Generate new RFA’s for screening, brief interventions; (2) Develop a web training site for screening, brief interventions (NIDAMED went live April 2009); (3) Develop a prescription drug screening strategy; (4) Implement SBIRT in NIDA treatment programs. 16. NIAAA. Stimulated SBIRT services for alcohol, with billing codes.

Treatment 17. Wrote criteria for improving quality and effectiveness of treatment in a number of documents: advocated a requirement for best practices for substance abuse treatment (maintaining electronic medical records, long term patient follow-up, psychiatric services, AIDS counseling, incentives for patient retention, relapse prevention, recovery support services, and others). 18. SAMHSA. successfully petitioned SAMHSA to conduct research and reporting of a new treatment program, Access to Recovery (ATR) and to develop an electronic ATR manual, to enable program replication in multiple sites and nations.

Drug Courts 19. Promoted best practices based on research outcomes and conducted events with drug courts to promote them. 20. Congress. Advocated expansion of drug court services in Congress. Drug court funding increased (2008). 21. ODR organized funding for the Drug Court Institute to train professionals for drug court service.

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Drug-free workplace 22. Increased the number of sites with prevention policies and programs by over 3 million person-reach and increased the percentage of person reporting they had access to educational information about drug and alcohol use in the workplace.

Prevention 23. Educated school officials on random student drug testing according to two Supreme Court rulings ; outreach led to highest number of school applications in RSDT program history. 24. Wrote articles and developed slide presentations on the biology of addiction and the special vulnerability of the developing adolescent brain. 25. Developed position papers and materials on medical marijuana debate. 26. Educated, in numerous venues, high school superintendents, principals, coaches, teachers, administrators on drugs and the developing brain, prevention programs and policies.

International 27. Mexico. Chaired and developed a bi-national meeting with Mexico and attended other meetings with Mexican officials to develop partnerships for implementation of evidence- based prevention, intervention and treatment programs in Mexico. Successfully petitioned Mexico to adopt screening, brief interventions, referral to treatment (SBIRT) programs in over 40 sites; to conduct trials on random student drug testing in over 43 sites; to implement Drug courts in Mexico, after changing Mexican law. 28. Emerging eastern European nations. Chaired an Eastern European conference on Demand Reduction to educate this sector of the Europe on evidence-based prevention, intervention and treatment programs. 29. Organization of American States (OAS)/CICAD (35 Western hemisphere nations), presented on several meetings evidence-based practices in US, including SBIRT, drug courts, ATR and RSDT. 30. Other nations. Presented evidence-based Demand Reduction programs to representatives of other countries, (e.g. China, Kazakhstan, Romania). 31. United Nations. Successfully petitioned UN to issue declaration in support of SBIRT.

Non-locale leadership role: Involvement in drug policy and education since 2008

Since returning to Boston, involvement in drug policy in various capacities is ongoing: A few examples are provided below:

1. An overview of my service and recommendations for drug policy were summarized in a manuscript (bibliography: Madras, 2010). 2. Major recommendations (circulated in 2008 prior to leaving and in a publication, Madras, 2010) have been incorporated into the annual National Drug Control Policy 2009-2013. 3. A manuscript detailing SBIRT outcome data with an n= ~ 460,000, from federally funded SBIRT programs was published. (Madras et al 2009) 4. Service on NIDA Council Workgroup to develop report on: “Adoption of NIDA’s Evidence- Based Treatments in Real World Settings”. Contributions included a table comparing NIDA Principles of Effective Treatment with the reality embodied in a survey of 14,060

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substance abuse treatment facilities in the US (2010 N-SSATS survey) which provides the latest results from an annual census of facilities providing substance abuse treatment. 5. Served on FDA-NIDA-CDC panel to discuss provisions of naloxone without prescription. 6. Served on CDC panel to generate initiatives on mainstreaming SBIRT into healthcare settings that focus on pregnant women, as a strategy to prevent exposure of the unborn fetus to alcohol. 7. Served on board of several non-profits, for-profits, for prevention, SBIRT dissemination, treatment approaches, education of physicians, others, in an advisory capacity. 8. Webinars to explain current issues in substance use disorders

Major curriculum offerings

’01-’05 Developed curriculum for a new Cold Spring Harbor Laboratory Course , “Cell Biology of Addiction”; Wrote successful grant and served as Course director, until ONDCP service. Co-edited book , “Cell Biology of Addiction”, based on this topic. ‘91- Developed curriculum for a new substance abuse and addictions course for 4th year Harvard Medical School students. Served as course director for ~15 years. ’94-’98 Developed first CD-ROM and associated guide to educate students and public on neurobiology of drug effects.

III Bibliography

Original articles

1. Madras BK, Sourkes TL. Metabolism of α-methyltryptophan. Biochem Pharmacol 1965, 14;1499-1506.

2. Madras BK, Sourkes TL. Formation of respiratory 14CO2 from variously labeled forms of tryptophan-14C in intact and adrenalectomized rats. Arch Biochem Biophys 1968; 125; 829-836.

3. Madras BK, Sourkes TL. Effects of drugs on the metabolism of tryptophan. Alpha-hydrazino tryptophan and other amino acid analogs. Biochem Pharmacol 1968;17;1037-1047.

4. Horowitz B, Madras BK, Meister A, Old LJ, Boyse EA, Stockert E. Asparagine synthetase activity of mouse leukemias. Science 1968; 160;533-535.

5. Sourkes TL, Missala K, Madras BK. Effect of yohimbine on tryptophan metabolism. J Pharmacol Exp Ther 1969; 165;289-293.

6. Lipsett D, Madras BK, Wurtman RJ, Munro HN. Serum tryptophan level after carbohydrate ingestion: Selective decline in non-albumin-bound tryptophan coincident with reduction in serum free fatty acids. Life Sci 1973; 12;57-64.

7. Madras BK, Cohen EL, Fernstrom JD, Larin F, Munro HN, Wurtman RJ. Dietary carbohydrate

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increases brain tryptophan and decreases serum-free tryptophan. Nature 1973; 244:34- 35.

8. Madras BK, Cohen EL, Messing RB, Munro HN, Wurtman RJ. Relevance of free tryptophan in serum to tissue tryptophan concentrations. Metabolism 1974; 23:1107-1116.

9. Madras BK, Cohen EL, Munro HN, Wurtman RJ. Elevation of serum free tryptophan, but not brain tryptophan, by serum nonesterified fatty acids. Adv Biochem Pharmacol 1974; 143- 151.

10. Fernstrom JD, Hirsch MJ, Madras BK, Sudarsky, L. Effects of skim milk, whole milk, light cream on serum tryptophan binding and brain tryptophan concentrations in the rat. J Nutr 1975:105:1359-1362.

11. Davis A, Madras BK, Seeman P. Solubilization of neuroleptic/dopamine receptors of human brain striatum. Eur J Pharmacol 1981; 70;321-329.

12. Burnham WM, Spero L, Okazaki MM, Madras BK. Saturable binding of [3H]phenytoin to rat brain particulate fractions. Can J Physiol Pharmacol 1981; 59;402-407.

13. Madras BK, Davis A, Chan B, Seeman P. Solubilized dopamine neuroleptic receptors (D2- type). Prog Neuropsychopharmacol. 1980; 5;543-548.

14. Chan B, Madras BK, Davis A, Seeman P. Assay for soluble dopamine receptors by the precipitation method. Eur J Pharmacol 1981;74;53-59.

15. Davis A, Madras BK, Seeman P. Solubilized receptors for [3H]dopamine (D3 binding sites) from canine brain. Biochem Pharmacol 1982; 31;1183-1187.

16. Chan B, Seeman P, Davis A, Madras BK. Ascorbate injury and EDTA (or manganese) protection of D2-dopamine receptors. Eur J Pharmacol 1982; 81;111-116.

17. Chan B, Madras BK. [3H]Mianserin binding to solubilized membranes of frontal cortex. Eur J Pharmacol 1982; 83;1-10.

18. Madras BK, Davis A, Seeman P. Comparison of soluble dopamine D2 receptors from three species. Eur J Pharmacol 1982; 78;431-438.

19. Okazaki MM, Madras BK, Livingston KE, Spero L, Burnham WM. Enhancement of [3H]phenytoin binding by diazepam and (+)-bicuculline. Life Sci 1983; 33;409-414.

20. Chan B, Madras BK. Partial purification of [3H]mianserin binding sites. Eur J Pharmacol 1983; 87:357-365.

21. Madras BK, Chan B. Modulation of dopamine receptor binding by ascorbic acid. Adv. Biochem. Psychopharmacol 1983; 31;275-287.

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22. Madras BK, Seeman P. Drug potencies on partially purified brain D2 dopamine receptors. J Neurochem 1985; 44:856-861.

23. Madras BK, Fahey MA, Canfield DR, Spealman RD. D1 and D2 dopamine receptors in caudate-putamen of nonhuman primates (Macaca fascicularis). J Neurochem 1988; 51:934-943.

24. Madras BK, Fahey MA, Bergman J, Canfield DR, Spealman RD. Effects of cocaine and related drugs in nonhuman primates; I. [3H]Cocaine binding sites in caudate-putamen. J Pharmacol Exp Ther 1989; 251:131-141.

25. Spealman RD, Madras BK, Bergman J. Effects of cocaine and related drugs in nonhuman primates; II. Stimulant effects on scheduled-controlled behavior. J Pharmacol Exp Ther 1989; 251:142-149.

26. Bergman J, Madras BK, Johnson SE, Spealman RD. Effects of cocaine and related drugs in nonhuman primates; III. Self-administration by squirrel monkeys. J Pharmacol Exp Ther 1989; 251:150-155.

27. Madras BK, Spealman RD, Fahey MA, Neumeyer JL, Saha JK, Milius RA. Cocaine receptors labeled by [3H]2β-carbomethoxy-3β-(4-fluorophenyl)tropane. Mol Pharmacol 1989; 36: 518-524.

28. Madras BK, Kamien JB, Fahey M, Canfield D, Milius RA, Saha JK, Neumeyer JL, Spealman RD. N-modified fluorophenyltropane analogs of cocaine with high affinity for [3H]cocaine receptors. Pharmacol Biochem Behav 1990; 35:949-953.

29. Madras BK, Canfield D, Pfaelzer C, Vittimberga FJ, DiFiglia, M, Aronin N, Bakthavachalam V, Baindur N, Neumeyer JL. Fluorescent and biotin probes for D1 and D2 dopamine receptors; affinity and selectivity for receptor subtypes. Mol Pharmacol 1990; 37;833- 839.

30. Canfield DR, Spealman RD, Kaufman MJ, Madras BK. Autoradiographic localization of cocaine receptors by [3H]CFT in monkey brain. Synapse 1990; 5;189-195.

31. Spealman RD, Bergman J, Madras BK, Melia KF. Discriminative-stimulus effects of cocaine in squirrel monkeys; involvement of dopamine receptor subtypes, J Pharmacol Exp Ther 1991; 258;945-953.

32. Milius RA, Saha JK, Madras BK, Neumeyer JL. Synthesis and receptor binding of 2- substituted tropane derivatives, high affinity ligands for the cocaine receptor. J Med Chem 1991; 34;1728-1731.

33. Kaufman MJ, and Madras BK. Severe depletion of cocaine recognition sites associated with the dopamine transporter in Parkinson’s diseased striatum, Synapse 1991; 9;43-49.

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34. Spealman RD, Bergman J, Madras BK. Self-administration of the high affinity cocaine analog 2β-carbomethoxy-3β-(4-fluorophenyl) tropane. Pharmacol Biochem Behav 1991; 39;1011-1013.

35. Bergman J, Madras BK, and Spealman RD. Behavioral effects of D1 and D2 dopamine receptor antagonists in squirrel monkeys. J Pharmacol Exp Ther 1991; 258;910-917.

36. Kaufman MJ, Spealman RD, Madras BK. Distribution of cocaine recognition sites in monkey brain. I. In vitro autoradiography with [3H]CFT. Synapse 1991; 9;177-187.

37. Bakthavachalam V, Baindur N, Madras BK, Neumeyer JL. Fluorescent probes for dopamine receptors; synthesis and characterization of fluorescein and 7-nitrobenz-2-oxa-1,3- diazol-4-yl (NBD) conjugates of D-1 and D-2 receptor ligands. J Med Chem 1991; 34;3235- 3241.

38. Rosenzweig-Lipson S, Bergman J, Spealman RD, and Madras BK. The behavioral effects of Lu 19-005 and its enantiomers in non-human primates; relationship to cocaine receptor binding. Psychopharmacology 1991 107;186-194.

39. Kaufman MJ and Madras BK. Cocaine recognition sites labeled by [3H]CFT and [125I]RTI-55 in monkey brain. II. Ex vivo autoradiographic distribution. Synapse 1992; 12; 99-111.

40. Hantraye P, Brownell A-L, Elmaleh D, Spealman RD, Wullner U, Brownell GL, Madras BK and Isacson O. Dopamine fiber detection by 11C-CFT and PET in a primate model of Parkinsonism. Neuro Reports 1992; 3:265-268.

41. Schumacher JM, Hantraye P, Brownell A-L, Riche D, Madras BK, Davenport PD, Maziere M, Elmaleh DR, Brownell GL, Isacson O. A primate model of Huntington’s Disease; functional neural transplantation and CT-guided stereotactic procedures. Cell Transplantation 1992; 1;313-322.

42. Spealman RD, Bergman J, Madras BK, Kamien JB, Melia KF. Role of D1 and D2 dopamine receptors in the behavioral effects of cocaine. Neurochem. Int 1992; 20:1475-1483.

43. Neumeyer JL, Baindur N, Bakthavachalam V, Yuan J, Madras BK, Kula NS, Campbell A, Baldessarini RJ. Selective probes for characterization of dopamine D1 and D2 receptors, Neurochem Int 1992; 20;63S - 68S.

44. Meltzer PC, Liang AY, Brownell A-L, Elmaleh DR, Madras BK. Substituted 3-phenyltropane analogs of cocaine; synthesis, inhibition of binding at cocaine recognition sites and positron emission tomography (PET) imaging. J Med Chem 1993; 36;855-862.

45. Kaufman MJ and Madras BK. [3H]CFT ([3H]WIN 35,428) accumulation in dopamine regions of monkey brain; comparison of a mature and an aged monkey. Brain Res 1993; 611;322- 328.

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46. Dutta A, Meltzer PC, Madras BK. Positional importance of the nitrogen atom in novel piperidine analogs of GBR 12909; affinity and selectivity for the dopamine transporter, Med Chem Res 1993; 3;209-222.

47. Brownell A-L, Hantraye, P, Wullner U, Hamberg L, Shoup T, Elmaleh DR, Frim DM, Madras BK, Brownell GL, Rosen BR, Isacson, O. PET and MRI based assessment of glucose utilization, dopamine receptor binding and hemodynamic changes after lesions to the caudate-putamen in primates. Exp Neurol 1994; 125; 41-51.

48. Madras, BK, Elmaleh, DE, Meltzer PC, Brownell A-L. Positron emission tomography of the dopamine transporter. 138;Imaging techniques in medications development; preclinical and clinical aspects NIDA Res Monograph 1994; 138; 57-69.

49. Madras, BK, Reith, MEA, Meltzer PC, Dutta, AK. O-526, a piperidine analog of GBR 12909, retains high affinity for the dopamine transporter in monkey caudate-putamen, Eur J Pharmacol 1994; 267; 167-173.

50. Madras BK and Kaufman MJ. Cocaine accumulates in dopamine-rich regions of primate brain after i.v. administration; Comparison with mazindol distribution. Synapse 1994; 18; 261-275.

51. Meltzer PC, Liang A, Madras BK. The discovery of an unusually selective and novel cocaine analog; Difluoropine (0-620). Synthesis and inhibition of binding at cocaine recognition sites. J Med Chem 1994; 37; 2001-2010.

52. Gracz LM, Madras BK. [3H]WIN 35,428 ([3H]CFT) binds to multiple charge-states of the solubilized dopamine transporter, J Pharmacol Exp Ther 1995; 273, 1224-1234.

53. Brownell A-L, Elmaleh DE, Meltzer PC, Shoup TM, Brownell GL, Fischman AJ, Madras BK. Cocaine congeners as PET imaging probes for dopamine terminals. J Nucl Med 1996; 37; 1186 - 1192.

54. Elmaleh DR, Shoup TM, Byon C, Hanson RN, Liang AY, Meltzer PC, Fischman AJ. Madras BK. Preparation and biological evaluation of iodine-125-IACFT; a selective SPECT agent for imaging dopamine transporter sites. J Nucl Med 1996; 37; 1197 - 1202.

55. Meltzer PC, Liang A-Y, Madras BK. 2-Carbomethoxy-3-(diarylmethoxy)-1 αH,5αH-tropane analogs; Benztropine analogs; Synthesis and inhibition of binding at the dopamine transporter and comparison with piperazines of the GBR series. J Med Chem 1996; 39; 371-379.

56. Bergman J, Spealman RD, Madras BK, Rosenzweig-Lipson S. Agonist efficacy and the behavioral effects of D1 receptor ligands: Drug interaction studies in squirrel monkeys. J Pharmacol Exp Ther 1996; 276; 942 - 950.

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57. Madras BK, Jones AG, Mahmood A, Zimmerman RE, Holman BL, Davison A, Blundell P, Meltzer PC. Technepine; A high affinity 99mtechnetium probe to label the dopamine transporter in brain. Synapse 1996; 22: 239 - 246.

58. Morris ED, Babich JW, Alpert NM, Bonab AA, Livni E, Weise S, Hsu H, Christian BT, Madras BK, Fischman AJ. Quantification of dopamine transporter density in monkeys by dynamic PET imaging of multiple injections of 11C-CFT; a pilot study. Synapse 1996; 24; 262-272.

59. Kaufman MJ and Madras BK. Neuroanatomical distribution of [3H]YM 09151-2 binding in monkey brain; comparison with dopamine transporter and dopamine D1 receptor distribution. Neuroscience-Net 1996; 1; #10006.

60. Fischman AJ, Bonab AA, Babich JW, Alpert NM, Elmaleh DR, Barrow SA, Graham W, Meltzer P, Hanson RN, Madras, BK. SPECT imaging of the dopamine transporter with [123I]-2β- carbomethoxy-3β-(4-fluorophenyl)-N-(1-iodoprop-en-3-yl)nortropane ([123I]IACFT); initial experience in humans. Neuroscience-Net 1996; 1.

61. Madras BK, Pristupa ZB, Niznik HB, Liang AY, Blundell P, Gonzalez, MD, Meltzer PC. Nitrogen-based drugs are not essential for blockade of monoamine transporters, Synapse 1996; 24; 340-348.

62. Fischman AJ, Babich JW, Elmaleh DE, Barrow SA, Meltzer PC, Madras BK. SPECT imaging of dopamine transporter sites in normal and MPTP treated Rhesus monkeys. J Nucl Med 1997; 38; 144-150.

63. Meltzer PC, Liang AY, Gonzalez MD, Blundell P, Madras BK. 2-Carbomethoxy-3-aryl-8- oxabicyclo[3.2.1]octanes; potent non-nitrogen inhibitors of monoamine transporters , J Med Chem 1997; 40; 2661- 2673.

64. Meltzer PC, Blundell P, Jones AG, Mahmood A, Garada B, Zimmerman RE, Davison A, Holman BL, Madras BK. A technetium- 99m SPECT imaging agent which targets the dopamine transporter in primate brain, J Med Chem 1997; 40; 1835-1844.

65. Madras BK, Meltzer PC, Liang AY, Hanson R, Elmaleh DE, Babich J, Fischman AJ. [125I]Altropane, a SPECT Imaging Probe for Dopamine Neurons; I. Dopamine Transporter Binding in nonhuman primate brain. Synapse 1998; 29; 93-104.

66. Madras BK, Gracz LM. Meltzer PC, Liang AY, Elmaleh DE, Kaufman MJ, Fischman AJ. [125I]Altropane, a SPECT imaging probe for dopamine neurons; II. In vitro and ex vivo distribution in primate brain. Synapse 1998; 29; 105-115.

67. Madras BK, Gracz LM, Meltzer, PC, Babich J, Fischman AJ. [125I]Altropane, a SPECT imaging probe for dopamine neurons; III. Human dopamine transporter in post-mortem normal and Parkinson’s diseased brain. Synapse 1998; 29;116-127.

68. Fischman AJ, Bonab AA, Babich JW, Palmer P, Alpert NM, Elmaleh DR, Barrow SA, Graham

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W, Meltzer PC, Hanson RH, Madras BK. Rapid detection of Parkinson’s disease with altropane, a SPECT ligand. Synapse 1998; 29; 128-141.

69. Meltzer PC, Blundell P, Madras BK. Structure activity relationships of inhibition of the dopamine transporter by 3-arylbicyclo[3.2.1]octanes. Med Chem Res 1998; 8;12-34.

70. Seeman P and Madras, BK. Anti-Hyperactivity Medications, Molecular Psychiatry, 1998; 3: 386-396.

71. Madras, BK. Imaging the dopamine transporter: a window on dopamine neurons. Advances in Neurodegenerative disorders. 1998. J. Marwah, H. Teitelbaum, Eds., Vol. 1. Parkinson’s disease, pp. 229- 253.

72. Meltzer PC, Blundell P, Chen Z, Yong YF, Madras BK. Bicyclo[3.2.1.]octanes: synthesis and inhibition of binding at the dopamine and serotonin transporters. Bioorg. Med. Chem. Letts.9: 857-862, 1999.

73. De La Garza II, R, Meltzer PC, Madras BK. A non-amine dopamine transporter probe [3H]tropoxene distributes to dopamine-rich regions of monkey brain. Synapse 34: 20-27, 1999.

74. Morris ED, Bonab AA, Alpert NM, Fischman AJ, Madras BK, Christian BT. Concentrations of dopamine transporters: to Bmax or not to Bmax? Synapse, 32: 136-140, 1999.

75. Dougherty, DD, Bonab AA, Spencer TJ, Rauch SL, Madras, BK, Fischman AJ. Dopamine transporter density is elevated in patients with attention deficit hyperactivity disorder. Lancet 354:2132-2133, 1999.

76. Mahmood A, Kronauge JF, Barbarics E, Freiberg E, Madras BK, Li J, Davison A, Jones AG. Technetium (V) and rhenium (V) analogues of Way 100635 5HT1A receptor binding complexes. In: Nicolini M, Mazzi U, eds. Technetium, rhenium and other metals in chemistry and nuclear medicine 5. Padova: Servizi Grafici Editorali; 1999: 393-399.

77. Meltzer PC, Blundell P, Huang H, Liu S, Yong YF, Madras BK. 3-Aryl-2- carbomethoxybicyclo[3.2.1]octenes inhibit WIN 35,428 binding potently and selectively at the dopamine transporter. Bioorg Med Chem 2000 Mar;8(3):581-90.

78. Meschler JP, Clarkson FA, Mathews PJ, Howlett AC, Madras BK. Cannabinoid and D2-like dopamine receptor agonists interact to produce profound sedation in nonhuman primates. J. Pharmacol. Exp. Ther. 292, 952-959, 2000.

79. De La Garza II R. and Madras BK. [3H]PNU-101958, a D4 dopamine receptor probe, accumulates in prefrontal cortex and hippocampus of nonhuman primate brain. Synapse, 37: 232-244, 2000.

80. Dougherty DD, Bonab AA, Spencer TJ, Madras BK, Fischman AJ. Dopamine transporter

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density in patients with ADHD. Lancet 355:1460-1462, 2000. (letter).

81. Goulet M, and Madras BK. D1 dopamine agonists are more effective in advanced than in mild Parkinsonism in MPTP-treated monkeys. J. Pharmacol. Exp. Ther., 292:714-724, 2000.

82. Madras BK, Miller GM, Meltzer PC, Brownell A-L, Fischman AJ. Molecular and regional targets of cocaine in primate brain: liberation from prosaic views. Addiction Biology, 5: 351-359, 2000.

83. Madras BK, Miller GM. DeLa Garza R., Dougherty DD, Bonab AA, Spencer TJ, Rauch SL, Fischman AJ. Brain Imaging of the Dopamine Transporter in ADHD. 6th Internet World Congress for Biomedical Sciences, INABIS, February 14-25, 2000.

84. Meltzer PC, Blundell P, Yong YF, Chen Z, George C, Gonzalez, MD, Madras BK. 2- Carbomethoxy-3,aryl-8-bicyclo[3.2.1]octanes: potent non-nitrogen inhibitors of monoamine transporters, J. Med. Chem., 43:2982-2991, 2000.

85. Dutta A, Reith ME, Madras BK. Synthesis and preliminary characterization of a high affinity novel radioligand for the dopamine transporter, Synapse, 39: 175-181, 2001.

86. Miller GM, De La Garza, R. Novak MA, Madras BK. Single nucleotide polymorphisms distinguish multiple dopamine transporter alleles in primates; implications for association with attention deficit hyperactivity disorder and other neuropsychiatric disorders, Molecular Psychiatry, 6: 50-58, 2001.

87. Miller GM, De La Garza R, Yatin S, Madras BK. Cloning of dopamine, norepinephrine and serotonin transporters from monkey brain: relevance to cocaine sensitivity. Mol. Brain Res., 87: 124-143, 2001.

88. Fischman AJ, Bonab AA, Babich JW, Livni E, Alpert NM, Meltzer PC, Madras BK. [11C, 127I]Altropane: a highly selective ligand for PET imaging of dopamine transporter sites. Synapse, 39: 332-342, 2001.

89. Meschler JP, Howlett AC, Madras, BK. Cannabinoid receptor agonist and antagonist effects on motor function in normal and MPTP (1-methyl-4-phenyl-1,2,5,6,-tetrahydropyridine) treated non-human primates. Psychopharmacology, 156: 79-85, 2001.

90. Meltzer PC, Wang B, Chen Z, Blundell P, Jayaraman M, Gonzalez MD, George C, Madras BK. Synthesis of 6- and 7-hydroxy-8-aza-bicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters. J Med Chem. 44:2619-2635, 2001.

91. Goulet M, Miller GM, Meltzer PC, Madras BK. Non-amines, drugs without an amine nitrogen, potently block serotonin transport (reuptake): novel anti-depressant candidates? Synapse, 42: 129-140, 2001.

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92. Miller GM and Madras BK. Polymorphisms in the 3’-untranslated region of human and monkey dopamine transporter genes affect reporter gene expression. Mol. Psychiatry 7: 44-55, 2002.

93. Madras BK Miller GM Fischman AJ. The dopamine transporter: relevance to attention deficit hyperactivity disorder (ADHD), Behavioral Brain Research 130: 57-63, 2002.

94. Seeman P and Madras B. Methylphenidate elevates resting dopamine which lowers the impulse-triggered release of dopamine: a hypothesis. Behavioral Brain Research 130: 79- 83, 2002.

95. Meltzer PC, Liu S, Blanchette HS, Blundell P, Madras BK. Design and synthesis of a mechanism based irreversible dopamine sparing cocaine antagonist, Bioorg. Med. Chem., 10 2002.

96. Zhdanova, IV, Geiger DA, Schwagerl AL, Leclair OU, Killiany R, Taylor JA, Rosene DL, Moss MB, Madras BK. Melatonin promotes sleep in three species of diurnal nonhuman primates. Physiology and Behavior 75: 523-529, 2002.

97. Yatin SM, Miller GM, Alvarez X, Madras BK. Dopamine transporter–dependent elevation of c-fos expression in HEK-293. Synapse, 45: 52-65, 2002.

98. Meltzer PC, Wang P, Blundell P Madras BK. Synthesis and evaluation of dopamine and serotonin transporter inhibition by oxacyclic and carbacyclic analogues of methylphenidate. J Med Chem. Apr 10;46(8):1538-45, 2003.

99. Madras BK, Fahey MA, Miller GM, De La Garza R, Goulet M, Spealman RD, Meltzer PC, George SR, O'Dowd BF, Bonab AA, Livni E, Fischman AJ. Non-amine-based dopamine transporter (reuptake) inhibitors retain properties of amine-based progenitors. Eur J Pharmacol. 479(1-3):41-51, 2003.

100. Meltzer PC, McPhee M, Madras BK. Synthesis and biological activity of 2-Carbomethoxy-3- catechol-8- azabicyclo[3.2.1]octanes. Bioorg Med Chem Lett. 13(22):4133-7, 2003.

101. Meltzer PC Blundell P, Zona T, Yang L, Huang H, Bonab AA, Livni E, Fischman AJ, Madras BK. A second generation 99mTechnetium SPECT agent that provides in vivo images of the dopamine transporter in primate brain. J Med Chem. 46(16):3483-3496, 2003.

102. Miller GM, Bendor, J, Tiefenbacher, S, Yang, D, Novak, MA, Madras BK. A mu-opioid receptor single nucleotide polymorphism in rhesus monkey: association with stress response and aggression. Mol. Psychiatry, 9(1):99-108, 2004.

103. Meltzer PC and Madras BK. DAT Imaging: from SPECulative to SPECTacular. NIDA Research Monograph 184: 76-79, 2004

105. Saka E, Goodrich, C, Harlan P, Madras BK, Graybiel, AM. Repetitive behaviors in monkeys

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are linked to specific striatal activation maps. J. Neurosci., 24: 7557-7565, 2004.

106. Spencer TJ, Biederman J, Madras KM, Faraone SV, Dougherty DD, Bonab AA, Fischman AJ. In Vivo Neuroreceptor Imaging in Attention-Deficit/Hyperactivity Disorder: A Focus on The Dopamine Transporter. Biological Psychiatry 57: 1293-1300, 2005.

107. Yatin S, Miller GM, Madras BK. Dopamine and norepinephrine transporter-dependent c- Fos production in vitro: relevance to neuroadaptation, J. Neurosci. Methods, 143(1): 69- 78, 2005.

108. Miller GM, Verrico CD, Jassen A, Konar M, Yang H, Panas H, Bahn M, Johnson R, Madras BK. Primate trace amine receptor 1 modulation by the dopamine transporter. J Pharmacol Exp Ther. 2005 Jun;313(3):983-94.

109. Fischman AJ, Madras BK. The Neurobiology of Attention-Deficit/Hyperactivity Disorder. (commentary) Biological Psychiatry 57: 1374-1376, 2005.

110. Madras BK, Miller GM, Fischman AJ. The Dopamine Transporter and Attention Deficit Hyperactivity Disorder (ADHD). Biological Psychiatry, 57(11):1397-1409, 2005.

111. Jassen A, Brown JM, Panas H, Miller GM, Xiao D, Madras BK. Size Variants of the Vesicular Monoamine Transporter2 (VMAT2). Molecular Brain Research, 2005 Oct 3;139(2):251-7.

112. Andersen CM, Maas LC, Cowen RL, Bendor J, Lukas SE, Madras BK, Renshaw PF, Kaufman MJ. Cocaine cues activate cerebellar vermis: evidence for a vermis role in drug-seeking behaviors. Neuropsychopharmacology, 2006 Jun;31(6):1318-26.

113. Verrico C, Miller GM, Madras BK. MDMA (Ecstasy) and Human Dopamine, Norepinephrine and Serotonin Transporters: Implications for MDMA-Induced Neurotoxicity and Treatment. Psychopharmacology, 2007 Jan;189(4):489-503

114. Xiao D, Miller GM, Westmoreland SV, Pauley D, Madras BK. EphA4 and ephrin-B2, implicated in memory and drug-induced neuroadaptation, are expressed in the adult primate brain, Brain Research, 1067: 67-77, 2006.

115. Spencer TJ, Biederman J, Ciccone P, Madras BK, Dougherty D, Bonab A, Livni E, Fischman, AJ. A PET Study Examining Pharmacokinetics, Detection and Likeability, and Dopamine Transporter Receptor Occupancy Of Short and Long-Acting Orally Administered Formulations of Methylphenidate in Adults. American Journal Psychiatry, Mar 163(3), 387-395, 2006.

116. Torun L, Liu SH, Madras BK, Meltzer PC. Synthesis of 3-(4-Heteroaryl-phenyl)-8- oxabicyclo[3.2.1]octane-2-carboxylic Acid Methyl Ester, Tetrahedron Letters 47: 599-603, 2006.

117. Meltzer PC, Butler D, Deschamps JR, Madras BK.1-(4-Methylphenyl)-2-pyrrolidin-1-yl-

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pentan-1-one (Pyrovalerone) analogs. A promising class of monoamine uptake inhibitors. J. Med. Chem., 2006 Feb 23;49(4):1420-32.

118. Jassen AK, Yang H, Miller GM, Calder E, and Madras BK. Receptor regulation of axon guidance molecule gene expression. Mol. Pharmacol. 70: 71-77, 2006.

119. Madras BK, Fahey MA, Goulet M, Lin Z, Bendor J, Goodrich C, Meltzer PC, Elmaleh DR, Livni E, Bonab AA, Fischman AJ. Dopamine Transporter (DAT) Inhibitors Alleviate Specific Parkinsonian Deficits in Monkeys: Association with DAT Occupancy in Vivo. J Pharmacol Exp Ther. 2006 Nov;319(2):570-85.

120. Madras BK, Xie Z, Lin Z, Jassen A, Panas H, Lynch L, Johnson R, Livni E, Spencer TJ, Bonab AA, Miller GM, Fischman AJ. Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro. J Pharmacol Exp Ther. 2006 Nov;319(2):561-9.

121. Pham-Huu D-P, Deschamps JR, Liu S, Madras BK, Meltzer PC. Synthesis of 8- Thiabicyclo[3.2.1]octanes and Their Binding Affinity for the Dopamine and Serotonin Transporters, Bioorg Med Chem. 2007 Jan 15;15(2):1067-82.

122. Spencer TJ, Biederman J, Madras BK, Dougherty DD, Bonab AA, Livni E, Meltzer PC, Martin J, Rauch S, Fischman AJ. Further Evidence of Dopamine Transporter Dysregulation in ADHD: A Controlled PET Imaging Study Using Altropane. Biol Psychiatry 2007 May 16; epub; Biol Psychiatry. 2007 Nov 1;62(9):1059-61.

123. Xie Z, Westmoreland SV, Bahn ME, Chen GL, Yang H, Vallender EJ, Yao WD, Madras BK, Miller GM. Rhesus monkey trace amine-associated receptor 1 signaling: enhancement by monoamine transporters and attenuation by the D2 autoreceptor in vitro. J Pharmacol Exp Ther. 2007 Apr;321(1):116-27.

128. Verrico CD, Lynch L, Fahey MA, Fryer AK, Miller GM, Madras BK. MDMA-induced impairment in primates: antagonism by a selective norepinephrine or serotonin, but not by a dopamine/norepinephrine transport inhibitor. J Psychopharmacol. 2008 Mar;22(2):187-202.

129. Madras BK. Compton WM, Avula D, Stegbauer T, Stein JB, Clark HW. Screening, brief interventions, referral to treatment (SBIRT) for illicit drug and alcohol use at multiple healthcare sites: comparison at intake and 6 months later. Drug Alcohol Depend. 2009 Jan 1;99(1-3):280-95.

130. Madras, BK. Office of National Drug Control Policy: A Scientist in Drug Policy in Washington, DC, Annals of the NY Acad. Sci. 1187: 370-402, 2010.

131. Madras BK. Candidate performance measures for screening for, assessing, and treating unhealthy substance use in hospitals. Ann Intern Med. 2011 Jan 4;154(1):72-3; author reply 73-4.

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132. Purushotham M, Sheri A, Pham-Huu DP, Madras BK, Janowsky A, Meltzer PC. The synthesis and biological evaluation of 2-(3-methyl or 3-phenylisoxazol-5-yl)-3-aryl-8- thiabicyclo[3.2.1]octanes. Bioorg Med Chem Lett. 2011 Jan 1;21(1):48-51.

133. Spencer TJ, Madras BK, Bonab AA, Dougherty DD, Clarke A, Mirto T, Martin J, Fischman AJ. A positron emission tomography study examining the dopaminergic activity of armodafinil in adults using [¹¹C]altropane and [¹¹C]raclopride. Biol Psychiatry. 2010 Nov 15;68(10):964-70.

134. Westmoreland SV, Annamalai L, Lentz MR, Ratai EM, Assaf B, Boisvert K, Huynh T, Vallender EJ, Miller GM, Madras BK, Gonzalez RG. Growth associated protein-43 and Ephrin B3 Induction in the Brain of Adult SIV-infected Rhesus Macaques. Journal of Neurovirology. 2011 Oct;17(5):455-68.

135. Torun L, Madras BK, Meltzer PC. Synthesis and structure-activity relationship studies of 3- biaryl-8-oxabicyclo[3.2.1]octane-2-carboxylic acid methyl esters. Bioorg Med Chem. 2012, 20: 2762-2772.

136. Madras, BK. History of the Discovery of the Antipsychotic Dopamine D2 Receptor, a Basis for the Dopamine Hypothesis of Schizophrenia. Journal of the History of the Neurosciences: Basic and Clinical Perspectives, 22:1, 62-78, 2013.

137. NP Katz, MD, H Birnbaum, MJ Brennan, JD Freedman, GP Gilmore, D Jay, GA Kenna, BK Madras, L McElhaney, RD Weiss, AG White. Prescription Opioid Abuse: Challenges and Opportunities for Payers. The American Journal of Managed Care 19: 295-302, 2013.

138. Spencer, T, Madras BK, Fischman AJ. Krause, J, La Fougere, C. Striatal dopamine transporter binding in adults with ADHD. Am. J. Psychiatry, 2012 169: 665.

139. Spencer TJ, Biederman J, Faraone SV, Madras BK, Bonab AA, Dougherty DD, Batchelder H, Clarke A, Fischman AJ. Functional Genomics of Attention-Deficit/Hyperactivity Disorder (ADHD) Risk Alleles on Dopamine Transporter Binding in ADHD and Healthy Control Subjects. Biol. Psychiatry 74: 84-89, 2013.

140. Faraone SV, Spencer TJ, Madras BK, Zhang-James Y, Biederman J. Functional Effects of Dopamine Transporter Gene Genotypes on in vivo Dopamine Transporter Functioning: A Meta-Analysis, Mol Psychiatry. 2013 Sep 24. doi:10.1038/mp.2013.126

141. Faraone SV, Spencer TJ, Madras BK, Zhang-James Y, Biederman J.Response to Selveraj et al. Mol Psychiatry. 2014 Apr 1. doi: 10.1038/mp.2014.26. [Epub ahead of print]

142. Madras BK. Invited Commentary, Dopamine Challenge Reveals Neuroadaptive Changes in Marijuana Abusers. Proc Natl Acad Sci, USA, 2014, in press.

In preparation (partial list)

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Madras BK, Miller GM, Verrico CD, Lin Z, Panas, H, Jassen AK. [3H]Phenethylamine transport blockade by therapeutic and addictive drugs: implications for mechanisms of therapeutic and addictive processes, in preparation. Madras BK et al., PET imaging of the dopamine transporter, a window on dopamine neuron regeneration? In preparation. Goulet, M and Madras BK. Juvenile rhesus monkeys response to methylphenidate depends on baseline level of activity: a naturalistic primate model of ADHD? Madras BK. Imaging the dopamine system in neuropsychiatric disorders: Parkinson’s disease, ADHD, stimulant abuse, in preparation. Madras BK, Vallender E, Miller GM, Constant B, Walsh, T. Dopamine receptor agonists alter expression of genes implicated in neurodevelopment in hippocampus. Madras BK, Meltzer PC, Bonab AA, Fischman AJ. Dopamine Transporter (DAT) Occupancy of Stimulant Drugs With PET: Relevance to Abuse Liability and Drug Scheduling . Madras BK et al, Methamphetamine, MDMA and THC affect neurodevelopmental genes, activity and markers for dopamine neurons differently in adolescent and adult brain, in preparation.

Proceedings of Meetings

1. Fernstrom JD, Madras BK, Munro HN, Wurtman RJ. Nutritional control of the synthesis of 5- hydroxytryptamine in the brain. Aromatic amino acids in the brain. Amsterdam; ASP Elsevier 1974; 153-173. 2. Madras BK, Davis A, Kunashko P, Seeman P. Solubilization of dopamine receptors from dog and human brains. In; Yamamura HI, Olsen RW, Usdin E, eds. Psychopharmacology and Biochemistry of Neurotransmitter receptors North Holland; Elsevier 1980; 411-419. 3. Madras BK Chan B. Modulation of dopamine receptor binding by ascorbic acid. Adv. Biochem Psychopharmacol. 1983; 37: 275-287.

4. Spealman RD, Bergman J, Madras BK, Kamien JB, Melia KF Role of D1 and D2 dopamine receptors in the behavioral effects of cocaine. Neurochem. Int 1992; 20:1475-1483. 5. Neumeyer JL, Baindur N, Bakthavachalam V, Yuan J, Madras BK, Kula NS, Campbell A, Baldessarini RJ. Selective probes for characterization of dopamine D1 and D2 receptors, Neurochem Int 1992; 20;63S - 68S.

Books, monographs, text books

1. Madras BK, Colvis CM, Pollack JD, Rutter JL, Shurtleff D, von Zastrow M, (eds.) Cell Biology of Addiction. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2006. 2. Robert L. DuPont, Bertha K. Madras, & Per Johansson. Section 12: Policy Issues, Chapter 77, Drug policy: A biological science perspective. In J. H. Lowinson & P. Ruiz (Eds.) Substance Abuse: A Comprehensive Textbook (5th ed.). Lippincott Williams & Wilkins, 530 Walnut Street Philadelphia, PA 19106, 2011.

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3. Madras B.K. and Kuhar, MJ, (Eds.) The Effects of Drug Abuse on the Human Nervous System, Elsevier Press, 2014. 4. Seeman, P and Madras BK, editors. Imaging of the Human Brain in Health and Disease Elsevier Press, 2014.

Reviews, Chapters, Editorials, Commentary

1. Madras BK. Schizophrenia and drugs. Report of the Director, Office of Research Administration, University of Toronto; 1981; 22-23; 321-329. 2. Madras BK. Schizophrenia; The biochemical story. Future Health; 1982; 4;7-8. 3. Whitaker PM, Kish SJ, Madras BK. Direct binding assays in determining psychotropic drug mechanism of action. Revs in Pure and Applied Pharmacol. Sci. 1983; 4;271-338. 4. Madras BK. Dopamine. In; Lajtha A, ed. Handbook of Neurochemistry. New York; Plenum Press, 1984; 6;71-106. 5. Madras BK. Book Review; Neuromethods; Series 1; Neurochemistry. J Med Chem 1987; 30;956. 6. Madras BK. Book Review; Neuromethods Vol. 1. J Med Chem. 1987; 30: 956-957. 7. Madras BK. Book Review; Neuromethods Vol. 2. J Med Chem. 1987; 30: 957. 8. Madras BK. Book Review; Neuromethods Vol. 3 J Med Chem. 1987; 30: 957-958 9. Madras, BK. The Pathophysiology of Schizophrenia. The Dopamine Hypothesis in Schizophrenia Management; Emerging perspectives. 1992; Vol.1, 1-4 10. Madras, BK. Changing your mind; drugs in the brain. Treatment Today, 1997; 9, #1; 16 11. Madras BK. Imaging the dopamine transporter: a window on dopamine neurons. Advances in Neurodegenerative disorders. 1998 (J. Marwah and H. Teitelbaum, eds.) Vol. 1 Parkinson’s disease, pp. 229- 253. Prominent Press, Scottsdale, AZ 12. Miller GM and Madras BK. Genetic variation and phenotype associations common to rhesus monkeys and humans, in The Laboratory Primate, Sonia Wolfe-Coote editor, Elsevier Academic Press, October 2005. 13. Lin Z and Madras BK Human Genetics of Neurotransmitter Transporters, in Handbook of Experimental Pharmacology, Neurotransmitters Transporters M Freissmuth and H Sitte, editors, Springer-Verlag, 175: 327-371, 2006. 14. BK Madras. The Biology of Addiction, in New Strategies for Success, New pathways to drug abuse prevention. ONDCP publication, Vol. 1 No 1.Fall/Winter, 2006. 15. BK Madras. The Biology of Addiction: Volunteer behavior and genetics. in New Strategies for Success, New pathways to drug abuse prevention. ONDCP publication, Vol. 1 No 3. Summer/Fall, 2008 16. BK Madras. Changing your mind: methamphetamine and MDMA in the brain. New Strategies for Success, New pathways to drug abuse prevention. ONDCP publication, Vol. 1 No 3. Summer/fall, 2008.

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17. BK Madras. Introduction to “Cell Biology of Addiction”. Editors: Madras BK, Colvis CM, Pollack JD, Rutter JL, Shurtleff D, von Zastrow M, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp 1-12, 2006. 18. Madras BK and von Zastrow, M Preface to “Cell Biology of Addiction” Madras et al, Editors, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp ix-x, 2006. 19. Madras BK and Lin, Z. Cocaine Neurobiology: From targets to treatment approaches, in “Cell Biology of Addiction”, Editors, Madras BK, Colvis CM, Pollack JD, Rutter JL, Shurtleff D, von Zastrow M, Editors, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp 239-269, 2006. 20. Madras BK. “Unique Consequences of Addiction” in the American Psychological Association Addiction Syndrome Handbook, HJ Shaffer, Ed., 2012. 21. Madras, B.K. Drug use and Consequences (2014) In: The Effects of Drug Abuse on the Human Nervous System; B. Madras and M.J. Kuhar (Eds.), Elsevier, in press. www.neuroscience.com. 22. Madras BK. Prop 19: Indifference to Public Health. The Journal of Global Drug Policy and Practice vol. 4 (#3), Fall, 2010. 23. Madras BK. Designer Drugs: An Escalating Public Health Challenge, The J. Global Drug Policy and Practice, 6:(3): 1-57, 2012. 24. Madras BK. Medical Marijuana Reflects an Indifference to Public Health, The J. Global Drug Policy and Practice. 8(2): 11 pages, Sept 2014.

Letters to the Editor, other commentaries

1. Madras, BK. C-11-WIN 35,428 for detecting dopamine depletion in mild Parkinson’s disease. Ann. Neurology, 1994; 35;376-377. (letter)

2. Meltzer PC, Madras BK. Imaging of dopamine transporters in humans with technetium-99m TRODAT-1. Eur. J. Nucl. Med., 1997; 24; 462. (letter)

3. Dougherty DD. Bonab AA, Spencer TJ, Madras BK, Fischman AJ. Dopamine transporter density in patients with ADHD. Lancet 355: 1460-1462, 2000. (letter)

4. Madras BK, Medical Marijuana, The Economist 2006. 5. Madras BK, Congressional testimony to the US House of Representatives on “:the availability and effectiveness of programs to treat victims of the methamphetamine epidemic”, House of Representatives Committee on Government Reform, Subcommittee on Criminal Justice, Drug Policy and Human Resources, June, 2006.

6. Madras BK, Congressional testimony to the US House of Representatives on “Government Response to Prescription Drug Abuse, Committee on Government Reform Subcommittee on Criminal Justice, Drug Policy, and Human Resources. July, 2006.

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7. Madras BK, Comments to US House of Representatives, House Government Reform Committee, Zero Tolerance Roundtable on Anabolic Steroids, August 30, 2006,

8. Madras BK, Should medical marijuana be approved? Massachusetts Lawyers’ Weekly March 2010.

9. Madras, BK. Candidate performance measures for screening, assessing, and treating unhealthy substance use in hospitals. Ann Intern Med. 2011 Jan 4;154(1):72-3.

10. Faraone SV, Spencer TJ, Madras BK, Zhang-James Y, Biederman J. Mol. Psychiatry, letter to the Editor, Paper #2014MP000010R

Patents: issued

1. 5,493,026: Elmaleh DE, Madras BK, Hanson R, Meltzer PC Substituted 2-carboxyalkyl-3- (fluorophenyl)-8-(3-halopropen-2-yl)nortropanes and their use as imaging agents for neurodegenerative disorders. Feb 20, 1996.

2. 5,506,359: Madras BK and Meltzer PC. Cocaine analogues and their use as cocaine drug therapies and therapeutic and imaging agents for neurodegenerative disorders. April 9, 1996.

3. 5,770,180. Madras BK and Meltzer PC. Bridge-substituted tropanes for methods of imaging and therapy. June 23 1998.

4. 5,853,696. Elmaleh DE, Madras BK, Meltzer PC, Hanson RN. Substituted 2-carboxyalkyl-3(fluorophenyl)-8-(3-halopropen-2-yl) nortropanes and their use as imaging agents for neurodegenerative disorders. Dec 29, 1998.

5. 5,948,933. Meltzer PC, Madras BK Blundell P Chen Z. Tropane analogs and methods for inhibition of dopamine transport, Sept 7, 1999.

6. 6,171,576. Meltzer PC, Madras BK, Davison A, Blundell P, Mahmood A, Jones AG. Dopamine transporter imaging agent. Jan 9, 2001.

7. 6,291,512.Meltzer; PC. Madras; BK.; Blundell; P; Chen; Z. Sept. 18, 2001 (withdrawn)

8. 6,353,105. Meltzer; PC; Madras; BK.; Blundell; P; Chen; Z. Tropane analogs and methods for inhibition of monoamine transport, March 5, 2002.

9. 6,417,221. Meltzer; Peter C; Madras; BK.; Blundell; P Chen; Z. Tropane analogs and methods for inhibition of monoamine transport. July 9, 2002.

10. 6,525,206. Meltzer PC, Blundell P, Wang P, Madras BK. Compounds with high monoamine transporter affinity. February 25, 2003.

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11. 6,548,041. Meltzer PC, Blundell P, Madras BK, Fischman AJ, Jones AG., Mahmood A. Dopamine transporter imaging agents. April 15, 2003.

12. 6,670,375. Meltzer PC, Madras BK, Blundell P, Chen Z. Tropane analogs and methods for inhibition of monoamine transport December 30, 2003.

13. 6,677,338. Madras BK and Meltzer PC. Serotonin transport inhibitors, January 13 2004.

14. 7,026,516. Meltzer; Peter C. Blundell; Paul Wang; Pinglang Madras; Bertha K. Compounds with high monoamine transporter affinity April 11, 2006.

15. 7,081,238. Madras; BK. Fischman; AJ. Meltzer; PC. Methods for diagnosing and monitoring treatment ADHD by assessing the dopamine transporter level July 25, 2006.

16. 7,105,678. Meltzer, Peter C, Blundell, Paul, Madras, Bertha K. Boat tropanes. September 12, 2006.

17. 7,199,132. Meltzer, Peter C., Madras; Bertha K., Blundell; Paul. Tropane analogs and methods for inhibition of monoamine transport April 3, 2007.

18. 7,439,264. Meltzer, Peter C. Madras, Bertha K. Blundell, Paul, Liu, Shanghao. Therapeutic compounds, October 21, 2008.

19. 7,476,740 Blundell, Paul, Meltzer, Peter C., Madras, Bertha K. Tropane compounds, January 13, 2009.

20. 7,553,478. Madras; Bertha K. Fischman; Alan J., Meltzer; Peter C. Methods for diagnosing and monitoring treatment ADHD by assessing the dopamine transporter level. June 30, 2009.

Educational Materials

1. BK Madras, Syllabus for Substance abuse; addictive processes, Advanced Biomedical Sciences Course, Harvard Medical School. (2001-)

2. BK Madras, Syllabus for Cold Spring Harbor Laboratory Course Cell Biology of Addiction. (2001-2005)

3. BK Madras, 12-page Guide for CD-ROM, “Changing Your Mind: Drugs in the Brain.” (1995- 1996)

4. BK Madras and L Sato, CD-ROM “Changing Your Mind: Drugs in the Brain.” (1994-1996)

5. BK Madras and M Kopelow. Webcast for physicians, of screening, brief intervention and referral to treatment services. Accreditation Counsel for Continuing Medical Education (ACCME), Chicago, IL, 2008-present.

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Museum Exhibits

1. Madras BK and Museum of Science, Boston personnel. Museum Exhibit; “Changing your mind; drugs in the brain”. On exhibit at Museum of Science, Boston, 1994-1997; 1999- 2005, after national tour.

2. Traveling exhibit and abbreviated version of above mentioned exhibit, “Changing your mind; drugs in the brain”, for Danish Year of the Brain, 1997.

3. DEA-NIDA Museum Exhibit. Contributed to storyboard and images for exhibit, 1 Times Square, NYC, NY

Non-print materials (partial listing; numerous TV, radio and print interviews have not been documented)

1. Madras BK, 2013-2014: CNN International, NPR, NBC, Al Jazeera, NECN interviews. 2. Madras BK., 2013: Designer Drugs, Webinar broadcast nationally DFA 3. Madras BK, 2012: Gil Kerlikowske, Steve Pasierb, Sofia; Jeff VanVonderen, A&E channel webinar on The Medicine Abuse Project. 4. Madras, BK. 2006-2012: Over 165 radio, TV, newspaper, magazine interviews and articles, including NY Times, NPR, CBS local affiliate, CNN, Fox news, etc. No formal records kept. 5. Madras BK. 2008: Webcast of ACCME discussion (Parts 1 and 2) on screening, brief intervention referral to treatment. 6. Madras BK, 2001, March: Discovery Health Channel, Drug Addiction Research 7. Madras BK, 2000: Neurotransmitter receptors, videotape, ASPET course 8. 1997: Audiotape, National Public Radio, Grey Matters; Alcohol, Drugs in the Brain. 9. 1996: Videotape of presentation, “Changing your mind: drugs in the mature brain, AARP 10. 1996: Audiotape of presentation, “Changing your mind: drugs in the brain”, Smithsonian Institute. 11. Madras BK and Sato L, CD-ROM; “Changing your mind; drugs in the brain”, on exhibit with Museum exhibit in U.S. and in Denmark. Over 3,500 copies distributed in 1996-1998. 12. Madras BK. Neurotransmitter Receptor Course. Videotape. American College of Neuroradiology, 1990 13. Madras BK, with cast of approximately 15. Television commercial and public transit ads for schizophrenia research, Ontario, Canada. 14. Madras, BK. Neurotransmitter and receptor update course, audiotape. Congress of Neurological Surgeons, 1982

Abstracts (Partial list of recent abstracts, of > 200)

1. Madras, AA Bonab, AJ. Fischman Dopamine Transporter Binding Potential Increases Following an Acute Dose of MDMA (Ecstasy), SNM annual meeting, 2009. J Nuclear Med. 2009: 50 (Supple 2) 1223.

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2. Madras, BK and Panas, H. A link between β-phenethylamine (PEA), the dopamine transporter, and the behavioral effects of cocaine, methylphenidate. SFN abstract, 2009.

3. Madras BK. The case for mainstreaming screening, brief interventions and referral to treatment (SBIRT) for substance abuse, into our healthcare system, SFN abstract, 26.7/HH31; 2009.

4. BK. Madras, G Miller, E Vallender. Axonal guidance molecules in mouse hippocampus, CPDD, 2010.

5. Madras BK, Miller GM, Vallender E. Methamphetamine modulates axonal guidance molecules in mouse hippocampus, SFN abstract, 2010.

6. Madras BK, Vallender E, Miller, GM, Constant B. MDMA (ecstasy) regulates activity and genes implicated in neurodevelopment differently in brain of adolescent and adult mice. ACNP, annual meeting Dec 2010.

7. Madras BK, Vallender E, Miller GM. Methamphetamine produces contrasting effects on expression of neurodevelopmental genes in adolescent and adult mice: relevance to adolescent addiction? CPDD, 2011.

8. Madras, BK, Meltzer, PC, Bonab AA, Livni E, Fischman, AJ. PET Imaging Detects Dopamine Transporter (DAT) Occupancy by Pyrovalerone Analogs: A Novel Class of potentially abusable drugs. SNM, 2011.

9. Spencer TJ, Madras BK, Bonab AA, Dougherty DD, Clarke A, Mirto T, Martin J, Fischman AJ. Comparing Dopaminergic Activity (PET) of Armodafinil and Methylphenidate. AACAP/CACAP Joint annual meeting, Oct 18-23, 2011, Toronto, ON Canada.

10. Madras BK, Constant B, Walsh T, Ogawa L, Miller GM, Vallender E, Westmoreland S. Peripheral Markers of Psychostimulant Abuse, ACNP Waikoloa, HI, 2011.

11. Madras, BK. Cocaine analogs and the Dopamine Transporter: The Path from Addiction to Drug Development, in Symposium Imaging Studies of Drug Transport and Response. American Society of Clinical Pharmacology and Therapeutics: Maryland, March 2012.

12. Madras BK. MDMA and Methamphetamine elicit contrasting behavioral and molecular responses in the adolescent and adult mouse in Symposium: Drug effects on the adolescent brain. CPDD annual meeting, Palm Springs, CA, 2012

13. Madras, BK. A scientist in the media spotlight: converging and conflicting missions. CPDD annual meeting, Palm Springs, CA, June 2012

14. Thomas J Spencer, Joseph Biederman, Stephen V. Faraone, Bertha K. Madras, Ali A. Bonab, Darin D. Dougherty, Holly Batchelder, Allison Clarke, and Alan J. Fischman. Functional

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Genomics of ADHD Risk Alleles on DAT Binding in ADHD and Healthy Controls. AACAP/CACAP Joint annual meeting, 2012.

15. Alan J. Fischman, Ali A. Bonab, Joseph Biederman, Bertha K. Madras, Darin D. Dougherty, MD, Thomas J. Spencer. Effects of DAT Gene polymorphisms and ADHD Status on DAT Binding Measured with PET. Soc, Nuclear Medicine, annual meeting June 2012.

16. Madras, Bertha K, Meltzer, Peter, Bonab, Ali A., Fischman, Alan J. Drug potencies in vitro do not predict dopamine transporter (DAT) occupancy in living brain. Soc. Nuclear Medicine, annual meeting, June 2012.

17. Madras, Bertha K, Meltzer, Peter, Bonab, Ali A., Fischman, Alan J Dopamine transporter (DAT) occupancy of stimulant designer drugs with PET: relevance to abuse liability and drug scheduling . SNM, 2013

18. Bertha K Madras, Tim Walsh, Lisa Ogawa, Karen Boisvart, Eric Vallendar, Gregory Miller, Susan Westmoreland. Dopamine systems in adolescent and adult brain respond differently to methamphetamine. CPDD annual meeting, 2013

19. Bertha K Madras, Gregory Miller, Lisa Ogawa, Josh Zimmer, Karen Boisvart, Eric Vallendar, Gregory Miller, Susan Westmoreland, Yasmin Hurd. THC Elicits Temporary or Persistent Changes in Expression of Genes Implicated in Neurodevelopment in Adolescent Rat Brain Regions, ACNP annual meeting, 2013.

20. Bertha K Madras, Gregory Miller, Lisa Ogawa, Josh Zimmer, Karen Boisvart, Eric Vallendar, Gregory Miller, Susan Westmoreland, Yasmin Hurd. THC (Δ9-tetrahydrocannabinol) elicits persistent changes in expression of genes implicated in adolescent neurodevelopment, CPDD abstract. 2014

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Exhibit B

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Reference List

Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, Kelly ME, Rowbotham MC, Petersen KL. Cannabis in painful HIV-associated sensory neuropathy: A randomized placebo- controlled trial. Neurology 2007 68: 515-521.

Aceto MD, Scates SM, Lowe JA, Martin BR. Cannabinoid precipitated withdrawal by the selective cannabinoid receptor antagonist, SR 141716A. Eur J Pharmacol 1995;282(1-3): R1-2.

Adams IB, Martin BR. Cannabis: pharmacology and toxicology in animals and humans. Addiction 1996;91(11):1585-614.

Adler JN, Colbert JA. Clinical decisions, Medicinal use of marijuana--polling results, N Engl J Med. 2013 May 0;368(22):e30

Agrawal A; Pergadia ML; Lynskey MT: Is there evidence for symptoms of cannabis withdrawal in the National Epidemiologic Survey on Alcohol and Related Conditions? Am J Addict 2008; 17:199–208

Andréasson S, Allebeck P, Engström A, Rydberg U. Cannabis and schizophrenia. A longitudinal study of Swedish conscripts. Lancet. 1987 Dec 26;2(8574):1483-6..

Arnold JC, Hone P, Holland ML, Allen JD. CB2 and TRPV1 receptors mediate cannabinoid actions on MDR1 expression in multidrug resistant cells. Pharmacol Rep. 2012;64(3):751-7.

Arseneault L, Cannon M, Witton J, Murray RM. Causal association between cannabis and psychosis: examination of the evidence. Br J Psychiatry. 2004 Feb;184:110-7. Review.

Barnett G, Chiang CW, Perez-Reyes M, Owens SM. Kinetic study of smoking marijuana. J Pharmacokinet Biopharm 1982;10(5):495-506.

Baselt RC. Drug effects on psychomotor performance. Biomedical Publications, Foster City, CA; pp 403-415;2001.

Battistella G, Fornari E, Annoni JM, Chtioui H, Dao K, Fabritius M, Favrat B, Mall JF, Maeder P, Giroud C. Long-term effects of cannabis on brain structure. Neuropsychopharmacology. 2014 Aug;39(9):2041-8.

Bayewitch M, Rhee MH, Avidor-Reiss T, Breuer A, Mechoulam R, Vogel Z (-)-Delta9- tetrahydrocannabinol antagonizes the peripheral cannabinoids receptor-mediated inhibition of adenylyl cyclase. J Biol Chem. 1996 Apr 26;271(17):9902-5.

Bedi G, Foltin RW, Gunderson EW, Rabkin J, Hart CL, Comer SD, Vosburg SK, Haney M. Efficacy and tolerability of high-dose dronabinol maintenance in HIV-positive marijuana smokers: a controlled laboratory study. Psychopharmacology (Berl). 2010 Dec;212(4):675-86.

Ex. B-1 Case 2:11-cr-00449-KJM Document 324-2 Filed 07/29/14 Page 3 of 18

Ben Amar M. Cannabinoids in medicine: A review of their therapeutic potential. J Ethnopharmacol. 2006 Apr 21;105(1-2):1-25.

Bicher HI, Mechoulam R. Pharmacological effects of two active constituents of marihuana. Arch Int Pharmacodyn Ther. 1968 Mar;172(1):24-31.

Böcker KB, Gerritsen J, Hunault CC, Kruidenier M, Mensinga TT, Kenemans JL. Cannabis with high δ9-THC contents affects perception and visual selective attention acutely: an event-related potential study. Pharmacol Biochem Behav. 2010 Jul;96(1):67-74.

Bostwick JM, Reisfield GM, DuPont RL. Clinical decision, Medicinal use of marijuana. N Engl J Med. 2013 Feb 28;368(9):866-8

Brady JE and Li G, Trends in Alcohol and Other Drugs Detected in Fatally Injured Drivers in the United States, 1999-2010, Am J Epidemiol. 17: 692-699, 2014

Brady KT, Balster RL. The effects of delta 9-tetrahydrocannabinol alone and in combination with cannabidiol on fixed-interval performance in rhesus monkeys. Psychopharmacology (Berl). 1980;72(1):21-6.

Budney AJ; Hughes JR; Moore BA; Vandrey R: Review of the validity and significance of cannabis withdrawal syndrome. Am J Psychiatry 2004; 161:1967–1977.

Budney AJ; Moore BA; Vandrey RG; Hughes JR: The time course and significance of cannabis withdrawal. J Abnorm Psychol 2003; 112:393–402.

Budney AJ; Hughes JR: The cannabis withdrawal syndrome. Curr Opin Psychiatry 2006; 19:233–238

Budney AJ; Vandrey RG; Hughes JR; Moore BA; Bahrenburg B: Oral delta-9- tetrahydrocannabinol suppresses cannabis withdrawal symptoms. Drug Alcohol Depend 2007; 86:22–29

Budney AJ; Vandrey RG; Hughes JR; Thostenson JD; Bursac Z: Comparison of cannabis and tobacco withdrawal: severity and contribution to relapse. J Subst Abuse Treat 2008; 35:362–368

Buckner JD, Ecker AH, Cohen AS. Mental health problems and interest in marijuana treatment among marijuana-using college students. Addict Behav. 2010 Sep;35(9):826-33.

Burstein SH, Audette CA, Breuer A, Devane WA, Colodner S, Doyle SA, Mechoulam R. Synthetic nonpsychotropic cannabinoids with potent antiinflammatory, analgesic, and leukocyte antiadhesion activities. J Med Chem. 1992 Aug 21;35(17):3135-41.

Ex. B-2 Case 2:11-cr-00449-KJM Document 324-2 Filed 07/29/14 Page 4 of 18

Caldeira KM, Kasperski SJ, Sharma E, Vincent KB, O'Grady KE, Wish ED, Arria AM. College students rarely seek help despite serious substance use problems. J Subst Abuse Treat. 2009 Dec;37(4):368-78.

Caldeira KM, Arria AM, O'Grady KE, Vincent KB, Wish ED. The occurrence of cannabis use disorders and other cannabis-related problems among first-year college students. Addict Behav. 2008 Mar;33(3):397-411.

Callaghan RC, Cunningham JK, Verdichevski M, Sykes J, Jaffer SR, Kish SJ.All-cause mortality among individuals with disorders related to the use of methamphetamine: a comparative cohort study. Drug Alcohol Depend. 2012 Oct1;125(3):290-4.

Calvigioni D, Hurd YL, Harkany T, Keimpema E. Neuronal substrates and functional consequences of prenatal cannabis exposure. Eur Child Adolesc Psychiatry. 2014 May 3.

Cannabis-In-Cachexia-Study-Group, Strasser F, Luftner D, Possinger K, Ernst G, Ruhstaller T, Meissner W, Ko YD, Schnelle M, Reif M, Cerny T. Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia- cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group. J Clin Oncol. 2006 Jul 20;24(21):3394-400.

Chadwick B, Miller ML, Hurd YL. Cannabis Use during Adolescent Development: Susceptibility to Psychiatric Illness. Front Psychiatry. 2013 Oct 14;4:129.

Cooper ZD, Haney M. Opioid antagonism enhances marijuana's effects in heavy marijuana smokers. Psychopharmacology (Berl). 2010 Aug;211(2):141-8.

Cooper ZD, Comer SD, Haney M. Comparison of the analgesic effects of dronabinol and smoked marijuana in daily marijuana smokers. Neuropsychopharmacology. 2013 Sep;38(10):1984-92.

Corey-Bloom J, Wolfson T, Gamst A, Jin S, Marcotte T, Bentley H, Gouaux B. (2012). Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. CMAJ, 184 (10):1143-50.

Cornelius JR; Chung T; Martin C; Wood DS; Clark DB: Cannabis withdrawal is common among treatment-seeking adolescents with cannabis dependence and major depression, and is associated with rapid relapse to dependence. Addict Behav 2008; 33:1500–1505

Consroe P, Benedito MA, Leite JR, Carlini EA, Mechoulam R. Effects of cannabidiol on behavioral seizures caused by convulsant drugs or current in mice. Eur J Pharmacol. 1982 Sep 24;83(3-4):293-8.

Chung T; Martin CS; Cornelius JR; Clark DB: Cannabis withdrawal predicts severity of cannabis involvement at 1-year follow-up among treated adolescents. Addiction 2008; 103:787–

Ex. B-3 Case 2:11-cr-00449-KJM Document 324-2 Filed 07/29/14 Page 5 of 18

799

Copersino ML; Boyd SJ; Tashkin DP; Huestis MA; Heishman SJ; Dermand JC; Simmons MS; Gorelick DA: Cannabis withdrawal among non-treatment-seeking adult cannabis users. Am J Addict 2006; 15:8–14

Crean RD, Tapert SF, Minassian A, Macdonald K, Crane NA, Mason BJ. Effects of chronic, heavy cannabis use on executive functions. J Addict Med. 2011

Crean RD, Crane NA, Mason BJ. An evidence based review of acute and long-term effects of cannabis use on executive cognitive functions. J Addict Med. 2011 Mar;5(1):1-8

Degenhardt L, Ferrari AJ, Calabria B, Hall WD, Norman RE, McGrath J, Flaxman AD, Engell RE, Freedman GD, Whiteford HA, Vos T. The global epidemiology and contribution of cannabis use and dependence to the global burden of disease: results from the GBD 2010 study. PLoS One. 2013 Oct 24;8(10):e76635.

Degenhardt L, Coffey C, Romaniuk H, Swift W, Carlin JB, Hall WD, Patton GC. The persistence of the association between adolescent cannabis use and common mental disorders into young adulthood. Addiction. 2013 Jan;108(1):124-33.

Degenhardt L, Hall WD. The adverse effects of cannabinoids: implications for use of medical marijuana. CMAJ. 2008 Jun 17;178(13):1685-6.

Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, Katz R, Di Marzo V, Jutras-Aswad D, Notcutt WG, Martinez-Orgado J, Robson PJ, Rohrback BG, Thiele E, Whalley B, Friedman D. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014 Jun;55(6):791-802

D'Souza DC, Abi-Saab WM, Madonick S, Forselius-Bielen K, Doersch A, Braley G, Gueorguieva R, Cooper TB, Krystal JH. Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction. Biol Psychiatry. 2005 Mar 15;57(6):594- 608

D'Souza DC, Perry E, MacDougall L, Ammerman Y, Cooper T, Wu YT, Braley G, Gueorguieva R, Krystal JH. The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology. 2004 Aug;29(8):1558-72.

D'Souza DC. Cannabinoids and psychosis. Int Rev Neurobiol. 2007;78:289-326.Review.

D'Souza DC, Ranganathan M, Braley G, Gueorguieva R, Zimolo Z, Cooper T, Perry E, Krystal J. Blunted psychotomimetic and amnestic effects of delta-9-tetrahydrocannabinol in frequent users of cannabis. Neuropsychopharmacology. 2008 Sep;33(10):2505-16

Ex. B-4 Case 2:11-cr-00449-KJM Document 324-2 Filed 07/29/14 Page 6 of 18

DuPont RL, Madras BK, Johansson P. Section 12: Policy Issues, Chapter 77, Drug policy: A biological science perspective. In J. H. Lowinson & P. Ruiz (Eds.) Substance Abuse: A Comprehensive Textbook (5th ed.). Lippincott Williams & Wilkins, 530 Walnut Street Philadelphia, PA 19106, 2011.

Di Forti M, Sallis H, Allegri F, Trotta A, Ferraro L, Stilo SA, Marconi A, La Cascia C, Reis Marques T, Pariante C, Dazzan P, Mondelli V, Paparelli A, Kolliakou A, Prata D, Gaughran F, David AS, Morgan C, Stahl D, Khondoker M, Maccabe JH, Murray RM. Daily Use, Especially of High-Potency Cannabis, Drives the Earlier Onset of Psychosis in Cannabis Users. Schizophr Bull. 2014 Mar 19

Durst R, Danenberg H, Gallily R, Mechoulam R, Meir K, Grad E, Beeri R, Pugatsch T, Tarsish E, Lotan C. Cannabidiol, a nonpsychoactive Cannabis constituent, protects against myocardial ischemic reperfusion injury. Am J Physiol Heart Circ Physiol. 2007 Dec;293(6):H3602-7.

Ellis RJ, Toperoff W, Vaida F, van den Brande G, Gonzales J, Gouaux B, Bentley H, Atkinson JH. (2009). Smoked Medicinal Cannabis for Neuropathic Pain in HIV: A Randomized, Crossover Clinical Trial. Neuropsychopharmacology, 34(3), 672-80.

ElSohly, MA, NIDA Marijuana Project, Potency Monitoring Program Quarterly Report Number 119 Reporting Period: 09/16/2012 - 12/15/2012

FDA epilepsy trials: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ucm401879.htm

Fergusson DM, Boden JM. Cannabis use and later life outcomes. Addiction. 2008 Jun;103(6):969-76; discussion 977-8.

Fontes MA, Bolla KI, Cunha PJ, Almeida PP, Jungerman F, Laranjeira RR, Bressan RA, Lacerda AL. Cannabis use before age 15 and subsequent executive functioning. Br J Psychiatry. 2011 Jun;198(6):442-7.

Gertsch J, Pertwee RG, Di Marzo V. Phytocannabinoids beyond the Cannabis plant - do they exist? Br J Pharmacol. 2010 Jun;160(3):523-9.

Gilman JM, Kuster JK, Lee S, Lee MJ, Kim BW, Makris N, van der Kouwe A, Blood AJ, Breiter HC. Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users. J Neurosci. 2014Apr 16;34(16):5529-38.

Green B, Kavanagh D, Young R. Being stoned: a review of self-reported cannabis effects. Drug Alcohol Rev. 2003 Dec;22(4):453-60. Review.

Greenberg HS, Werness SA, Pugh JE, Andrus RO, Anderson DJ, Domino EF. Short-term effects of smoking marijuana on balance in patients with multiple sclerosis and normal volunteers. Clin Pharmacol Ther. 1994 Mar;55(3):324-8.

Ex. B-5 Case 2:11-cr-00449-KJM Document 324-2 Filed 07/29/14 Page 7 of 18

Greer GR, Grob CS, Halberstadt AL. PTSD symptom reports of patients evaluated for the New Mexico Medical Cannabis Program. J Psychoactive Drugs. 2014 Jan-Mar;46(1):73-7.

Hall W, Degenhardt L. The adverse health effects of chronic cannabis use. Drug Test Anal. 2014 Jan-Feb;6(1-2):39-45.

Hall W, Degenhardt L. Cannabis and the increased incidence and persistence of psychosis. BMJ. 2011 Mar 1;342:d719.

Hall W, Degenhardt L. Adverse health effects of non-medical cannabis use. Lancet. 2009 Oct 17;374(9698):1383-91. Hanson KL, Winward JL, Schweinsburg AD, Medina KL, Brown SA, Tapert SF. Longitudinal study of cognition among adolescent marijuana users over three weeks of abstinence. Addict Behav. 2010 Nov;35(11):970-6

Hansteen RW, Miller RD, Lonero L, Reid LD, Jones B. Effects of cannabis and alcohol on automobile driving and psychomotor tracking. Ann NY Acad Sci 1976;282:240-56.

Haney M; Hart CL; Vosburg SK; Nasser J; Bennett A; Zubaran C; Foltin RW: Marijuana withdrawal in humans: effects of oral THC or divalproex. Neuropsychopharmacology 2004; 29:158–170

Haney M, Gunderson EW, Rabkin J, Hart CL, Vosburg SK, Comer SD, Foltin RW. Dronabinol and marijuana in HIV-positive marijuana smokers. Caloric intake, mood, and sleep. J Acquir Immune Defic Syndr. 2007 Aug 15;45(5):545-54.

Harley M, Kelleher I, Clarke M, Lynch F, Arseneault L, Connor D, Fitzpatrick C, Cannon M. Cannabis use and childhood trauma interact additively to increase the risk of psychotic symptoms in adolescence. Psychol Med. 2010Oct;40(10):1627-34.

Hasin, DS, O’Brien CP, Auriacombe M, Borges G, Bucholz K, Budney A, Compton WM, Crowley T, Ling W, Petry NM, Schuckit M, Grant BF. DSM-5 Criteria for Substance Use Disorders: Recommendations and Rationale. Am J Psychiatry 2013;170:834-851.

Hasin DS; Keyes KM; Alderson D; Wang S; Aharonovich E; Grant BF: Cannabis withdrawal in the United States: results from NESARC. J Clin Psychiatry 2008; 69:1354–1363

Heishman SJ. Effects of abused drugs on human performance: Laboratory assessment. In: Drug Abuse Handbook. Karch SB, ed. New York, NY: CRC Press, 1998, p219.

Hirvonen J, Goodwin RS, Li CT, Terry GE, Zoghbi SS, Morse C, Pike VW, Volkow ND, Huestis MA, Innis RB. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Mol Psychiatry. 2012 Jun;17(6):642-9.

Hosking R, Zajicek J. Pharmacology: Cannabis in neurology-a potted review. Nat Rev Neurol. 2014 Jul 8.

Ex. B-6 Case 2:11-cr-00449-KJM Document 324-2 Filed 07/29/14 Page 8 of 18

Huestis MA. Cannabis (Marijuana) - Effects on Human Performance and Behavior. Forens Sci Rev 2002;14(1/2):15-60.

Huestis MA, Sampson AH, Holicky BJ, Henningfield JE, Cone EJ. Characterization of the absorption phase of marijuana smoking. Clin Pharmacol Ther 1992;52(1):31-41.

Hurd YL, Michaelides M, Miller ML, Jutras-Aswad D. Trajectory of adolescent cannabis use on addiction vulnerability. Neuropharmacology. 2014 Jan;76 Pt B:416-24.

Iannotti FA, Hill CL, Leo A, Alhusaini A, Soubrane C, Mazzarella E, Russo E Whalley BJ, Di Marzo V, Stephens GJ. The non-psychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability. ACS Chem Neurosci. 2014 Jul 16. [Epub ahead of print]

The India Hemp Drugs Commission Report, 1894 (from other sources)

Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci. 2009 Oct;30(10):515-27

Jacobus J, Tapert SF. Effects of cannabis on the adolescent brain. Curr Pharm Des. 2014;20(13):2186-93.

Janefjord E, Mååg JL, Harvey BS, Smid SD. Cannabinoid effects on β amyloid fibril and aggregate formation, neuronal and microglial-activated neurotoxicity in vitro. Cell Mol Neurobiol. 2014 Jan;34(1):31-42.

Kalant H. Smoked marijuana as medicine: not much future. Clin Pharmacol Ther. 2008 Apr;83(4):517-9.

Kalant H. Adverse effects of cannabis on health: an update of the literature since 1996. Prog Neuropsychopharmacol Biol Psychiatry. 2004 Aug;28(5):849-63.

Kalant H Effects of Cannabis and Cannabinoids in the Human Nervous System, in The Effects of Drug Abuse on the Human Nervous System; B. Madras and M.J. Kuhar (Eds.), Elsevier, 2014

Karschner EL, Darwin WD, McMahon RP, Liu F, Wright S, Goodwin RS, Huestis MA. Subjective and physiological effects after controlled Sativex and oral THC administration. Clin Pharmacol Ther. 2011 Mar;89(3):400-7.

Katz NP, Birnbaum H, Brennan MJ, Freedman JD, Gilmore GP, Jay D, Kenna GA Madras BK, McElhaney L, Weiss RD, White AG. Prescription opioid abuse: challenges and opportunities for payers. Am J Manag Care. 2013 Apr;19(4):295-302.

Klonoff H. Marijuana and driving in real-life situations. Science 1974;186(4161);317-24.

Ex. B-7 Case 2:11-cr-00449-KJM Document 324-2 Filed 07/29/14 Page 9 of 18

Kogan NM, Schlesinger M, Priel E, Rabinowitz R, Berenshtein E, Chevion M, Mechoulam R. HU-331, a novel cannabinoid-based anticancer topoisomerase II inhibitor. Mol Cancer Ther. 2007 Jan;6(1):173-83.

Koppel BS, Brust JC, Fife T, Bronstein J, Youssof S, Gronseth G, Gloss D. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014 Apr 29;82(17):1556-63.

Kouri EM; Pope HG Jr: Abstinence symptoms during withdrawal from chronic marijuana use. Exp Clin Psychopharmacol 2000; 8:483–492

Leirer VO, Yesavage JA, Morrow DG. Marijuana carry-over effects on aircraft pilot performance. Aviat Space Environ Med 1991;62(3):221-7.

Levin KH; Copersino ML; Heishman SJ; Liu F; Kelly DL; Boggs DL; Gorelick DA: Cannabis withdrawal symptoms in non-treatment-seeking adult cannabis smokers. Drug Alcohol Depend 2010; 111:120–127

Lichtman AH; Martin BR: Marijuana withdrawal syndrome in the animal model. J Clin Pharmacol 2002; 42(suppl):20S–27S

Lutge EE, Gray A, Siegfried N. The medical use of cannabis for reducing morbidity and mortality in patients with HIV/AIDS.ochrane Database Syst Rev. 2013 Apr 30;4:CD005175.

Lynch ME, Campbell F.Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Br J Clin Pharmacol. 2011 Nov;72(5):735-44

Maa E, Figi P. The case for medical marijuana in epilepsy. Epilepsia. 2014 Jun;55(6):783-6.

Madras BK, Miller G, Ogawa L, Zimmer J, Boisvart K, Vallendar E, Westmoreland S, Hurd Y. THC (Δ9-tetrahydrocannabinol) elicits persistent changes in expression of genes implicated in adolescent neurodevelopment, CPDD abstract, 2014.

Madras BK. Invited Commentary, Dopamine Challenge Reveals Neuroadaptive Changes in Marijuana Abusers. Proc Natl Acad Sci, USA, 2014, in press.

Madras BK. “Unique Consequences of Addiction” in the American Psychological Association Addiction Syndrome Handbook, HJ Shaffer, Ed., 2012.

Madras, B.K. Drug use and Consequences (2014) In: The Effects of Drug Abuse on the Human Nervous System; B. Madras and M.J. Kuhar (Eds.), Elsevier, in press.

Madras B.K. and Kuhar, MJ, (Eds.) The Effects of Drug Abuse on the Human Nervous System, Elsevier Press, 2014.

Ex. B-8 Case 2:11-cr-00449-KJM Document 324-2 Filed 07/29/14 Page 10 of 18

Madras BK. “Cell Biology of Addiction”. Editors: Madras BK, Colvis CM, Pollack JD,Rutter JL, Shurtleff D, von Zastrow M, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp 1-12, 2006. Madras BK and von Zastrow, M Preface to “Cell Biology of Addiction” Madras et al, Editors, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp ix-x, 2006.

Madras BK and Lin, Z. Cocaine Neurobiology: From targets to treatment approaches, in “Cell Biology of Addiction”, Editors, Madras BK, Colvis CM, Pollack JD, Rutter JL, Shurtleff D, von Zastrow M, Editors, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp 239- 269, 2006.

Madras BK. Candidate performance measures for screening for, assessing, and treating unhealthy substance use in hospitals. Ann Intern Med. 2011 Jan 4;154(1):72-3;

Madras BK. Office of National Drug Control Policy: a scientist in drug policy in Washington, DC. Ann N Y Acad Sci. 2010 Feb;1187:370-402.

Madras BK, Compton WM, Avula D, Stegbauer T, Stein JB, Clark HW. Screening, brief interventions, referral to treatment (SBIRT) for illicit drug and alcohol use at multiple healthcare sites: comparison at intake and 6 months later. Drug Alcohol Depend. 2009 Jan 1;99(1-3):280- 95.

Mahmood OM, Jacobus J, Bava S, Scarlett A, Tapert SF. Learning and memory performances in adolescent users of alcohol and marijuana: interactive effects. J Stud Alcohol Drugs. 2010 Nov;71(6):885-94.

Malfait AM, Gallily R, Sumariwalla PF, Malik AS, Andreakos E, Mechoulam R, Feldmann M. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9561-6.

Manrique-Garcia E, Zammit S, Dalman C, Hemmingsson T, Andreasson S, Allebeck P. Prognosis of schizophrenia in persons with and without a history of cannabis use. Psychol Med. 2014 Sep;44(12):2513-21.

Marijuana and Medicine: Assessing the Science Base, 2003, Janet E. Joy, Stanley J. Watson, Jr., and John A. Benson, Jr., Editors Division of Neuroscience and Behavioral Health, Institute Of Medicine, National Academy Press Washington, D.C.

Marks MA, Chaturvedi AK, Kelsey K, Straif K, Berthiller J, Schwartz SM, Smith E, Wyss A, Brennan P, Olshan AF, Wei Q, Sturgis EM, Zhang ZF, Morgenstern H, Muscat J, Lazarus P, McClean M, Chen C, Vaughan TL, Wunsch-Filho V, Curado MP, Koifman S, Matos E, Menezes A, Daudt AW, Fernandez L, Posner M, Boffetta P, Lee YC, Hashibe M, D'Souza G. Association of marijuana smoking with oropharyngeal and oral tongue cancers: pooled analysis from the INHANCE consortium. Cancer Epidemiol Biomarkers Prev. 2014 Jan;23(1):160-71.

Martín-Sánchez E, Furukawa TA, Taylor J, Martin JL. Systematic review and meta-analysis of cannabis treatment for chronic pain. Pain Med. 2009 Nov;10(8):1353-68

Ex. B-9 Case 2:11-cr-00449-KJM Document 324-2 Filed 07/29/14 Page 11 of 18

Mason AP, McBay AJ. Cannabis: pharmacology and interpretation of effects. J Forensic Sci 1985;30(3):615-31.

Mechoulam R, Shani A, Edery H, Grunfeld Y. Chemical basis of hashish activity. Science. 1970 Aug 7;169(3945):611-2.

Mechoulam R, Parker L. Towards a better cannabis drug. Br J Pharmacol. 2013 Dec;170 (7):1363-4.

Medina KL, Nagel BJ, Tapert SF. Abnormal cerebellar morphometry in abstinent adolescent marijuana users. Psychiatry Res. 2010 May 30;182(2):152-9.

Meier MH, Caspi A, Ambler A, Harrington H, Houts R, Keefe RS, McDonald K,Ward A, Poulton R, Moffitt TE. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci U S A. 2012 Oct2;109(40):E2657-64.

Meschler JP, Howlett AC, Madras BK. Cannabinoid receptor agonist and antagonist effects on motor function in normal and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)-treated non-human primates. Psychopharmacology (Berl). 2001 Jun;156(1):79-85.

Meschler JP, Clarkson FA, Mathews PJ, Howlett AC, Madras BK. D(2), but not D(1) dopamine receptor agonists potentiate cannabinoid-induced sedation in nonhuman primates. J Pharmacol Exp Ther. 2000 Mar;292(3):952-9.

Milin R; Manion I; Dare G; Walker S: Prospective assessment of cannabis withdrawal in adolescents with cannabis dependence: a pilot study. J Am Acad Child Adolesc Psychiatry 2008; 47:174–178

Milazzo S, Ernst E, Lejeune S, Boehm K, Horneber M., Laetrile treatment for cancer, Cochrane Database Syst Rev. 2011 Nov 9;(11):CD005476

Moir et al, A Comparison of Mainstream and Sidestream Marijuana and Tobacco Cigarette Smoke Produced under Two Machine Smoking Conditions. Chem. Res. Toxicol., 2008, 21 (2), pp 494–502

Morgan CJ, Gardener C, Schafer G, Swan S, Demarchi C, Freeman TP, Warrington P, Rupasinghe I, Ramoutar A, Tan N, Wingham G, Lewis S, Curran HV. Sub-chronic impact of cannabinoids in street cannabis on cognition, psychotic-like symptoms and psychological well- being. Psychol Med. 2012 Feb;42(2):391-400.

Morgan CJ, Freeman TP, Schafer GL, Curran HV. Cannabidiol attenuates the appetitive effects of Delta 9-tetrahydrocannabinol in humans smoking their chosen cannabis. Neuropsychopharmacology. 2010 Aug;35(9):1879-85.

Ex. B-10 Case 2:11-cr-00449-KJM Document 324-2 Filed 07/29/14 Page 12 of 18

Morgan CJ, Schafer G, Freeman TP, Curran HV. Impact of cannabidiol on the acute memory and psychotomimetic effects of smoked cannabis: naturalistic study: naturalistic study [corrected]. Br J Psychiatry. 2010 Oct;197(4):285-90. Erratum in: Br J Psychiatry. 2010 Nov;197:416.

MTF (Monitoring the Future): Johnston, L. D., O'Malley, P. M., Bachman, J. G., & Schulenberg, J. E. (December 18, 2013). "American teens more cautious about using synthetic drugs." University of Michigan News Service: Ann Arbor, MI. Retrieved 07/25/2104 from http://www.monitoringthefuture.org

Mukhopadhyay P, Rajesh M, Horváth B, Bátkai S, Park O, Tanchian G, Gao RY, Patel V, Wink DA, Liaudet L, Haskó G, Mechoulam R, Pacher P. Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death. Free Radic Biol Med. 2011 May 15;50(10):1368-81.

Murray RM, Morrison PD, Henquet C, Di Forti M. McGrath et al, Association Between Cannabis use and Psychosis-related outcomes using sibling pair analysis in a cohort of young adults. Arch Gen Psychiatry 2010: 67: 440-447

Neavyn MJ, Blohm E, Babu KM, Bird SB.Medical Marijuana and Driving: a Review. J Med Toxicol. 2014 Mar 20. [Epub ahead of print]

Niesink RJ, van Laar MW. Does Cannabidiol Protect Against Adverse Psychological Effects of THC? Front Psychiatry. 2013 Oct 16;4:130

NSDUH (National Survey on Drug Use and Health): Substance Abuse and Mental Health Services Administration, Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-46, HHS Publication No. (SMA) 13-4795. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013

Palmer RS, McMahon TJ, Moreggi DI, Rounsaville BJ, Ball SA. College Student Drug Use: Patterns, Concerns, Consequences, and Interest in Intervention. J Coll Stud Dev. 2012 Jan;53(1).

Parker LA, Mechoulam R, Schlievert C. Cannabidiol, a non-psychoactive component of cannabis and its synthetic dimethylheptyl homolog suppress nausea in an experimental model with rats. Neuroreport. 2002 Apr 16;13(5):567-70.

Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, Greasley PJ, Hansen HS, Kunos G, Mackie K, Mechoulam R, Ross RA. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂. Pharmacol Rev. 2010 Dec;62(4):588-631

Phillips TJ, Cherry CL, Cox S, Marshall SJ, Rice AS. Pharmacological treatment of painful HIV- associated sensory neuropathy: a systematic review and meta-analysis of randomised controlled trials. PLoS One. 2010 Dec 28;5(12):e14433.

Ex. B-11 Case 2:11-cr-00449-KJM Document 324-2 Filed 07/29/14 Page 13 of 18

Plasse TF, Gorter RW, Krasnow SH, Lane M, Shepard KV, Wadleigh RG. Recent clinical experience with Dronabinol. Pharmacol Biochem Behav 1991;40(3):695-700.

Pope HG Jr, Yurgelun-Todd D. The residual cognitive effects of heavy marijuana use in college students. JAMA 1996;275(7):521-7.

Pope HG Jr, et al. Early-onset cannabis use and cognitive deficits: what is the nature of the association? Drug Alcohol Depend. 2003 Apr 1;69(3):303-10;

Radhakrishnan R, Wilkinson ST, D'Souza DC. Gone to Pot - A Review of the Association between Cannabis and Psychosis. Front Psychiatry. 2014 May 22;5:54.

Ramaekers JG, Robbe HW, O’Hanlon JF. Marijuana, alcohol and actual driving performance. Hum Psychopharmacol 2000;15(7):551-8.

Ramaekers JG, Theunissen EL, de Brouwer M, Toennes SW, Moeller MR, Kauert G. Tolerance and cross-tolerance to neurocognitive effects of THC and alcohol in heavy cannabis users. Psychopharmacology (Berl). 2011 Mar;214(2):391-401.

Ranganathan M, D'Souza DC. The acute effects of cannabinoids on memory in humans: a review. Psychopharmacology (Berl). 2006 Nov;188(4):425-44.

Reilly D, Didcott P, Swift W, Hall W. Long-term cannabis use: characteristics of users in an Australian rural area. Addiction. 1998 Jun;93(6):837-46.

Robbe HW, O'Hanlon JF. Marijuana and actual driving performance. US Department of Transportation/National Highway Traffic Safety Administration November: 1-133 (1993). DOT HS 808 078.

Robson PJ. Therapeutic potential of cannabinoid medicines. Drug Test Anal. 2014 Jan-Feb;6(1- 2):24-30.

Robson P. Abuse potential and psychoactive effects of δ-9-tetrahydrocannabinol and cannabidiol oromucosal spray (Sativex), a new cannabinoid medicine. Expert Opin Drug Saf. 2011 Sep;10(5):675-85.

Rock EM, Bolognini D, Limebeer CL, Cascio MG, Anavi-Goffer S, Fletcher PJ, Mechoulam R, Pertwee RG, Parker LA. Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT(1A) somatodendritic autoreceptors in the dorsal raphe nucleus. Br J Pharmacol. 2012 Apr;165(8):2620-34.

Rog DJ. Cannabis-based medicines in multiple sclerosis--a review of clinical studies. Immunobiology. 2010 Aug;215(8):658-72.

Ex. B-12 Case 2:11-cr-00449-KJM Document 324-2 Filed 07/29/14 Page 14 of 18

Salomonsen-Sautel S, Min SJ(2), Sakai JT, Thurstone C, Hopfer C., Trends in fatal motor vehicle crashes before and after marijuana commercialization in Colorado, Drug Alcohol Depend. 2014 Apr 23 epub

Sarne Y, Mechoulam R. Cannabinoids: between neuroprotection and neurotoxicity. Curr Drug Targets CNS Neurol Disord. 2005 Dec;4(6):677-84. Review.

Schoedel KA, Chen N, Hilliard A, White L, Stott C, Russo E, Wright S, Guy G Romach MK, Sellers EM. A randomized, double-blind, placebo-controlled, crossover study to evaluate the subjective abuse potential and cognitive effects of nabiximols oromucosal spray in subjects with a history of recreational cannabis use. Hum Psychopharmacol. 2011 Apr;26(3):224-36.

Schweinsburg AD, Schweinsburg BC, Nagel BJ, Eyler LT, Tapert SF. Neural correlates of verbal learning in adolescent alcohol and marijuana users. Addiction. 2011 Mar;106(3):564-73.

Seeman P. Discovery of why acute lymphoblastic leukaemia cells are killed by asparaginase: Adventures of a young post-doctoral student, Bertha K Madras. J Med Biogr. 2013 Sep 27;22(2):90-92.

Seeman, P and Madras BK, editors. Imaging of the Human Brain in Health and Disease Elsevier Press, 2014.

Selvarajah D, Gandhi R, Emery CJ, Tesfaye S. Randomized placebo-controlled double-blind clinical trial of cannabis-based medicinal product (Sativex) in painful diabetic neuropathy: depression is a major confounding factor. Diabetes Care. 2010 Jan;33(1):128-30.

Serpell M, Ratcliffe S, Hovorka J, Schofield M, Taylor L, Lauder H, Ehler E. A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment. Eur J Pain. 2014 Aug;18(7):999-1012

Sewell RA, Schnakenberg A, Elander J, Radhakrishnan R, Williams A, Skosnik PD, Pittman B, Ranganathan M, D'Souza DC. Acute effects of THC on time perception in frequent and infrequent cannabis users. Psychopharmacology (Berl). 2013 Mar;226(2):401-13.

Sewell RA, Ranganathan M, D'Souza DC. Cannabinoids and psychosis. Int Rev Psychiatry. 2009 Apr;21(2):152-62. doi: 10.1080/09540260902782802. Review.

Sewell RA, Schnakenberg A, Elander J, Radhakrishnan R, Williams A, Skosnik PD, Pittman B, Ranganathan M, D'Souza DC. Acute effects of THC on time perception in frequent and infrequent cannabis users. Psychopharmacology (Berl). 2013 Mar;226(2):401-13

Shohami E, Novikov M, Mechoulam R. A nonpsychotropic cannabinoid, HU-211, has cerebroprotective effects after closed head injury in the rat. J Neurotrauma. 1993 Summer;10(2):109-19.

Ex. B-13 Case 2:11-cr-00449-KJM Document 324-2 Filed 07/29/14 Page 15 of 18

Skosnik PD, Ranganathan M, D'Souza DC. Cannabinoids, working memory, and schizophrenia. Biol Psychiatry. 2012 Apr 15;71(8):662-3.

Skosnik PD, Krishnan GP, D'Souza DC, Hetrick WP, O'Donnell BF. Disrupted Gamma-Band Neural Oscillations During Coherent Motion Perception in Heavy Cannabis Users. Neuropsychopharmacology. 2014 Jul 3. [epub]

Smiley A, Moskowitz HM, Ziedman K. Effects of drugs on driving: Driving simulator tests of secobarbital, diazepam, marijuana, and alcohol. In Clinical and Behavioral Pharmacology Research Report. J.M. Walsh, Ed. U.S. Department of Health and Human Services, Rockville, 1985, pp 1-21.

Smith MJ, Cobia DJ, Wang L, Alpert KI, Cronenwett WJ, Goldman MB, Mamah D, Barch DM, Breiter HC, Csernansky JG. Cannabis-related working memory deficits and associated subcortical morphological differences in healthy individuals and schizophrenia subjects. Schizophr Bull. 2014 Mar;40(2):287-99.

Snedecor SJ, Sudharshan L, Cappelleri JC, Sadosky A, Mehta S, Botteman M. Systematic review and meta-analysis of pharmacological therapies for painful diabetic peripheral neuropathy. Pain Pract. 2014 Feb;14(2):167-84

Snedecor SJ, Sudharshan L, Cappelleri JC, Sadosky A, Desai P, Jalundhwala Y, Botteman M. Systematic review and meta-analysis of pharmacological therapies for pain associated with postherpetic neuralgia and less common neuropathic conditions. Int J Clin Pract. 2014 Jul;68(7):900-18.

Söderpalm AH, Schuster A, de Wit H. Antiemetic efficacy of smoked marijuana: subjective and behavioral effects on nausea induced by syrup of ipecac. Pharmacol Biochem Behav. 2001 Jul- Aug;69(3-4):343-50.

Solowij N, Michie PT, Fox AM. Differential impairment of selective attention due to frequency and duration of cannabis use. Biol Psychiatry 1995;37(10):731-9.

Solowij N, Walterfang M, Lubman DI, Whittle S, Lorenzetti V, Styner M, Velakoulis D, Pantelis C, Yücel M. Alteration to hippocampal shape in cannabis users with and without schizophrenia. Schizophr Res. 2013 Jan;143(1):179-84.

Solowij N, Yücel M, Respondek C, Whittle S, Lindsay E, Pantelis C, Lubman DI. Cerebellar white-matter changes in cannabis users with and without schizophrenia. Psychol Med. 2011 Nov;41(11):2349-59.

Solowij N, Battisti R. The chronic effects of cannabis on memory in humans: a review. Curr Drug Abuse Rev. 2008 Jan;1(1):81-98. Review.

Ex. B-14 Case 2:11-cr-00449-KJM Document 324-2 Filed 07/29/14 Page 16 of 18

Stefanis NC, Dragovic M, Power BD, Jablensky A, Castle D, Morgan VA. The effect of drug use on the age at onset of psychotic disorders in an Australian cohort. Schizophr Res. 2014 Jul;156(2-3):211-6.

Stefanis NC, Dragovic M, Power BD, Jablensky A, Castle D, Morgan VA. Age at initiation of cannabis use predicts age at onset of psychosis: the 7- to 8-year trend. Schizophr Bull. 2013 Mar;39(2):251-4.

Syed YY, McKeage K, Scott LJ. Delta-9-tetrahydrocannabinol/cannabidiol (sativex(®)): a review of its use in patients with moderate to severe spasticity due to multiple sclerosis. Drugs. 2014 Apr;74(5):563-78.

Szutorisz H, DiNieri JA, Sweet E, Egervari G, Michaelides M, Carter JM, Ren Y, Miller ML, Blitzer RD, Hurd YL. Parental THC exposure leads to compulsive heroin-seeking and altered striatal synaptic plasticity in the subsequent generation. Neuropsychopharmacology. 2014 May;39(6):1315-23.

Thornicroft G. Cannabis and psychosis. Is there epidemiological evidence for an association? Br J Psychiatry 1990;157:25-33.

Taffe MA. Δ⁹Tetrahydrocannabinol impairs visuo-spatial associative learning and spatial working memory in rhesus macaques. J Psychopharmacol. 2012 Oct;26(10):1299-306.

TEDS Report, Feb 2 2012, Marijuana admissions reporting daily use at treatment entry.

Thomas G, Kloner RA, Rezkalla S. Adverse cardiovascular, cerebrovascular, and peripheral vascular effects of marijuana inhalation: what cardiologists need to know. Am J Cardiol. 2014 Jan 1;113(1):187-90

Todaro B. Cannabinoids in the treatment of chemotherapy-induced nausea and vomiting. J Natl Compr Canc Netw. 2012 Apr;10(4):487-92.

Tortoriello G, Morris CV, Alpar A, Fuzik J, Shirran SL, Calvigioni D, Keimpema E, Botting CH, Reinecke K, Herdegen T, Courtney M, Hurd YL, Harkany T. Miswiring the brain: Δ9- tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin-2 degradation pathway. EMBO J. 2014 Apr 1;33(7):668-85.

Varma VK, Malhotra AK, Dang R, Das K, Nehra R. Cannabis and cognitive functions: a prospective study. Drug Alcohol Depend 1988;21(2):147-52.

Vindenes V, Strand DH, Kristoffersen L, Boix F, Mørland J. Has the intake of THC by cannabis users changed over the last decade? Evidence of increased exposure by analysis of blood THC concentrations in impaired drivers. Forensic Sci Int. 2013 Mar 10;226(1-3):197-201.

Ex. B-15 Case 2:11-cr-00449-KJM Document 324-2 Filed 07/29/14 Page 17 of 18

Vogel Z, Barg J, Levy R, Saya D, Heldman E, Mechoulam R. Anandamide, a brain endogenous compound, interacts specifically with cannabinoid receptors and inhibits adenylate cyclase. J Neurochem. 1993 Jul;61(1):352-5.

Volkow ND, Wang GJ, Telang F, Fowler JS, Alexoff D, Logan J, Jayne M, Wong C, Tomasi D. Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity. Proc Natl Acad Sci U S A. 2014 Jul 14.

Volkow ND, Baler RD, Compton WM, Weiss SR. Adverse health effects of marijuana use. N Engl J Med. 2014 Jun 5;370(23):2219-27.

Wadsworth EJ, Moss SC, Simpson SA, Smith AP. Cannabis use, cognitive performance and mood in a sample of workers. J Psychopharmacol 2006;20(1):14-23

Ware MA, Wang T, Shapiro S, Robinson A, Ducruet T, Huynh T, Gamsa A, Bennett GJ, Collet JP. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ. 2010 Oct 5;182(14):E694-701.

Wilkinson ST, D'Souza DC. Problems with the medicalization of marijuana. JAMA. 2014 Jun 18;311(23):2377-8. doi: 10.1001/jama.2014.6175. PubMed PMID: 24845238.

Wilkinson ST, D'Souza DC. Problems with the medicalization of marijuana. JAMA. 2014 Jun 18;311(23):2377-8.

Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, Donaghe H. (2013). Low-Dose Vaporized Cannabis Significantly Improves Neuropathic Pain. J Pain, 14(2):136-48.

Wilsey B, Marcotte T, Tsodikov A, Millman J, Bentley H, Gouaux B, Fishman S. (2008) A Randomized, Placebo-Controlled, Crossover Trial of Cannabis Cigarettes in Neuropathic Pain. J Pain, 9(6):506-21.

Wright MJ Jr, Vandewater SA, Taffe MA. Cannabidiol attenuates deficits of visuospatial associative memory induced by Δ(9) tetrahydrocannabinol. Br J Pharmacol. 2013 Dec;170(7):1365-73.

Yücel M, Solowij N, Respondek C, Whittle S, Fornito A, Pantelis C, Lubman DI. Regional brain abnormalities associated with long-term heavy cannabis use. Arch Gen Psychiatry. 2008 Jun;65(6):694-701.

Yücel M, Zalesky A, Takagi MJ, Bora E, Fornito A, Ditchfield M, Egan GF, Pantelis C, Lubman DI. White-matter abnormalities in adolescents with long-term inhalant and cannabis use: a diffusion magnetic resonance imaging study. JPsychiatry Neurosci. 2010 Nov;35(6):409-12.

Zalesky A, Solowij N, Yücel M, Lubman DI, Takagi M, Harding IH, Lorenzetti V, Wang R, Searle K, Pantelis C, Seal M. Effect of long-term cannabis use on axonal fibre connectivity. Brain. 2012 Jul;135(Pt 7):2245-55.

Ex. B-16 Case 2:11-cr-00449-KJM Document 324-2 Filed 07/29/14 Page 18 of 18

Zeltser R, Seltzer Z, Eisen A, Feigenbaum JJ, Mechoulam R. Suppression of neuropathic pain behavior in rats by a non-psychotropic synthetic cannabinoids with NMDA receptor-blocking properties. Pain. 1991 Oct;47(1):95-103.

Ex. B-17 Case 2:11-cr-00449-KJM Document 324-3 Filed 07/29/14 Page 1 of 40

Exhibit C

Case 2:11-cr-00449-KJM Document 324-3 Filed 07/29/14 Page 2 of 40

Vol. 76 Friday, No. 131 July 8, 2011

Part IV

Department of Justice

Drug Enforcement Administration 21 CFR Chapter II Denial of Petition To Initiate Proceedings To Reschedule Marijuana; Proposed Rule

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DEPARTMENT OF JUSTICE Services (DHHS). DHHS concluded that The statutory mandate of 21 U.S.C. marijuana has a high potential for abuse, 812(b) is dispositive. Congress Drug Enforcement Administration has no accepted medical use in the established only one schedule, schedule United States, and lacks an acceptable I, for drugs of abuse with ‘‘no currently 21 CFR Chapter II level of safety for use even under accepted medical use in treatment in the [Docket No. DEA–352N] medical supervision. Therefore, DHHS United States’’ and ‘‘lack of accepted recommended that marijuana remain in safety for use under medical Denial of Petition To Initiate schedule I. The scientific and medical supervision.’’ 21 U.S.C. 812(b). Proceedings To Reschedule Marijuana evaluation and scheduling Accordingly, and as set forth in detail recommendation that DHHS submitted in the accompanying DHHS and DEA AGENCY: Drug Enforcement to DEA is attached hereto. documents, there is no statutory basis Administration (DEA), Department of Based on the DHHS evaluation and all Justice. under the CSA for DEA to grant your other relevant data, DEA has concluded petition to initiate rulemaking ACTION: Denial of petition to initiate that there is no substantial evidence that proceedings to reschedule marijuana. proceedings to reschedule marijuana. marijuana should be removed from Your petition is, therefore, hereby schedule I. A document prepared by denied. SUMMARY: By letter dated June 21, 2011, DEA addressing these materials in detail the Drug Enforcement Administration also is attached hereto. In short, Sincerely, (DEA) denied a petition to initiate marijuana continues to meet the criteria Michele M. Leonhart, rulemaking proceedings to reschedule 1 for schedule I control under the CSA Administrator. marijuana. Because DEA believes that because: this matter is of particular interest to (1) Marijuana has a high potential for Attachments: members of the public, the agency is abuse. The DHHS evaluation and the Marijuana. Scheduling Review Document: publishing below the letter sent to the additional data gathered by DEA show Eight Factor Analysis petitioner (denying the petition), along that marijuana has a high potential for Basis for the recommendation for with the supporting documentation that abuse. maintaining marijuana in schedule I of the was attached to the letter. (2) Marijuana has no currently Controlled Substances Act FOR FURTHER INFORMATION CONTACT: accepted medical use in treatment in Date: June 30, 2011 Imelda L. Paredes, Office of Diversion the United States. According to Michele M. Leonhart Control, Drug Enforcement established case law, marijuana has no Administrator Administration, 8701 Morrissette Drive, ‘‘currently accepted medical use’’ Department of Health and Human Services, Springfield, Virginia 22152; Telephone because: The drug’s chemistry is not Office of the Secretary Assistant Secretary for (202) 307–7165. known and reproducible; there are no Health, Office of Public Health and Science SUPPLEMENTARY INFORMATION: adequate safety studies; there are no Washington, D.C. 20201. December 6, 2006. June 21, 2011. adequate and well-controlled studies proving efficacy; the drug is not The Honorable Karen P. Tandy Dear Mr. Kennedy: accepted by qualified experts; and the Administrator, Drug Enforcement On October 9, 2002, you petitioned scientific evidence is not widely Administration, U.S. Department of Justice, Washington, D.C. 20537 the Drug Enforcement Administration available. (DEA) to initiate rulemaking (3) Marijuana lacks accepted safety Dear Ms. Tandy: This is in response to your request of July proceedings under the rescheduling for use under medical supervision. At provisions of the Controlled Substances 2004, and pursuant to the Controlled present, there are no U.S. Food and Substances Act (CSA), 21 U.S.C. 811(b), (c), Act (CSA). Specifically, you petitioned Drug Administration (FDA)-approved and (f), the Department of Health and Human DEA to have marijuana removed from marijuana products, nor is marijuana Services (DHHS) recommends that marijuana schedule I of the CSA and rescheduled under a New Drug Application (NDA) continue to be subject to control under as cannabis in schedule III, IV or V. evaluation at the FDA for any Schedule I of the CSA. You requested that DEA remove indication. Marijuana does not have a Marijuana is currently controlled under marijuana from schedule I based on currently accepted medical use in Schedule I of the CSA. Marijuana continues your assertion that: treatment in the United States or a to meet the three criteria for placing a substance in Schedule I of the CSA under 21 (1) Cannabis has an accepted medical currently accepted medical use with use in the United States; U.S.C. 812(b)(l). As discussed in the attached severe restrictions. At this time, the analysis, marijuana has a high potential for (2) Cannabis is safe for use under known risks of marijuana use have not abuse, has no currently accepted medical use medical supervision; been shown to be outweighed by in treatment in the United States, and has a (3) Cannabis has an abuse potential specific benefits in well-controlled lack of an accepted level of safety for use lower than schedule I or II drugs; and clinical trials that scientifically evaluate under medical supervision. Accordingly, (4) Cannabis has a dependence safety and efficacy. HHS recommends that marijuana continue to liability that is lower than schedule I or You also argued that cannabis has a be subject to control under Schedule I of the CSA. Enclosed is a document prepared by II drugs. dependence liability that is lower than In accordance with the CSA FDA’s Controlled Substance Staff that is the schedule I or II drugs. Findings as to the basis for this recommendation. rescheduling provisions, after gathering physical or psychological dependence the necessary data, DEA requested a Should you have any questions regarding of a drug are only one of eight factors this recommendation, please contact Corinne scientific and medical evaluation and to be considered. As discussed further P. Moody, of the Controlled Substance Staff, scheduling recommendation from the in the attached documents, DHHS states Center for Drug Evaluation and Research. Ms. Department of Health and Human that long-term, regular use of marijuana Moody can be reached at 301–827–1999. can lead to physical dependence and Sincerely yours, 1 Note that ‘‘marihuana’’ is the spelling originally withdrawal following discontinuation John O. Agwunobi, used in the Controlled Substances Act (CSA). This Assistant Secretary for Health. document uses the spelling that is more common as well as psychic addiction or in current usage, ‘‘marijuana.’’ dependence. Enclosure:

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Basis for the Recommendation for abuse. The term ‘‘abuse’’ is not defined in the a. There is evidence that individuals are Maintaining Marijuana in Schedule I of the CSA. However, the legislative history of the taking the substance in amounts sufficient to Controlled Substances Act CSA suggests the following in determining create a hazard to their health or to the whether a particular drug or substance has a safety of other individuals or to the BASIS FOR THE RECOMMENDATION FOR potential for abuse: community. MAINTAINING MARIJUANA IN a. Individuals are taking the substance in Marijuana is a widely abused substance. SCHEDULE I OF THE CONTROLLED amounts sufficient to create a hazard to their The pharmacology of the psychoactive SUBSTANCES ACT health or to the safety of other individuals or constituents of marijuana, including delta9- On October 9, 2002, the Coalition for to the community. tetrahydrocannabinol (delta9-THC), the Rescheduling Cannabis (hereafter known as b. There is a significant diversion of the primary psychoactive ingredient in the Coalition) submitted a petition to the drug or substance from legitimate drug marijuana, has been studied extensively in Drug Enforcement Administration (DEA) channels. animals and humans and is discussed in requesting that proceedings be initiated to c. Individuals are taking the substance on more detail below in Factor 2, ‘‘Scientific repeal the rules and regulations that place their own initiative rather than on the basis Evidence of its Pharmacological Effects, if marijuana in Schedule I of the Controlled of medical advice from a practitioner Known.’’ Data on the extent of marijuana Substances Act (CSA). The petition contends licensed by law to administer such abuse are available from HHS through NIDA that cannabis has an accepted medical use in substances. and the Substance Abuse and Mental Health the United States, is safe for use under d. The substance is so related in its action Services Administration (SAMHSA). These medical supervision, and has an abuse to a substance already listed as having a data are discussed in detail under Factor 4, potential and a dependency liability that is potential for abuse to make it likely that it ‘‘Its History and Current Pattern of Abuse;’’ lower than Schedule I or II drugs. The will have the same potential for abuse as Factor 5, ‘‘The Scope, Duration, and petition requests that marijuana be such substance, thus making it reasonable to Significance of Abuse;’’ and Factor 6, ‘‘What, rescheduled as ‘‘cannabis’’ in either Schedule assume that there may be significant if any, Risk There is to the Public Health?’’ III, IV, or V of the CSA. In July 2004, the DEA diversions from legitimate channels, According to SAMHSA’s 2004 National Administrator requested that the Department significant use contrary to or without medical Survey on Drug Use and Health (NSDUH; the of Health and Human Services (HHS) provide advice, or that it has a substantial capability database formerly known as the National a scientific and medical evaluation of the of creating hazards to the health of the user Household Survey on Drug Abuse (NHSDA)), available information and a scheduling or to the safety of the community. the latest year for which complete data are recommendation for marijuana, in Comprehensive Drug Abuse Prevention and available, 14.6 million Americans have used accordance with the provisions of 21 U.S.C. Control Act of 1970, H.R. Rep. No. 91– marijuana in the past month. This is an 811(b). 1444, 91st Cong., Sess. 1 (1970) reprinted increase of 3.4 million individuals since In accordance with 21 U.S.C. 811(b), DEA in U.S.C.C.A.N. 4566, 4603. 1999, when 11.2 million individuals reported has gathered information related to the 2 In considering these concepts in a variety using marijuana monthly. (See the discussion control of marijuana (Cannabis sativa) of NSDUH data under Factor 4). under the CSA. Pursuant to 21 U.S.C. 811(b), of scheduling analyses over the last three decades, the Secretary has analyzed a range The Drug Abuse Warning Network the Secretary is required to consider in a (DAWN), sponsored by SAMHSA, is a scientific and medical evaluation eight of factors when assessing the abuse liability national probability survey of U.S. hospitals factors determinative of control under the of a substance. These factors have included with emergency departments (EDs) designed CSA. Following consideration of the eight the prevalence and frequency of use in the to obtain information on ED visits in which factors, if it is appropriate, the Secretary must general public and in specific sub- recent drug use is implicated; 2003 is the make three findings to recommend populations, the amount of the material that latest year for which complete data are scheduling a substance in the CSA. The is available for illicit use, the ease with available. Marijuana was involved in 79,663 findings relate to a substance’s abuse which the substance may be obtained or ED visits (13 percent of drug-related visits). potential, legitimate medical use, and safety manufactured, the reputation or status of the There are a number of risks resulting from or dependence liability. substance ‘‘on the street,’’ as well as evidence both acute and chronic use of marijuana Administrative responsibilities for relevant to population groups that may be at evaluating a substance for control under the particular risk. which are discussed in full below under CSA are performed by the Food and Drug Abuse liability is a complex determination Factors 2 and 6. Administration (FDA), with the concurrence with many dimensions. There is no single b. There is significant diversion of the of the National Institute on Drug Abuse test or assessment procedure that, by itself, substance from legitimate drug channels. (NIDA), as described in the Memorandum of provides a full and complete At present, cannabis is legally available Understanding (MOU) of March 8, 1985 (50 characterization. Thus, no single measure of through legitimate channels for research FR 9518–20). abuse liability is ideal. Scientifically, a purposes only and thus has a limited In this document, FDA recommends the comprehensive evaluation of the relative potential for diversion. In addition, the lack continued control of marijuana in Schedule abuse potential of a drug substance can of significant diversion of investigational I of the CSA. Pursuant to 21 U.S.C. 811(c), include consideration of the drug’s receptor supplies may result from the ready the eight factors pertaining to the scheduling binding affinity, preclinical pharmacology, availability of illicit cannabis of equal or of marijuana are considered below. reinforcing effects, discriminative stimulus greater quality. The magnitude of the demand effects, dependence producing potential, for illicit marijuana is evidenced by DEA/ 1. ITS ACTUAL OR RELATIVE POTENTIAL pharmacokinetics and route of Office of National Drug Control Policy FOR ABUSE administration, toxicity, assessment of the (ONDCP) seizure statistics. Data on marijuana The first factor the Secretary must consider clinical efficacy-safety database relative to seizures can often highlight trends in the is marijuana’s actual or relative potential for actual abuse, clinical abuse liability studies, overall trafficking patterns. DEA’s Federal- and the public health risks following Wide Drug Seizure System (FDSS) provides 2 The CSA defines marijuana as the following: introduction of the substance to the general information on total federal drug seizures. all parts of the plant Cannabis Sativa L., whether population. It is important to note that abuse FDSS reports total federal seizures of growing or not; the seeds thereof; the resin may exist independent of a state of tolerance 2,700,282 pounds of marijuana in 2003, the extracted from any part of such plant; and every or physical dependence, because drugs may latest year for which complete data are compound, manufacture, salt, derivative, mixture, be abused in doses or in patterns that do not available (DEA, 2003). This represents nearly or preparation of such plant, its seeds or resin. Such induce these phenomena. Animal data, a doubling of marijuana seizures since 1995, term does not include the mature stalks of such human data, and epidemiological data are all when 1,381,107 pounds of marijuana were plant, fiber produced from such stalks, oil or cake used in determining a substance’s abuse seized by federal agents. made from the seeds of such plant, any other liability. Epidemiological data can also be an c. Individuals are taking the substance on compound, manufacture, salt, derivative, mixture, or preparation of such mature stalks (except the important indicator of actual abuse. Finally, their own initiative rather than on the basis resin extracted there from), fiber, oil, or cake, or the evidence of clandestine production and illicit of medical advice from a practitioner sterilized seed of such plant which is incapable of trafficking of a substance are also important licensed by law to administer such germination (21 U.S.C. 802(16)). factors. substances.

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The 2004 NSDUH data show that 14.6 Neurochemistry and Pharmacology of norepinephrine, and glutamate release from million American adults use marijuana on a Marijuana specific areas of the brain. These effects monthly basis (SAMHSA, 2004), confirming Some 483 natural constituents have been might represent a potential cellular that marijuana has reinforcing properties for identified in marijuana, including mechanism underlying the antinociceptive many individuals. The FDA has not approximately 66 compounds that are and psychoactive effects of cannabinoids evaluated or approved a new drug classified as cannabinoids (Ross and El (Ameri, 1999). When cannabinoids are given application (NDA) for marijuana for any Sohly, 1995). Cannabinoids are not known to subacutely to rats, there is a down-regulation therapeutic indication, although several exist in plants other than marijuana, and of CB1 receptors, as well as a decrease in investigational new drug (IND) applications most of the cannabinoid compounds that GTPgammaS binding, the second messenger are currently active. Based on the large occur naturally have been identified system coupled to CB1 receptors (Breivogel et number of individuals who use marijuana, it chemically. Delta9-THC is considered the al., 2001). can be concluded that the majority of major psychoactive cannabinoid constituent Delta9-THC displays similar affinity for individuals using cannabis do so on their of marijuana (Wachtel et al., 2002). The CB1 and CB2 receptors but behaves as a weak own initiative, not on the basis of medical structure and function of delta9-THC was agonist for CB2 receptors, based on inhibition advice from a practitioner licensed to first described in 1964 by Gaoni and of adenylate cyclase. The identification of administer the drug in the course of Mechoulam. synthetic cannabinoid ligands that professional practice. The site of action of delta9-THC and other selectively bind to CB2 receptors but do not d. The substance is so related in its action cannabinoids was verified with the cloning have the typical delta9-THC-like to a substance already listed as having a of cannabinoid receptors, first from rat brain psychoactive properties suggests that the potential for abuse to make it likely that it tissue (Matsuda et al., 1990) and then from psychotropic effects of cannabinoids are will have the same potential for abuse as human brain tissue (Gerard et al., 1991). Two mediated through the activation of CB1- such substance, thus making it reasonable to cannabinoid receptors, CB1 and CB2, have receptors (Hanus et al., 1999). Naturally- assume that there may be significant subsequently been characterized (Piomelli, occurring cannabinoid agonists, such as diversions from legitimate channels, 2005). delta9-THC, and the synthetic cannabinoid significant use contrary to or without Autoradiographic studies have provided agonists such as WIN–55,212–2 and CP– medical advice, or that it has a substantial information on the distribution of 55,940 produce hypothermia, analgesia, capability of creating hazards to the health cannabinoid receptors. CB1 receptors are hypoactivity, and cataplexy in addition to of the user or to the safety of the community. found in the basal ganglia, hippocampus, and their psychoactive effects. The primary psychoactive compound in cerebellum of the brain (Howlett et al., 2004) In 2000, two endogenous cannabinoid botanical marijuana is delta9-THC. Other as well as in the immune system. It is receptor agonists, anandamide and cannabinoids also present in the marijuana believed that the localization of these arachidonyl glycerol (2–AG), were plant likely contribute to the psychoactive receptors may explain cannabinoid discovered. Anandamide is a low efficacy effects. interference with movement coordination agonist (Breivogel and Childers, 2000), 2–AG There are two drug products containing and effects on memory and cognition. The is a highly efficacious agonist (Gonsiorek et cannabinoid compounds that are structurally concentration of CB1 receptors is al., 2000). Cannabinoid endogenous ligands related to the active components in considerably lower in peripheral tissues than are present in central as well as peripheral marijuana. Both are controlled under the in the central nervous system (Henkerham et tissues. The action of the endogenous ligands CSA. Marinol is a Schedule III drug product al., 1990 and 1992). is terminated by a combination of uptake and 9 containing synthetic delta -THC, known CB2 receptors are found primarily in the hydrolysis. The physiological role of generically as dronabinol, formulated in immune system, predominantly in B endogenous cannabinoids is an active area of sesame oil in soft gelatin capsules. lymphocytes and natural killer cells research (Martin et al., 1999). Dronabinol is listed in Schedule I. Marinol (Bouaboula et al., 1993). It is believed that Progress in cannabinoid pharmacology, was approved by the FDA in 1985 for the the CB2-type receptor is responsible for including further characterization of the treatment of two medical conditions: nausea mediating the immunological effects of cannabinoid receptors, isolation of and vomiting associated with cancer cannabinoids (Galiegue et al., 1995). endogenous cannabinoid ligands, synthesis chemotherapy in patients that had failed to However, CB2 receptors also have recently of agonists and antagonists with variable respond adequately to conventional anti- been localized in the brain, primarily in the affinity, and selectivity for cannabinoid emetic treatments, and for the treatment of cerebellum and hippocampus (Gong et al., receptors, provide the foundation for the anorexia associated with weight loss in 2006). potential elucidation of cannabinoid- patients with acquired immunodeficiency The cannabinoid receptors belong to the mediated effects and their relationship to syndrome or AIDS. Cesamet is a drug product family of G-protein-coupled receptors and psychomotor disorders, memory, cognitive containing the Schedule II substance, present a typical seven transmembrane- functions, analgesia, anti-emesis, intraocular nabilone, that was approved for marketing by spanning domain structure. Many G-protein- and systemic blood pressure modulation, the FDA in 1985 for the treatment of nausea coupled receptors are linked to adenylate bronchodilation, and inflammation. and vomiting associated with cancer cyclase either positively or negatively, chemotherapy. All other structurally related depending on the receptor system. Central Nervous System Effects cannabinoids in marijuana are already listed Cannabinoid receptors are linked to an Human Physiological and Psychological as Schedule I drugs under the CSA. inhibitory G-protein (Gi), so that when the Effects receptor is activated, adenylate cyclase 2. SCIENTIFIC EVIDENCE OF ITS activity is inhibited, which prevents the Subjective Effects PHARMACOLOGICAL EFFECTS, IF conversion of adenosine triphosphate The physiological, psychological, and KNOWN (ATP)to the second messenger cyclic behavioral effects of marijuana vary among The second factor the Secretary must adenosine monophosphate (cAMP). individuals. Common responses to consider is scientific evidence of marijuana’s Examples of inhibitory-coupled receptors cannabinoids, as described by Adams and pharmacological effects. There are abundant include: opioid, muscarinic cholinergic, Martin (1996) and others (Hollister, 1986 and scientific data available on the alpha 2-adrenoreceptors, dopamine (D2), and 1988; Institute of Medicine, 1982) are listed neurochemistry, toxicology, and serotonin (5–HT1). below: pharmacology of marijuana. This section It has been shown that CB1, but not CB2 1) Dizziness, nausea, tachycardia, facial includes a scientific evaluation of receptors, inhibit N- and P/Q type calcium flushing, dry mouth, and tremor initially marijuana’s neurochemistry, pharmacology, channels and activate inwardly rectifying 2) Merriment, happiness, and even and human and animal behavioral, central potassium channels (Mackie et al., 1995; exhilaration at high doses nervous system, cognitive, cardiovascular, Twitchell et al., 1997). Inhibition of the N- 3) Disinhibition, relaxation, increased autonomic, endocrinological, and type calcium channels decreases sociability, and talkativeness immunological system effects. The overview neurotransmitter release from several tissues 4) Enhanced sensory perception, giving presented below relies upon the most current and this may be the mechanism by which rise to increased appreciation of music, art, research literature on cannabinoids. cannabinoids inhibit acetylcholine, and touch

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5) Heightened imagination leading to a subjective or performance measures the day income than controls, a difference that subjective sense of increased creativity after subjects were exposed to 1.8 percent or persisted after confounding variables were 6) Time distortions 3.6 percent smoked delta9-THC. taken into account. Additionally, the users 7) Illusions, delusions, and hallucinations, The effects of chronic marijuana use have also reported negative effects of marijuana especially at high doses also been investigated. Marijuana did not use on cognition, memory, career, social life, 8) Impaired judgment, reduced co- appear to have residual effects on and physical and mental health (Gruber et ordination and ataxia, which can impede performance of a comprehensive al., 2003). driving ability or lead to an increase in risk- neuropsychological battery when 54 Association with Psychosis taking behavior monozygotic male twins (one of whom used 9) Emotional lability, incongruity of affect, marijuana, one of whom did not) were Extensive research has been conducted dysphoria, disorganized thinking, inability to compared 1–20 years after cessation of recently to investigate whether exposure to converse logically, agitation, paranoia, marijuana use (Lyons et al., 2004). This marijuana is associated with schizophrenia confusion, restlessness, anxiety, drowsiness, conclusion is similar to the results from an or other psychoses. While many studies are and panic attacks, especially in earlier study of marijuana’s effects on small and inferential, other studies in the inexperienced users or in those who have cognition in 1,318 participants over a 15-year literature utilize hundreds to thousands of taken a large dose period, where there was no evidence of long- subjects. 10) Increased appetite and short-term term residual effects (Lyketsos et al., 1999). At present, the data do not suggest a memory impairment In contrast, Solowij et al. (2002) causative link between marijuana use and the These subjective responses to marijuana demonstrated that 51 long-term cannabis development of psychosis. Although some are pleasurable to many humans and are users did less well than 33 non-using individuals who use marijuana have received associated with drug-seeking and drug-taking controls or 51 short-term users on certain a diagnosis of psychosis, most reports (Maldonado, 2002). tasks of memory and attention, but users in conclude that prodromal symptoms of The short-term perceptual distortions and this study were abstinent for only 17 hours schizophrenia appear prior to marijuana use psychological alterations produced by at time of testing. A recent study noted that (Schiffman et al., 2005). When psychiatric marijuana have been characterized by some heavy, frequent cannabis users, abstinent for symptoms are assessed in individuals with researchers as acute or transient psychosis at least 24 hours, performed significantly chronic psychosis, the ‘‘schizophrenic (Favrat et al., 2005). However, the full worse than controls on verbal memory and cluster’’ of symptoms is significantly response to cannabinoids is dissimilar to the psychomotor speed tests (Messinis et al, observed among individuals who do not have DSM–IV–TR criteria for a diagnosis of one of 2006). a history of marijuana use, while ‘‘mood the psychotic disorders (DSM–IV–TR, 2000). Pope et al. (2003) reported that no cluster’’ symptoms are significantly observed As with many psychoactive drugs, an differences were seen in neuropsychological in individuals who do have a history of individual’s response to marijuana can be performance in early- or late-onset users marijuana use (Maremmani et al., 2004). influenced by that person’s medical/ compared to non-using controls, after In the largest study evaluating the link psychiatric history and history with drugs. adjustment for intelligence quotient (IQ). In between psychosis and drug use, 3 percent of Frequent marijuana users (greater than 100 another cohort of chronic, heavy marijuana 50,000 Swedish conscripts who used times) were better able to identify a drug users, some deficits were observed on marijuana more than 50 times went on to effect from low dose delta9-THC than memory tests up to a week following develop schizophrenia (Andreasson et al., infrequent users (less than 10 times) and supervised abstinence, but these effects 1987). This was interpreted by the authors to were less likely to experience sedative effects disappeared by day 28 of abstinence suggest that marijuana use increased the risk from the drug (Kirk and deWit, 1999). Dose (Harrison et al., 2002). The authors for the disorder only among those preferences have been demonstrated for concluded that, ‘‘cannabis-associated individuals who were predisposed to marijuana in which higher doses (1.95 cognitive deficits are reversible and related to develop psychosis. A similar conclusion was 9 percent delta -THC) are preferred over lower recent cannabis exposure, rather than drawn when the prevalence of schizophrenia 9 doses (0.63 percent delta -THC) (Chait and irreversible and related to cumulative was modeled against marijuana use across Burke, 1994). lifetime use.’’ Other investigators have birth cohorts in Australia between the years Behavioral Impairment reported neuropsychological deficits in 1940 to 1979 (Degenhardt et al., 2003). Acute administration of smoked marijuana memory, executive functioning, psychomotor Although marijuana use increased over time impairs performance on tests of learning, speed, and manual dexterity in heavy in adults born during the 4-decade period, associative processes, and psychomotor marijuana smokers who had been abstinent there was not a corresponding increase in behavior (Block et al., 1992). These data for 28 days (Bolla et al., 2002). A follow up diagnoses for psychosis in these individuals. demonstrate that the short-term effects of study of heavy marijuana users noted The authors conclude that marijuana may marijuana can interfere significantly with an decision-making deficits after 25 days of precipitate schizophrenic disorders only in individual’s ability to learn in the classroom abstinence (Bolla et al., 2005). Finally, when those individuals who are vulnerable to or to operate motor vehicles. Administration IQ was contrasted in adolescents at 9–12 developing psychosis. Thus, marijuana per se to human volunteers of 290 micrograms per years and at 17–20 years, current heavy does not appear to induce schizophrenia in kilogram (μg/kg) delta9-THC in a smoked marijuana users showed a 4-point reduction the majority of individuals who try or marijuana cigarette resulted in impaired in IQ in later adolescence compared to those continue to use the drug. perceptual motor speed and accuracy, two who did not use marijuana (Fried et al., However, as might be expected, the acute skills that are critical to driving ability 2002). intoxication produced by marijuana does (Kurzthaler et al., 1999). Similarly, Age of first use may be a critical factor in exacerbate the perceptual and cognitive administration of 3.95 percent delta9-THC in persistent impairment resulting from chronic deficits of psychosis in individuals who have a smoked marijuana cigarette increased marijuana use. Individuals with a history of been previously diagnosed with the disequilibrium measures, as well as the marijuana-only use that began before the age condition (Schiffman et al., 2005; Hall et al., latency in a task of simulated vehicle of 16 were found to perform more poorly on 2004; Mathers and Ghodse, 1992; braking, at a rate comparable to an increase a visual scanning task measuring attention Thornicroft, 1990). This is consistent with a in stopping distance of 5 feet at 60 mph than individuals who started using marijuana 25-year longitudinal study of over 1,000 (Liguori et al., 1998). after age 16 (Ehrenreich et al., 1999). Kandel individuals who had a higher rate of The effects of marijuana may not fully and Chen (2000) assert that the majority of experiencing some symptoms of psychosis resolve until at least 1 day after the acute early-onset marijuana users do not go on to (but who did not receive a diagnosis of psychoactive effects have subsided, following become heavy users of marijuana, and those psychosis) if they were daily marijuana users repeated administration. Heishman et al. that do tend to associate with delinquent than if they were not (Fergusson et al., 2005). (1990) showed that impairment on memory social groups. A shorter, 3-year longitudinal study with tasks persists for 24 hours after smoking Heavy marijuana users were contrasted over 4,000 subjects similarly showed that marijuana cigarettes containing 2.57 percent with an age matched control group in a case- psychotic symptoms, but not diagnoses, were delta9-THC. However, Fant et al. (1998) control design. The heavy users reported more prevalent in subjects who used showed minimal residual alterations in lower educational achievement and lower marijuana (van Os et al., 2002).

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Additionally, schizophrenic individuals a ‘‘gateway drug,’’ leading to subsequent had previous experience with other drugs of stabilized with antipsychotics do not respond abuse of other illicit drugs, lacks conclusive abuse. However, when squirrel monkeys are differently to marijuana than healthy controls evidence (Institute of Medicine, 1999). first trained to self-administer intravenous (D’Souza et al., 2005), suggesting that Recently, Fergusson et al. (2005) in a 25-year cocaine, they will continue to bar-press at the psychosis and/or antipsychotics do not study of 1,256 New Zealand children same rate as when delta9-THC is substituted biochemically alter cannabinoid systems in concluded that use of marijuana correlates to for cocaine, at doses that are comparable to the brain. an increased risk of abuse of other drugs, those used by humans who smoke marijuana Interestingly, cannabis use prior to a first including cocaine and heroin. Other sources, (Tanda et al., 2000). This effect is blocked by psychotic episode appeared to spare however, do not support a direct causal the cannabinoid receptor antagonist, SR neurocognitive deficits compared to patients relationship between regular marijuana and 141716. New studies show that monkeys who had not used marijuana (Stirling et al., other illicit drug use. In general, such studies without a history of any drug exposure can 2005). Although adolescents diagnosed with are selective in recruiting individuals who, in be successfully trained to self-administer a first psychotic episode used more addition to having extensive histories of delta9-THC intravenously (Justinova et al., marijuana than adults who had their first marijuana use, are influenced by myriad 2003). The maximal rate of responding is 4 psychotic break, adolescents and adults had social, biological, and economic factors that μg/kg/injection, which is 2–3 times greater similar clinical outcomes 2 years later contribute to extensive drug abuse (Hall and than that observed in previous studies using (Pencer et al., 2005). Lynskey, 2005). For most studies that test the cocaine-experienced monkeys. Heavy marijuana users, though, do not hypothesis that marijuana causes abuse of These data demonstrate that under specific perform differently than non-users on the harder drugs, the determinative measure of pretreatment conditions, an animal model of Stroop task, a classic psychometric choice is any drug use, rather than DSM–IV– reinforcement by cannabinoids now exists for instrument that measures executive cognitive TR criteria for drug abuse or dependence future investigations. Rats will self- functioning. Since psychotic individuals do (DSM–IV–TR, 2000). administer delta9-THC when it is applied not perform the Stroop task well, alterations According to Golub & Johnson (2001), the intracerebroventricularly (i.c.v.), but only at in executive functioning consistent with a rate of progression to hard drug use by youth the lowest doses tested (0.01–0.02 μg/ psychotic profile were not apparent born in the 1970’s, as opposed to youth born infusion) (Braida et al., 2004). This effect is following chronic exposure to marijuana between World War II and the 1960’s, is antagonized by the cannabinoid antagonist (Gruber and Yurgelun-Todd, 2005; Eldreth et significantly decreased, although overall SR141716 and by the opioid antagonist al., 2004). marijuana use among youth appears to be naloxone (Braida et al., 2004). Additionally, Alteration in Brain Structure increasing. Nace et al. (1975) reported that mice will self-administer WIN 55212, a CB1 Although evidence suggests that some even in the Vietnam-era soldiers who receptor agonist with a non-cannabinoid drugs of abuse can lead to changes in the extensively abused marijuana and heroin, structure (Martellotta et al., 1998). density or structure of the brain in humans, there was a lack of correlation of a causal There may be a critical dose-dependent there are currently no data showing that relationship demonstrating marijuana use effect, though, since aversive effects, rather exposure to marijuana can induce such leading to heroin addiction. A recent than reinforcing effects, have been described alterations. A recent comparison of long-term longitudinal study of 708 adolescents in rats that received high doses of WIN 55212 marijuana smokers to non-smoking control demonstrated that early onset marijuana use (Chaperon et al., 1998) or delta9-THC subjects using magnetic resonance imaging did not lead to problematic drug use (Kandel (Sanudo-Pena et al., 1997). SR 141716 (MRI) did not reveal any differences in the and Chen, 2000). Similarly, among 2,446 reversed these aversive effects in both volume of grey or white matter, in the adolescents followed longitudinally, studies. hippocampus, or in cerebrospinal fluid cannabis dependence was uncommon but Conditioned Place Preference when it did occur, it was predicted primarily volume, between the two groups (Tzilos et Conditioned place preference (CPP) is a al., 2005). by parental death, deprived socio-economic status, and baseline use of illicit drugs other less rigorous method than self-administration Behavioral Effects of Prenatal Exposure than marijuana (von Sydow et al., 2002). of determining whether drugs have The impact of in utero marijuana exposure rewarding properties. In this behavioral test, on performance in a series of cognitive tasks Animal behavioral effects animals are given the opportunity to spend has been studied in children at different Self-Administration time in two distinct environments: one where they previously received a drug and one stages of development. However, since many Self-administration is a method that marijuana users have abused other drugs, it where they received a placebo. If the drug is assesses whether a drug produces rewarding reinforcing, animals will choose to spend is difficult to determine the specific impact effects that increase the likelihood of of marijuana on prenatal exposure. more time in the environment paired with behavioral responses in order to obtain the drug than the one paired with the Differences in several cognitive domains additional drug. Drugs that are self- distinguished the 4-year-old children of placebo, when both options are presented administered by animals are likely to simultaneously. heavy marijuana users. In particular, memory produce rewarding effects in humans, which and verbal measures are negatively Animals show CPP to delta9-THC, but only is indicative of abuse liability. Generally, a at the lowest doses tested (0.075–0.75 mg/kg, associated with maternal marijuana use good correlation exists between those drugs (Fried and Watkinson, 1987). Maternal i.p.) (Braida et al., 2004). This effect is that are self-administered by rhesus monkeys antagonized by the cannabinoid antagonist, marijuana use is predictive of poorer and those that are abused by humans (Balster performance on abstract/visual reasoning SR141716, as well as by the opioid and Bigelow, 2003). tasks, although it is not associated with an antagonist, naloxone (Braida et al., 2004). Interestingly, self-administration of overall lowered IQ in 3-year old children However, SR141716 may be a partial agonist, hallucinogenic-like drugs, such as (Griffith et al., 1994). At 6 years of age, rather than a full antagonist, since it is also cannabinoids, lysergic acid diethylamide prenatal marijuana history is associated with able to induce CPP (Cheer et al., 2000). (LSD), and mescaline, has been difficult to an increase in omission errors on a vigilance Interestingly, in knockout mice, animals demonstrate in animals (Yanagita, 1980). task, possibly reflecting a deficit in sustained without μ-opioid receptors do not develop However, when it is known that humans attention (Fried et al., 1992). When the effect CPP to delta9-THC (Ghozland et al., 2002). voluntarily consume a particular drug (such of prenatal exposure in 9–12 year old Drug Discrimination Studies children is analyzed, in utero marijuana as cannabis) for its pleasurable effects, the exposure is negatively associated with inability to establish self-administration with Drug discrimination is a method in which executive function tasks that require impulse that drug in animals has no practical animals indicate whether a test drug control, visual analysis, and hypothesis importance in the assessment of abuse produces physical or psychic perceptions testing, and it is not associated with global potential. This is because the animal test is similar to those produced by a known drug intelligence (Fried et al., 1998). a predictor of human behavioral response in of abuse. In this test, an animal learns to the absence of naturalistic data. press one bar when it receives the known Marijuana as a ‘‘Gateway Drug’’ The experimental literature generally drug of abuse and another bar when it The Institute of Medicine (IOM) reported reports that naı¨ve animals will not self- receives placebo. A challenge session with that the widely held belief that marijuana is administer cannabinoids unless they have the test drug determines which of the two

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bars the animal presses more often, as an 1985). In chronic marijuana users, though, a slowing and blood pressure lowering indicator of whether the test drug is like the marijuana withdrawal syndrome has been (Benowitz and Jones, 1975). Both plant- known drug of abuse. described that consists of restlessness, derived cannabinoids and endocannabinoids Animals, including monkeys and rats irritability, mild agitation, insomnia, sleep have been shown to elicit hypotension and (Gold et al., 1992), as well as humans (Chait, EEG disturbances, nausea, and cramping that bradycardia via activation of peripherally- 1988), can discriminate cannabinoids from resolves within a few days (Haney et al., located CB1 receptors (Wagner et al., 1998). other drugs or placebo. Discriminative 1999). However, the American Psychiatric This study suggests that the mechanism of 9 stimulus effects of delta -THC are Association’s Diagnostic and Statistical this effect is through presynaptic CB1 pharmacologically specific for marijuana- Manual (DSM–IV–TR, 2000) does not include receptor-mediated inhibition of containing cannabinoids (Balster and a listing for cannabis withdrawal syndrome norepinephrine release from peripheral Prescott, 1992; Barnett et al., 1985; Browne because, ‘‘symptoms of cannabis withdrawal sympathetic nerve terminals, with possible and Weissman, 1981; Wiley et al., 1993; . . . have been described . . . but their additional direct vasodilation via activation Wiley et al., 1995). Additionally, the major clinical significance is uncertain.’’ A review of vascular cannabinoid receptors. active metabolite of delta9-THC, 11-hydroxy- of all current clinical studies on cannabis The impaired circulatory responses delta9-THC, also generalizes to the stimulus withdrawal led to the recommendation by following delta9-THC administration to cue elicited by delta9-THC (Browne and Budney et al. (2004) that the DSM introduce standing, exercise, Valsalva maneuver, and Weissman, 1981). Twenty-two other a listing for cannabis withdrawal that cold pressor testing suggest that cannabinoids found in marijuana also fully includes such symptoms as sleep difficulties, cannabinoids induce a state of sympathetic substitute for delta9-THC. strange dreams, decreased appetite, insufficiency. In humans, tolerance can The discriminative stimulus effects of the decreased weight, anger, irritability, and develop to the orthostatic hypotension cannabinoid group appear to provide unique anxiety. Based on clinical descriptions, this (Jones, 2002; Sidney, 2002), possibly related effects because stimulants, hallucinogens, syndrome appears to be mild compared to to plasma volume expansion, but does not opioids, benzodiazepines, barbiturates, classical alcohol and barbiturate withdrawal develop to the supine hypotensive effects NMDA antagonists, and antipsychotics do syndromes, which can include more serious (Benowitz and Jones, 1975). During chronic not fully substitute for delta9-THC. symptoms such as agitation, paranoia, and marijuana ingestion, nearly complete tolerance develops to tachycardia and Tolerance and Physical Dependence seizures. A recent study comparing marijuana and tobacco withdrawal symptoms psychological effects when subjects are Tolerance is a state of adaptation in which in humans demonstrated that the magnitude challenged with smoked marijuana. exposure to a drug induces changes that and timecourse of the two withdrawal Electrocardiographic changes are minimal result in a diminution of one or more of the syndromes are similar (Vandrey et al., 2005). even after large cumulative doses of delta9- drug’s effects over time (American Academy The production of an overt withdrawal THC. (Benowitz and Jones, 1975). of Pain Medicine, American Pain Society and syndrome in animals following chronic It is notable that marijuana smoking by American Society of Addiction Medicine delta9-THC administration has been variably older patients, particularly those with some consensus document, 2001). Physical demonstrated under conditions of natural degree of coronary artery or cerebrovascular dependence is a state of adaptation discontinuation. This may be the result of the disease, poses risks related to increased manifested by a drug class-specific slow release of cannabinoids from adipose cardiac work, increased catecholamines, withdrawal syndrome produced by abrupt storage, as well as the presence of the major carboxyhemoglobin, and postural cessation, rapid dose reduction, decreasing psychoactive metabolite, 11-hydroxy-delta9- hypotension (Benowitz and Jones, 1981; blood level of the drug, and/or THC. When investigators have shown such a Hollister, 1988). administration of an antagonist (ibid). withdrawal syndrome in monkeys following Respiratory Effects The presence of tolerance or physical the termination of cannabinoid dependence does not determine whether a administration, the behaviors included Transient bronchodilation is the most drug has abuse potential, in the absence of transient aggression, anorexia, biting, typical effect following acute exposure to other abuse indicators such as rewarding irritability, scratching, and yawning (Budney marijuana (Gong et al., 1984). Long-term use properties. Many medications that are not et al., 2004). However, in rodents treated of marijuana can lead to an increased associated with abuse or addiction, such as with a cannabinoid antagonist following frequency of chronic bronchitis and antidepressants, beta-blockers, and centrally subacute administration of delta9-THC, pharyngitis, as well as chronic cough and acting antihypertensive drugs, can produce pronounced withdrawal symptoms, increased sputum. Pulmonary function tests physical dependence and withdrawal including wet dog shakes, can be provoked reveal that large-airway obstruction can occur symptoms after chronic use. (Breivogel et al., 2003). with chronic marijuana smoking, as can Tolerance to the subjective and cellular inflammatory histopathological performance effects of marijuana has not Behavioral Sensitization abnormalities in bronchial epithelium been demonstrated in studies with humans. Sensitization to the effects of drugs is the (Adams and Martin, 1996; Hollister, 1986). For example, reaction times are not altered opposite of tolerance: instead of a reduction The evidence that marijuana may lead to by acute administration of marijuana in long in behavioral response upon repeated drug cancer associated with respiratory effects is term marijuana users (Block and Wittenborn, administration, animals that are sensitized inconsistent, with some studies suggesting a 1985). This may be related to recent demonstrate an increase in behavioral positive correlation while others do not electrophysiological data showing that the response. Cadoni et al. (2001) demonstrated (Tashkin, 2005). Several cases of lung cancer ability of delta9-THC to increase neuronal that repeated exposure to delta9-THC can have been reported in young marijuana users firing in the ventral tegmental area (a region induce sensitization to a variety of with no history of tobacco smoking or other known to play a critical role in drug cannabinoids. These same animals also have significant risk factors (Fung et al., 1999). reinforcement and reward) is not reduced a sensitized response to administration of Marijuana use may dose-dependently interact following chronic administration of the drug opioids, an effect known as cross- with mutagenic sensitivity, cigarette smoking (Wu and French, 2000). On the other hand, sensitization. Conversely, when animals were and alcohol use to increase the risk of head tolerance can develop in humans to sensitized to the effects of morphine, there and neck cancer (Zhang et al., 1999). marijuana-induced cardiovascular and was cross-sensitization to cannabinoids. However, in the largest study to date with autonomic changes, decreased intraocular Thus, the cannabinoid and opioids systems 1,650 subjects, no positive association was pressure, and sleep alterations (Jones et al., appear to operate symmetrically in terms of found between marijuana use and lung 1981). Down-regulation of cannabinoid cross-sensitization. cancer (Tashkin et al., 2006). This finding receptors has been suggested as the held true regardless of extent of marijuana mechanism underlying tolerance to the Cardiovascular and Autonomic Effects use, when tobacco use and other potential effects of marijuana (Rodriguez de Fonseca et Single smoked or oral doses of delta9-THC confounding factors were controlled. al., 1994; Oviedo et al., 1993). produce tachycardia and may increase blood The lack of evidence for carcinogenicity Acute administration of marijuana pressure (Capriotti et al., 1988; Benowitz and related to cannabis may be related to the fact containing 2.1 percent delta9-THC does not Jones, 1975). However, prolonged delta9-THC that intoxication from marijuana does not produce ‘‘hangover effects’’ (Chait et al., ingestion produces significant heart rate require large amounts of smoked material.

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This may be especially pertinent since in 62 AIDS patients who were taking protease Marijuana is a mixture of the dried marijuana is reportedly more potent today inhibitors. Subjects received one of the flowering tops and leaves from the plant and than a generation ago. Thus, individuals may following three times a day: smoked is variable in content and potency (Agurell et consume much less marijuana than in marijuana cigarette containing 3.95 percent al., 1984 and 1986; Graham, 1976; previous decades to reach the desired delta9-THC; oral tablet containing delta9-THC Mechoulam, 1973). Marijuana is usually subjective effects, exposing them to less (2.5 mg oral dronabinol); or oral placebo. smoked in the form of rolled cigarettes while potential carcinogens. There were no changes in CD4+ and CD8+ hashish and hash oil are smoked in pipes. cell counts or HIV RNA levels or protease Potency of marijuana, as indicated by Endocrine System inhibitor levels between groups, cannabinoid content, has been reported to The presence of in vitro delta9-THC demonstrating no short-term adverse average from as low as 1 to 2 percent to as reduces binding of the corticosteroid, virologic effects from using cannabinoids in high as 17 percent. dexamethasone, in hippocampal tissue from individuals with compromised immune The concentration of delta9-THC and other adrenalectomized rats, suggesting an systems. cannabinoids in marijuana varies with interaction with the glucocorticoid receptor These human data contrast with data growing conditions and processing after (Eldridge et al., 1991). Acute delta9-THC generated in immunodeficient mice showing harvest. Other variables that can influence releases corticosterone, but tolerance that exposure to delta9-THC in vivo the strength, quality, and purity of marijuana develops to this effect with chronic suppresses immune function, increases HIV are genetic differences among the cannabis administration (Eldridge et al., 1991). co-receptor expression, and acts as a cofactor plant species and which parts of the plant are Experimental administration of marijuana to enhance HIV replication (Roth et al., collected (flowers, leaves, stems, etc.) to humans does not consistently alter 2005). (Adams and Martin, 1996; Agurell et al., endocrine parameters. In an early study, male 3. THE STATE OF CURRENT SCIENTIFIC 1984; Mechoulam, 1973). In the usual subjects who experimentally received mixture of leaves and stems distributed as smoked marijuana showed a significant KNOWLEDGE REGARDING THE DRUG OR OTHER SUBSTANCE marijuana, the concentration of delta9-THC depression in luteinizing hormone and a ranges widely from 0.3 to 4.0 percent by significant increase in cortisol were observed The third factor the Secretary must weight. However, specially grown and (Cone et al., 1986). However, two later consider is the state of current scientific selected marijuana can contain even 15 studies showed no changes in hormones. knowledge regarding marijuana. Thus, this percent or greater delta9-THC. Thus, a 1 gm Male subjects who were experimentally section discusses the chemistry, human marijuana cigarette might contain as little as exposed to smoked delta9-THC (18 mg/ pharmacokinetics, and medical uses of 3 mg or as much as 150 mg or more of delta9- marijuana cigarette) or oral delta9-THC (10 marijuana. THC. mg t.i.d. for 3 days and on the morning of the Hashish consists of the cannabinoid-rich fourth day) showed no changes in plasma Chemistry resinous material of the cannabis plant, prolactin, ACTH, cortisol, luteinizing According to the DEA, Cannabis sativa is which is dried and compressed into a variety hormone, or testosterone levels (Dax et al., the primary species of cannabis currently of forms (balls, cakes, etc.). Pieces are then 1989). Similarly, a study with 93 men and 56 marketed illegally in the United States of women showed that chronic marijuana use America. From this plant, three derivatives broken off, placed into a pipe and smoked. did not significantly alter concentrations of are sold as separate illicit drug products: DEA reports that cannabinoid content in testosterone, luteinizing hormone, follicle marijuana, hashish, and hashish oil. hashish averages 6 percent. stimulating hormone, prolactin, or cortisol Each of these derivatives contains a Hash oil is produced by solvent extraction (Block et al., 1991). complex mixture of chemicals. Among the of the cannabinoids from plant material. Relatively little research has been components are the 21 carbon terpenes found Color and odor of the extract vary, depending performed on the effects of experimentally in the plant as well as their carboxylic acids, on the type of solvent used. Hash oil is a administered marijuana on female analogues, and transformation products viscous brown or amber-colored liquid that reproductive system functioning. In known as cannabinoids (Agurell et al., 1984 contains approximately 15 percent monkeys, delta9-THC administration and 1986; Mechoulam, 1973). The cannabinoids. One or two drops of the liquid suppressed ovulation (Asch et al., 1981) and cannabinoids appear to naturally occur only placed on a cigarette purportedly produce the reduced progesterone levels (Almirez et al., in the marijuana plant and most of the equivalent of a single marijuana cigarette 1983). However, when women were studied botanically-derived cannabinoids have been (DEA, 2005). following experimental exposure to smoked identified. Among the cannabinoids, delta9- The lack of a consistent concentration of marijuana, no hormonal or menstrual cycle THC (alternate name delta1-THC) and delta- delta9-THC in botanical marijuana from changes were observed (Mendelson and 8-tetrahydrocannabinol (delta8-THC, diverse sources complicates the Mello, 1984). Brown and Dobs (2002) suggest alternate name delta6-THC) are both found in interpretation of clinical data using that the discrepancy between animal and marijuana and are able to produce the marijuana. If marijuana is to be investigated human hormonal response to cannabinoids characteristic psychoactive effects of more widely for medical use, information may be attributed to the development of marijuana. Because delta9-THC is more and data regarding the chemistry, tolerance in humans. abundant than delta8-THC, the activity of manufacturing, and specifications of Recent data suggest that cannabinoid marijuana is largely attributed to the former. marijuana must be developed. Delta8-THC is found only in few varieties of agonists may have therapeutic value in the Human Pharmacokinetics treatment of prostate cancer, a type of the plant (Hively et al., 1966). carcinoma in which growth is stimulated by Delta9-THC is an optically active resinous Marijuana is generally smoked as a androgens. Research with prostate cancer substance, insoluble in water, and extremely cigarette (weighing between 0.5 and 1.0 gm), 9 cells shows that the mixed CB1/CB2 agonist, lipid soluble. Chemically delta -THC is (6aR- or in a pipe. It can also be taken orally in WIN–55212–2, induces apoptosis in prostate trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl- foods or as extracts of plant material in cancer cell growth, as well as decreases in 3-pentyl-6H-dibenzo-[b,d]pyran-1-ol or ethanol or other solvents. expression of androgen receptors and (-)-delta9-(trans)-tetrahydrocannabinol. The The absorption, metabolism, and prostate-specific antigens (Sarfaraz et al., (-)-trans isomer of delta9-THC is pharmacokinetic profile of delta9-THC (and 2005). pharmacologically 6 to 100 times more other cannabinoids) in marijuana or other potent than the (+)-trans isomer (Dewey et drug products containing delta9-THC vary Immune System al., 1984). with route of administration and formulation Immune functions are altered by Other cannabinoids, such as cannabidiol (Adams and Martin, 1996; Agurell et al., 1984 cannabinoids, but there can be differences (CBD) and cannabinol (CBN), have been and 1986). When marijuana is administered between the effects of synthetic, natural, and characterized. CBD is not considered to have by smoking, delta9-THC in the form of an endogenous cannabinoids, often in an cannabinol-like psychoactivity, but is aerosol is absorbed within seconds. The apparently biphasic manner depending on thought to have significant anticonvulsant, psychoactive effects of marijuana occur dose (Croxford and Yamamura, 2005). sedative, and anxiolytic activity (Adams and immediately following absorption, with Abrams et al. (2003) investigated the effect Martin, 1996; Agurell et al., 1984 and 1986; mental and behavioral effects measurable up of marijuana on immunological functioning Hollister, 1986). to 6 hours (Grotenhermen, 2003; Hollister,

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1986 and 1988). Delta9-THC is delivered to In contrast to smoking, the onset of effects research in the United States. In May 1999, the brain rapidly and efficiently as would be after oral administration of delta9-THC or HHS provided guidance on the procedures expected of a very lipid-soluble drug. marijuana is 30 to 90 min, which peaks after for providing research-grade marijuana to The bioavailability of the delta9-THC from 2 to 3 hours and continues for 4 to 12 hours scientists who intend to study marijuana in marijuana in a cigarette or pipe can range (Grotenhermen, 2003; Adams and Martin, scientifically valid investigations and well- from 1 to 24 percent with the fraction 1996; Agurell et al., 1984 and 1986). Oral controlled clinical trials (DHHS, 1999). This absorbed rarely exceeding 10 to 20 percent bioavailability of delta9-THC, whether pure action was prompted by the increasing (Agurell et al., 1986; Hollister, 1988). The or in marijuana, is low and extremely interest in determining whether relatively low and variable bioavailability variable, ranging between 5 and 20 percent cannabinoids have medical use through results from the following: significant loss of (Agurell et al., 1984 and 1986). Following scientifically valid investigations. delta9-THC in side-stream smoke, variation oral administration of radioactive-labeled In February 1997, a National Institutes of in individual smoking behaviors, delta9-THC, delta9-THC plasma levels are Health (NIH)-sponsored workshop analyzed cannabinoid pyrolysis, incomplete low relative to those levels after smoking or available scientific information and absorption of inhaled smoke, and metabolism intravenous administration. There is inter- concluded that ‘‘in order to evaluate various in the lungs. A individual’s experience and and intra-subject variability, even when hypotheses concerning the potential utility of technique with smoking marijuana is an repeated dosing occurs under controlled marijuana in various therapeutic areas, more important determinant of the dose that is conditions. The low and variable oral and better studies would be needed’’ (NIH, absorbed (Herning et al., 1986; Johansson et bioavailability of delta9-THC is a 1997). In addition, in March 1999, the al., 1989). consequence of its first-pass hepatic Institute of Medicine (IOM) issued a detailed 9 After smoking, venous levels of delta -THC elimination from blood and erratic report that supported the need for evidence- decline precipitously within minutes, and absorption from stomach and bowel. It is based research into the effects of marijuana within an hour are about 5 to 10 percent of more difficult for a user to titrate the oral and cannabinoid components of marijuana, the peak level (Agurell et al., 1986; Huestis delta9-THC dose than marijuana smoking for patients with specific disease conditions. et al., 1992a and 1992b). Plasma clearance of The IOM report also emphasized that smoked 9 because of the delay in onset of effects after delta -THC is approximately 950 ml/min or an oral dose (typically 1 to 2 hours). marijuana is a crude drug delivery system greater, thus approximating hepatic blood Cannabinoid metabolism is extensive. that exposes individuals to a significant flow. The rapid disappearance of delta9-THC number of harmful substances and that ‘‘if Delta9-THC is metabolized via microsomal from blood is largely due to redistribution to there is any future for marijuana as a hydroxylation to both active and inactive other tissues in the body, rather than to medicine, it lies in its isolated components, metabolites (Lemberger et al., 1970, 1972a, metabolism (Agurell et al., 1984 and 1986). the cannabinoids and their synthetic and 1972b; Agurell et al., 1986; Hollister, Metabolism in most tissues is relatively slow derivatives.’’ As such, the IOM recommended 9 1988) of which the primary active metabolite or absent. Slow release of delta -THC and 9 that clinical trials should be conducted with other cannabinoids from tissues and was 11-hydroxy-delta -THC. This metabolite the goal of developing safe delivery systems 9 subsequent metabolism results in a long is approximately equipotent to delta -THC in (Institute of Medicine, 1999). Additionally, elimination half-life. The terminal half-life of producing marijuana-like subjective effects state-level public initiatives, including delta9-THC is estimated to range from (Agurell et al., 1986; Lemberger and Rubin, referenda in support of the medical use of approximately 20 hours to as long as 10 to 1975). After oral administration, metabolite marijuana, have generated interest in the 9 13 days (Hunt and Jones, 1980), though levels may exceed that of delta -THC and medical community for high quality clinical reported estimates vary as expected with any thus contribute greatly to the investigation and comprehensive safety and 9 slowly cleared substance and the use of pharmacological effects of oral delta -THC or effectiveness data. assays of variable sensitivities. Lemberger et marijuana. In addition to 11-hydroxy-delta9- For example, in 2000, the state of al. (1970) determined the half-life of delta9- THC, some inactive carboxy metabolites have California established the Center for THC to range from 23 to 28 hours in heavy terminal half-lives of 50 hours to 6 days or Medicinal Cannabis Research (CMCR) marijuana users to 60 to 70 hours in naı¨ve more. The latter substances serve as long- (www.cmcr.ucsd.edu) ‘‘in response to users. term markers of earlier marijuana use in scientific evidence for therapeutic Characterization of the pharmacokinetics urine tests. The majority of the absorbed possibilities of cannabis and local legislative of delta9-THC and other cannabinoids from delta9-THC dose is eliminated in feces, and initiatives in favor of compassionate use’’ smoked marijuana is difficult (Agurell et al., about 33 percent in urine. Delta9-THC enters (Grant, 2005). State legislation establishing 1986; Herning et al., 1986; Huestis et al., enterohepatic circulation and undergoes the CMCR called for high quality medical 1992a), in part because a subject’s smoking hydroxylation and oxidation to 11-nor-9- research that will ‘‘enhance understanding of behavior during an experiment is variable. carboxy-delta9-THC. The glucuronide is the efficacy and adverse effects of marijuana Each puff delivers a discrete dose of delta9- excreted as the major urine metabolite along as a pharmacological agent,’’ but stressed that THC. An experienced marijuana smoker can with about 18 nonconjugated metabolites. the project ‘‘should not be construed as titrate and regulate the dose to obtain the Frequent and infrequent marijuana users are encouraging or sanctioning the social or desired acute psychological effects and to similar in the way they metabolize delta9- recreational use of marijuana.’’ CMCR has avoid overdose and/or minimize undesired THC (Agurell et al., 1986). thus far funded studies on the potential use effects. For example, under naturalistic of cannabinoids for the treatment of multiple Medical Uses for Marijuana conditions, users will hold marijuana smoke sclerosis, neuropathic pain, appetite in the lungs for an extended period of time, A NDA for marijuana/cannabis has not suppression and cachexia, and severe pain in order to prolong absorption and increase been submitted to the FDA for any indication and nausea related to cancer or its treatment psychoactive effects. The effect of experience and thus no medicinal product containing by chemotherapy. To date, though, no NDAs in the psychological response may explain botanical cannabis has been approved for utilizing marijuana for these indications have why venous blood levels of delta9-THC marketing. However, small clinical studies been submitted to the FDA. correlate poorly with intensity of effects and published in the current medical literature However, FDA approval of an NDA is not level of intoxication (Agurell et al., 1986; demonstrate that research with marijuana is the sole means through which a drug can be Barnett et al., 1985; Huestis et al., 1992a). being conducted in humans in the United determined to have a ‘‘currently accepted Additionally, puff and inhalation volume States under FDA-authorized investigational medical use’’ under the CSA. According to changes with phase of smoking, tending to be new drug (IND) applications. established case law, a drug has a ‘‘currently highest at the beginning and lowest at the HHS states in a published guidance that it accepted medical use’’ if all of the following end of smoking a cigarette. Some studies is committed to providing ‘‘research-grade five elements have been satisfied: found frequent users to have higher puff marijuana for studies that are the most likely a. the drug’s chemistry is known and volumes than less frequent marijuana users. to yield usable, essential data’’ (HHS, 1999). reproducible; During smoking, as the cigarette length The opportunity for scientists to conduct b. there are adequate safety studies; shortens, the concentration of delta9-THC in clinical research with botanical marijuana c. there are adequate and well-controlled the remaining marijuana increases; thus, each has increased due to changes in the process studies proving efficacy; successive puff contains an increasing for obtaining botanical marijuana from NIDA, d. the drug is accepted by qualified concentration of delta9-THC. the only legitimate source of the drug for experts; and

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e. the scientific evidence is widely or a ‘‘currently accepted medical use with population) using it monthly. Thus, regular available. severe restrictions.’’ illicit drug use, and more specifically marijuana use, for rewarding responses is [Alliance for Cannabis Therapeutics v. DEA, 4. ITS HISTORY AND CURRENT PATTERN increasing. The 2004 NSDUH estimated that 15 F.3d 1131, 1135 (D.C. Cir. 1994)] OF ABUSE Although the structures of many 96.8 million individuals (40.2 percent of the The fourth factor the Secretary must U.S. population) have tried marijuana at least cannabinoids found in marijuana have been consider is the history and current pattern of characterized, a complete scientific analysis once during their lifetime. Thus, 15 percent abuse of marijuana. A variety of sources of those who have tried marijuana on one of all the chemical components found in provide data necessary to assess abuse marijuana has not been conducted. Safety occasion go on to use it monthly, but 85 patterns and trends of marijuana. The data percent of them do not. studies for acute or subchronic indicators of marijuana use include NSDUH, administration of marijuana have been Monitoring the Future (MTF), DAWN, and Monitoring the Future carried out through a limited number of Treatment Episode Data Set (TEDS), which MTF (2005, http:// Phase 1 clinical investigations approved by are described below: the FDA, but there have been no NDA-quality www.monitoringthefuture.org) is a NIDA- studies that have scientifically assessed the National Survey on Drug Use and Health sponsored annual national survey that tracks drug use trends among adolescents in the efficacy and full safety profile of marijuana The National Survey on Drug Use and United States. The MTF surveys 8th, 10th, for any medical condition. A material Health (NSDUH, 2004; http:// and 12th graders every spring in randomly conflict of opinion among experts precludes oas.samhsa.gov/nsduh.htm) is conducted selected U.S. schools. The MTF survey has a finding that marijuana has been accepted annually by SAMHSA, an agency of HHS. been conducted since 1975 for 12th graders by qualified experts. At this time, it is clear NSDUH provides estimates of the prevalence that there is not a consensus of medical and incidence of illicit drug, alcohol, and and since 1991 for 8th and 10th graders by opinion concerning medical applications of tobacco use in the United States. This the Institute for Social Research at the marijuana. Finally, the scientific evidence database was known until 2001 as the University of Michigan under a grant from regarding the safety or efficacy of marijuana National Household Survey on Drug Abuse. NIDA. The 2005 sample sizes were 17,300— is typically available only in summarized The survey is based on a nationally 8th graders; 16,700—10th graders; and form, such as in a paper published in the representative sample of the civilian, non- 15,400—12th graders. In all, a total of 49,300 medical literature, rather than in a raw data institutionalized population 12 years of age students in 402 schools participated. format. As such, there is no opportunity for and older. The survey identifies whether an Since 1999, illicit drug use among teens adequate scientific scrutiny of whether the individual used a drug during a certain decreased and held steady through 2005 in data demonstrate safety or efficacy. period, but not the amount of the drug used all three grades (Table 1). Marijuana Alternately, a drug can be considered to on each occasion. Excluded groups include remained the most widely used illicit drug, have ‘‘a currently accepted medical use with homeless people, active military personnel, though its use has steadily decreased since severe restrictions’’ (21 U.S.C. 812(b)(2)(B)), and residents of institutions, such as jails. 1999. For 2005, the annual prevalence rates as allowed under the stipulations for a According to the 2004 NSDUH, 19.1 for marijuana use in grades 8, 10, and 12 Schedule II drug. However, as stated above, million individuals (7.9 percent of the U.S. were, respectively, 12.2 percent, 26.6 a material conflict of opinion among experts population) illicitly used drugs other than percent, and 33.6 percent. Current monthly precludes a finding that marijuana has been alcohol and nicotine on a monthly basis, prevalence rates for marijuana use were 6.6 accepted by qualified experts, even under compared to 14.8 million (6.7 percent of the percent, 15.2 percent, and 19.8 percent. (See conditions where its use is severely U.S. population) users in 1999. This is an Table 1). According to Gruber and Pope restricted. Thus, to date, research on the increase from 1999 of 4.3 million (2.0 percent (2002), when adolescents who used medical use of marijuana has not progressed of the U.S. population). The most frequently marijuana reach their late 20’s, the vast to the point that marijuana can be considered used illicit drug was marijuana, with 14.6 majority of these individuals will have to have a ‘‘currently accepted medical use’’ million individuals (6.1 percent of the U.S. stopped using marijuana.

TABLE 1—TRENDS IN ANNUAL AND MONTHLY PREVALENCE OF USE OF VARIOUS DRUGS FOR EIGHTH, TENTH, AND TWELFTH GRADERS, FROM MONITORING THE FUTURE. PERCENTAGES REPRESENT STUDENTS IN SURVEY RESPOND- ING THAT THEY HAD USED A DRUG EITHER IN THE PAST YEAR OR IN THE PAST 30 DAYS

Annual 30-Day 2003 2004 2005 2003 2004 2005

Any illicit drug (a): 8th Grade...... 16.1 15.2 15.5 9.7 8.4 8.5 10th Grade...... 32.0 31.1 29.8 19.5 18.3 17.3 12th Grade...... 39.3 38.8 38.4 24.1 23.4 23.1 Any illicit drug other than cannabis (a): 8th Grade...... 8.8 7.9 8.1 4.7 4.1 4.1 10th Grade...... 13.8 13.5 12.9 6.9 6.9 6.4 12th Grade...... 19.8 20.5 19.7 10.4 10.8 10.3 Marijuana/hashish: 8th Grade...... 12.8 11.8 12.2 7.5 6.4 6.6 10th Grade...... 28.2 27.5 26.6 17.0 15.9 15.2 12th Grade...... 34.9 34.3 33.6 21.2 19.9 19.8 SOURCE: The Monitoring the Future Study, the University of Michigan. a. For 12th graders only, ‘‘any illicit drug’’ includes any use of marijuana, LSD, other hallucinogens, crack, other cocaine, or heroin, or any use of other opiates, stimulants, barbiturates, or tranquilizers not under a doctor’s orders. For 8th and 10th graders, the use of other opiates and bar- biturates was excluded.

Drug Abuse Warning Network designed to obtain information on ED visits weighted to produce national estimates. It is DAWN (2006, http:// in which recent drug use is implicated. The critical to note that DAWN data and dawninfo.samhsa.gov/) is a national ED data from a representative sample of estimates for 2004 are not comparable to probability survey of U.S. hospitals with EDs hospital emergency departments are those for any prior years because of vast

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changes in the methodology used to collect TEDS is an admission-based system, and the drug most frequently associated with ED the data. Further, estimates for 2004 are the TEDS admissions do not represent visits for individuals under the age of 18 first to be based on a new, redesigned sample individuals. Thus, a given individual years. of hospitals. Thus, the most recent estimates admitted to treatment twice within a given Data from TEDS show that 15.5 percent of available are for 2004. year would be counted as two admissions. all admissions were for primary marijuana Many factors can influence the estimates of Additionally, TEDS does not include all abuse. Approximately 90 percent of these ED visits, including trends in the ED usage admissions to substance abuse treatment. primary marijuana admissions were for in general. Some drug users may have visited TEDS includes facilities that are licensed or individuals under the age of 18 years. EDs for a variety of reasons, some of which certified by the States to provide substance may have been life-threatening, whereas abuse treatment and that are required by the 6. WHAT, IF ANY, RISK THERE IS TO THE others may have sought care at the ED for States to provide TEDS client-level data. PUBLIC detoxification because they needed Facilities that report TEDS data are those that The sixth factor the Secretary must certification before entering treatment. receive State alcohol and/or drug agency consider is the risk marijuana poses to the DAWN data do not distinguish the drug funds for the provision of alcohol and/or public health. The risk to the public health responsible for the ED visit from others used drug treatment services. The primary goal for as measured by emergency room episodes, concomitantly. As stated in a recent DAWN TEDS is to monitor the characteristics of marijuana-related deaths, and drug treatment report, ‘‘Since marijuana/hashish is treatment episodes for substance abusers. admissions is discussed in full under Factors frequently present in combination with other Primary marijuana abuse accounted for 1, 4, and 5, above. Accordingly, Factor 6 drugs, the reason for the ED contact may be 15.5 percent of TEDS admissions in 2003, the focuses on the health risks to the individual more relevant to the other drug(s) involved latest year for which data are available. user. in the episode.’’ Three-quarters of the individuals admitted All drugs, both medicinal and illicit, have For 2004, DAWN estimates a total of for marijuana were male and 55 percent of a broad range of effects on the individual 1,997,993 (95 percent confidence interval the admitted individuals were white. The user that are dependent on dose and duration [CI]: 1,708,205 to 2,287,781) drug-related ED average age at admission was 23 years. The of use among others. FDA-approved drug visits for the entire United States. During this largest proportion (84 percent) of admissions products can produce adverse events (or period, DAWN estimates 940,953 (CI: to ambulatory treatment was for primary ‘‘side effects’’) in some individuals even at 773,124 to 1,108,782) drug-related ED visits marijuana abuse. More than half (57 percent) doses in the therapeutic range. When involved a major drug of abuse. Thus, nearly of marijuana treatment admissions were determining whether a drug product is safe half of all drug-related visits involved alcohol referred through the criminal justice system. and effective for any indication, FDA or an illicit drug. Overall, drug-related ED Between 1993 and 2003, the percentage of performs an extensive risk-benefit analysis to visits averaged 1.6 drugs per visit, including admissions for primary marijuana use determine whether the risks posed by the illicit drugs, alcohol, prescription and over- increased from 6.9 percent to 15.5 percent, drug product’s potential or actual side effects the-counter (OTC) pharmaceuticals, dietary comparable to the increase for primary are outweighed by the drug product’s supplements, and non-pharmaceutical opioid use from 13 percent in 1993 to 17.6 potential benefits. As marijuana is not FDA- inhalants. percent in 2003. In contrast, the percentage approved for any medicinal use, any Marijuana was involved in 215,665 (CI: of admissions for primary cocaine use potential benefits attributed to marijuana use 175,930 to 255,400) ED visits, while cocaine declined from 12.6 percent in 1993 to 9.8 have not been found to be outweighed by the was involved in 383,350 (CI: 284,170 to percent in 2003, and for primary alcohol use risks. However, cannabinoids are generally 482,530) ED visits, heroin was involved in from 56.9 percent in 1993 to 41.7 percent in potent psychoactive substances and are 162,137 (CI: 122,414 to 201,860) ED visits, 2003. pharmacologically active on multiple organ and stimulants, including amphetamine and Twenty-six percent of those individuals systems. methamphetamine, were involved in 102,843 who were admitted for primary use of The discussion of marijuana’s central (CI: 61,520 to 144,166) ED visits. Other illicit marijuana reported its daily use, although nervous system, cognitive, cardiovascular, drugs, such as PCP, MDMA, and GHB, were 34.6 percent did not use marijuana in the autonomic, respiratory, and immune system much less frequently associated with ED past month. Nearly all (96.2 percent) of effects are fully discussed under Factor 2. visits. primary marijuana users utilized the drug by Consequences of marijuana use and abuse are Approximately 18 percent of ED visits smoking it. Over 90 percent of primary discussed below in terms of the risk from involving marijuana were for patients under marijuana admissions used marijuana for the acute and chronic use of the drug to the the age of 18, whereas this age group first time before the age of 18. individual user (Institute of Medicine, 1999). accounts for less than 1 percent of the ED 5. THE SCOPE, DURATION, AND visits involving heroin/morphine and Risks from acute use of marijuana SIGNIFICANCE OF ABUSE approximately 3 percent of the visits Acute use of marijuana impairs involving cocaine. Since the size of the The fifth factor the Secretary must consider psychomotor performance, including population differs across age groups, a is the scope, duration, and significance of performance of complex tasks, which makes measure standardized for population size is marijuana abuse. According to 2004 data it inadvisable to operate motor vehicles or useful to make comparisons. For marijuana, from NSDUH and MTF, marijuana remains heavy equipment after using marijuana the rates of ED visits per 100,000 population the most extensively used illegal drug in the (Ramaekers et al., 2004). Dysphoria and were highest for patients aged 18 to 20 (225 United States, with 40.6 percent of U.S. psychological distress, including prolonged ED visits per 100,000) and for patients aged individuals over age 12 (96.6 million) and anxiety reactions, are potential responses in 21 to 24 (190 ED visits per 100,000). 44.8 percent of 12th graders having used a minority of individuals who use marijuana marijuana at least once in their lifetime. (Haney et al., 1999). Treatment Episode Data Set While the majority of individuals over age 12 TEDS (TEDS, 2003; http://oas.samhsa.gov/ (85 percent) who have used marijuana do not Risks from chronic use of marijuana dasis.htm#teds2) system is part of use the drug monthly, 14.6 million Chronic exposure to marijuana smoke is SAMHSA’s Drug and Alcohol Services individuals (6.1 percent of the U.S. considered to be comparable to tobacco Information System (Office of Applied population) report that they used marijuana smoke with respect to increased risk of Science, SAMHSA). TEDS comprises data on within the past 30 days. An examination of cancer, lung damage, and poor pregnancy treatment admissions that are routinely use among various age cohorts in NSDUH outcome. Although a distinctive marijuana collected by States in monitoring their demonstrates that monthly use occurs withdrawal syndrome has been identified, substance abuse treatment systems. The primarily among college age individuals, indicating that marijuana produces physical TEDS report provides information on the with use dropping off sharply after age 25. dependence, this phenomenon is mild and demographic and substance use DAWN data show that marijuana was short-lived (Budney et al., 2004), as described characteristics of the 1.8 million annual involved in 79,663 ED visits, which amounts above under Factor 2. admissions to treatment for abuse of alcohol to 13 percent of all drug-related ED visits. The Diagnostic and Statistical Manual and drugs in facilities that report to Minors accounted for 15 percent of these (DSM–IV–TR, 2000) of the American individual State administrative data systems. marijuana-related visits, making marijuana Psychiatric Association states that the

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consequences of cannabis abuse are as admitted for substance abuse treatment or in While there are INDs for marijuana active at follows: individuals who had been given marijuana the FDA, marijuana does not have a currently [P]eriodic cannabis use and intoxication on a daily basis during research conditions. accepted medical use for treatment in the can interfere with performance at work or Withdrawal symptoms can also be induced United States, nor does it have an accepted school and may be physically hazardous in in animals following administration of a medical use with severe restrictions. situations such as driving a car. Legal cannabinoid antagonist after chronic delta9- A drug has a ‘‘currently accepted medical problems may occur as a consequence of THC administration (Breivogel et al., 2003). use’’ if all of the following five elements have arrests for cannabis possession. There may be Tolerance is a state of adaptation in which been satisfied: arguments with spouses or parents over the exposure to a drug induces changes that a. The drug’s chemistry is known and possession of cannabis in the home or its use result in a diminution of one or more of the reproducible; in the presence of children. When drug’s effects over time (American Academy b. There are adequate safety studies; psychological or physical problems are of Pain Medicine, American Pain Society and c. There are adequate and well-controlled associated with cannabis in the context of American Society of Addiction Medicine studies proving efficacy; compulsive use, a diagnosis of Cannabis consensus document, 2001). Tolerance can d. The drug is accepted by qualified Dependence, rather than Cannabis Abuse, develop to marijuana-induced cardiovascular experts; and should be considered. and autonomic changes, decreased e. The scientific evidence is widely Individuals with Cannabis Dependence intraocular pressure, sleep and sleep EEG, available. have compulsive use and associated and mood and behavioral changes (Jones et [Alliance for Cannabis Therapeutics v. DEA, problems. Tolerance to most of the effects of al., 1981). Down-regulation of cannabinoid 15 F.3d 1131, 1135 (D.C. Cir. 1994)] receptors has been suggested as the cannabis has been reported in individuals Although the structures of many mechanism underlying tolerance to the who use cannabis chronically. There have cannabinoids found in marijuana have been effects of marijuana (Rodriguez de Fonseca et also been some reports of withdrawal characterized, a complete scientific analysis al., 1994). Pharmacological tolerance does symptoms, but their clinical significance is of all the chemical components found in not indicate the physical dependence uncertain. There is some evidence that a marijuana has not been conducted. Safety liability of a drug. majority of chronic users of cannabinoids studies for acute or subchronic report histories of tolerance or withdrawal 8. WHETHER THE SUBSTANCE IS AN administration of marijuana have been and that these individuals evidence more IMMEDIATE PRECURSOR OF A carried out through a limited number of severe drug-related problems overall. SUBSTANCE ALREADY CONTROLLED Phase 1 clinical investigations approved by Individuals with Cannabis Dependence may UNDER THIS ARTICLE the FDA, but there have been no NDA-quality use very potent cannabis throughout the day studies that have scientifically assessed the The eighth factor the Secretary must over a period of months or years, and they efficacy of marijuana for any medical consider is whether marijuana is an may spend several hours a day acquiring and condition. A material conflict of opinion immediate precursor of a controlled using the substance. This often interferes among experts precludes a finding that substance. Marijuana is not an immediate with family, school, work, or recreational marijuana has been accepted by qualified precursor of another controlled substance. activities. Individuals with Cannabis experts. At this time, it is clear that there is Dependence may also persist in their use RECOMMENDATION not a consensus of medical opinion despite knowledge of physical problems (e.g., After consideration of the eight factors concerning medical applications of chronic cough related to smoking) or discussed above, HHS recommends that marijuana. Finally, the scientific evidence psychological problems (e.g., excessive marijuana remain in Schedule I of the CSA. regarding the safety or efficacy of marijuana sedation and a decrease in goal-oriented Marijuana meets the three criteria for placing is typically available only in summarized activities resulting from repeated use of high a substance in Schedule I of the CSA under form, such as in a paper published in the doses). 21 U.S.C. 812(b)(1): medical literature, rather than in a raw data format. As such, there is no opportunity for 7. ITS PSYCHIC OR PHYSIOLOGIC 1) Marijuana has a high potential for abuse: adequate scientific scrutiny of whether the DEPENDENCE LIABILITY The large number of individuals using data demonstrate safety or efficacy. The seventh factor the Secretary must marijuana on a regular basis, its widespread Alternately, a drug can be considered to consider is marijuana’s psychic or use, and the vast amount of marijuana that have ‘‘a currently accepted medical use with physiologic dependence liability. Physical is available for illicit use are indicative of the severe restrictions’’ (21 U.S.C. 812(b)(2)(B)), dependence is a state of adaptation high abuse potential for marijuana. as allowed under the stipulations for a manifested by a drug class-specific Approximately 14.6 million individuals in Schedule II drug. However, as stated above, withdrawal syndrome produced by abrupt the United States (6.1 percent of the U.S. a material conflict of opinion among experts cessation, rapid dose reduction, decreasing population) used marijuana monthly in 2003. precludes a finding that marijuana has been blood level of the drug, and/or A 2003 survey indicates that by 12th grade, accepted by qualified experts, even under administration of an antagonist (American 33.6 percent of students report having used conditions where its use is severely Academy of Pain Medicine, American Pain marijuana in the past year, and 19.8 percent restricted. To date, research on the medical Society and American Society of Addiction report using it monthly. In Q3 to Q4 2003, use of marijuana has not progressed to the Medicine consensus document, 2001). Long- 79,663 ED visits were marijuana-related, point that marijuana can be considered to term, regular use of marijuana can lead to representing 13 percent of all drug-related have a ‘‘currently accepted medical use’’ or physical dependence and withdrawal episodes. Primary marijuana use accounted a ‘‘currently accepted medical use with following discontinuation as well as psychic for 15.5 percent of admissions to drug severe restrictions.’’ addiction or dependence. The marijuana treatment programs in 2003. Marijuana has withdrawal syndrome consists of symptoms 3) There is a lack of accepted safety for use dose-dependent reinforcing effects, as of marijuana under medical supervision. such as restlessness, mild agitation, demonstrated by data that humans prefer insomnia, nausea, and cramping that may higher doses of marijuana to lower doses. In At present, there are no FDA-approved resolve after 4 days, and may require in- addition, there is evidence that marijuana use marijuana products, nor is marijuana under hospital treatment. It is distinct from the can result in psychological dependence in at NDA evaluation at the FDA for any withdrawal syndromes associated with risk individuals. indication. Marijuana does not have a alcohol and heroin use (Budney et al., 1999; currently accepted medical use in treatment Haney et al., 1999). Lane and Phillips-Bute 2) Marijuana has no currently accepted in the United States or a currently accepted (1998) describes milder cases of dependence medical use in treatment in the United medical use with severe restrictions. The including symptoms that are comparable to States: Center for Medicinal Cannabis Research in those from caffeine withdrawal, including The FDA has not yet approved an NDA for California, among others, is conducting decreased vigor, increased fatigue, marijuana. The opportunity for scientists to research with marijuana at the IND level, but sleepiness, headache, and reduced ability to conduct clinical research with marijuana these studies have not yet progressed to the work. The marijuana withdrawal syndrome exists under the HHS policy supporting stage of submitting an NDA. Thus, at this has been reported in adolescents who were clinical research with botanical marijuana. time, the known risks of marijuana use have

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not been shown to be outweighed by specific Barnett, G., Licko, V., and Thompson, T. Budney, A.J., Hughes, J.R., Moore, B.A., and benefits in well-controlled clinical trials that Behavioral pharmacokinetics of marijuana. Vandrey, R. Review of the validity and scientifically evaluate safety and efficacy. Psychopharmacology. 1985: 85(1): 51–56. significance of cannabis withdrawal In addition, the agency cannot conclude Benowitz, N.L. and Jones, R.T. syndrome. Am J Psychiatry. 2004 Nov: that marijuana has an acceptable level of Cardiovascular effects of prolonged delta-9- 161(11): 1967–77. safety without assurance of a consistent and tetrahydrocannabinol ingestion. Clin Cadoni, C., Pisanu, A., Solinas, M., Acquas, predictable potency and without proof that Pharmacol Ther. 1975 Sep: 18(3): 287–97. E., and Di Chiara, G. Behavioural the substance is free of contamination. If Benowitz, N.L. and Jones, R.T. sensitization after repeated exposure to marijuana is to be investigated more widely Cardiovascular and metabolic Delta 9-tetrahydrocannabinol and cross- for medical use, information and data considerations in prolonged cannabinoid sensitization with morphine. regarding the chemistry, manufacturing, and administration in man. J Clin Pharmacol. Psychopharmacology (Berl). 2001 Nov: specifications of marijuana must be 1981 Aug–Sep: 21(8–9 Suppl): 214S–223S. 158(3): 259–66. developed. Therefore, HHS concludes that, Block, R.I. and Wittenborn, J.R. Marijuana Capriotti, R.M., Foltin, R.W., Brady, J.V., and even under medical supervision, marijuana effects on associative processes. Fischman, M.W. Effects of marijuana on has not been shown at present to have an Psychopharmacology (Berl). 1985: 85(4): the task-elicited physiological response. acceptable level of safety. 426–30. Drug Alcohol Depend. 1988 Jul: 21(3): 183– Block, R.I., Farinpour, R., and Schlechte, J.A. 7. REFERENCES Effects of chronic marijuana use on Chait, L.D., Fischman, M.W., and Schuster, Abrams, D.I., Hilton, J.F., Leiser, R.J., Shade, testosterone, luteinizing hormone, follicle C.R. ’‘‘Hangover’ effects the morning after S.B., Elbeik, T.A., Aweeka, F.T., Benowitz, stimulating hormone, prolactin and marijuana smoking. Drug Alcohol Depend. N.L., Bredt, B.M., Kosel, B., Aberg, J.A., cortisol in men and women. Drug Alcohol 1985 Jun:15(3): 229–38. Deeks, S.G., Mitchell, T.F., Mulligan, K., Depend. 1991 Aug: 28(2): 121–8. Chait, L.D., Evans, S.M., Grant, K.A., Kamien, Bacchetti, P., McCune, J.M., and Block, R.I., Farinpour, R., and Braverman, K. J.B., Johanson, C.E., and Schuster, C.R. Schambelan, M. Short-term effects of Acute effects of marijuana on cognition: Discriminative stimulus and subjective cannabinoids in patients with HIV–1 relationships to chronic effects and effects of smoked marijuana in humans. infection: a randomized, placebo- smoking techniques. Pharmacol Biochem Psychopharmacology (Berl). 1988: 94(2): controlled clinical trial. Ann Intern Med. Behav. 1992 Nov: 43(3): 907–17. 206–12. 2003 Aug 19: 139(4): 258–66. Bolla, K.I., Brown, K., Eldreth, D., Tate, K., Chait, L.D. and Burke, K.A. Preference for Adams, I.B. and Martin, B.R. Cannabis: and Cadet, J.L. Dose-related neurocognitive high- versus low-potency marijuana. Pharmacology and toxicology in animals effects of marijuana use. Neurology. 2002: Pharmacol Biochem Behav. 1994 Nov: and humans. Addiction. 1996: 91(11): 59: 1337–1343. 49(3): 643–7. Bolla, K.I., Eldreth, D.A., Matochik, J.A., and 1585–1614. Chaperon, F., Soubrie, P., Puech, A.J., and Cadet, J.L. Neural substrates of faulty Agurell, S., Dewey, W.L., and Willett, R.E., Thiebot, M.H. Involvement of central decision-making in abstinent marijuana eds. The Cannabinoids: Chemical, cannabinoid (CB1) receptors in the users. NeuroImage. 2005: 26: 480–492. Pharmacologic, and Therapeutic Aspects. establishment of place conditioning in rats. Bouaboula, M., Rinaldi, M., Carayon, P., New York: Academic Press. 1984. Psychopharmacology (Berl). 1998 Feb: Carillon, C., Delpech, B., Shire, D., Le Fur, 135(4): 324–32. Agurell, S., Halldin, M., Lindgren, J.E., G., and Casellas, P. Cannabinoid-receptor Cheer, J.F., Kendall, D.A., and Marsden, C.A. Ohlsson, A., Widman, M., Gillespie, H., expression in human leukocytes. Eur J and Hollister, L. Pharmacokinetics and Biochem. 1993 May 15: 214(1): 173–80. Cannabinoid receptors and reward in the metabolism of delta 1- Braida, D., Iosue, S., Pegorini, S., and Sala, rat: a conditioned place preference study. tetrahydrocannabinol and other M. Delta9-tetrahydrocannabinol-induced Psychopharmacology (Berl). 2000 cannabinoids with emphasis on man. conditioned place preference and Jul:151(1): 25–30. Pharmacol Rev. 1986: 38(1): 21–43. intracerebroventricular self-administration Community Epidemiology Work Group, Almirez, R.G., Smith, C.G., and Asch, R.H. in rats. Eur J Pharmacol. 2004 Dec 3: National Institutes of Health, National The effects of marijuana extract and delta 506(1): 63–9. Institute on Drug Abuse, Epidemiologic 9-tetrahydrocannabinol on luteal function Breivogel, C.S. and Childers, S.R. Trends in Drug Abuse, Volume I: in the rhesus monkey. Fertil Steril. 1983 Cannabinoid agonist signal transduction in Highlights and Executive Summary, June Feb: 39(2): 212–7. rat brain: comparison of cannabinoid 2000, http://www.nida.nih.gov/CEWG/ Ameri, A. The effects of cannabinoids on the agonists in receptor binding, G-protein pubs.html. brain. Progress in Neurobiology. 1999: 58 activation, and adenylyl cyclase inhibition. Cone, E.J., Johnson, R.E., Moore, J.D., and (4): 315–348. J Pharmacol Exp Ther. 2000 Oct: 295(1): Roache, J.D. Acute effects of smoking American Academy of Pain Medicine, 328–36. marijuana on hormones, subjective effects American Pain Society and American Breivogel, C.S., Griffin, G., Di Marzo, V., and and performance in male human subjects. Society of Addiction Medicine Consensus Martin, B.R. Evidence for a new G protein- Pharmacol Biochem Behav. 1986 Jun: Document. Definitions related to the use of coupled cannabinoid receptor in mouse 24(6): 1749–54. opioids for the treatment of pain. 2001. brain. Mol Pharmacol. 2001 Jul: 60(1): 155– Croxford, J.L. and Yamamura, T. Andreasson, S., Allebeck, .P, Engstrom, A., 63. Cannabinoids and the immune system: and Rydberg, U. Cannabis and Breivogel, C.S., Scates, S.M., Beletskaya, I.O., potential for the treatment of inflammatory schizophrenia. A longitudinal study of Lowery, O.B., Aceto, M.D., and Martin, diseases? J Neuroimmunol. 2005 Sep: Swedish conscripts. Lancet. 1987 Dec 26: B.R. The effects of delta9- 166(1–2): 3–18. Review. 2(8574): 1483–6. tetrahydrocannabinol physical dependence Dax, E.M., Pilotte, N.S., Adler, W.H., Nagel, Asch, R.H., Smith, C.G., Siler-Khodr, T.M., on brain cannabinoid receptors. Eur J J.E., and Lange, W.R. The effects of 9-ene- and Pauerstein, C.J. Effects of delta 9- Pharmacol. 2003 Jan 17: 459(2–3): 139–50. tetrahydrocannabinol on hormone release tetrahydrocannabinol during the follicular Brown, T.T. and Dobs, A.S. Endocrine effects and immune function. J Steroid Biochem. phase of the rhesus monkey (Macaca of marijuana. J Clin Pharmacol. 2002 Nov: 1989: 34(1–6): 263–70. mulatta). J Clin Endocrinol Metab. 1981 42(11 Suppl): 90S–96S. Degenhardt, L., Hall, W., and Lynskey, M. Jan: 52(1): 50–5. Browne, R.G. and Weissman, A. Testing hypotheses about the relationship Balster, R.L. and Prescott, W.R., delta9- Discriminative stimulus properties of delta between cannabis use and psychosis. Drug Tetrahydrocannabinol discrimination in 9-tetrahydrocannabinol: mechanistic Alcohol Depend. 2003 Jul 20: 71(1): 37–48. rats as a model for cannabis intoxication. studies. J Clin Pharmacol. 1981 Aug–Sep: Department of Health and Human Services. Neurosci. & Biobehav. Rev. 1992: 16(1): 21(8–9 Suppl): 227S–234S. Announcement of the Department of 55–62. Budney, A.J., Novy, P.L., and Hughes, J.R. Health and Human Services Guidance on Balster, R.L. and Bigelow, G.E. Guidelines Marijuana withdrawal among adults Procedures for the Provision of Marijuana and methodological reviews concerning seeking treatment for marijuana for Medical Research. May 21, 1999. drug abuse liability assessment. Drug and dependence. Addiction. 1999: 94(9): 1311– (http://grants.nih.gov/grants/guide/notice- Alcohol Dependence. 2003: 70: S13–S40. 22 files/not99-091.html).

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Dewey, W. L., Martin, B. R., and May, E. L. preliminary findings of a longitudinal Gruber, S.A. and Yurgelun-Todd, D.A. Cannabinoid stereoisomers: study of effects on IQ in young adults. Neuroimaging of marijuana smokers during pharmacological effects. In Smith, D. F. CMAJ. 2002 Apr 2: 166(7): 887–91. inhibitory processing: a pilot investigation. (Ed.) CRC Handbook of stereoisomers: Fung, M., Gallagher, C., and Machtay, M. Brain Res Cogn Brain Res. 2005 Apr: 23(1): drugs in psychopharmacology, 317–326 Lung and aeo-digestive cancers in young 107–18. (Boca Raton, FL, CRC Press), 1984. marijuana smokers. Tumori. 1999: 85 (2): Hall, W., Degenhardt, L., and Teesson, M. D’Souza, D.C., Abi-Saab, W.M., Madonick, S., 140–142. Cannabis use and psychotic disorders: an Forselius-Bielen, K., Doersch, A., Braley, Galiegue, S., Mary, S., Marchand, J., update. Drug Alcohol Rev. 2004 Dec: 23(4): G., Gueorguieva, R., Cooper, T.B., and Dussossoy, D., Carriere, D., Carayon, P., 433–43. Krystal, J.H. Delta-9-tetrahydrocannabinol Bouaboula, M., Shire, D., Le Fur, G., and Hall, W.D. and Lynskey, M. Is cannabis a effects in schizophrenia: implications for Casellas, P. Expression of central and gateway drug? Testing hypotheses about cognition, psychosis, and addiction. Biol peripheral cannabinoid receptors in human the relationship between cannabis use and Psychiatry. 2005 Mar 15: 57(6): 594–608. immune tissues and leukocyte the use of other illicit drugs. Drug Alcohol Drug Enforcement Administration, Federal- subpopulations. Eur J Biochem. 1995 Aug Rev. 2005 Jan: 24(1): 39–48. wide Drug Seizure System, 1989–2002 15: 232(1): 54–61. Haney, M., Ward, A.S., Comer, S.D., Foltin, (October 2002). Gaoni, Y. and Mechoulam, R. Isolation, R.W., and Fischman, M.W. Abstinence Drug Enforcement Administration, Drugs of structure, and partial synthesis of an active symptoms following smoked marijuana in Abuse, 2005. constituent of hashish. J. Am. Chem. Soc. humans. Psychopharmacology (Berl). 1999: Drug Enforcement Administration. 1964: 86: 1646–1947. 141(4): 395–404. Sourcebook of Criminal Justice Statistics, Gerard, C. M., Mollereau, C., Vassart, G., and Hanus, L., Breuer, A., Tchilibon, S., Shiloah, 2003. Parmentier, M. Molecular cloning of a S., Goldenberg, D., Horowitz, M., Pertwee, DSM–IV–TR: Diagnostic and Statistical human cannabinoid receptor which is also R.G., Roos, R. A., Mechoulam, R., and Manual of Mental Disorders, Fourth expressed in testis. Biochem J. 1991: 279: Fride, E. HU–308: a specific agonist for CB Edition, Text Revision. American 129–34. (2), a peripheral Cannabinoid receptor. Psychiatric Association. Arlington, VA: Ghozland, S., Matthes, H.W., Simonin, F., Proc. Natl. Acad. Sci. USA. 1999: 96: American Psychiatric Publishing, Inc., Filliol, D., Kieffer, B.L., and Maldonado, R. 14228–33. 2000. Motivational effects of cannabinoids are Harrison, G.P. Jr., Gruber, A.J., Hudson, J.I., Ehrenreich, H., Rinn, T., Kunert, H.J., mediated by mu-opioid and kappa-opioid Huestis, M.A., and Yurgelun-Todd, D. Moeller, M.R., Poser, W., Schilling, L., receptors. J Neurosci. 2002 Feb 1: 22(3): Cognitive measures in long-term cannabis Gigerenzer, G., and Hoehe, M.R. Specific 1146–54. users. J Clin Pharmacol. 2002 Nov: 42(11 attentional dysfunction in adults following Gold, L.H., Balster, R.L., Barrett, R.L., Britt, Suppl): 41S–47S. Review. D.T., and Martin, B.R. A comparison of the early start of cannabis use. Heishman, S.J., Huestis, M.A., Henningfield, discriminative stimulus properties of delta Psychopharmacology (Berl). 1999 Mar: J.E., and Cone, E.J. Acute and residual 9-tetrahydrocannabinol and CP 55,940 in 142(3): 295–301. effects of marijuana: profiles of plasma rats and rhesus monkeys. J Pharmacol Exp Eldreth, D.A., Matochik, J.A., Cadet, J.L., and THC levels, physiological, subjective, and Ther. 1992 Aug: 262(2): 479–86. performance measures. Pharmacol Bolla, K.I. Abnormal brain activity in Golub, A. and Johnson, B.D. Variation in Biochem Behav. 1990 Nov: 37(3): 561–5. prefrontal brain regions in abstinent youthful risks of progression from alcohol Herkenham, M. Cannabinoid receptor marijuana users. Neuroimage. 2004 Nov: and tobacco to marijuana and to hard drugs 23(3): 914–20. across generations. Am J Public Health. localization in brain: Relationship to motor Eldridge, J.C., Murphy, L.L., and Landfield, 2001 Feb: 91(2): 225–32. and reward systems. In: Kalivas, P.W., and P.W. Cannabinoids and the hippocampal Gong, H. Jr., Tashkin, D.P., Simmons, M.S., Samson, H.H., eds. The neurobiology of glucocorticoid receptor: recent findings Calvarese, B., and Shapiro, B.J. Acute and drug and alcohol addiction. Ann N Y Acad and possible significance. Steroids. 1991 subacute bronchial effects of oral Sci 1992: 654: 19–32. May: 56(5): 226–31. Review. cannabinoids. Clin Pharmacol Ther. 1984 Herkenham, M., Lynn, A. B., Little, M. D., Fant, R.V., Heishman, S.J., Bunker, E.B., and Jan: 35(1): 26–32. Johnson, M. R., Melvin, L. S., de Costa, B. Pickworth, W.B. Acute and residual effects Gong, J.P., Onaivi, E.S., Ishiguro, H., Liu, R., and Rice, K. C. Cannabinoid receptor of marijuana in humans. Pharmacol Q.R., Tagliaferro, P.A., Brusco, A., and Uhl, localization in Brain. Proc. Natl. Acad. Sci. Biochem Behav. 1998 Aug: 60(4): 777–84. G.R. Cannabinoid CB2 receptors: U S A. 1990: 87: 1932–1936. Favrat, B., Menetrey, A., Augsburger, M., Immunohistochemical localization in rat Herning, R.I., Hooker, W.D., and Jones, R.T. Rothuizen, L.E., Appenzeller, M., Buclin, brain. Brain Res. 2006 Feb 3: 1071(1): 10– Tetrahydrocannabinol content and T., Pin, M., Mangin, P., and Giroud, C. Two 23. differences in marijuana smoking behavior. cases of ‘‘cannabis acute psychosis’’ Gonsiorek, W., Lunn, C., Fan, X., Narula, S., Psychopharmacology. 1986: 90(2): 160– following the administration of oral Lundell, D., and Hipkin, R.W. 162. cannabis. BMC Psychiatry. 2005 Apr 1: Endocannabinoid 2-arachidonyl glycerol is Hively, R. L., Mosher, W. A., and Hoffman, D9 5(1): 17. a full agonist through human type 2 F. W. Isolation of trans- - Fergusson, D.M., Horwood, L.J., and Ridder, cannabinoid receptor: antagonism by tetrahydrocannabinol from marihuana. J. E.M. Tests of causal linkages between anandamide. Mol Pharmacol. 2000 May: Am. Chem. Soc. 1966: 88: 1832–1833. cannabis use and psychotic symptoms. 57(5): 1045–50. Hollister, L.E. Health aspects of cannabis. Addiction. 2005 Mar: 100(3): 354–66. Graham, J.D.P., ed. Cannabis and Health. Pharmacological Rev. 1986: 38: 1–20. Fried, P. A. and Watkinson, B. 36- and 48- New York: Academic Press, 1976. Hollister, L.E. Cannabis. (Literature review). month neurobehabioral follow-up of Grant I. Foreword by Igor Grant, M.D., Acta Psychiatr Scand (Suppl). 1988: 78: children prenatally exposed to marijuana, Director, Center for Medicinal Cannabis 108–118. cigarettes and alcohol. J. Dev. Behav. Research (CMCR). Neuropharmacology. Howlett, A.C., Breivogel, C.S., Childers, S.R., Pediatr. 1987: 8: 318–326. 2005 Jun: 48(8): 1067. Deadwyler, S.A., Hampson, R.E., and Fried, P. A., Watkinson, B., and Gray, R. A Griffith, D. R., Azuma, S. D., and Chasnoff, Porrino, L.J. Cannabinoid physiology and follow-up study of attentional behavior in I. J. Three-year outcome of children pharmacology: 30 years of progress. 6-year-old children exposed prenatally to exposed prenatally to drugs. J. Am. Acad. Neuropharmacology. 2004: 47 Suppl 1: marihuana, cigarettes and alcohol. Child Adolesc. Psychiatry. 1994: 33: 20–27. 345–58. Neurotoxicol. Teratol. 1992: 14: 299–311. Grotenhermen, F. Pharmacokinetics and Huestis, M. A., Sampson, A. H., Holicky, B. Fried, P. A., Watkinson, B., and Gray, R. pharmacodynamics of cannabinoids. Clin J., Henningfield, J. E., and Cone, E. J. Differential effects on cognitive functioning Pharmacokin et. 2003: 42(4): 327–60. Characterization of the absorption phase of in 9- to 12-year olds prenatally exposed to Gruber, A.J., Pope, H.G., Hudson, J.I., and marijuana smoking. Clin. Pharmacol. Ther. cigarettes and marihuana. Neurotoxicol. Yurgelun-Todd, D. Attributes of long-term 1992a: 52: 31–41. Teratol. 1998: 20(3): 293–306. heavy cannabis users: a case-control study. Huestis, M.A., Henningfield, J.E.,; and Cone, Fried, P., Watkinson, B., James, D., and Gray, Psychological Medicine. 2003: 33: 1415– E.J. Blood Cannabinoids. 1. Absorption of R. Current and former marijuana use: 1422. THC and formation of 11–OH–THC and

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THC COOH during and after smoking Lemberger, L. and Rubin, A. The physiologic Marijuana, February 19–20, 1997. marijuana. J Anal Toxicol. 1992b: 16(5): disposition of marihuana in man. Life Sci. (www.nih.gov/news/medmarijuana/ 276–282. 1975: 17: 1637–42. MedicalMarijuana.htm) Hunt, C.A. and Jones, R.T. Tolerance and Liguori, A., Gatto, C.P., and Robinson, J.H. Office of National Drug Control Policy. The disposition of tetrahydrocannabinol in Effects of marijuana on equilibrium, National Drug Control Strategy: 2000 man. J Pharmacol Exp Ther. 1980 Oct: psychomotor performance, and simulated Annual Report. Superintendent of 215(1): 35–44. driving. Behav Pharmacol. 1998 Nov: 9(7): Documents, Mail Stop: SSOP, Washington, Institute of Medicine. Division of Health 599–609. DC. Sciences Policy. Marijuana and Health: Lyketsos, C.G., Garrett, E., Liang, K.Y., and Oviedo, A., Glowa, J. and Herkenham, M. Report of a Study by a Committee of the Anthony, J.C. Cannabis use and cognitive Chronic cannabinoid administration alters Institute of Medicine, Division of Health decline in persons under 65 years of age. cannabinoid receptor binding in rat brain: Sciences Policy. Washington, DC: National Am J Epidemiol. 1999 May 1: 149(9): 794– a quantitative autoradiographic study. Academy Press, 1982. 800. Brain Res. 1993: 616: 293–302. Institute of Medicine, Division of Lyons, M.J., Bar, J.L., Panizzon, M.S., Pencer, A., Addington, J., and Addington, D. Neuroscience and Behavioral Health. Toomey, R., Eisen, S., Xian, H., and Outcome of a first episode of psychosis in Marijuana and Medicine: Assessing the Tsuang, M.T. Neuropsychological adolescence: a 2-year follow-up. Psychiatry Science Base. Washington D.C.: National consequences of regular marijuana use: a Res. 2005 Jan 30: 133(1): 35–43. Academy Press, 1999. twin study. Psychol Med. 2004 Oct: 34(7): Piomelli, D. The endocannabinoid system: a Johansson, E., Halldin, M.M., Agurell, S., 1239–50. drug discovery perspective. Curr Opin Hollister, L.E.; and Gillespie, H.K. Mackie, K., Lai, Y., Westenbroek, R., and Investig Drugs. 2005 Jul: 6(7): 672–9. Terminal elimination plasma half-life of Mitchell, R. Cannabinoids activate an Pope, H.G. Jr., Gruber, A.J., Hudson, J.I., delta 1-tetrahydrocannabinol (delta 1– inwardly rectifying potassium conductance Cohane, G., Huestis, M.A., and Yurgelun- THC) in heavy users of marijuana. Eur J and inhibit Q-type calcium currents in Todd, D. Early-onset cannabis use and Clin Pharmacol. 1989: 37(3): 273–277. AtT20 cells transfected with rat brain cognitive deficits: what is the nature of the Johnston, L. D., O’Malley, P. M., Bachman, J. cannabinoid receptor. J Neurosci. 1995 Oct: association? Drug Alcohol Depend. 2003 G., and Schulenberg, J. E. Monitoring the 15(10): 6552–61. Apr 1: 69(3): 303–10. Future national results on adolescent drug Maldonado, R. Study of cannabinoid Ramaekers, J.G., Berghaus, G., van Laar, M., use: Overview of key findings, 2005 (NIH dependence in animals. Pharmacol Ther. and Drummer, O.H. Dose related risk of Publication No. 06–5882). Bethesda, MD: 2002 Aug: 95(2): 153–64. motor vehicle crashes after cannabis use. National Institute on Drug Abuse, 2006: 67. Maremmani, I., Lazzeri, A., Pacini, M., Drug Alcohol Depend. 2004 Feb 7: 73(2): Jones, R.T., Benowitz, N.L., and Herning, R.I. Lovrecic, M., Placidi, G.F., and Perugi, G. 109–19. Clinical relevance of cannabis tolerance Diagnostic and symptomatological features Rodriguez de Fonseca, F., Gorriti, M.A., and dependence. J Clin Pharmacol. 1981: in chronic psychotic patients according to Fernandez-Ruiz, J.J., Palomo, T., and 21: 143S–152S. cannabis use status. J Psychoactive Drugs. Ramos, J.A. Downregulation of rat brain Jones, R.T. Cardiovascular system effects of 2004 Jun: 36(2): 235–41. cannabinoid binding sites after chronic marijuana. J Clin Pharmacol. 2002 Nov: Martellotta, M.C., Cossu, G., Fattore, L., delta 9-tetrahydrocannabinoil treatment. 42(11 Suppl): 58S–63S. Gessa, G.L., and Fratta, W. Self- Phamacol. Biochem. Behav. 1994: 47 (1): Justinova, Z., Tanda, G., Redhi, G.H., and administration of the cannabinoid receptor 33–40. Goldberg, S.R. Self-administration of agonist WIN 55,212–2 in drug-naive mice. Ross, S. A. and El Sohly, M. A. Constituents delta9-tetrahydrocannabinol (THC) by drug Neuroscience. 1998 Jul: 85(2): 327–30. of Cannabis Sativa L. A review of the naive squirrel monkeys. Mathers, D.C. and Ghodse, A.H. Cannabis natural constituents: 1980–1994. Zagazig J. Psychopharmacology (Berl). 2003 Sep: and psychotic illness. Br J Psychiatry. 1992 Pharm. Sci. 1995: 4 (2): 1–10. 169(2): 135–40. Nov: 161: 648–53. Roth, M.D., Tashkin, D.P., Whittaker, K.M., Kandel, D.B. and Chen, K. Types of Martin, B.R., Mechoulam, R., and Razdan, Choi, R., and Baldwin, G.C. marijuana users by longitudinal course. J R.K. Discovery and characterization of Tetrahydrocannabinol suppresses immune Stud Alcohol. 2000 May: 61(3): 367–78. endogenous cannabinoids. Life Sci. 1999: function and enhances HIV replication in Kirk, J.M. and de Wit, H. Responses to oral 65: 573–595. the huPBL-SCID mouse. Life Sci. 2005 Aug delta9-tetrahydrocannabinol in frequent Matsuda, L. A., Lolait, S. J., Brownstein, M. 19: 77(14): 1711–22. and infrequent marijuana users. Pharmacol J., Young, A. C., and Bonner, T.I. Structure Sarfaraz, S., Afaq, F., Adhami, V.M., and Biochem Behav. 1999 May: 63(1): 137–42. of a cannabinoid receptor and functional Mukhtar, H. Cannabinoid receptor as a Kurzthaler, I., Hummer, M., Miller, C., expression of the cloned cDNA. Nature. novel target for the treatment of prostate Sperner-Unterweger, B., Gunther, V., 1990: 346: 561–564. cancer. Cancer Res. 2005 Mar 1: 65(5): Wechdorn, H., Battista, H.J., and Mechoulam, R. Cannabinoid chemistry. In 1635–41. Fleischhacker, W.W. Effect of cannabis use Mechoulam, R. (ED.) Marijuana (New York, Sanudo-Pena, M. C., Tsou, K., Delay, E. R., on cognitive functions and driving ability. NY, Academic Press, Inc.), 1973: 2–88. Hohman, A. G., Force, M., and Walker, J. J Clin Psychiatry. 1999 Jun: 60(6): 395–9. Mendelson, J.H. and Mello, N.K. Effects of M. Endogenous cannabinoids as an Lane, J.D. and Phillips-Bute, B.G. Caffeine marijuana on neuroendocrine hormones in aversive or counter-rewarding system in deprivation affects vigilance performance human males and females. NIDA Res the rat. Neurosci. Lett. 1997: 223: 125–128. and mood. Physiol Behav. 1998: 65: 171– Monogr. 1984: 44: 97–114. Schiffman, J., Nakamura, B., Earleywine, M., 5. Messinis, L., Kyprianidou, A., Malefaki, S., and LaBrie, J. Symptoms of schizotypy Lemberger, L., Silberstein, S. D., Axelrod, J., and Papathanasopoulos, P. precede cannabis use. Psychiatry Res. 2005 and Kopin, I. J. Marihuana: studies on the Neuropsychological deficits in long-term Mar 30: 134(1): 37–42. disposition and metabolism of delta-9- frequent cannabis users. Neurology. 2006: Sidney, S. Cardiovascular consequences of tetrahydrocannabinol in man. Science. 66: 737–739. marijuana use. J Clin Pharmacol. 2002 Nov: 1970: 170: 1320–1322. Monitoring the Future. National Results on 42(11 Suppl): 64S–70S. Lemberger, L., Weiss, J. L., Watanabe, A. M., Adolescent Drug Use. Overview of 1999 Solowij, N., Stephens, R.S., Roffman, R.A., Galanter, I. M., Wyatt, R. J., and Cardon, P. Key findings, 1999. Department of Health Babor, T., Kadden, R., Miller, M., V. Delta-9-tetrahydrocannabinol: temporal and Human Services. National Institute on Christiansen, K., McRee, B., and Vendetti, correlation of the psychological effects and Drug Abuse. Rockville, MD. (http:// J. Marijuana Treatment Project Research blood levels after various routes of monitoringthefuture.org) Group. Cognitive functioning of long-term administration. New Eng. J. Med. 1972a: Nace, E.P., Meyers, A.L., Rothberg, J.M., and heavy cannabis users seeking treatment. 286(13): 685–688. Maleson, F. Addicted and nonaddicted JAMA. 2002 Mar 6: 287(9): 1123–31. Lemberger, L., Crabtree, R. E., and Rowe, H. drug users. A comparison of drug usage Stirling, J., Lewis, S., Hopkins, R., and White, M. 11-Hydroxy-D9-tetrahydrocannabinol: patterns. Arch Gen Psychiatry. 1975: 32(1): C. Cannabis use prior to first onset pharmacology, disposition and metabolism 77–80. psychosis predicts spared neurocognition of a major metabolite of marihuana in man. National Institutes of Health (NIH). at 10-year follow-up. Schizophr Res. 2005 Science. 1972b: 177: 62–63. Workshop on the medical Utility of Jun 1: 75(1): 135–7.

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Substance Abuse and Mental Health Services Wiley, J.L., Barrett, R.L., Britt, D.T., Balster, U.S.C. 811(b), after gathering the necessary Administration, Office of Applied Studies. R.L., and Martin, B.R. Discriminative data, the DEA requested a medical and Drug Abuse Warning Network, 2004: stimulus effects of delta 9- scientific evaluation and scheduling National Estimates of Drug-Related tetrahydrocannabinol and delta 9-11- recommendation for cannabis from the Emergency Department Visits. DAWN tetrahydrocannabinol in rats and rhesus Department of Health and Human Services Series D–28, HHS Publication No. (SMA) monkeys. Neuropharmacology. 1993 Apr: (DHHS) on July 12, 2004. On December 6, 06–4143, Rockville, MD, 2006. 32(4): 359–65. 2006, the DHHS provided its scientific and Substance Abuse and Mental Health Services Wiley, J.L., Huffman, J.W., Balster, R.L., and medical evaluation titled Basis for the Administration. Results from the 2004 Martin, B.R. Pharmacological specificity of Recommendation for Maintaining Marijuana National Survey on Drug Use and Health: the discriminative stimulus effects of delta in Schedule I of the Controlled Substances National Findings (Office of Applied 9-tetrahydrocannabinol in rhesus monkeys. Act and recommended that marijuana Studies, NSDUH Series H–28, HHS Drug Alcohol Depend. 1995 Nov: 40(1): 81– continue to be controlled in schedule I of the Publication No. SMA 05–4062). Rockville, 6. CSA. MD, 2005. Wu, X. and French, E.D. Effects of chronic The CSA requires DEA to determine Substance Abuse and Mental Health Services delta9-tetrahydrocannabinol on rat whether the DHHS scientific and medical Administration, Office of Applied Studies. midbrain dopamine neurons: an evaluation and scheduling recommendation Treatment Episode Data Set (TEDS). electrophysiological assessment. and ‘‘all other relevant data’’ constitute Highlights—2004. National Admissions to Neuropharmacology. 2000 Jan 28: 39(3): substantial evidence that the drug should be Substance Abuse Treatment Services, 391–8. rescheduled as proposed in the petition. 21 DASIS Series: S–31, HHS Publication No. Yanagita, T. Self-administration studies on U.S.C. 811(b). This document is prepared (SMA) 06–4140, Rockville, MD, 2006. psychological dependence. Trends in accordingly. Tanda, G., Munzar, P., and Goldberg, S.R. Pharmacological Sciences. 1979–1980: 1:1: The Attorney General ‘‘may by rule’’ Self-administration behavior is maintained 161–164. transfer a drug or other substance between by the psychoactive ingredient of Zhang, Z.F., Morgenstern, H., Spitz, M.R., schedules if he finds that such drug or other marijuana in squirrel monkeys. Nat Tashkin, D.P., Yu, G.P., Marshall, J.R., Hsu, substance has a potential for abuse, and Neurosci. 2000 Nov: 3(11): 1073–4. T.C., and Schantz, S.P. Marijuana use and makes with respect to such drug or other Tashkin, D.P. Smoked marijuana as a cause increased risk of squamous cell carcinoma substance the findings prescribed by of lung injury. Monaldi Arch Chest Dis. of the head and neck. Cancer Epidemiol subsection (b) of Section 812 for the schedule 2005 Jun: 63(2): 93–100. Biomarkers Prev. 1999 Dec: 8(12): 1071–8. in which such drug is to be placed. 21 U.S.C. Tashkin, D.P., Zhang, Z.F., Greenland, S., Marijuana 811(a)(1). In order for a substance to be Cozen, W., Mack, T.M., and Morgenstern, placed in schedule I, the Attorney General H. Marijuana Use and Lung Cancer: Results Scheduling Review Document: Eight Factor must find that: of a Case-Control Study. Abstract #A777, Analysis A. The drug or other substance has a high American Thoracic Society meeting, May Drug and Chemical Evaluation Section potential for abuse. 24, 2006. Office of Diversion Control B. The drug or other substance has no Thornicroft, G. Cannabis and psychosis. Is Drug Enforcement Administration, April currently accepted medical use in treatment there epidemiological evidence for an 2011 in the United States. association? Br J Psychiatry. 1990 Jul: 157: C. There is a lack of accepted safety for use 25–33. INTRODUCTION of the drug or other substance under medical Twitchell, W., Brown, S., and Mackie, K. On October 9, 2002, the Coalition for supervision. Cannabinoids inhibit N- and P/Q-type Rescheduling Cannabis submitted a petition 21 U.S.C. 812(b)(1)(A)–(C). To be classified in calcium channels in cultured rat to the Drug Enforcement Administration hippocampal neurons. J Neurophysiol. one of the other schedules (II through V), a (DEA) to initiate proceedings for a repeal of drug of abuse must have either a ‘‘currently 1997 Jul: 78(1): 43–50. the rules or regulations that place marijuana 3 Tzilos, G.K., Cintron, C.B., Wood, J.B., accepted medical use in treatment in the in schedule I of the Controlled Substances United States or a currently accepted medical Simpson, N.S., Young, A.D., Pope, H.G. Jr., Act (CSA). The petition requests that and Yurgelun-Todd, D.A. Lack of use with severe restrictions.’’ 21 U.S.C. marijuana be rescheduled as ‘‘cannabis’’ in 812(b)(2)–(5). If a controlled substance has no hippocampal volume change in long-term either schedule III, IV, or V of the CSA. The heavy cannabis users. Am J Addict. 2005 such currently accepted medical use, it must petitioner claims that: be placed in schedule I. See Notice of Denial Jan–Feb: 14(1): 64–72. 1. Cannabis has an accepted medical use in Vandrey, R.G., Budney, A.J., Moore, B.A., of Petition, 66 FR 20038, 20038 (Apr. 18, the United States; 2001) (‘‘Congress established only one and Hughes, J.R. A cross-study comparison 2. Cannabis is safe for use under medical of cannabis and tobacco withdrawal. Am J schedule—schedule I—for drugs of abuse supervision; with ‘no currently accepted medical use in Addict. 2005 Jan–Feb: 14(1): 54–63. 3. Cannabis has an abuse potential lower van Os, J., Bak, M., Hanssen, M., Bijl, R.V., treatment in the United States’ and ‘lack of than schedule I or II drugs; and accepted safety for use . . . under medical de Graaf, R., and Verdoux, H. Cannabis use 4. Cannabis has a dependence liability that supervision.’’’). and psychosis: a longitudinal population- is lower than schedule I or II drugs. In deciding whether to grant a petition to based study. Am J Epidemiol. 2002 Aug 15: The DEA accepted this petition for filing initiate rulemaking proceedings with respect 156(4): 319–27. on April 3, 2003. In accordance with 21 von Sydow, K., Lieb, R., Pfister, H., Hofler, to a particular drug, DEA must determine M., and Wittchen, H.U. What predicts whether there is sufficient evidence to 3 The Controlled Substances Act (CSA) defines conclude that the drug meets the criteria for incident use of cannabis and progression to marijuana as the following: abuse and dependence? A 4-year placement in another schedule based on the All parts of the plant Cannabis sativa L., whether criteria set forth in 21 U.S.C. 812(b). To do prospective examination of risk factors in growing or not; the seeds thereof; the resin a community sample of adolescents and extracted from any part of such plant; and every so, the CSA requires that DEA and DHHS young adults. Drug Alcohol Depend. 2002 compound, manufacture, salt, derivative, mixture, consider eight factors as specified in 21 Sep 1: 68(1): 49–64. or preparation of such plant, its seeds or resin. Such U.S.C. 811(c). This document is organized Wachtel, S.R., El Sohly, M.A., Ross, S.A., term does not include the mature stalks of such according to these eight factors. Ambre, J., and de Wit, H. Comparison of plant, fiber produced from such stalks, oil or cake With specific regard to the issue of whether the subjective effects of Delta (9)- made from the seeds of such plant, any other the drug has a currently accepted medical tetrahydrocannabinol and marijuana in compound, manufacture, salt, derivative, mixture, use in treatment in the United States, DHHS or preparation of such mature stalks (except the states that the FDA has not evaluated nor humans. Psychopharmacology (Berl). 2002 resin extracted there from), fiber, oil, or cake, or the Jun: 161(4): 331–9. sterilized seed of such plant which is incapable of approved a new drug application (NDA) for Wagner, J.A., Varga, K., and Kunos, G. germination. 21 U.S.C. 802(16). marijuana. The long-established factors Cardiovascular actions of cannabinoids Note that ‘‘marihuana’’ is the spelling originally applied by the DEA for determining whether and their generation during shock. J Mol used in the CSA. This document uses the spelling a drug has a ‘‘currently accepted medical Med. 1998 Nov–Dec: 76(12): 824–36. that is more common in current usage, ‘‘marijuana.’’ use’’ under the CSA are:

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1. The drug’s chemistry must be known period, marijuana was the most frequently existing clinical evidence is not adequate to and reproducible; identified drug exhibit in federal, state, and warrant rescheduling of marijuana under the 2. There must be adequate safety studies; local laboratories. High consumption of CSA. 3. There must be adequate and well- marijuana is fueled by increasing amounts of To the contrary, the data in this Scheduling controlled studies proving efficacy; both domestically grown and illegally Review document show that marijuana 4. The drug must be accepted by qualified smuggled foreign source marijuana, and an continues to meet the criteria for schedule I experts; and increasing percentage of seizures involve control under the CSA for the following 5. The scientific evidence must be widely high potency marijuana. reasons: available. 5. Scope, duration, and significance of 1. Marijuana has a high potential for abuse. 57 FR 10,499, 10,506 (1992); Alliance for abuse. Abuse of marijuana is widespread and 2. Marijuana has no currently accepted Cannabis Therapeutics v. DEA, 15 F.3d 1131, significant. In 2008, for example, an medical use in treatment in the United 1135 (D.C. Cir. 1994) (ACT) (upholding these estimated 3.9 million people aged 12 or older States. factors as valid criteria for determining used marijuana on a daily or almost daily 3. Marijuana lacks accepted safety for use ‘‘accepted medical use’’). A drug will be basis over a 12-month period. In addition, a under medical supervision. deemed to have a currently accepted medical significant proportion of all admissions for treatment for substance abuse are for primary FACTOR 1: THE DRUG’S ACTUAL OR use for CSA purposes only if all five of the RELATIVE POTENTIAL FOR ABUSE foregoing elements are demonstrated. This marijuana abuse: in 2007, 16 percent of all test is considered here under the third factor. admissions were for primary marijuana Marijuana is the most commonly abused Accordingly, as the eight factor analysis abuse, representing 287,933 individuals. Of illegal drug in the United States. It is also the sets forth in detail below, the evidence individuals under the age of 19 admitted to most commonly used illicit drug by shows: substance abuse treatment, more than half American high-schoolers. Marijuana is the 1. Actual or relative potential for abuse. were treated for primary marijuana abuse. most frequently identified drug in state, local Marijuana has a high abuse potential. It is the 6. Risk, if any, to public health. Together and federal forensic laboratories, with most widely used illicit substance in the with the health risks outlined in terms of increasing amounts both of domestically United States. Preclinical and clinical data pharmacological effects above, public health grown and of illicitly smuggled marijuana. show that it has reinforcing effects risks from acute use of marijuana include Marijuana’s main psychoactive ingredient, D9 characteristic of drugs of abuse. National impaired psychomotor performance, -THC, is an effective reinforcer in databases on actual abuse show marijuana is including impaired driving, and impaired laboratory animals, including primates and the most widely abused drug, including performance on tests of learning and rodents. These animal studies both predict D9 significant numbers of substance abuse associative processes. Public health risks and support the observations that -THC, treatment admissions. Data on marijuana from chronic use of marijuana include whether smoked as marijuana or seizures show widespread availability and respiratory effects, physical dependence, and administered by other routes, produces trafficking. psychological problems. reinforcing effects in humans. Such 2. Scientific evidence of its 7. Psychic or physiological dependence reinforcing effects can account for the pharmacological effect. The scientific liability. Long-term, regular use of marijuana repeated abuse of marijuana. can lead to physical dependence and understanding of marijuana, cannabinoid A. Indicators of Abuse Potential receptors, and the endocannabinoid system withdrawal following discontinuation, as has improved. Marijuana produces various well as psychic addiction or dependence. DHHS has concluded in its document, pharmacological effects, including subjective 8. Immediate precursor. Marijuana is not ‘‘Basis for the Recommendation for (e.g., euphoria, dizziness, disinhibition), an immediate precursor of any controlled Maintaining Marijuana in Schedule I of the cardiovascular, acute and chronic substance. Controlled Substances Act’’, that marijuana respiratory, immune system, cognitive This review shows, in particular, that the has a high potential for abuse. The finding of impairment, and prenatal exposure effects as evidence is insufficient with respect to the ‘‘abuse potential’’ is critical for control under well as possible increased risk of specific issue of whether marijuana has a the Controlled Substances Act (CSA). schizophrenia among those predisposed to currently accepted medical use under the Although the term is not defined in the CSA, guidance in determining abuse potential is psychosis. five-part test. The evidence was insufficient provided in the legislative history of the Act 3. Current scientific knowledge. There is no in this regard on the prior two occasions (Comprehensive Drug Abuse Prevention and currently accepted medical use for marijuana when DEA considered petitions to 4 Control Act of 1970, H.R. Rep. No. 91–144, in the United States. Under the five-part test reschedule marijuana in 1992 (57 FR 10499) 5 91st Cong., Sess.1 (1970), reprinted in 1970 for currently accepted medical use approved and in 2001 (66 FR 20038). Little has U.S.C.C.A.N. 4566, 4603). Accordingly, the in ACT, 15 F.3d at 1135, there is no complete changed since then with respect to the lack following items are indicators that a drug or scientific analysis of marijuana’s chemical of clinical evidence necessary to establish other substance has potential for abuse: components; there are no adequate safety that marijuana has a currently accepted • There is evidence that individuals are studies; there are no adequate and well- medical use: only a limited number of FDA- approved Phase 1 clinical investigations have taking the drug or other substance in controlled efficacy studies; there is not a amounts sufficient to create a hazard to their consensus of medical opinion concerning been carried out, and there have been no studies that have scientifically assessed the health or to the safety of other individuals or medical applications of marijuana; and the to the community; or scientific evidence regarding marijuana’s efficacy and full safety profile of marijuana for any medical condition.6 The limited • There is significant diversion of the drug safety and efficacy is not widely available. or other substance from legitimate drug While a number of states have passed voter 4 Petition for review dismissed, Alliance for channels; or referenda or legislative actions authorizing • Individuals are taking the drug or the use of marijuana for medical purposes, Cannabis Therapeutics v. DEA, 15 F.3d 1131 (D.C. Cir. 1994). substance on their own initiative rather than this does not establish a currently accepted 5 Petition for review dismissed, Gettman v. DEA, on the basis of medical advice from a medical use under federal law. To date, 290 F.3d 430 (D.C. Cir. 2002). practitioner licensed by law to administer scientific and medical research has not 6 Clinical trials generally proceed in three phases. such drugs; or progressed to the point that marijuana has a See 21 CFR 312.21 (2010). Phase I trials encompass • The drug is a new drug so related in its currently accepted medical use, even under initial testing in human subjects, generally action to a drug or other substance already conditions where its use is severely involving 20 to 80 patients. Id. They are designed listed as having a potential for abuse to make restricted. primarily to assess initial safety, tolerability, it likely that the drug substance will have the pharmacokinetics, pharmacodynamics, and 4. History and current pattern of abuse. same potential for abuse as such drugs, thus Marijuana use has been relatively stable from preliminary studies of potential therapeutic benefit. 2002 to 2009, and it continues to be the most 62 FR 66113, 1997. Phase II and Phase III studies involve successively larger groups of patients: and to demonstrate or confirm (Phase III) widely used illicit drug. In 2009, there were usually no more than several hundred subjects in therapeutic efficacy and benefit in patients. 62 FR 16.7 million current users. There were also Phase II, and usually from several hundred to 66113, 1997. See also Riegel v. Medtronic, Inc., 128 2.4 million new users, most of whom were several thousand in Phase III. 21 CFR 312.21. These S.Ct. 999, 1018–19 n.15 (2008) (Ginsburg, J., less than 18 years of age. During the same studies are designed primarily to explore (Phase II) dissenting).

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making it reasonable to assume that there 3. Individuals are taking the drug or demonstrates that marijuana has a high may be significant diversion from legitimate substance on their own initiative rather than potential for abuse. Indeed, marijuana is channels, significant use contrary to or on the basis of medical advice from a abused in amounts sufficient to create without medical advice, or that it has a practitioner licensed by law to administer hazards to public health and safety; there is substantial capability of creating hazards to such drugs. significant trafficking of the substance; the health of the user or to the safety of the 16.7 million adults over the age of 12 individuals are using marijuana on their own community. Of course, evidence of actual reported having used marijuana in the past initiative, for the vast majority, rather than on abuse of a substance is indicative that a drug month, according to the 2009 National the basis of medical advice; and finally, has a potential for abuse. Survey on Drug Use and Health (NSDUH), as marijuana exhibits several properties After considering the above items, DHHS further described later in this factor. DHHS common to those of drugs already listed as has found that marijuana has a high potential states in its 2006 analysis of the petition that having abuse potential. for abuse. the FDA has not evaluated or approved a new The petitioner states that, ‘‘widespread use 1. There is evidence that individuals are drug application (NDA) for marijuana for any of cannabis is not an indication of its abuse taking the drug or other substance in therapeutic indication, although several potential [...] .’’ (Exh. C, Section IV(15), pg. amounts sufficient to create a hazard to their investigational new drug (IND) applications 87). health or to the safety of other individuals or are currently active. Based on the large To the contrary, according to the indicators to the community. number of individuals who use marijuana, set forth in the legislative history of the CSA Marijuana is the most highly used illicit DHHS concludes that the majority of as described above, the fact that ‘‘Individuals substance in the United States. Smoked individuals using cannabis do so on their are taking the drug or substance on their own marijuana exerts a number of cardiovascular own initiative, not on the basis of medical initiative rather than on the basis of medical and respiratory effects, both acutely and advice from a practitioner licensed to advice from a practitioner licensed by law to chronically and can cause chronic bronchitis administer the drug in the course of administer such drugs’’ is indeed one of and inflammatory abnormalities of the lung professional practice. several indicators that a drug has high tissue. Marijuana’s main psychoactive 4. The drug is a new drug so related in its potential for abuse. D9 ingredient -THC alters immune function action to a drug or other substance already B. Abuse Liability Studies and decreases resistance to microbial listed as having a potential for abuse to make infections. The cognitive impairments caused it likely that the drug substance will have the In addition to the indicators suggested by by marijuana use that persist beyond same potential for abuse as such drugs, thus the CSA’s legislative history, data as to behaviorally detectable intoxication may making it reasonable to assume that there preclinical and clinical abuse liability have significant consequences on workplace may be significant diversions from legitimate studies, as well as actual abuse, including performance and safety, academic channels, significant use contrary to or clandestine manufacture, trafficking, and achievement, and automotive safety, and without medical advice, or that it has a diversion from legitimate sources, are adolescents may be particularly vulnerable to substantial capability of creating hazards to considered in this factor. marijuana’s cognitive effects. Prenatal the health of the user or to the safety of the Abuse liability evaluations are obtained exposure to marijuana was linked to community. Of course, evidence of actual from studies in the scientific and medical children’s poorer performance in a number of abuse of a substance is indicative that a drug literature. There are many preclinical cognitive tests. Data on the extent and scope has a potential for abuse. measures of a drug’s effects that when taken of marijuana abuse are presented under Marijuana is not a new drug. Marijuana’s together provide an accurate prediction of the factors 4 and 5 of this analysis. DHHS’s primary psychoactive ingredient delta-9- human abuse liability. Clinical studies of the discussion of the harmful health effects of tetrahydrocannabinol (D9-THC) is controlled subjective and reinforcing effects in humans marijuana and additional information in schedule I of the CSA. DHHS states that and epidemiological studies provide gathered by DEA are presented under factor there are two drug products containing quantitative data on abuse liability in 2, and the assessment of risk to the public cannabinoid compounds that are structurally humans and some indication of actual abuse trends. Both preclinical and clinical studies health posed by acute and chronic marijuana related to the active components in have clearly demonstrated that marijuana abuse is presented under factor 6 of this marijuana. Both are controlled under the and D9-THC possess the attributes associated analysis. CSA. Marinol is a schedule III drug product with drugs of abuse: they function as a 2. There is significant diversion of the drug containing synthetic D9-THC, known positive reinforcer to maintain drug-seeking or other substance from legitimate drug generically as dronabinol, formulated in behavior, they function as a discriminative channels. sesame oil in soft gelatin capsules. Marinol stimulus, and they have dependence DHHS states that at present, marijuana is was approved by the FDA in 1985 for the potential. legally available through legitimate channels treatment of two medical conditions: nausea Preclinical and most clinical abuse liability for research only and thus has a limited and vomiting associated with cancer studies have been conducted with the potential for diversion. (DEA notes that while chemotherapy in patients that had failed to psychoactive constituents of marijuana, a number of states have passed voter respond adequately to conventional anti- primarily D9-THC and its metabolite, 11-OH- referenda or legislative actions authorizing emetic treatments, and for the treatment of D9-THC. D9-THC’s subjective effects are the use of marijuana for medical purposes, anorexia associated with weight loss in considered to be the basis for marijuana’s this does not establish a currently accepted patients with acquired immunodeficiency abuse liability. The following studies provide medical use under federal law.) In addition, syndrome (AIDS). Cesamet is a drug product a summary of that data. the lack of significant diversion of containing the schedule II substance, investigational supplies may result from the nabilone, that was approved for marketing by 1. Preclinical Studies ready availability of illicit cannabis of equal the FDA in 1985 for the treatment of nausea Delta-9-THC is an effective reinforcer in or greater quality. and vomiting associated with cancer laboratory animals, including primates and DEA notes that the magnitude of the chemotherapy. All other structurally related rodents, as these animals will self-administer demand for illicit marijuana is evidenced by cannabinoids in marijuana are already listed D9-THC. These animal studies both predict information from a number of databases as Schedule I drugs under the CSA. and support the observations that D9-THC, presented under factor 4. Briefly, marijuana In addition, DEA notes that marijuana and whether smoked as marijuana or is the most commonly abused illegal drug in its active ingredient D9-THC are related in administered by other routes, produces the United States. It is also the most their action to other controlled drugs of abuse reinforcing effects in humans. Such commonly used illicit drug by American when tested in preclinical and clinical tests reinforcing effects can account for the high-schoolers. Marijuana is the most of abuse potential. Data showing that repeated abuse of marijuana. frequently identified drug in state, local, and marijuana and D9-THC exhibit properties federal forensic laboratories, with increasing common to other controlled drugs of abuse a. Discriminative Stimulus Effects amounts both of domestically grown and of in those tests are described below in this The drug discrimination paradigm is used illicitly smuggled marijuana. An observed factor. as an animal model of human subjective increase in the potency of seized marijuana In summary, examination of the indicators effects (Solinas et al., 2006). This procedure also raises concerns. set forth in the legislative history of the CSA provides a direct measure of stimulus

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specificity of a test drug in comparison with DHHS states that self-administration of DHHS states that animals exhibit CPP to a known standard drug or a neutral stimulus hallucinogenic-like drugs, such as D9-THC, but only at the lowest doses tested (e.g., injection of saline water). The light- cannabinoids, lysergic acid diethylamide (0.075–0.75 mg/kg, i.p.) (Braida et al., 2004). headedness and warmth associated with (LSD), and mescaline, has been difficult to The effect is antagonized by the cannabinoid drinking alcohol or the jitteriness and demonstrate in animals (Yanagita, 1980). antagonist, rimonabant, as well as the opioid increased heart rate associated with drinking DHHS further states that an inability to antagonist, naloxone. The effect of naloxone coffee are examples of substance-specific establish self-administration has no practical on CPP to D9-THC raises the possibility that stimulus effects. The drug discrimination importance in the assessment of abuse the opioid system may be involved in the paradigm is based on the ability of potential, because it is known that humans rewarding properties of D9-THC and nonhuman and human subjects to learn to voluntarily consume a particular drug (such marijuana. DEA notes a recent review identify the presence or absence of these as cannabis) for its pleasurable effects. (Murray and Bevins, 2010) that further stimuli and to differentiate among the DHHS states that the experimental explores the currently available knowledge constellation of stimuli produced by different literature generally reports that naı¨ve animals on D9-THC’s ability to induce CPP and pharmacological classes. In drug will not self-administer cannabinoids unless conditioned place aversion (CPA), and discrimination studies, the drug stimuli they have had previous experience with further supports that low doses of D9-THC function as cues to guide behavioral choice, other drugs of abuse, however, animal appear to have conditioned rewarding effects, which is subsequently reinforced with other research in the past decade has provided whereas higher doses have aversive effects. rewards. Repeated pairing of the reinforcer several animal models of reinforcement by 2. Clinical Studies with only drug-appropriate responses can cannabinoids to allow for pre-clinical engender reliable discrimination between research into cannabinoids’ reinforcing DHHS states that the physiological, drug and no-drug or amongst several drugs. effects. Squirrel monkeys trained to self- psychological, and behavioral effects of Because some interoceptive stimuli are administer intravenous cocaine will continue marijuana vary among individuals and believed to be associated with the reinforcing to respond at the same rate as when D9-THC presents a list of common responses to effects of drugs, the drug discrimination is substituted for cocaine, at doses that are cannabinoids, as described in the scientific paradigm is used to evaluate the abuse comparable to those used by humans who literature (Adams and Martin, 1996; potential of new substances. smoke marijuana (Tanda et al., 2000). This Hollister, 1986, 1988; Institute of Medicine, DHHS states that in the drug effect is blocked by the cannabinoid receptor 1982): discrimination test, animals are trained to antagonist, SR 141716. Squirrel monkeys 1. Dizziness, nausea, tachycardia, facial respond by pressing one bar when they without a history of any drug exposure can flushing, dry mouth and tremor initially D9 receive the known drug of abuse and another be successfully trained to self-administer - 2. Merriment, happiness and even bar when they receive placebo. THC intravenously (Justinova et al., 2003). exhilaration at high doses μ DHHS states that cannabinoids appear to The maximal rate of responding is 4 g/kg/ 3. Disinhibition, relaxation, increased provide unique discriminative stimulus injection, which is 2–3 times greater than sociability, and talkativeness effects because stimulants, non-cannabinoid that observed in previous studies using 4. Enhanced sensory perception, giving rise hallucinogens, opioids, benzodiazepines, cocaine-experienced monkeys. Rats will self- to increased appreciation of music, art and D9 barbiturates, NMDA antagonists and administer -THC when it is applied touch D9 intracerebroventricularly (i.c.v.), but only at 5. Heightened imagination leading to a antipsychotics do not fully substitute for - μ THC (Browne and Weissman, 1981; Balster the lowest doses tested (0.01:–0.02/ g/ subjective sense of increased creativity and Prescott, 1992, Gold et al., 1992; Barrett infusion) (Braida et al., 2004). This effect is 6. Time distortions et al., 1995; Wiley et al., 1995). Animals, antagonized by the cannabinoid antagonist 7. Illusions, delusions and hallucinations including monkeys and rats (Gold et al., SR141716 and by the opioid antagonist are rare except at high doses 1992), as well as humans (Chait et al., 1988), naloxone (Braida et al., 2004). Additionally, 8. Impaired judgment, reduced can discriminate cannabinoids from other mice will self-administer WIN 55212, a coordination and ataxia, which can impede drugs or placebo. synthetic CB1 receptor agonist with a non- driving ability or lead to an increase in risk- DEA notes several studies that show that cannabinoid structure (Martellotta et al., taking behavior 1998). the discriminative stimulus effects of D9-THC 9. Emotional lability, incongruity of affect, DEA notes a study showing that the opioid are mediated via a cannabinoid receptor, dysphoria, disorganized thinking, inability to antagonist naltrexone reduces the self- specifically, the CB receptor subtype, and converse logically, agitation, paranoia, 1 administration responding for D9-THC in that the CB antagonist rimonabant (SR confusion, restlessness, anxiety, drowsiness 1 squirrel monkeys (Justinova et al., 2004). 141716A) antagonizes the discriminative and panic attacks may occur, especially in These investigators, using second-order stimulus effects of D9-THC in several species inexperienced users or in those who have schedules of drug-seeking procedures, also (Pe´rio et al., 1996; Mansbach et al., 1996; taken a large dose showed that pre-session administration of D9- Ja¨rbe et al., 2001). The subjective effects of 10. Increased appetite and short-term D9 THC and other cannabinoid agonists, or memory impairment are common marijuana and -THC are, therefore, D9 morphine, but not cocaine, reinstates the - These subjective responses to marijuana mediated by a neurotransmitter system in the THC seeking behavior following a period of brain that is specific to D9-THC and are pleasurable to many humans and are abstinence (Justinova et al., 2008). associated with drug-seeking and drug-taking cannabinoids. Furthermore, the endogenous cannabinoid (Maldonado, 2002). DHHS states that, as with anandamide and its synthetic analog b. Self-Administration Studies most psychoactive drugs, an individual’s methanandamide are self-administered by Self-administration is a behavioral assay response to marijuana can be influenced by squirrel monkeys, and CB receptor that measures the rewarding effects of a drug 1 a person’s medical/psychiatric history as antagonism blocks the reinforcing effect of that increase the likelihood of continued well as their experience with drugs. Frequent both substances (Justinova et al., 2005). drug-taking behavior. Drugs that are self- marijuana users (used more than 100 times) administered by animals are likely to c. Place Conditioning Studies were better able to identify a drug effect from produce rewarding effects in humans. A Conditioned place preference (CPP) is low-dose D9-THC than infrequent users (used strong correlation exists between drugs and another behavioral assay used to determine if less than 10 times) and were less likely to other substances that are abused by humans a drug has rewarding properties. In this test, experience sedative effects from the drug and those that maintain self-injection in animals in a drug-free state are given the (Kirk and de Wit, 1999). However, dose laboratory animals (Schuster and Thompson, opportunity to spend time in two distinct preferences have been demonstrated for 1969; Griffiths et al., 1980). As a result, environments: one where they previously marijuana in which higher doses (1.95 intravenous self-injection of psychoactive received a drug and one where they received percent D9-THC) are preferred over lower substances in laboratory animals is a placebo. If the drug is reinforcing, animals doses (0.63 percent D9-THC) (Chait and considered to be useful for the prediction of in a drug-free state will choose to spend more Burke, 1994). human abuse liability of these compounds time in the environment paired with the drug DEA notes that an extensive review of the (Johanson and Balster, 1978; Collins et al., when both environments are presented reinforcing effects of marijuana in humans 1984). simultaneously. was included in DEA/DHHS’s prior review of

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marijuana (Notice of Denial of Petition, 66 FR subjective reports and physiological markers dependence. DHHS provided in its 2006 20038, 2001). While additional studies have of being ‘‘high’. documents data relevant to actual abuse of been published on the reinforcing effects of THC and its major metabolite, 11-OH-THC, marijuana including data from the National marijuana in humans (e.g., see review by have similar psychoactive and Survey on Drug Use and Health (NSDUH; Cooper and Haney, 2009), they are consistent pharmacokinetic profiles in man (Wall et al., formally known as the National Household with the information provided in DEA/ 1976; DiMarzo et al., 1998; Lemberger et al., Survey on Drug Abuse), the Drug Abuse DHHS’s prior review of this matter. Excerpts 1972). Perez-Reyes et al. (1972) reported that Warning Network (DAWN), Monitoring the are provided below, with some citations THC and 11-OH-THC were equipotent in Future (MTF) survey, and the Treatment omitted. generating a ‘‘high’’ in human volunteers. Episode Data Set (TEDS). These data Both marijuana and THC can serve as However, the metabolite, 11-OH-THC, collection and reporting systems provide positive reinforcers in humans. Marijuana crosses the blood-brain barrier faster than the quantitative data on many factors related to and D9-THC produced profiles of behavioral parent THC compound (Ho et al., 1973; abuse of a particular substance, including and subjective effects that were similar Perez-Reyes et al., 1976). Therefore, the incidence, pattern, consequence and profile regardless of whether the marijuana was changes in THC plasma concentrations in of the abuser of specific substances. DEA smoked or taken orally, as marijuana in humans may not be the best predictive provides here updates to these databases as brownies, or orally as THC-containing marker for the subjective and physiological well as additional data on trafficking and capsules, although the time course of effects effects of marijuana in humans. Cocchetto et illicit availability of marijuana using differed substantially. There is a large al. (1981) have used hysteresis plots to information from databases it produces, such clinical literature documenting the clearly demonstrate that plasma THC as the National Forensic Laboratory subjective, reinforcing, discriminative concentration is a poor predictor of Information System (NFLIS), the System to stimulus, and physiological effects of simultaneous occurring physiological (heart Retrieve Information from Drug Evidence marijuana and THC and relating these effects rate) and psychological (‘‘high’’) (STRIDE) and the Federal-wide Drug Seizure to the abuse potential of marijuana and THC pharmacological effects. Cocchetto et al. System (FDSS), as well as other sources of (e.g., Chait et al., 1988; Lukas et al., 1995; demonstrated that the time course of data specific to marijuana, including the Kamien et al., 1994; Chait and Burke, 1994; tachycardia and psychological responses Potency Monitoring Project and the Domestic Chait and Pierri, 1992; Foltin et al., 1990; lagged behind the plasma THC Cannabis Eradication and Suppression Azorlosa et al., 1992; Kelly et al., 1993, 1994; concentration-time profile. As recently Program (DCE/SP). Chait and Zacny, 1992; Cone et al., 1988; summarized by Martin and Hall (1997, 1998) 1. National Survey on Drug Use and Health Mendelson and Mello, 1984). ‘‘There is no linear relationship between (NSDUH) These listed studies represent a fraction of blood [THC] levels and pharmacological the studies performed to evaluate the abuse effects with respect to time, a situation that The National Survey on Drug Use and potential of marijuana and THC. In general, hampers the prediction of cannabis-induced Health, formerly known as the National these studies demonstrate that marijuana and impairment based on THC blood levels Household Survey on Drug Abuse (NHSDA), THC dose-dependently increases heart rate (p90)’’. is conducted annually by the Department of and ratings of ‘‘high’’ and ‘‘drug liking’’, and Drug craving is an urge or desire to re- Health and Human Service’s Substance alters behavioral performance measures (e.g., experience the drug’s effects and is Abuse and Mental Health Services Azorlosa et al., 1992; Kelly et al., 1993, 1994; considered to be one component of drug Administration (SAMHSA). It is the primary Chait and Zacny, 1992; Kamien et al., 1994; dependence, in part responsible for source of estimates of the prevalence and Chait and Burke, 1994; Chait and Pierri, continued drug use and relapse after incidence of pharmaceutical drugs, illicit 1992; Foltin et al., 1990; Cone et al., 1988; treatment or during periods of drug drugs, alcohol, and tobacco use in the United Mendelson and Mello, 1984). Marijuana also abstinence. DEA notes that Budney and States. The survey is based on a nationally serves as a discriminative stimulus in colleagues (1999) reported that 93 percent of representative sample of the civilian, non- humans and produces euphoria and marijuana-dependent adults seeking institutionalized population 12 years of age alterations in mood. These subjective treatment reported experiencing mild craving and older. The survey excludes homeless changes were used by the subjects as the for marijuana, and 44 percent rated their past people who do not use shelters, active basis for the discrimination from placebo craving as severe. Heishman and colleagues military personnel, and residents of (Chait et al., 1988). developed in 2001 a Marijuana Craving institutional group quarters such as jails and In addition, smoked marijuana Questionnaire (MCQ). When they hospitals. administration resulted in multiple brief administered their MCQ to 217 current According to the 2009 NSDUH report, episodes of euphoria that were paralleled by marijuana smokers who were not attempting marijuana was the most commonly used rapid transient increases in EEG alpha power to quit or reduce their marijuana use, they illicit drug (16.7 million past month users) in (Lukas et al., 1995); these EEG changes are found that marijuana craving can be the United States. (Note that NSDUH figures thought to be related to CNS processes of measured in current smokers that are not on marijuana use include hashish use; the reinforcement (Mello, 1983). seeking treatment. Most subjects (83 percent) relative proportion of hashish use to To help elucidate the relationship between reported craving marijuana 1–5 times per marijuana use is very low). Marijuana was the rise and fall of plasma THC and the self- day, and 82 percent reported that each also the most widely abused drug. The 2009 reported psychotropic effects, Harder and craving episode lasted 30 minutes or less. NSDUH report stated that 4.3 million persons Rietbrock (1997) measured both the plasma Furthermore, they determined that craving were classified with substance dependence levels of THC and the psychological ‘‘high’’ for marijuana can be characterized by four or abuse of marijuana in the past year based obtained from smoking a marijuana cigarette components: (1) compulsivity, an inability to on criteria specified in the Diagnostic and containing 1% THC. As can be seen from control marijuana use; (2) emotionality, use Statistical Manual of Mental Disorders, 4th these data, a rise in plasma THC of marijuana in anticipation of relief from edition (DSM–IV). Among persons aged 12 or concentrations results in a corresponding withdrawal or negative mood; (3) expectancy, older, the past month marijuana use in 2009 increase in the subjectively reported feelings anticipation of positive outcomes from (6.6 percent) was statistically significantly of being ‘‘high’’. However, as THC levels smoking marijuana; and (4) purposefulness, higher than in 2008 (6.1 percent). In 2008, drop the subjectively reported feelings of intention and planning to use marijuana for among adults aged 18 or older who first tried ‘‘high’’ remain elevated. The subjective positive outcomes. marijuana at age 14 or younger, 13.5 percent effects seem to lag behind plasma THC levels. were classified with illicit drug dependence Similarly, Harder and Rietbrock compared C. Actual Abuse of Marijuana—National or abuse, higher than the 2.2 percent of lower doses of 0.3% THC-containing and Databases Related to Marijuana Abuse and adults who had first used marijuana at age 18 0.1% THC-containing cigarettes in human Trafficking or older. subjects. Marijuana use has been relatively stable In 2008, among past year marijuana users As can be clearly seen from these data, from 2002 to 2008, and it continues to be the aged 12 or older, 15.0 percent used marijuana even low doses of marijuana, containing 1%, most widely used illicit drug. Evidence of on 300 or more days within the previous 12 0.3% and even 0.1% THC, typically referred actual abuse can be defined by episodes/ months. This translates into 3.9 million to as ‘‘non-active’’, are capable of producing mentions in databases indicative of abuse/ people using marijuana on a daily or almost

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daily basis over a 12-month period, higher related ED visits, as estimated by DAWN ED three substances at the time of admission, but than the estimate of 3.6 million (14.2 percent for the entire United States. This compares to only three are recorded in TEDS. of past year users) in 2007. Among past a higher number of ED visits involving Admissions for primary abuse of month marijuana users, 35.7 percent (5.4 cocaine (422,896), and lower numbers of ED marijuana/hashish accounted for 16 percent million) used the drug on 20 or more days visits involving heroin (213,118) and of all treatment admissions reported to the in the past month. stimulants (amphetamine, TEDS system in 2006 and 2007. In 2006, 2. Monitoring the Future methamphetamine) (93,562). Visits involving 2007 and 2008, 1,933,206, 1,920,401 and the other major illicit drugs, such as MDMA, 2,016,256 people were admitted to drug and Monitoring the Future (MTF) is a national GHB, LSD and other hallucinogens, PCP, and alcohol treatment in the United States, survey conducted by the Institute for Social inhalants, were much less frequent, respectively. The marijuana/hashish Research at the University of Michigan under comparatively. admissions represented 16 percent (308,670), a grant from the National Institute on Drug In young patients, marijuana is the illicit 16 percent (307,123) and 17.2 percent Abuse (NIDA) that tracks drug use trends drug most frequently involved in ED visits (346,679) of the total drug/alcohol treatment among American adolescents in the 8th, according to DAWN estimates, with 182.2 per admissions in 2006, 2007 and 2008, 10th, and 12th grades. Marijuana was the respectively. In 2008, 65.8 percent of the most commonly used illicit drug reported in 100,000 population aged 12 to 17, 484.8 per the 2010 MTF report. Approximately 8.0 100,000 population aged 18 to 20, and 360.2 individuals admitted for marijuana were aged percent of 8th graders, 16.7 percent of the per 100,000 population aged 21 to 24. 12–17, 18–20 and 21–25 (30.5 percent, 15.3 10th graders, and 21.4 percent of 12th graders percent and 20.0 percent, respectively). 4. Treatment Episode Data Set (TEDS) Among the marijuana/hashish admissions in surveyed in 2010 reported marijuana use System during the past month prior to the survey. 2007 in which age of first use was reported Monitoring the Future participants reported Users can become dependent on marijuana (286,194), 25.1 percent began using a statistically significant increase of daily use to the point that they seek treatment to stop marijuana at age 12 or younger. abusing it or are referred to a drug abuse in the past month in 2010, compared to 2009, 5. Forensic Laboratory Data 1.2 percent, 3.3 percent, and 6.1 percent of treatment program. The TEDS system is part eighth, tenth and twelfth graders, of the SAMHSA Drug and Alcohol Services Marijuana is widely available in the United respectively. Information System. TEDS comprises data on States, fueled by increasing marijuana treatment admissions that are routinely production at domestic grow sites as well as 3. DAWN ED (Emergency Department) collected by states in monitoring their increasing production in Mexico and Canada. The Drug Abuse Warning Network substance abuse treatment systems. The Data on marijuana seizures from federal, (DAWN) is a public health surveillance primary goal of the TEDS is to monitor the state, and local law enforcement laboratories system that monitors drug-related hospital characteristics of treatment episodes for have indicated that there is significant emergency department (ED) visits to track the substances abusers. The TEDS report trafficking of marijuana. The National impact of drug use, misuse, and abuse in the provides information on both the Forensic Laboratory Information System United States. DAWN provides a picture of demographic and substance use (NFLIS) is a program sponsored by the Drug the impact of drug use, misuse, and abuse on characteristics of admissions to treatment for Enforcement Administration’s Office of metropolitan areas and across the nation. abuse of alcohol and drugs in facilities that Diversion Control. NFLIS compiles DAWN gathers data on drug abuse-related ED report to individual state administrative data information on exhibits analyzed in state and visits from a representative sample of systems. TEDS does not include all local law enforcement laboratories. The hospitals in the coterminous United States. admissions to substance abuse treatment. It System to Retrieve Information from Drug DAWN ED gathers data on emergency includes admissions to facilities that are Evidence (STRIDE) is a DEA database which department visits relating to substance use licensed or certified by the state substance compiles information on exhibits analyzed in including, but not limited to, alcohol, illicit abuse agency to provide substance abuse DEA laboratories. NFLIS and STRIDE drugs, and other substances categorized as treatment (or are administratively tracked by together capture data for all substances psychotherapeutic, central nervous system, the agency for other reasons). In general, reported by forensic laboratory analyses. respiratory, cardiovascular, alternative facilities reporting to TEDS are those that More than 1,700 unique substances are medication, anti-infective, hormone, reported to these two databases. nutritional product and gastrointestinal receive state alcohol and/or drug agency agents. For the purposes of DAWN, the term funds (including federal block grant funds) NFLIS showed that marijuana was the most ‘‘drug abuse’’ applies if the following for the provision of alcohol and/or drug frequently identified drug in state and local conditions are met: (1) the case involved at treatment services. The primary substances laboratories from January 2001 through least one of the following: use of an illegal reported by TEDS are alcohol, cocaine, December 2010. Marijuana accounted for drug; use of a legal drug contrary to marijuana (marijuana is considered together between 34 percent and 38 percent of all directions; or inhalation of a non- with hashish), heroin, other opiates, PCP, drug exhibits analyzed during that time pharmaceutical substance and (2) the hallucinogens, amphetamines, other frame. Similar to NFLIS, STRIDE data substance was used for one of the following stimulants, tranquilizers, sedatives, inhalants showed that marijuana was the most reasons: because of drug dependence; to and other/unknown. TEDS defines Primary frequently identified drug in DEA commit suicide (or attempt to commit Substance of Abuse as the main substance of laboratories for the same reporting period. suicide); for recreational purposes; or to abuse reported at the time of admission. From January 2001 through December 2010, achieve other psychic effects. TEDS also allows for the recording of two a range of between 17 percent and 21 percent In 2009, marijuana was involved in other substances of abuse (secondary and of all exhibits analyzed in DEA laboratories 376,467 ED visits, out of 1,948,312 drug- tertiary). A client may be abusing more than were identified as marijuana (Table 1).

TABLE 1—MARIJUANA (OTHER THAN HASHISH) (EXHIBITS AND CASES) REPORTED BY NFLIS AND STRIDE, 2001–2010, FORENSIC LABORATORY DATA

NFLIS STRIDE Exhibits Exhibits (percent total Cases (percent total Cases exhibits) exhibits)

2001 ...... 314,002 (37.9%) 261,191 16,523 (20.7%) 13,256 2002 ...... 373,497 (36.6%) 312,161 14,010 (19.4%) 11,306 2003 ...... 407,046 (36.7%) 339,995 13,946 (19.9%) 10,910 2004 ...... 440,964 (35.5%) 371,841 13,657 (18.4%) 10,569 2005 ...... 469,186 (33.5%) 394,557 14,004 (18.3%) 10,661

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TABLE 1—MARIJUANA (OTHER THAN HASHISH) (EXHIBITS AND CASES) REPORTED BY NFLIS AND STRIDE, 2001–2010, FORENSIC LABORATORY DATA—Continued

NFLIS STRIDE Exhibits Exhibits (percent total Cases (percent total Cases exhibits) exhibits)

2006 ...... 506,472 (33.6%) 421,943 13,597 (18.5%) 10,277 2007 ...... 512,082 (34.7%) 423,787 13,504 (19.2%) 10,413 2008 ...... 513,644 (35.1%) 421,782 12,828 (18.8%) 10,109 2009 ...... 524,827 (35.6%) 414,006 12,749 (17.7%) 10,531 2010 ...... 464,059 (36.3%) 362,739 11,293 (16.7%) 7,158 Data queried 03–04–2011.

TABLE 2—HASHISH (EXHIBITS AND CASES) REPORTED BY NFLIS AND STRIDE, 2001–2010, FORENSIC LABORATORY DATA

NFLIS STRIDE Exhibits Cases Exhibits Cases

2001 ...... 1,689 1,671 53 50 2002 ...... 2,278 2,254 40 38 2003 ...... 2,533 2,503 48 42 2004 ...... 2,867 2,829 63 51 2005 ...... 2,674 2,639 122 90 2006 ...... 2,836 2,802 102 76 2007 ...... 3,224 3,194 168 122 2008 ...... 2,988 2,920 124 102 2009 ...... 2,952 2,843 119 96 2010 ...... 2,473 2,392 141 84 Data queried 03–04–2011.

Since 2001, the total number of exhibits Administration, the Federal Bureau of which is a repository for information on and cases of marijuana and the amount of Investigation, United States Customs and clandestine laboratory, contraband marijuana seized federally has remained high Border Protection, and United States (chemicals and precursors, currency, drugs, and the number of marijuana plants Immigration and Customs Enforcement, equipment and weapons). FDSS reports total eradicated has considerably increased (see within the jurisdiction of the United States. federal drug seizures (kg) of substances such data from Federal-wide Drug Seizure System It also records maritime seizures made by the as cocaine, heroin, MDMA, and Domestic Cannabis Eradication and United States Coast Guard. Drug seizures methamphetamine, and cannabis (marijuana Suppression Program below). made by other Federal agencies are included and hashish). The yearly volume of cannabis 6. Federal-wide Drug Seizure System in the FDSS database when drug evidence seized (Table 3), consistently exceeding a The Federal-wide Drug Seizure System custody is transferred to one of the agencies thousand metric tons per year, shows that (FDSS) contains information about drug identified above. FDSS is now incorporated cannabis is very widely trafficked in the seizures made by the Drug Enforcement into the National Seizure System (NSS), United States. TABLE 3—TOTAL FEDERAL SEIZURES OF CANNABIS [Expressed in kg]

2002 2003 2004 2005 2006 2007 2008 2009 2009

Cannabis ...... 1,103,173 1,232,711 1,179,230 1,116,977 1,141,915 1,459,220 1,590,793 1,911,758 1,858,808 Marijuana ...... 1,102,556 1,232,556 1,179,064 1,116,589 1,141,737 1,458,883 1,590,505 1,910,775 1,858,422 Hashish ...... 618 155 166 388 178 338 289 983 386

7. Potency Monitoring Project Institute on Drug Abuse (NIDA), analyzes and potency marijuana, subjects chose the high- D9 Rising availability of high potency (i.e., compiles data on the -THC concentrations potency marijuana significantly more often with high D9-THC concentrations) marijuana of cannabis, hashish and hash oil samples than the low-potency marijuana (Chait and has pushed the average marijuana potency to provided by DEA regional laboratories and by Burke, 1994), supporting the hypothesis that its highest recorded level. The University of state and local police agencies. the reinforcing effects of marijuana, and Mississippi’s Potency Monitoring Project DEA notes studies showing that when possibly its abuse liability, are positively (PMP), through a contract with the National given the choice between low- and high- related to THC content.

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8. The Domestic Cannabis Eradication and the program had expanded to 25 states and and Hawaii. Significant quantities of Suppression Program by 1985 all fifty states were participants. marijuana were also eradicated from indoor The Domestic Cannabis Eradication and Cannabis is cultivated in remote locations cultivation operations. There were 414,604 Suppression Program (DCE/SP) was and frequently on public lands. Data indoor plants eradicated in 2009 compared to established in 1979 to reduce the supply of provided by the DCE/SP (Table 4) shows that 217,105 eradicated in 2000. As indoor domestically cultivated marijuana in the in 2009, there were 9,980,038 plants cultivation is generally associated with United States. The program was designed to eradicated in outdoor cannabis cultivation plants that have higher concentrations of serve as a partnership between federal, state, areas in the United States. Marijuana is D9-THC, the larger numbers of indoor grow and local agencies. Only California and illicitly grown in all states. Major domestic facilities may be impacting the higher Hawaii were active participants in the outdoor cannabis cultivation areas were average D9-THC concentrations of seized program at its inception. However, by 1982 found in California, Kentucky, Tennessee materials. TABLE 4—DOMESTIC CANNABIS ERADICATION, OUTDOOR AND INDOOR PLANTS SEIZED, 2000–2009 [Source: Domestic Cannabis Eradication/Suppression Program]

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Outdoor ...... 2,597,798 3,068,632 3,128,800 3,427,923 2,996,144 3,938,151 4,830,766 6,599,599 7,562,322 9,980,038 Indoor ...... 217,105 236,128 213,040 223,183 203,896 270,935 400,892 434,728 450,986 414,604

Total ...... 2,814,903 3,304,760 3,341,840 3,651,106 3,200,040 4,209,086 5,231,658 7,034,327 8,013,308 10,394,642

The recent statistics from these various DHHS states, to the contrary, ‘‘the large discriminative stimuli to maintain drug- surveys and databases show that marijuana number of individuals using marijuana on a seeking behavior. continues to be the most commonly used regular basis, its widespread use, and the vast In addition, marijuana is the most highly illicit drug, with considerable rates of heavy amount of marijuana that is available for abused and trafficked illicit substance in the abuse and dependence. They also show that illicit use are indicative of the high abuse United States. Chronic abuse has resulted in marijuana is the most readily available illicit potential for marijuana.’’ Indeed, the data a considerable number of individuals seeking drug in the United States. presented in this section shows that substance abuse treatment according to marijuana has a high potential for abuse as The petitioner states that, ‘‘The abuse national databases such as TEDS. Abuse of determined using the indicators identified in potential of cannabis is insufficient to justify marijuana is associated with significant the CSA’s legislative history. Both clinical the prohibition of medical use.’’ The and preclinical studies have demonstrated public health and safety risks that are petitioner also states that, ‘‘[s]everal studies that marijuana and its principal psychoactive described under factors 2, 6 and 7. demonstrate that abuse rates for cannabis are constituent D9-THC possess the attributes The issue of whether marijuana has a lower than rates for other common drugs.’’ associated with drugs of abuse. They currently accepted medical use is discussed (Exh. C, Section IV(16), pg. 92). function as positive reinforcers and as under Factor 3.

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The petitioner claims that, ‘‘[…]widespread immune systems, as well as its effects on inwardly rectifying potassium channels use of marijuana without dependency mental health and cognitive function and the (Mackie et al., 1995; Twitchell et al., 1997). supports the argument that marijuana is safe effect of prenatal exposure to marijuana. Inhibition of N-type calcium channels for use under medical supervision.’’ (Exh. C, decreases neurotransmitter release from a Section IV(15), pg. 87). Neurochemistry of the Psychoactive number of tissues and may be the mechanism Petitioner’s claim of widespread use Constituents of Marijuana by which cannabinoids inhibit acetylcholine, without dependency is not supported by DHHS states that of 483 natural norepinephrine, and glutamate release from abuse-related data. In particular, this claim constituents identified in marijuana, 66 are specific areas of the brain. These effects on disregards the high numbers of admissions to classified as cannabinoids (Ross and El G protein-mediated pathways and on calcium treatment facilities for marijuana abuse. Sohly, 1995). Cannabinoids are not known to and potassium channels may represent Indeed, TEDS admissions for primary abuse exist in plants other than marijuana and most potential cellular mechanisms underlying the of marijuana/hashish accounted for roughly of the cannabinoid compounds have been antinociceptive and psychoactive effects of 17 percent of all treatment admissions in identified chemically. The activity of cannabinoids (Ameri, 1999). 2008. In 2008, 2,016,256 people were marijuana is largely attributed to D9-THC Delta9-THC displays similar affinity for admitted to drug and alcohol treatment in the (Wachtel et al., 2002). both cannabinoid receptors but behaves as a United States and 346,679 of those DEA notes that D9-THC and delta-8- weak agonist at CB2 receptors, based on admissions were for marijuana/hashish tetrahydrocannabinol (D8-THC) are the only inhibition of adenylate cyclase. The abuse. These drug treatment numbers are not known compounds in the cannabis plant identification of synthetic cannabinoid consistent with this claim. Marijuana is not which show all the psychoactive effects of ligands that selectively bind to CB2 receptors D9 safe for use under medical supervision, and marijuana. D9-THC is more abundant than D8- but do not have the typical -THC-like this point is addressed further in Factor 3. THC and D9-THC concentrations vary within psychoactive properties, along with the The petitioner also claims that, ‘‘Data on portions of the cannabis plant (Hanus and respective anatomical distribution of the two both drug treatment and emergency room Subiva´, 1989; Hanus et al., 1975). The receptor subtypes suggests that the admissions also distinguishes the abuse pharmacological activity of D9-THC is psychoactive effects of cannabinoids are potential of marijuana from that of other stereospecific: the (-)-trans isomer is 6–100 mediated through the activation of CB1 drugs and establishes its relative abuse times more potent than the (+)-trans isomer receptors (Hanus et al., 1999). Naturally potential as lower than schedule I drugs such (Dewey et al., 1984). occurring cannabinoids and synthetic as heroin and schedule II drugs such as The mechanism of action of D9-THC was cannabinoid agonists (such as WIN-55,212-2 cocaine.’’ (Exh. C, Section IV(17), pg. 99). verified with the cloning of cannabinoid and CP-55,940) produce hypothermia, The petitioner then presents data from TEDS receptors, first from rat brain tissue (Matsuda analgesia, hypoactivity, and catalepsy in in 1998, in which a larger proportion of all et al., 1990) and then from human brain addition to their psychoactive effects. marijuana treatment admissions are referred tissue (Gerard et al., 1991). Two cannabinoid In 2000, two endogenous cannabinoid to by the criminal justice system (54 percent), receptors have been identified and receptor agonists were discovered, anandamide and arachidonyl glycerol (2-AG). compared to much smaller percentages for characterized, CB1 and CB2 (Piomelli, 2005). heroin and cocaine. The petitioner argues Autoradiographic studies have provided Anandamide is a low efficacy agonist (Breivogel and Childers, 2000) and 2-AG is a that the abuse potential of these other drugs information on the distribution of CB1 and highly efficacious agonist (Gonsiorek et al., is more severe such that addicts seek CB2 receptors. High densities of CB1 2000). These endogenous ligands are present treatment on their own or through persuasion receptors are found in the basal ganglia, in both central and peripheral tissues. The of their associates, and claims that this hippocampus, and cerebellum of the brain physiological role of these endogenous difference establishes marijuana’s relative (Howlett et al., 2004; Herkenham et al., 1990; ligands is an active area of research (Martin abuse potential as lower than the other drugs. Herkenham, 1992). These brain regions are et al., 1999). Petitioner’s claim is not supported by an associated with movement coordination and In summary, two receptors have been examination of the absolute numbers of cognition and the location of CB1 receptors cloned, CB (found in the central nervous admissions for treatment for each drug in these areas may explain cannabinoid 1 system) and CB2 (predominantly found in interference with these functions. Although discussed. Regardless of proportions of the periphery), that bind D9-THC and other CB receptors are predominantly expressed referrals from the criminal justice systems, 1 cannabinoids. Activation of these inhibitory in the brain, they have also been detected in the absolute numbers of admissions for G-protein-coupled receptors inhibits calcium the immune system (Bouaboula et al., 1993). treatment for marijuana, heroin, or cocaine channels and adenylate cyclase. Endogenous CB receptors are primarily located in B dependence are very high. Furthermore, data 2 cannabinoid agonists have been identified, lymphocytes and natural killer cells of the from TEDS in 2007 (SAMHSA, 2009) show anandamide and arachidonyl glycerol (2-AG). that both primary marijuana and immune system and it is believed that this methamphetamine/amphetamine admissions receptor is responsible for mediating Pharmacological Effects of Marijuana had the largest proportion of admissions immunological effects of cannabinoids Marijuana produces a number of central referred through the criminal justice system (Galiegue et al., 1995). Recently, however, nervous system effects. Many of these effects (57 percent each), followed by PCP (54 CB2 receptors have been localized in the are directly related to the abuse potential of percent). Both methamphetamine/ brain, primarily in the cerebellum and marijuana, and are discussed in Factor 1. amphetamine and PCP have very high hippocampus (Gong et al., 2006). Other effects are discussed herein. potential for abuse (Lile, 2006; Crider, 1986). Cannabinoid receptors are linked to an Accordingly, this illustrates that it is not inhibitory G-protein (Breivogel and Childers, Cardiovascular and Autonomic Effects possible to establish or predict relative abuse 2000). When the receptor is activated, DHHS states that acute use of marijuana potentials from the ranking of proportions of adenylate cyclase activity is inhibited, causes an increase in heart rate (tachycardia) treatment admissions referred by the criminal preventing the conversion of adenosine and may cause a modest increase in blood justice system. triphosphate (ATP) to the second messenger pressure as well (Capriotti et al., 1988; cyclic adenosine monophosphate (cAMP). Benowitz and Jones, 1975). Conversely, FACTOR 2: SCIENTIFIC EVIDENCE OF THE Other examples of inhibitory-coupled chronic exposure to marijuana will produce DRUG’S PHARMACOLOGICAL EFFECTS, receptors include opioid, muscarinic a decrease in heart rate (bradycardia) and IF KNOWN cholinergic, alpha2-adrenoreceptors, decrease of blood pressure. In heavy smokers DHHS states that there are abundant dopamine and serotonin receptors. However, of marijuana, the degree of increased heart scientific data available on the several studies also suggest a link to rate is diminished due to the development of neurochemistry, toxicology, and stimulatory G-proteins, through which tolerance (Jones, 2002 and Sidney, 2002). pharmacology of marijuana. Following is a activation of CB1 stimulates adenylate These effects are thought to be mediated summary of the current scientific cyclase activity (Glass and Felder, 1997; through peripherally located, presynaptic understanding of the endogenous Maneuf and Brotchie, 1997; Felder et al., CB1 receptor inhibition of norepinephrine cannabinoid system and of marijuana’s 1998). release with possible direct activation of pharmacological effects, including its effects Activation of CB1 receptors inhibits N-and vascular cannabinoid receptors (Wagner et on the cardiovascular, respiratory, and P/Q-type calcium channels and activate al., 1998).

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DHHS cites a review (Jones, 2002) of also cites other studies reporting lung cancer al., 1986). However, later studies in male studies showing that smoked marijuana occurrences in young marijuana users with subjects receiving smoked D9-THC (18 mg/ causes orthostatic hypotension (sympathetic no history of tobacco smoking (Fung et al., marijuana cigarette) or oral D9-THC (10 mg insufficiency, a sudden drop in blood 1999), and suggesting a dose-dependent t.i.d. for 3 days) showed no changes in pressure upon standing up) often effect of marijuana on the risk of head and plasma prolactin, ACTH, cortisol, luteinizing accompanied by dizziness. DHHS states that neck cancer (Zhang et al., 1999). hormone or testosterone levels (Dax et al., tolerance can develop to this effect. DEA notes the publication of a more recent 1989). Similarly, a study with 93 males and Marijuana smoking by older patients, case–control study of lung cancer in adults 56 female subjects showed that chronic particularly those with some degree of under 55 years of age, conducted in New marijuana use did not significantly alter coronary artery or cerebrovascular disease, Zealand by Aldington and colleagues (2008). concentrations of testosterone, luteinizing poses risks related to increased cardiac work, Interviewer-administered questionnaires hormone, follicle stimulating hormone, increased catecholamines, were used to assess possible risk factors, prolactin or cortisol (Block et al., 1991). carboxyhemoglobin, and postural including cannabis use. In total, 79 cases of DHHS cites a study (Sarfaraz et al., 2005) hypotension (Benowitz and Jones, 1981; lung cancer and 324 controls were included which showed that the cannabinoid agonist Hollister, 1988). in the study. The risk of lung cancer WIN 55,212-2 induces apoptosis in prostate DEA further notes studies in which increased 8 percent (95 percent confidence cancer cells growth and decreases expression marijuana has been administered under interval (CI) 2–15) for each joint-year of of androgen receptors. DHHS states that this controlled conditions to marijuana- cannabis smoking (one joint-year being data suggests a potential therapeutic value for experienced users that showed that equivalent to one joint per day for a year), cannabinoid agonists in the treatment of marijuana causes a substantial increase, after adjustment for confounding variables prostate cancer, an androgen-stimulated type compared to placebo, in heart rate including cigarette smoking; it went up 7 of carcinoma. (tachycardia) ranging from 20 percent to 100 percent (95 percent CI 5–9) for each pack- In summary, while animal studies have percent above baseline. This effect was seen year of cigarette smoking (one pack-year suggested that cannabinoids can alter as usually greatest starting during the 10 being equivalent to one pack per day for a multiple hormonal systems, the effects in minutes or so it takes to smoke a marijuana year), after adjustment for confounding humans, in particular the consequences of cigarette and lasting 2 to 3 hours (reviewed variables including cannabis smoking. Thus, long-term marijuana abuse, remain unclear. in Jones et al., 2002). a major differential risk between cannabis DEA also notes a randomized, double- and cigarette smoking was observed, with Immune System Effects blind, placebo-controlled study by Mathew one joint of cannabis being similar to 20 DHHS states that cannabinoids alter and colleagues (2003) that examined pulse cigarettes for risk of lung cancer. Users immune function but that there can be rate, blood pressure (BP), and plasma D9-THC reporting over 10.5 joint-years of exposure differences between the effects of synthetic, levels during reclining and standing for 10 had a significantly increased risk of natural, and endogenous cannabinoids minutes before and after smoking one developing lung cancer (relative risk 5.7 (95 (Croxford and Yamamura, 2005). marijuana cigarette (3.55 percent D9-THC) by percent CI 1.5–21.6)) after adjustment for DHHS cites a study by Roth et al. (2005) twenty-nine volunteers. Marijuana induced confounding variables including cigarette that examined the effect of D9-THC exposure postural dizziness, with 28 percent of smoking. DEA notes that the authors of this on immune function and response to HIV subjects reporting severe symptoms. study concluded from their results that long- infection in immunodeficient mice that were Intoxication and dizziness peaked term cannabis use increases the risk of lung implanted with human blood cells infected immediately after drug intake. The severe cancer in young adults. with HIV. The study shows that exposure to dizziness group showed the most marked Some studies discuss marijuana smoke and D9-THC in vivo suppresses immune function, postural drop in blood pressure and showed tobacco smoke. DHHS states that chronic increases HIV co-receptor expression and a drop in pulse rate after an initial increase exposure to marijuana smoke is considered to acts as a cofactor to enhance HIV replication. during standing. be comparable to tobacco smoke with respect DEA notes that the authors of this study state to increased risk of cancer and lung damage. that their results suggest a dynamic Respiratory Effects DEA notes studies showing that marijuana interaction between D9-THC, immunity, and Both acute and chronic respiratory effects smoke contains several of the same the pathogenesis of HIV and support are associated with marijuana smoking. carcinogens and co-carcinogens as tobacco epidemiologic studies that have identified DHHS states that acute exposure to smoke and suggesting that pre-cancerous marijuana use as a risk factor for HIV marijuana produces transient lesions in bronchial epithelium also seem to infection and the progression of AIDS. bronchodilation (Gong et al., 1984). DHHS be caused by long-term marijuana smoking However, DHHS discusses a recent study by states that long-term use of smoked (Roth et al., 1998). Abrams et al. (2003) that investigated the marijuana can lead to increased frequency of In summary, studies are still needed to effect of marijuana on immunological chronic cough, increased sputum, large clarify the impact of marijuana on the risk of functioning in 67 AIDS patients who were airway obstruction, as well as cellular developing lung cancer as well as head and taking protease inhibitors. Subjects received inflammatory histopathological abnormalities neck cancer. DHHS states that the evidence one of three treatments, three times a day: in bronchial epithelium (Adams and Martin, that marijuana may lead to cancer is smoked marijuana cigarette containing 3.95 1996; Hollister, 1986). inconsistent, with some studies suggesting a percent D9-THC; oral tablet containing D9- DEA notes a study showing that both positive correlation while others do not. THC (2.5 mg oral dronabinol); or oral smoked marijuana and oral D9-THC increases placebo. There were no changes in HIV-RNA specific airway conductance in asthmatic Endocrine Effects levels between groups, demonstrating no subjects (Tashkin et al., 1974). In addition, DHHS states that D9-THC reduces binding short-term adverse virologic effects from other studies have suggested that chronic of the corticosteroid dexamethasone in using cannabinoids. marijuana smoking is also associated with hippocampal tissue from adrenalectomized DEA notes a review suggesting that D9-THC increased incidence of emphysema and rats and acute D9-THC releases and cannabinoids decrease resistance to asthma (Tashkin et al., 1987). corticosterone, with tolerance developing to microbial infections in experimental animal DHHS states that the evidence that this effect with chronic administration models and in vitro (see review by Cabral and marijuana may lead to cancer is inconsistent, (Eldridge et al., 1991). These data suggest Staab, 2005). Various studies have been with some studies suggesting a positive that D9-THC may interact with the conducted in drug-abusing human subjects, correlation while others do not. DHHS cited glucocorticoid receptor system. experimental animals exposed to marijuana a large clinical study with 1,650 subjects in DHHS states that experimental smoke or injected with cannabinoids, and in which no positive correlation was found administration of marijuana to humans does in vitro models using immune cell cultures between marijuana use and lung cancer not consistently alter the endocrine system. treated with various cannabinoids. DEA (Tashkin et al., 2006). This finding held true In an early study, four male subjects notes that for the most part, these studies regardless of the extent of marijuana use administered smoked marijuana showed a suggest that cannabinoids modulate the when both tobacco use and other potential significant depression in luteinizing hormone function of various cells of the human confounding factors were controlled. DHHS and a significant increase in cortisol (Cone et immune system, including T- and B-

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lymphocytes as well as natural killer (NK) individuals who claimed, on admission, to (McGrath et al., 2010). This study found a cells and macrophages. Macrophages engulf have taken marijuana on more than 50 dose-response relationship where the longer and destroy foreign matter, NK cells target occasions were six times more likely to be the duration of time since the first cannabis cells (e.g., cancerous cells) and destroy them, diagnosed with schizophrenia in the use, the higher the risk of psychosis-related B-lymphocytes produce antibodies against following 15 years than those who had never outcome. Those patients with early-onset infective organisms, and T-lymphocytes kill consumed the drug. When confounding psychotic symptoms were also likely to cells or trigger the activity of other cells of factors were taken into account, the risk of report early marijuana use. Authors suggest the immune system. developing schizophrenia remained that their results support the hypothesis that In addition to studies examining statistically significant. The authors early cannabis use is a risk-modifying factor cannabinoid effects on immune cell function, concluded that marijuana users who are for psychosis-related outcomes in young DEA also notes other reports which have vulnerable to developing psychoses are at the adults. documented that cannabinoids modulate greatest risk for schizophrenia. DHHS states Cognitive Effects resistance to various infectious agents. that therefore marijuana per se does not Viruses such as herpes simplex virus and appear to induce schizophrenia in the DHHS states that acute administration of murine retrovirus have been studied as well majority of individuals who try or continue smoked marijuana impairs performance on as bacterial agents such as members of the to use the drug. tests of learning, associative processes, and genera Staphylococcus, Listeria, Treponema, DHHS discusses another large longitudinal psychomotor behavior (Block et al., 1992; and Legionella. These studies suggest that study in which the prevalence of Heishman et al., 1990). Marijuana may cannabinoids modulate host resistance, schizophrenia was modeled against therefore considerably interfere with an especially the secondary immune response marijuana use across birth cohorts in individual’s ability to learn in a classroom or (reviewed in Cabral and Dove-Pettit, 1998). Australia from 1940 to 1979 (Degenhardt et to operate motor vehicles. DHHS cites a study conducted by Kurzthalar and Finally, DEA notes a review suggesting that al., 2003). The authors found that marijuana colleagues (1999) with human volunteers, in cannabinoids modulate the production and use may precipitate disorders in vulnerable which the administration of 290 μg/kg of D9- function of cytokines as well as modulate the individuals and worsen the course of the THC in a smoked cigarette resulted in activity of network cells such as macrophages disorder among those that have already impaired perceptual motor speed and and T helper cells. Cytokines are the developed it. They did not find any causal relationship between marijuana use and accuracy, skills of paramount importance for chemicals produced by cells of the immune safe driving. Similarly, administration of 3.95 increased incidence of schizophrenia. system in order to communicate and percent D9-THC in a smoked cigarette DEA notes that Degenhardt and colleagues orchestrate the attack. Binding to specific increased disequilibrium measures, as well (2003) acknowledged that several receptors on target cells, cytokines recruit as the latency in a task of simulated vehicle environmental risk factors for schizophrenia many other cells and substances to the field braking (Liguori et al., 1998). had been reduced (i.e., poor maternal of action. Cytokines also encourage cell DHHS states that the effects of marijuana nutrition, infectious disease and poor growth, promote cell activation, direct may not be fully resolved until at least one antenatal and prenatal care) and that the cellular traffic, and destroy target cells (see day after the acute psychoactive effects have diagnostic criteria for schizophrenia had review by Klein et al., 2000). subsided, following repeated administration. changed over the span of this study making In summary, as DHHS states, cannabinoids Heishman and colleagues (1988) showed that alter immune function, but there can be the classification of schizophrenia more impairment on memory tasks persists for 24 differences between the effects of synthetic, rigorous. These confounders could reduce hours after smoking marijuana cigarettes natural, and endogenous cannabinoids. the reported prevalence of schizophrenia. containing 2.57 percent D9-THC. However, While there is a large body of evidence to DHHS also discusses several longitudinal Fant and colleagues (1998) showed minimal D9 suggest that -THC alters immune function, studies that found a dose-response residual alterations in subjective or research is still needed to clarify the effects relationship between marijuana use and an performance measures the day after subjects of cannabinoids and marijuana on the increasing risk of psychosis among those who were exposed to 1.8 percent or 3.6 percent immune system in humans, in particular the are vulnerable to developing psychosis smoked D9-THC. risks posed by smoked marijuana in (Fergusson et al., 2005; van Os et al., 2002). DHHS discussed a study by Lyons and immunocompromized individuals. DEA notes several longitudinal studies colleagues (2004) on the neuropsychological (Arseneault et al., 2002, Caspi et al., 2005; Association with Psychosis consequences of regular marijuana use in Henquet et al., 2005) that found increased fifty-four monozygotic male twin pairs, with The term psychosis is generally used in rates of psychosis or psychotic symptoms in one subject being a regular user and its co- research as a generic description of severe people using cannabis. Finally, DEA notes twin a non-user, and neither twin having mental illnesses characterized by the some studies that observe that individuals used any other illicit drug regularly. presence of delusions, hallucinations and with psychotic disorders have higher rates of Marijuana-using twins significantly differed other associated cognitive and behavioral cannabis use compared to the general from their non-using co-twins on the general impairments. Psychosis is measured either by population (Regier et al., 1990; Green et al., intelligence domain. However, only one using standardized diagnostic criteria for 2005). significant difference was noted between psychotic conditions such as schizophrenia DEA also notes that, more recently, Moore marijuana-using twins and their non-using or by using validated scales that rank the and colleagues (2007) performed a meta- co-twins on measures of cognitive level of psychotic symptoms from none to analysis of the longitudinal studies on the functioning. Authors of the study proposed severe (Fergusson et al., 2006). link between cannabis use and subsequent that the results indicate an absence of any DHHS states that extensive research has psychotic symptoms. Authors observed that marked long-term residual effects of been conducted recently to investigate there was an increased risk of any psychotic marijuana use on cognitive abilities. This whether exposure to marijuana is associated outcome in individuals who had ever used conclusion is similar to the results found by with schizophrenia or other psychoses. cannabis (pooled adjusted odds ratio=1.41, Lyketsos and colleagues (1999), who DHHS states that, at the time of their review, 95 percent CI 1.20–1.65). Furthermore, investigated the possible adverse effects of the data does not suggest a causative link findings were consistent with a dose- cannabis use on cognitive decline after 12 between marijuana use and the development response effect, with greater risk in people years in persons under 65 years of age. There of psychosis. who used cannabis most frequently (2.09, were no significant differences in cognitive DHHS discusses an early epidemiological 1.54–2.84). The authors concluded that their decline between heavy users, light users, and study conducted by Andreasson and results support the view that cannabis nonusers of cannabis. The authors conclude colleagues (1987), which examined the link increases risk of psychotic outcomes that over long time periods, in persons under between psychosis and marijuana use. In this independently of confounding and transient age 65 years, cognitive decline occurs in all study, 45,000 18- and 19-year-old male intoxication effects. age groups. This decline is closely associated Swedish subjects provided detailed DEA also notes another more recent study with aging and educational level but does not information on their drug-taking history. The examining the association between marijuana appear to be associated with cannabis use. incidence of schizophrenia was then use and psychosis-related outcome in pairs of DEA notes that while Lyketsos and recorded over the next 15 years. Those young adult siblings in Brisbane, Australia colleagues (1999) propose that their results

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provide strong evidence of the absence of a another cohort of chronic, heavy marijuana learning, associative processes, and long term residual effect of cannabis use on users, some deficits were observed on psychomotor behavior. The effects of chronic cognition, they also acknowledge a number memory tests up to a week following marijuana use have also been studied. While of limitations to their study. Notably, authors supervised abstinence but these effects a few studies did not observe strong remark that it is possible that some cannabis disappeared by day 28 of abstinence (Pope et persistent neurocognitive consequences of users in the study may have used cannabis al., 2002). The authors concluded that long-term cannabis use (Lyketsos et al., 1999; on the day the test was administered. Given ‘‘cannabis-associated cognitive deficits are Lyons et al., 2004), others provide support the acute effects on cannabis on cognition, reversible and related to recent cannabis for the existence of persistent consequences this would have tended to reduce their test exposure rather than irreversible and related (Bolla et al., 2002, 2005). The cognitive score on that day. This may have adversely to cumulative lifetime use.’’ Conversely, impairments that are observed 12 hours to affected accurate measurement of test score DHHS notes that other investigators have seven days after marijuana use (Messinis et changes over time in cannabis users. The reported persistent neuropsychological al., 2006; Solowij et al., 2002; Harrison et al., authors also noted, as another important deficits in memory, executive functioning, 2002), and that persist beyond behaviorally limitation, that the test used is not intended psychomotor speed, and manual dexterity in detectable intoxication, are noteworthy and for the purpose for which it was used in this heavy marijuana smokers who had been may have significant consequences on study and is not a very sensitive measure of abstinent for 28 days (Bolla et al., 2002). workplace performance and safety, academic cognitive decline, even though it specifically Furthermore, when dividing the group into achievement, and automotive safety. In tests memory and attention. Thus, small or light, middle, and heavy user groups, Bolla addition, adolescents may be particularly subtle effects of cannabis use on cognition or and colleagues (2002) found that the heavy vulnerable to the long-lasting deleterious psychomotor speed may have been missed. user group performed significantly below the effects of marijuana on cognition. The overall DHHS also discussed a study by Solowij light user group on 5 of 35 measures. A significant effect on general intelligence as and colleagues (2002) which examined the follow-up study of heavy marijuana users measured by IQ should also not be effects of duration of cannabis use on specific noted decision-making deficits after 25 days overlooked. areas of cognitive functioning among users of abstinence (Bolla et al., 2005). When IQ seeking treatment for cannabis dependence. was contrasted in adolescents 9–12 years of Behavioral Effects of Prenatal Exposure They compared 102 near-daily cannabis age and at 17–20 years of age, current heavy The impact of in utero marijuana exposure users (51 long-term users: mean, 23.9 years marijuana users showed a 4-point reduction on performance in a series of cognitive tasks of use; 51 shorter-term users: mean, 10.2 in IQ in later adolescence compared to those has been studied in children of various ages. years of use) with 33 nonuser controls. They who did not use marijuana (Fried et al., DHHS concludes in its analysis of the collected measures from nine standard 2002). presently examined petition that since many neuropsychological tests that assessed DHHS states that age of first use may be a marijuana users have abused other drugs, it attention, memory, and executive critical factor in persistent impairment from is difficult to determine the specific impact functioning, and that were administered chronic marijuana use. Individuals with a of marijuana on prenatal exposure. Fried and prior to entry to a treatment program and history of marijuana-only use that began Watkinson (1990) found that four year old following a median 17-hour abstinence. before the age of 16 were found to perform children of heavy marijuana users have Authors found that long-term cannabis users more poorly on a visual scanning task deficits in memory and verbal measures. performed significantly less well than measuring attention than individuals who Maternal marijuana use is predictive of shorter-term users and controls on tests of started using marijuana after 16 (Ehrenreich poorer performance on abstract/visual memory and attention. Long-term users et al., 1999). DHHS’s document noted that reasoning tasks of three year old children showed impaired learning, retention, and Kandel and Chen (2000) assert that the (Griffith et al., 1994) and an increase in retrieval compared with controls. Both user majority of early-onset marijuana users do omission errors on a vigilance task of six year groups performed poorly on a time not go on to become heavy users of olds (Fried et al., 1992). When the effect of estimation task. Performance measures often marijuana, and those that do tend to associate prenatal exposure in nine to 12 year old correlated significantly with the duration of with delinquent social groups. children is analyzed, in utero exposure to cannabis use, being worse with increasing DEA notes an additional recent study that marijuana is negatively associated with years of use, but were unrelated to indicates that because neuromaturation executive function tasks that require impulse withdrawal symptoms and persisted after continues through adolescence, results on the control, visual analysis, and hypothesis controlling for recent cannabis use and other long-lasting cognitive effects of marijuana use testing (Fried et al., 1998). drug use. Authors of this study state that in adults cannot necessarily generalize to DEA notes studies showing that D9-THC their results support the hypothesis that long- adolescent marijuana users. Medina and passes the placental barrier (Idanpaan- term heavy cannabis users show impairments colleagues (2007) examined Heikkila et al., 1969) and that fetal blood in memory and attention that endure beyond neuropsychological functioning in 31 concentrations are at least equal to those the period of intoxication and worsen with adolescent abstinent marijuana users, after a found in the mother’s blood (Grotenhermen, increasing years of regular cannabis use. period of abstinence from marijuana of 23 to 2003). DHHS cited a study by Messinis and 28 days, and in 34 demographically similar In summary, smoked marijuana exerts a colleagues (2006) which examined control adolescents, all 16–18 years of age. number of cardiovascular and respiratory neurophysiological functioning for heavy, After controlling for lifetime alcohol use and effects, both acutely and chronically. frequent cannabis users. The study compared depressive symptoms, adolescent marijuana Marijuana’s main psychoactive ingredient D9- 20 long-term (LT) and 20 shorter-term (ST) users demonstrated slower psychomotor THC alters immune function. The cognitive heavy, frequent cannabis users after speed (p .05), and poorer complex attention impairments caused by marijuana use that abstinence for at least 24 hours prior to (p .04), story memory (p .04), and planning persist beyond behaviorally detectable testing with 24 non-using controls. LT users and sequencing ability (p .001) compared intoxication may have significant performed significantly worse on verbal with nonusers. The number of lifetime consequences on workplace performance and memory and psychomotor speed. LT and ST marijuana use episodes was associated with safety, academic achievement, and users had a higher proportion of deficits on poorer cognitive function, even after automotive safety, and adolescents may be verbal fluency, verbal memory, attention and controlling for lifetime alcohol use. The particularly vulnerable to marijuana’s psychomotor speed. Authors conclude from general pattern of results suggested that, even cognitive effects. Prenatal exposure to their study that specific cognitive domains after a month of monitored abstinence, marijuana was linked to children’s poorer appear to deteriorate with increasing years of adolescent marijuana users demonstrate performance in a number of cognitive tests. heavy frequent cannabis use. subtle neuropsychological deficits compared DHHS discussed a study by Pope and with nonusers. The authors of this study FACTOR 3: THE STATE OF THE CURRENT colleagues (2003) which reported no suggest that frequent marijuana use during SCIENTIFIC KNOWLEDGE REGARDING differences in neuropsychological adolescence may negatively influence THE DRUG OR SUBSTANCE performance in early- or late-onset users neuromaturation and cognitive development. DHHS states that marijuana is a mixture of compared to non-using controls, after In summary, acute administration of the dried leaves and flowering tops of the adjustment for intelligence quotient (IQ). In marijuana impairs performance on tests of cannabis plant (Agurell et al., 1984; Graham,

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1976; Mechoulam, 1973). These portions of contaminate cannabis, and states that these To support its claim that marijuana has an the plant have the highest levels of D9-THC, contaminants have the potential to harm the accepted medical use in the United States, the primary psychoactive ingredient in user without harming the plant. Other the petitioner listed supporting evidence that marijuana. The most potent product (i.e., that sources of contaminants discussed by included the following: having the highest percentage of D9-THC) of McLaren and colleagues (2008) include • Evidence from clinical research and dried material is sinsemilla, derived from the growth enhancers and pest control products reviews of earlier clinical research (Exh. C, unpollinated flowering tops of the female related to marijuana cultivation and storage. Section I (4, 6), pg. 29) cannabis plant. Generally, this potent • Acceptance of the medical use of Human Pharmacokinetics marijuana product is associated with indoor marijuana by eight states since 1996 and state grow sites and may have a D9-THC content DHHS states that marijuana is generally officials in these states establishing that of 15 to 20 percent or more. Other, less smoked as a cigarette (weighing between 0.5 marijuana has an accepted medical use in the common forms of marijuana found on the and 1.0 gm; Jones, 1980) or in a pipe. It can United States (Exh. C, Section I (1), pg. 13) illicit market are hashish and hashish oil. also be taken orally in foods or as extracts of • Increased recognition by health care Hashish is a D9-THC-rich resinous material of plant material in ethanol or other solvents. professionals and the medical community, the cannabis plant which is dried and The absorption, metabolism, and including the Institute of Medicine (IOM) D9 compressed into a variety of forms (balls, pharmacokinetic profile of -THC (and other (Exh. C, Section I (2), pg. 15) cakes or sticks). Dried pieces are generally cannabinoids) in marijuana or other drug • Patients’ experience in which they D9 broken off and smoked. D9-THC content is products containing -THC vary with route reported benefits from smoking marijuana usually about five percent. The Middle East, of administration and formulation (Adams (Exh. C, Section I (3), pg. 22) North Africa and Pakistan/Afghanistan are and Martin, 1996; Agurell et al., 1984, 1986). • Evidence from clinical research (Exh. C, the main sources of hashish. Hashish oil is When marijuana is administered by smoking, Section I (4, 6), pg. 29) D9 produced by extracting the cannabinoids -THC in the form of an aerosol is absorbed DHHS states that a new drug application from plant material with a solvent. Hashish within seconds. The psychoactive effects of (NDA) for marijuana has not been submitted oil is a light to dark brown viscous liquid marijuana occur immediately following to the FDA for any indication and thus no with a D9-THC content of about 15 percent. absorption, with mental and behavioral medicinal product containing botanical effects measurable up for to six hours after The oil is often sprinkled on cigarettes, cannabis has been approved for marketing. absorption (Grotenhermen, 2003; Hollister, Only small clinical studies published in the allowed to dry, and then smoked. D9 1986, 1988). -THC is delivered to the brain current medical literature demonstrate that Chemistry rapidly and efficiently as would be expected research with marijuana is being conducted DHHS states that some 483 natural of a highly lipid-soluble drug. in humans in the United States under FDA- constituents have been identified in The petitioner provided a discussion of authorized investigational new drug (IND) marijuana, including 66 compounds that are new, or less common, routes and methods of applications. classified as cannabinoids (Ross and El administration being currently explored (pg. There are ongoing clinical studies of the Sohly, 1995). Cannabinoids are not known to 57, line 1). These include vaporization for the potential utility of marijuana in medical exist in plants other than marijuana, and inhalation route, as well as rectal, sublingual, applications. DHHS states that in 2000, the and transdermal routes. most naturally occurring cannabinoids have state of California established the Center for DEA notes that respiratory effects are only been identified chemically. The psychoactive Medicinal Cannabis Research (CMCR) which part of the harmful health effects of properties of cannabis are attributed to one has funded studies on the potential use of prolonged marijuana exposure, as described or two of the major cannabinoid substances, cannabinoids for the treatment of multiple further under factor 2 of this document. DEA namely delta-9- tetrahydrocannabinol (D9- sclerosis, neuropathic pain, appetite also notes that at this time, the majority of THC) and delta-8-tetrahydrocannabinol (D8- suppression and cachexia, and severe pain studies exploring the potential therapeutic THC). Other natural cannabinoids, such as and nausea related to cancer or its treatment uses of marijuana use smoked marijuana, and cannabidiol (CBD) and cannabinol (CBN), by chemotherapy. To date, though, no NDAs the pharmacokinetics and bioavailability have been characterized. CBD does not utilizing marijuana for these indications have from routes of administration other than D9 been submitted to the FDA. possess -THC-like psychoactivity. Its smoked and oral are not well-known. To establish accepted medical use, among pharmacological properties appear to include The pharmacokinetics of smoked and anticonvulsant, anxiolytic and sedative orally ingested marijuana are thoroughly other criteria, the effectiveness of a drug must properties (Agurell et al., 1984, 1986; reviewed in DHHS’s review document. be established in well-controlled scientific Hollister, 1986). studies performed in a large number of DHHS states that D9-THC is an optically Medical Utility patients. To date, such studies have not been active resinous substance, extremely lipid The petition filed by the Coalition to performed for marijuana. Small clinical trial soluble, and insoluble in water. Chemically, Reschedule Cannabis (Marijuana) aims to studies with limited patients and short D9 -THC is known as (6aR-trans)-6a,7,8,10a- repeal the rule placing marijuana in schedule duration such as those cited by the petitioner tetrahydro-6,6,9-trimethyl-3-pentyl-6H- I of the CSA, based in part on the proposition are not sufficient to establish medical utility. D9 dibenzo-[b,d]pyran-1-ol or (-) -(trans)- that marijuana has an accepted medical use Larger studies of longer duration are needed tetrahydrocannabinol. The pharmacological in the United States. However DHHS has to fully characterize the drug’s efficacy and activity of D9-THC is stereospecific: the (-)- concluded in its 2006 analysis that marijuana safety profile. Anecdotal reports, patients’ trans isomer is 6–100 times more potent than has no accepted medical use in treatment in self-reported effects, and isolated case reports the (+)-trans isomer (Dewey et al., 1984). the United States. Following is a discussion are not adequate evidence to support an DEA notes a review of the contaminants of the petitioner’s specific points and a accepted medical use of marijuana (57 FR and adulterants that can be found in presentation of DHHS’s evaluation and 10499, 1992). marijuana (McPartland, 2002). In particular, recommendation on the question of accepted In addition to demonstrating efficacy, DEA notes that many studies have reported medical use for marijuana. adequate safety studies must be performed to contamination of both illicit and NIDA- The petitioner states (pg. 48, line 2), show that the drug is safe for treating the grown marijuana with microbial ‘‘Results from clinical research demonstrated targeted disease. DHHS states that safety contaminants, bacterial or fungal (McLaren et that both dronabinol and whole plant studies for acute or subchronic al., 2008; McPartland, 1994, 2002; cannabis can offer a safe and effective administration of marijuana have been Ungerleider et al., 1982; Taylor et al., 1982; treatment for the following illnesses: muscle carried out through a limited number of Kurup et al., 1983). Other microbial spasm in multiple sclerosis, Tourette Phase 1 clinical investigations approved by contaminants include Klebsiella syndrome, chronic pain, nausea and the FDA, but there have been no NDA-quality pneumoniae, salmonella enteritidis, and vomiting in HIV/AIDS and cancer studies that have scientifically assessed the group D Streptococcus (Ungerlerder et al., chemotherapy, loss of appetite from cancer, efficacy and full safety profile of marijuana 1982; Kagen et al., 1983; Taylor et al., 1982). hyperactivity of the bladder in patients with for any medical condition. DEA notes that a review by McLaren and multiple sclerosis and spinal cord injury, and DEA further notes that a number of clinical colleagues (2008) discusses studies showing dyskinesia caused by levodopa in studies from CMCR have been discontinued. that heavy metals present in soil may also Parkinson’s disease.’’ Most of these discontinuations were due to

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recruitment difficulties (http:// 2. Scientific evidence of its trials that scientifically evaluate safety and www.cmcr.ucsd.edu/geninfo/research.htm pharmacological effect, if known; efficacy. (last retrieved 07/07/2010) (listing 6 3. The state of current scientific knowledge DHHS further states that it cannot discontinued studies, 5 of which were regarding the drug; conclude that marijuana has an acceptable discontinued because of recruitment issues)). 4. Its history and current pattern of abuse; level of safety without assurance of a The petitioner states that the 5. The scope, duration, and significance of consistent and predictable potency and pharmacological effects are well established abuse; without proof that the substance is free of for marijuana and D9-THC, using the 6. What, if any, risk there is to the public contamination. argument that Marinol (containing synthetic health; As discussed in Factors 1 and 2, current D9-THC, known generically as dronabinol) 7. The drug’s psychic or physiological data suggest that marijuana use produces and Cesamet (containing nabilone, a dependence liability; and adverse effects on the respiratory system, synthetic cannabinoid not found in 8. Whether the substance is an immediate memory and learning. Marijuana use is marijuana) are approved for several precursor of a substance already controlled associated with dependence and addiction. therapeutic indications. The approvals of under the CSA. In addition, large epidemiological studies Marinol and Cesamet were based on well- 21 U.S.C. 811(c). These factors embody indicate that marijuana use may exacerbate controlled clinical studies that established Congress’s view of the specialized agency symptoms in individuals with schizophrenia. the efficacy and safety of these drugs as a expertise required for drug rescheduling Therefore DHHS concludes that, even medicine. Smoked marijuana has not been decisions. The CSA’s statutory text thus under medical supervision, marijuana has demonstrated to be safe and effective in further evidences that Congress did not not been shown to have an accepted level of treating these medical conditions. Marijuana envision such a role for state law in safety. Furthermore, if marijuana is to be is a drug substance composed of numerous establishing the schedules of controlled investigated more widely for medical use, cannabinoids and other constituents; hence substances under the CSA. See Krumm v. information and data regarding the the safety and efficacy of marijuana cannot be Holder, 2009 WL 1563381, at *16 (D.N.M. chemistry, manufacturing, and specifications evaluated solely on the effects of D9-THC. 2009) (‘‘The CSA does not contemplate that of marijuana must be developed. state legislatures’ determinations about the Adequate and well-controlled studies must 3. There must be adequate and well- use of a controlled substance can be used to be performed with smoked marijuana to controlled studies proving efficacy establish efficacy and safety. DHHS states bypass the CSA’s rescheduling process.’’). that there is a lack of accepted safety for the The long-established factors applied by DHHS states that no studies have been use of marijuana under medical supervision. DEA for determining whether a drug has a conducted with marijuana showing efficacy The petitioner has not submitted any new ‘‘currently accepted medical use’’ under the for any indication in controlled, large scale, data meeting the requisite scientific CSA are: clinical trials. standards to support the claim that marijuana 1. The drug’s chemistry must be known To establish accepted medical use, the has an accepted medical use in the United and reproducible; effectiveness of a drug must be established in States. Hence, the new information provided 2. There must be adequate safety studies; well-controlled, well-designed, well- by the petitioner does not change the federal 3. There must be adequate and well- conducted, and well-documented scientific government’s evaluation of marijuana’s controlled studies proving efficacy; studies, including studies performed in a medical use in the United States. 4. The drug must be accepted by qualified large number of patients (57 FR 10499, 1992). • experts; and To date, such studies have not been Petitioner’s claim of acceptance of the performed. The small clinical trial studies medical use of marijuana by eight states since 5. The scientific evidence must be widely available. with limited patients and short duration are 1996 and state officials in these states not sufficient to establish medical utility. 57 FR 10,499, 10,506 (1992), ACT, 15 F.3d at establishing that marijuana has an accepted Studies of longer duration are needed to fully medical use in the United States 1135 (upholding these factors as valid criteria for determining ‘‘currently accepted medical characterize the drug’s efficacy and safety Petitioner argues that, ‘‘[t]he acceptance of profile. Scientific reliability must be cannabis’s medical use by eight states since use’’). A drug will be deemed to have a currently accepted medical use for CSA established in multiple clinical studies. 1996 and the experiences of patients, doctors, Furthermore, anecdotal reports and isolated and state officials in these states establish purposes only if all five of the foregoing elements are demonstrated. The following is case reports are not adequate evidence to marijuana’s accepted medical use in the support an accepted medical use of United States.’’ Petition at 10, 13. This a summary of information as it relates to each of these five elements. marijuana (57 FR 10499, 1992). The evidence argument is contrary to the CSA’s statutory from clinical research and reviews of earlier scheme. The CSA does not assign to the 1. The drug’s chemistry must be known and clinical research does not meet this standard. states the authority to make findings relevant reproducible As noted, DHHS states that a limited to CSA scheduling determinations. Rather, DHHS states that although the structures of number of Phase I investigations have been the CSA expressly delegates the task of many cannabinoids found in marijuana have conducted as approved by the FDA. Clinical making such findings—including whether a been characterized, a complete scientific trials, however, generally proceed in three substance has any currently accepted analysis of all the chemical components phases. See 21 C.F.R. 312.21 (2010). Phase I medical use in treatment in the United found in marijuana has not been conducted. trials encompass initial testing in human States—to the Attorney General. 21 U.S.C. DEA notes that in addition to changes due subjects, generally involving 20 to 80 811(a). The CSA also expressly tasks the to its own genetic plasticity, marijuana and patients. Id. They are designed primarily to Secretary of DHHS to provide a scientific and its chemistry have been throughout the ages, assess initial safety, tolerability, medical evaluation and scheduling and continue to be, modified by pharmacokinetics, pharmacodynamics, and recommendations to inform the Attorney environmental factors and human preliminary studies of potential therapeutic General’s findings. 21 U.S.C. 811(b); see also manipulation (Paris and Nahas, 1984). benefit. (62 FR 66113, 1997). Phase II and 21 C.F.R. 308.43. That Congress explicitly Phase III studies involve successively larger provided scheduling authority to these two 2. There must be adequate safety studies groups of patients: usually no more than federal entities in this comprehensive and DHHS states that safety studies for acute or several hundred subjects in Phase II and exclusive statutory scheme precludes the subchronic administration of marijuana have usually from several hundred to several argument that state legislative action can been carried out only through a limited thousand in Phase III. 21 C.F.R. 312.21. establish accepted medical use under the number of Phase 1 clinical investigations These studies are designed primarily to CSA. approved by the FDA. There have been no explore (Phase II) and to demonstrate or The CSA explicitly provides that in making NDA-quality studies that have scientifically confirm (Phase III) therapeutic efficacy and a scheduling determination, the Attorney assessed the safety profile of marijuana for benefit in patients. (62 FR 66113, 1997). No General shall consider the following eight any medical condition. DHHS also states that Phase II or Phase III studies of marijuana factors: at this time, the known risks of marijuana use have been conducted. Even in 2001, DHHS 1. The drug’s actual or relative potential for have not been shown to be outweighed by acknowledged that there is ‘‘suggestive abuse specific benefits in well-controlled clinical evidence that marijuana may have beneficial

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therapeutic effects in relieving spasticity medical use with severe restrictions.’’ 21 2005) show that a slight majority of medical associated with multiple sclerosis, as an U.S.C. 812(b)(2)(B)). Additionally, scientific doctors polled were opposed to the analgesic, as an antiemetic, as an appetite evidence as to the safety or efficacy of legalization of medical prescription of stimulant and as a bronchodilator.’’ (66 FR marijuana is not widely available. marijuana. This supports the finding that 20038, 2001). But there is still no data from • Petitioner’s claim of increased there is a material conflict of opinion among adequate and well-controlled clinical trials recognition by health care professionals and medical professionals. that meets the requisite standard to warrant the medical community, including the • Patients’ experience in which they rescheduling. Institute of Medicine (IOM) reported benefits from smoking marijuana DHHS states in a published guidance that The petitioner states (pg. 15 line 2), (Exh. C, Section I(3), pg. 22); it is committed to providing ‘‘research-grade ‘‘Cannabis’s accepted medical use in the Under the petition’s section C. I. 3., the marijuana for studies that are the most likely United States is increasingly recognized by petitioner proposes both anecdotal self- to yield usable, essential data’’ (DHHS, 1999). healthcare professionals and the medical reported effects by patients and clinical DHHS states that the opportunity for community, including the Institute of studies. The petitioner states (pg. 22, line 2), scientists to conduct clinical research with Medicine.’’ [. . .] an increasing number of patients have botanical marijuana has increased due to DHHS describes that in February 1997, a collected experience with cannabis. Many changes in the process for obtaining botanical National Institutes of Health (NIH)-sponsored marijuana from NIDA, the only legitimate workshop analyzed available scientific reported benefits from its use. Some of this source of the drug for research in the United evidence on the potential utility of experience has been confirmed in reports and States. It further states that in May 1999, marijuana. In March 1999, the Institute of clinical investigations or stimulated clinical DHHS provided guidance on the procedures Medicine (IOM) issued a detailed report on research that confirmed these patients’ for providing research-grade marijuana to the potential medical utility of marijuana. experience on other patients suffering from scientists who intend to study marijuana in Both reports concluded that there need to be the same disease. scientifically valid investigations and well- more and better studies to determine Anecdotal self-reported effects by patients controlled clinical trials (DHHS, 1999). potential medical applications of marijuana. are not adequate evidence for the The IOM report also recommended that determination of a drug’s accepted medical 4. The drug must be accepted by qualified clinical trials should be conducted with the use. DEA previously ruled in its final order experts goal of developing safe delivery systems denying the petition of the National A material conflict of opinion among (NIH, 1997; IOM, 1999). Organization for Reform of Marijuana Laws experts precludes a finding that marijuana DEA notes that in its recommendations, the (NORML) to reschedule marijuana from has been accepted by qualified experts (57 FR 1999 IOM report states, Schedule I to Schedule II of the Controlled 10499, 1992). DHHS states that, at this time, If there is any future for marijuana as a Substances Act (57 FR 10499, 1992) that, it is clear that there is not a consensus of medicine, it lies in its isolated components, Lay testimonials, impressions of physicians, medical opinion concerning medical the cannabinoids and their synthetic isolated case studies, random clinical applications of marijuana, even under derivatives. Isolated cannabinoids will experience, reports so lacking in details they conditions where its use is severely provide more reliable effects than crude plant cannot be scientifically evaluated, and all restricted. DHHS also concludes that, to date, mixtures. Therefore, the purpose of clinical other forms of anecdotal proof are entirely research on the medical use of marijuana has trials of smoked marijuana would not be to irrelevant. develop marijuana as a licensed drug but not progressed to the point that marijuana DEA further explained in the same ruling rather to serve as a first step toward the can be considered to have a ‘‘currently that, accepted medical use’’ or a ‘‘currently development of nonsmoked rapid-onset accepted medical use with severe cannabinoid delivery systems. Scientists call [stories by marijuana users restrictions.’’ Thus, while the IOM report did support who claim to have been helped by the drug] further research into therapeutic uses of anecdotes. They do not accept them as 5. The scientific evidence must be widely cannabinoids, the IOM report did not reliable proofs. The FDA’s regulations, for available ‘‘recognize marijuana’s accepted medical example, provide that in deciding whether a DHHS states that the scientific evidence use’’ but rather the potential therapeutic new drug is a safe and effective medicine, regarding the safety or efficacy of marijuana utility of cannabinoids. ‘‘isolated case reports will not be is typically available only in summarized DEA notes that the lists presented by the considered.’’ 21 CFR 314.126(e). Why do form, such as in a paper published in the petitioner (pg. 16–18) of ‘‘Organizations scientists consider stories from patients and medical literature, rather than in a raw data Supporting Access to Therapeutic Cannabis’’ their doctors to be unreliable? format. As such, there is no opportunity for (emphasis added) and ‘‘[Organizations First, sick people are not objective adequate scientific scrutiny of whether the Supporting] No Criminal Penalty’’ contain a scientific observers, especially when it comes data demonstrate safety or efficacy. majority of organizations that do not to their own health. [. . .] Second, most of Furthermore, as stated before, there have specifically represent medical professionals. the stories come from people who took only been a limited number of small clinical By contrast, the petitioner also provides a list marijuana at the same time they took trials and no controlled, large-scale clinical of ‘‘Organizations Supporting Research on prescription drugs for their symptoms. [. . .] trials have been conducted with marijuana the Therapeutic Use of Cannabis’’ (emphasis Third, any mind-altering drug that produces on its efficacy for any indications or its added), which does contain a majority of euphoria can make a sick person think he safety. organizations specifically representing feels better. [. . .] Fourth, long-time abusers In summary, from DHHS’s statements on medical professionals. of marijuana are not immune to illness. the five cited elements required to make a The petitioner discusses (pg. 20, line 11) [. . .] Thanks to scientific advances and to determination of ‘‘currently accepted medical the results of a United States survey the passage of the Federal Food, Drug and use’’ for marijuana, DEA has determined that presented at the annual meeting of the Cosmetic Act (FDCA) in 1906, 21 U.S.C. 301 none has been fulfilled. A complete scientific American Society of Addiction Medicine, et seq., we now rely on rigorous scientific analysis of all the chemical components and states that the study’s results, proof to assure the safety and effectiveness of found in marijuana is still missing. There has indicate that physicians are divided on the new drugs. Mere stories are not considered been no NDA-quality study that has assessed medical use of cannabis (Reuters of 23 April an acceptable way to judge whether the efficacy and full safety profile of 2001). Researchers at Rhode Island Hospital dangerous drugs should be used as marijuana for any medical use. At this time, in Providence asked 960 doctors about their medicines. it is clear that there is not a consensus of attitude towards the statement, ‘‘Doctors Thus, patients’ anecdotal experiences with medical opinion concerning medical should be able to legally prescribe marijuana marijuana are not adequate evidence when applications of marijuana. To date, research as medical therapy.’’ 36 percent of the evaluating whether marijuana has a currently on the medical use of marijuana has not responders agreed, 38 percent disagreed and accepted medical use. progressed to the point that marijuana can be 26 percent were neutral. In summary, marijuana contains some 483 considered to have a ‘‘currently accepted DEA notes that the results of the study, natural constituents and exists in several medical use’’ or even a ‘‘currently accepted later published in full (Charuvastra et al., forms, including dried leaves and flowering

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tops, hashish and hashish oil. It is generally eighth graders, 33.4 percent of tenth graders, States, and it is used by a large percentage smoked as a cigarette. Research with and 43.8 percent of twelfth graders reported of American high-schoolers. Marijuana is the marijuana is being conducted in humans in lifetime use (i.e., any use in their lifetime) of most frequently identified drug in state, local the United States under FDA-authorized IND marijuana. In addition, 13.7, 27.5 and 34.8 and federal forensic laboratories, with applications, and using marijuana cigarettes percent of eighth, tenth and twelfth graders, increasing amounts both of domestically provided by NIDA. Adequate studies have respectively, reported using marijuana in the grown and of illicitly smuggled marijuana. not been published to support the safety and past year. A number of high-schoolers An observed increase in the potency of efficacy of marijuana as a medicine. No NDA reported daily use in the past month, seized marijuana also raises concerns. for marijuana has been submitted to the FDA including 1.2, 3.3 and 6.1 percent of eighth, FACTOR 5: THE SCOPE, DURATION, AND for any indication and thus no medicinal tenth and twelfth graders, respectively. SIGNIFICANCE OF ABUSE product containing botanical cannabis has The prevalence of marijuana use and abuse been approved for marketing. DEA notes that is also indicated by criminal investigations Abuse of marijuana is widespread and state laws do not establish a currently for which drug evidences were analyzed in significant. DHHS presented data from the accepted medical use under federal law. DEA and state laboratories. The National NSDUH, and DEA has updated this Furthermore, DEA previously ruled that Forensic Laboratory System (NFLIS), which information. As previously noted, according anecdotal self-reported effects by patients are compiles information on exhibits analyzed in to the NSDUH, in 2009, an estimated 104.4 not adequate evidence of a currently state and local law enforcement laboratories, million Americans age 12 or older had used accepted medical use under federal law. A showed that marijuana was the most marijuana or hashish in their lifetime, 28.5 material conflict of opinion among experts frequently identified drug from January 2001 million had used it in the past year, and 16.7 precludes a finding that marijuana has been through December 2010: In 2010, marijuana million (6.6 percent) had used it in the past accepted by qualified experts. At present, accounted for 36.3 percent (464,059) of all month. In 2008, an estimated 15.0 percent of there is no consensus of medical opinion drug exhibits in NFLIS. Similar findings were past year marijuana users aged 12 or older concerning medical applications of reported by the System to Retrieve used marijuana on 300 or more days within the past 12 months. This translates into 3.9 marijuana. In short, the limited number of Information from Drug Evidence (STRIDE), a million persons using marijuana on a daily clinical trials involving marijuana that have DEA database which compiles information or almost daily basis over a 12-month period. been conducted to date—none of which have on exhibits analyzed in DEA laboratories, for In 2008, an estimated 35.7 percent (5.4 progressed beyond phase 1 of the three the same reporting period. From January 2001 through December 2010, marijuana was million) of past month marijuana users aged phases needed to demonstrate safety and 12 or older used the drug on 20 or more days the most frequently identified drug. In 2010, efficacy for purposes of FDA approval—fails in the past month (SAMHSA, NSDUH and there were 11,293 marijuana exhibits by a large measure to provide a basis for any TEDS). Chronic use of marijuana is associated with 7,158 law enforcement cases alteration of the prior conclusions made by associated with a number of health risks (see representing 16.7 percent of all exhibits in HHS and DEA (in 1992 and in 2001) that Factors 2 and 6). STRIDE. marijuana has no currently accepted medical Marijuana’s widespread availability is The high consumption of marijuana is use in treatment in the United States. being fueled by increasing marijuana being fueled by increasing amounts of production domestically and increased illicit FACTOR 4: ITS HISTORY AND CURRENT domestically grown marijuana as well as PATTERN OF ABUSE importation from Mexico and Canada. increased amounts of foreign source Domestically both indoor and outdoor grow Marijuana use has been relatively stable marijuana being illicitly smuggled into the sites have been encountered. In 2009, nearly from 2002 to 2009, and it continues to be the United States. In 2009, the Domestic 10 million marijuana plants were seized from most widely used illicit drug. According to Cannabis Eradication and Suppression outdoor grow sites and over 410,000 were the NSDUH, there were 2.4 million new users Program (DCE/SP) reported that 9,980,038 seized from indoor sites for a total of over 10 (6,000 initiates per day) in 2009 and 16.7 plants were eradicated in outdoor cannabis million plants in 2009 compared to about 2.8 million current (past month) users of cultivation areas in the United States. Major million plants in 2000 (Domestic Cannabis marijuana aged 12 and older. Past month use domestic outdoor cannabis cultivation areas Eradication/Suppression Program). An of marijuana was statistically significantly were found in California, Kentucky, increasing percentage of the available higher in 2009 (16.7 million) than in 2008 Tennessee and Hawaii. Significant quantities marijuana being trafficked in the United (15.2 million), according to NSDUH. An of marijuana were also eradicated from States is higher potency marijuana derived estimated 104.4 million Americans age 12 or indoor cultivation operations. There were from the indoor, closely controlled older had used marijuana or hashish in their 414,604 indoor plants eradicated in 2009 cultivation of marijuana plants in both the lifetime and 28.5 million had used it in the compared to 217,105 eradicated in 2000. US and Canada (Domestic Cannabis past year. In 2008, most (62.2 percent) of the Most foreign-source marijuana smuggled into Eradication/Suppression Program) and the 2.2 million new users were less than 18 years the United States enters through or between average percentage of D9-THC in seized of age. In 2008, marijuana was used by 75.7 points of entry at the United States-Mexico marijuana increased almost two-fold from percent of current illicit drug users and was border. However, drug seizure data show that 2000 to 2008 (The University of Mississippi the only drug used by 57.3 percent of these the amount of marijuana smuggled into the Potency Monitoring Project). Additional users. In 2008, among past year marijuana United States from Canada via the United studies are needed to clarify the impact of users aged 12 or older, 15.0 percent used States-Canada border has risen to a greater potency, but DEA notes one study marijuana on 300 or more days within the significant level. In 2009, the Federal-wide showing that higher levels of D9-THC in the previous 12 months. This translates into 3.9 Drug Seizure System (FDSS) reported body are associated with greater psychoactive million people using marijuana on a daily or seizures of 1,910,600 kg of marijuana. effects (Harder and Rietbrock, 1997), which almost daily basis over a 12-month period. In While most of the marijuana available in can be correlated with higher abuse potential 2008, among past month marijuana users, the domestic drug markets is lower potency (Chait and Burke, 1994). 35.7 percent (5.4 million) used the drug on commercial-grade marijuana, usually derived Data from TEDS show that in 2008, 17.2 20 or more days in the past month. from outdoor cannabis grow sites in Mexico percent of all admissions were for primary Marijuana is also the illicit drug with the and the United States, an increasing marijuana abuse. In 2007, more than half of highest rate of past year dependence or percentage of the available marijuana is high the drug-related treatment admissions abuse. According to the 2009 NSDUH report, potency marijuana derived from indoor, involving individuals under the age of 15 4.3 million persons were classified with closely controlled cannabis cultivation in (60.8 percent) and more than half of the drug- marijuana dependence or abuse based on Canada and the United States. The rising related treatment admissions involving criteria specified in the Diagnostic and prevalence of high potency marijuana is individuals 15 to 19 years of age (55.9 Statistical Manual of Mental Disorders, 4th evidenced by a nearly two-fold increase in percent), were for primary marijuana abuse. edition (DSM–IV). average potency of tested marijuana samples, In 2007, among the marijuana/hashish According to the 2010 Monitoring the from 4.87 percent D9-THC in 2000 to 8.49 admissions (286,194), 25.1 percent began Future (MTF) survey, marijuana is used by a percent D9-THC in 2008. using marijuana at age 12 or younger. large percentage of American youths. Among In summary, marijuana is the most In summary, the recent statistics from these students surveyed in 2010, 17.3 percent of commonly used illegal drug in the United various surveys and databases show that

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marijuana continues to be the most et al., 1992). DHHS also describes studies DEA also notes a study by Bedard and commonly used illicit drug, with significant showing that administration to human colleagues (2007), which used a cross- rates of heavy use and dependence in volunteers of D9-THC in a smoked marijuana sectional, case-control design with drivers teenagers and adults. cigarette produced impaired perceptual aged 20–49 who were involved in a fatal The petitioner states, ‘‘The use and abuse motor speed and accuracy, two skills that are crash in the United States from 1993 to 2003. of cannabis has been widespread in the critical to driving ability (Kurzthaler et al., Drivers were included if they had been tested United States since national drug use surveys 1999) and produced increases in for the presence of cannabis and had a began in the 1970s. A considerable number disequilibrium measures, as well as in the confirmed blood alcohol concentration of of cannabis users suffer from problems that latency in a task of simulated vehicle zero. Cases were drivers who had at least one meet the criteria for abuse. However, the braking, at a rate comparable to an increase potentially unsafe driving action recorded in large majority of cannabis users do not in stopping distance of 5 feet at 60 mph relation to the crash (e.g., speeding); controls experience any relevant problems related to (Liguori et al., 1998). were drivers who had no such driving action their use.’’ (pg. 4, line 31). The petitioner states that (pg., 65, line 10), recorded. Authors calculated the crude and Petitioner acknowledges that a ‘‘Although the ability to perform complex adjusted odds ratios (ORs) of any potentially considerable number of cannabis users suffer cognitive operations is assumed to be unsafe driving action in drivers who tested from problems that meet the criteria for impaired following acute marijuana smoking, positive for cannabis but negative for alcohol abuse. DEA provides data under this Factor, complex cognitive performance after acute consumption. Five percent of drivers tested as well as Factors 1, 2, and 7, that support marijuana use has not been adequately positive for cannabis. The crude OR of a this undisputed issue. Briefly, current data assessed under experimental conditions.’’ As potentially unsafe action was 1.39 (99 suggest that marijuana use produces adverse described above, DHHS presents evidence of percent CI = 1.21–1.59) for drivers who tested effects on the respiratory system, memory marijuana’s acute effects on complex positive for cannabis. Even after controlling and learning. Marijuana use is associated cognitive tasks. for age, sex, and prior driving record, the with dependence and addiction. In addition, DHHS states that dysphoria and presence of cannabis remained associated large epidemiological studies indicate that psychological distress, including prolonged with a higher risk of a potentially unsafe marijuana use may exacerbate symptoms in anxiety reactions, are potential responses in driving action (1.29, 99 percent CI = 1.11– individuals with schizophrenia, and may a minority of individuals who use marijuana 1.50). Authors of the study concluded that precipitate schizophrenic disorders in those (Haney et al., 1999). DEA notes reviews of cannabis had a negative effect on driving, as individuals who are vulnerable to developing studies describing that some users report predicted from various human performance psychosis. unpleasant psychological reactions. Acute studies. anxiety reactions to cannabis may include In 2001, estimates derived from the United FACTOR 6: WHAT, IF ANY, RISK THERE IS restlessness, depersonalization, derealization, States Census Bureau and Monitoring the TO THE PUBLIC HEALTH sense of loss of control, fear of dying, panic Future show that approximately 600,000 of The risk marijuana poses to the public and paranoid ideas (see reviews by Thomas, the nearly 4 million United States high- health may manifest itself in many ways. 1993 and Weil, 1970). school seniors drive under the influence of Marijuana use may affect the physical and/ DEA notes a review of studies showing that marijuana. Approximately 38,000 seniors or psychological functioning of an individual the general depressant effect of moderate to reported that they had crashed while driving user, but may also have broader public high doses of cannabis might contribute to under the influence of marijuana in 2001 impacts, for example, from a marijuana- slowed reaction times, inability to maintain (MTF, 2001). impaired driver. The impacts of marijuana concentration and lapses in attention (see DEA further notes studies suggesting that abuse and dependence are more disruptive review by Chait and Pierri, 1992). The review marijuana can affect the performance of for an abuser, but also for the abuser’s family, suggests that fine motor control and manual pilots. Yeswavage and colleagues (1985) friends, work environment, and society in dexterity are generally adversely affected evaluated the acute and delayed effects of general. Data regarding marijuana health although simple reaction time may or may smoking one marijuana cigarette containing risks are available from many sources, not be. DEA also notes studies showing that 1.9 percent D9-THC (19 mg of D9-THC) on the including forensic laboratory analyses, crime choice or complex reaction time is more performance of aircraft pilots. Ten subjects laboratories, medical examiners, poison likely to be affected, with reaction time were trained in a flight simulator prior to control centers, substance abuse treatment consistently increasing with the difficulty of marijuana exposure. Flight simulator centers, and the scientific and medical the task (e.g., Block and Wittenborn, 1985). performance was measured by the number of literature. Risks have been associated with DEA also notes additional studies showing aileron (lateral control) and elevator (vertical both acute and chronic marijuana use, marijuana use interferes with the ability to control) and throttle changes, the size of including risks for the cardiovascular and operate motor vehicles. Studies show that these control changes, the distance off the respiratory systems, as well as risks for marijuana use can cause impairment in center of the runaway on landing, and the mental health and cognitive function and driving (Robbe and O’Hanlon, 1999). The average lateral and vertical deviation from an risks related to prenatal exposure to National Highway Traffic Safety ideal glideslope and center line over the final marijuana. The risks of marijuana use and Administration (NHTSA) conducted a study mile of the approach. Compared to the abuse have previously been discussed in with the Institute for Human baseline performance, significant differences terms of the scientific evidence of its Psychopharmacology at Maastricht occurred at 4 hours. Most importantly, at 24 pharmacological effects on physical systems University in the Netherlands (Robbe and hours after a single marijuana cigarette, there under Factor 2. Below, some of the risks of O’Hanlon, 1999) to evaluate the effects of low were significant impairments in the number marijuana use and abuse are discussed in and high doses of smoked D9-THC alone and and size of aileron changes, size of elevator broader terms of the effects on the individual in combination with alcohol on the following changes, distance off-center on landing, and user and the public from acute and chronic tests: 1) the Road Tracking Test, which vertical and lateral deviations on approach to use of the drug. measures the driver’s ability to maintain a landing. Interestingly, despite these constant speed of 62 mph and a steady lateral performance deficits, the pilots reported no Risks Associated with Acute Use of position between the boundaries of the right significant subjective awareness of their Marijuana traffic lane; and 2) the Car Following Test, impairments at 24 hours. DHHS states that acute use of marijuana which measures a driver’s reaction times and DEA notes a review of the contaminants impairs psychomotor performance, including ability to maintain distance between vehicles and adulterants that can be found in performance of complex tasks, which makes while driving 164 ft behind a vehicle that marijuana (McPartland, 2002). In particular, it inadvisable to operate motor vehicles or executes a series of alternating accelerations DEA notes that many studies have reported heavy equipment after using marijuana and decelerations. Mild to moderate contamination of both illicit and NIDA- (Ramaekers et al., 2004). DHHS further impairment of driving was observed in the grown marijuana with microbial describes a study showing that acute subjects after treatment with marijuana. The contaminants, bacterial or fungal (McLaren et administration of smoked marijuana impairs study found that marijuana in combination al., 2008; McPartland, 1994, 2002; performance on tests of learning, associative with alcohol had an additive effect resulting Ungerleider et al., 1982; Taylor et al., 1982; processes, and psychomotor behavior (Block in severe driving impairment. Kurup et al., 1983). In a study by Kagen and

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colleagues (1983), fungi was found in 13 of use very potent cannabis throughout the day discussed a 25-year study of 1,256 New the 14 samples, and evidence of exposure to over a period of months or years, and they Zealand children, Fergusson et al. (2005), Aspergillus fungi was found in the majority may spend several hours a day acquiring and which concluded that the use of marijuana of marijuana smokers (13 of 23), but only one using the substance. This often interferes correlates to an increased risk of abuse of of the 10 control participants. Aspergillus with family, school, work, or recreational other drugs. Other studies, however, do not can cause aspergillosis, a fatal lung disease activities. Individuals with Cannabis support a direct causal relationship between and DEA notes studies suggesting an Dependence may also persist in their use regular marijuana use and other illicit drug association between this disease and despite knowledge of physical problems (e.g., abuse. DHHS cited the IOM report (1999), cannabis smoking among patients with chronic cough related to smoking) or which states that marijuana is a ‘‘gateway compromised immune systems (reviewed in psychological problems (e.g., excessive drug’’ in the sense that its use typically McLaren et al., 2008). Other microbial sedation and a decrease in goal-oriented precedes rather than follows initiation of contaminants include bacteria such as activities resulting from repeated use of high other illicit drug use. However, as cited by Klebsiella pneumoniae, salmonella doses). DHHS, the IOM states that, ‘‘[t]here is no enteritidis, and group D Streptococcus In addition, DHHS states that marijuana conclusive evidence that the drug effects of (Ungerlerder et al., 1982; Kagen et al., 1983; use produces acute and chronic adverse marijuana are causally linked to the Taylor et al., 1982). DEA notes reports that effects on the respiratory system, memory subsequent abuse of other illicit drugs.’’ Salmonella outbreaks have been linked to and learning. Regular marijuana smoking DHHS noted that for most studies that test marijuana (Taylor et al., 1982, CDC, 1981). produces a number of long-term pulmonary the hypothesis that marijuana causes abuse of Risks Associated with Chronic Use of consequences, including chronic cough and harder drugs, the determinative measure for Marijuana sputum (Adams and Martin, 1996), and testing this hypothesis is whether marijuana histopathologic abnormalities in bronchial leads to ‘‘any drug use’’ rather than that DHHS states that chronic exposure to epithelium (Adams and Martin, 1996). DEA marijuana leads to ‘‘drug abuse and marijuana smoke is considered to be also notes studies suggesting marijuana use dependence’’ as defined by DSM–IV criteria. comparable to tobacco smoke with respect to leads to evidence of widespread airway increased risk of cancer and lung damage. inflammation and injury (Roth et al., 1998, FACTOR 7: ITS PSYCHIC OR DEA notes studies showing that marijuana Fligiel et al., 1997) and PHYSIOLOGICAL DEPENDENCE LIABILITY smoke contains several of the same immunohistochemical evidence of DHHS states that many medications that carcinogens and co-carcinogens as tobacco dysregulated growth of respiratory epithelial are not associated with abuse or addiction, smoke and suggesting that pre-cancerous cells that may be precursors to lung cancer such as antidepressants, beta-blockers, and lesions in bronchial epithelium also seem to (Baldwin et al., 1997). In addition, very large centrally acting antihypertensive drugs, can be caused by long-term marijuana smoking epidemiological studies indicate that produce physical dependence and (Roth et al., 1998). DEA also notes the marijuana may increase risk of psychosis in withdrawal symptoms after chronic use. publication of a recent case-control study of vulnerable populations, i.e., individuals However, psychological and physical lung cancer in adults (Aldington et al., 2008), predisposed to develop psychosis dependence of drugs that have abuse in which users reporting over 10.5 joint-years (Andreasson et al., 1987) and exacerbate potential are important factors contributing of exposure had a significantly increased risk psychotic symptoms in individuals with to increased or continued drug taking. This of developing lung cancer, leading the schizophrenia (Schiffman et al., 2005; Hall et section provides scientific evidence that study’s authors to conclude that long-term al., 2004; Mathers and Ghodse, 1992; marijuana causes physical and psychological cannabis use increases the risk of lung cancer Thornicroft, 1990; see Factor 2). dependence. in young adults. In addition, a distinctive The petitioner cited ‘‘The Missoula marijuana withdrawal syndrome has been Chronic Clinical Cannabis Use Study’’ as Physiological (Physical) Dependence in identified, indicating that marijuana evidence that long-term use of marijuana Humans produces physical dependence (Budney et does not cause significant harm in patients Physical dependence is a state of al., 2004), as described in Factor 7. (Russo et al., 2002). DEA notes that this adaptation manifested by a drug class- DHHS further quotes the Diagnostic and article describes the case histories and specific withdrawal syndrome produced by Statistical Manual (DSM–IV–TR, 2000) of the clinical examination of only four patients abrupt cessation, rapid dose reduction, American Psychiatric Association, which that were receiving marijuana cigarettes from decreasing blood level of the drug, and/or states that the consequences of cannabis the National Institute on Drug Abuse for a administration of an antagonist (American abuse are as follows: variety of medical conditions. The number of Academy of Pain Medicine, American Pain [P]eriodic cannabis use and intoxication patients included in the study is not Society and American Society of Addiction can interfere with performance at work or adequate for this evaluation. Medicine consensus document, 2001). school and may be physically hazardous in The petitioner states, ‘‘Studies have shown DHHS states that long-term, regular use of situations such as driving a car. Legal the long-term use of cannabis to be safe. In marijuana can lead to physical dependence problems may occur as a consequence of contrast to many other medicinal drugs, the and withdrawal following discontinuation as arrests for cannabis possession. There may be long-term use of cannabis does not harm well as psychic addiction or dependence. arguments with spouses or parents over the stomach, liver, kidneys and heart.’’ (Exh. C, The marijuana withdrawal syndrome consists possession of cannabis in the home or its use Section II (10), pg. 66). of symptoms such as restlessness, irritability, in the presence of children. When However, DHHS states that marijuana has mild agitation, insomnia, EEG disturbances, psychological or physical problems are not been shown to have an accepted level of nausea, cramping and decrease in mood and associated with cannabis in the context of safety for medical use. There have been no appetite that may resolve after 4 days, and compulsive use, a diagnosis of Cannabis NDA-quality studies that have scientifically may require in-hospital treatment (Haney et Dependence, rather than Cannabis Abuse, assessed the full safety profile of marijuana al., 1999). It is distinct and mild compared should be considered. for any medical condition. DEA notes in to the withdrawal syndromes associated with Individuals with Cannabis Dependence addition, as described above, the risks alcohol and heroin use (Budney et al., 1999; have compulsive use and associated associated with chronic marijuana use, Haney et al., 1999). DEA notes that Budney problems. Tolerance to most of the effects of including, as described in Factor 2, risks for et al. (1999) examined the withdrawal cannabis has been reported in individuals the cardiovascular and respiratory systems, symptomatology in 54 chronic marijuana who use cannabis chronically. There have as well as risks for mental health and abusers seeking treatment for their also been some reports of withdrawal cognitive function and risks related to dependence. The majority of the subjects (85 symptoms, but their clinical significance is prenatal exposure to marijuana. percent) reported that they had experienced uncertain. There is some evidence that a symptoms of at least moderate severity. Fifty majority of chronic users of cannabinoids Marijuana as a ‘‘Gateway Drug’’ seven percent (57 percent) reported having report histories of tolerance or withdrawal A number of studies have examined the six or more symptoms of a least moderate and that these individuals evidence more widely held premise that marijuana use leads severity while 47 percent experienced four or severe drug-related problems overall. to subsequent abuse of other illicit drugs, more symptoms rated as severe. The most Individuals with Cannabis Dependence may thus functioning as a ‘‘gateway drug.’’ DHHS reported mood symptoms associated with the

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withdrawal were irritability, nervousness, 3. Unsuccessful efforts to cut down or individuals in the United States (6.6 percent depression, and anger. Some of the other control cannabis use: Persistent desire or of the United States population) used behavioral characteristics of the marijuana unsuccessful efforts to cut down or control marijuana monthly in 2009. A 2009 national withdrawal syndrome were craving, cannabis use. survey that tracks drug use trends among restlessness, sleep disruptions, strange 4. Great deal of time spent in using high school students showed that by 12th dreams, changes in appetite, and violent cannabis, or recovering from hangovers. grade, 32.8 percent of students reported outbursts. 5. Cannabis caused reduction in social, having used marijuana in the past year, 20.6 DHHS discusses a study by Lane and occupational or recreational activities: percent reported using it in the past month, Phillips-Bute (1998) which describes milder Important social, occupational, or and 5.2 percent reported having used it daily cases of dependence including symptoms recreational activities given up or reduced in the past month. Its widespread availability that are comparable to those from caffeine because of cannabis use. is being fueled by increasing marijuana withdrawal, including decreased vigor, 6. Continued using cannabis despite production domestically and increased increased fatigue, sleepiness, headache, and knowing it caused significant problems: trafficking from Mexico and Canada. reduced ability to work. The marijuana Cannabis use is continued despite knowledge Marijuana has dose-dependent reinforcing withdrawal syndrome has been reported in of having a persistent or recurrent physical effects that encourage its abuse. Both clinical adolescents who were admitted for substance or psychological problem that is likely to and preclinical studies have clearly abuse treatment or in individuals who had have been worsened by cannabis. demonstrated that marijuana and its been given marijuana on a daily basis during In addition, the DSM–IV added a specifier principle psychoactive constituent, D9-THC, research conditions. Withdrawal symptoms to this diagnostic by which it can be with or possess the pharmacological attributes can also be induced in animals following without physiological (physical) dependence. associated with drugs of abuse. They administration of a cannabinoid antagonist DEA notes additional clinical studies function as discriminative stimuli and as D9 after chronic -THC administration showing that frequency of D9-THC use (most positive reinforcers to maintain drug use and (Maldonado, 2002; Breivogel et al., 2003). often as marijuana) escalates over time. drug-seeking behavior. DHHS also discusses a study comparing Individuals increase the number, doses, and Significant numbers of chronic users of marijuana and tobacco withdrawal symptoms potency of marijuana cigarettes. Several marijuana seek substance abuse treatment. in humans (Vandrey et al., 2005) which studies have reported that patterns of Compared to all other specific drugs demonstrated that the magnitude and time marijuana smoking and increased quantity of included in the 2008 NSDUH survey, course of the two withdrawal syndromes are marijuana smoked were related to social marijuana had the highest levels of past year similar. context and drug availability (Kelly et al., dependence and abuse. DHHS states that a review by Budney and 1994; Mendelson and Mello, 1984; Mello, colleagues (2004) of studies of cannabinoid 1989). 2. Marijuana has no currently accepted withdrawal, with a particular emphasis on DEA further notes that Budney et al. (1999) medical use in treatment in the United States human studies, led to the recommendation reported that 93 percent of marijuana- DHHS states that the FDA has not that the Diagnostic and Statistical Manual of dependent adults seeking treatment reported evaluated nor approved an NDA for Mental Disorders (DSM) introduce a listing experiencing mild craving for marijuana, and marijuana. The long-established factors for cannabis withdrawal. In this listing, 44 percent rated their past craving as severe. applied by DEA for determining whether a common symptoms would include anger or Craving for marijuana has also been drug has a ‘‘currently accepted medical use’’ aggression, decreased appetite or weight loss, documented in marijuana users not seeking under the CSA are as follows. A drug will be irritability, nervousness/anxiety, restlessness treatment (Heishman et al., 2001). Two deemed to have a currently accepted medical and sleep difficulties including strange hundred seventeen marijuana users use for CSA purposes only if all of the dreams. Less common symptoms/equivocal completed a 47-item Marijuana Craving following five elements have been satisfied. symptoms would include chills, depressed Questionnaire and forms assessing As set forth below, none of these elements mood, stomach pain, shakiness and sweating. demographics, drug use history, marijuana- has been fulfilled: Psychological Dependence in Humans quit attempts and current mood. The results indicate that craving for marijuana was i. The drug’s chemistry must be known and In addition to physical dependence, DHHS characterized by 1) the inability to control reproducible states that long-term, regular use of marijuana marijuana use (compulsivity); 2) the use of Although the structures of many can lead to psychic addiction or dependence. marijuana in anticipation of relief from cannabinoids found in marijuana have been Psychological dependence on marijuana is withdrawal or negative mood (emotionality); characterized, a complete scientific analysis defined by the American Psychiatric 3) anticipation of positive outcomes from of all the chemical components found in Association in the DSM–IV and cited by smoking marijuana (expectancy); and 4) marijuana has not been conducted. DHHS. intention and planning to use marijuana for Furthermore, many variants of the marijuana The Diagnostic and Statistical Manual of positive outcomes (purposefulness). plant are found due to its own genetic Mental Disorders (DSM–IV) is published by In summary, long-term, regular use of plasticity and human manipulation. the American Psychiatric Association (2000), marijuana can lead to physical dependence and provides diagnostic criteria to improve ii. There must be adequate safety studies and withdrawal following discontinuation as the reliability of diagnostic judgment of well as psychic addiction or dependence. Safety studies for acute or sub-chronic mental disorders by mental health administration of marijuana have been professionals. DSM–IV currently defines FACTOR 8: WHETHER THE SUBSTANCE IS carried out through a limited number of ‘‘Cannabis Dependence’’ (DSM–IV diagnostic AN IMMEDIATE PRECURSOR OF A Phase I clinical investigations approved by category 304.30) as follows: SUBSTANCE ALREADY CONTROLLED the FDA, but there have been no NDA-quality Cannabis dependence: A destructive UNDER THE CSA studies that have scientifically assessed the pattern of cannabis use, leading to clinically Marijuana is not an immediate precursor of full safety profile of marijuana for any significant impairment or distress, as any controlled substance. medical condition. Large, controlled studies manifested by three (or more) of the have not been conducted to evaluate the risk- following, occurring when the cannabis use DETERMINATION benefit ratio of marijuana use, and any was at its worst: After consideration of the eight factors potential benefits attributed to marijuana use 1. Cannabis tolerance, as defined by either discussed above and of DHHS’s currently do not outweigh the known risks. of the following: recommendation, DEA finds that marijuana iii. There must be adequate and well- a. A need for markedly increased amounts meets the three criteria for placing a of cannabis to achieve intoxication, substance in Schedule I of the CSA under 21 controlled studies proving efficacy b. Markedly diminished effect with U.S.C. 812(b)(1): DHHS states that there have been no NDA- continued use of the same amount of quality studies that have scientifically cannabis. 1. Marijuana has a high potential for abuse assessed the efficacy of marijuana for any 2. Greater use of cannabis than intended: Marijuana is the most highly abused and medical condition. To establish accepted Cannabis was often taken in larger amounts trafficked illicit substance in the United medical use, the effectiveness of a drug must or over a longer period than was intended. States. Approximately 16.7 million be established in well-controlled, well-

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designed, well-conducted, and well- REFERENCES Pharmacology and Therapeutics. 18(3): documented scientific studies, including Abrams, D.I., Hilton, J.F., Leiser, R.J., Shade, 287–97, studies performed in a large number of S.B., Elbeik, T.A., Aweeka, F.T., Benowitz, N.L. and Jones, R T. (1981). patients. To date, such studies have not been Benowitz, N.L., Bredt, B.M., Kosel, B., Cardiovascular and metabolic performed for any indications. Aberg, J.A., Deeks, S.G., Mitchell, T.F., considerations in prolonged cannabinoid administration in man. Journal of Clinical Small clinical trial studies with limited Mulligan, K., Bacchetti, P., McCune, J.M., and Schambelan, M. (2003). Short- Pharmacology. 21 (8–9 Supp): 214S–223S. patients and short duration are not sufficient Block, R.I. and Wittenborn, J.R. (1985). to establish medical utility. Studies of longer term effects of cannabinoids in patients with HIV–1 infection: a randomized, Marijuana effects on associative processes. duration are needed to fully characterize the Psychopharmacology (Berl). 85(4):426–430. placebo-controlled clinical trial. Annals drug’s efficacy and safety profile. Scientific Block, R.I., Farinpour, R., and Braverman, K. of Internal Medicine. 139(4):258–266. reliability must be established in multiple (1992). Acute effects of marijuana on Adams, I.B. and Martin, B.R. (1996). clinical studies. Anecdotal reports and cognition: relationships to chronic effects Cannabis: Pharmacology and toxicology in isolated case reports are not sufficient and smoking techniques. Pharmacology, animals and humans. Addiction. 91:1585– evidence to support an accepted medical use Biochemistry and Behavior. 43(3):907–917. 1614. of marijuana. The evidence from clinical Block, R.I., Farinpour, R., and Schlechte, J.A. Agurell, S., Dewey, W., and Willett, R.E., eds. research and reviews of earlier clinical (1991). Effects of chronic marijuana use on (1984). The Cannabinoids: Chemical, research does not meet the requisite testosterone, luteinizing hormone, follicle standards. Pharmacologic, and Therapeutic Aspects. stimulating hormone, prolactin and New York: Academic Press. cortisol in men and women. Drug and iv. The drug must be accepted by qualified Agurell, S., Halldin, M., Lindgren, J.E., Alcohol Dependence. 28(2):121–128. experts Ohlsson, A., Widman, M., Gillespie, H., Bolla, K.I., Brown, K., Eldreth, D., Tate, K., At this time, it is clear that there is no and Hollister, L. (1986). Pharmacokinetics and Cadet, J.L. (2002). Dose-related consensus of opinion among experts and metabolism of delta-1- neurocognitive effects of marijuana use. concerning medical applications of tetrahydrocannabinol and other Neurology. 59:1337–1343. cannabinoids with an emphasis on man. marijuana. To date, research on the medical Bolla, K.I., Eldreth, D.A., Matochik, J.A., and Pharmacological Reviews. 38(1):21–43. use of marijuana has not progressed to the Cadet, J.L. (2005). Neural substrates of Aldington S, Harwood M, Cox B, Weatherall point that marijuana can be considered to faulty decision-making in abstinent M, Beckert L, Hansell A, Pritchard A, have a ‘‘currently accepted medical use’’ or marijuana users. NeuroImage. 26:480–492. Robinson G, Beasley R; Cannabis and a ‘‘currently accepted medical use with Bouaboula, M., Rinaldi, M., Carayon, P., Respiratory Disease Research Group (2008). severe restrictions. Carillon, C., Delpech, B., Shire, D., Le Fur, Cannabis use and risk of lung cancer: a G., and Casellas, P.(1993). Cannabinoid- v. The scientific evidence must be widely case-control study. European Respiratory receptor expression in human leukocytes. available Journal. 31(2):280–6. European Journal of Biochemistry. Ameri, A. The effects of cannabinoids on the DHHS states that the scientific evidence 214(1):173–180. brain. Progress in Neurobiology. 1999: 58 regarding the safety and efficacy of marijuana Braida, D., Iosue, S., Pegorini, S., and Sala, (4): 315–348. is typically available only in summarized M. (2004). Delta9-tetrahydrocannabinol- Andreasson, S., Allebeck, P., Engstro¨m, A., induced conditioned place preference and form, such as in a paper published in the and Rydberg, U. (1987). Cannabis and medical literature, rather than in a raw data intracerebroventricular self-administration schizophrenia: A longitudinal study of in rats. European Journal of Pharmacology. format. In addition, as noted, there have only Swedish conscripts. Lancet. 1: 483–1483. been a limited number of small clinical trials 506(1):63–69. Arseneault, L., Cannon, M., Poulton, R., Breivogel, C.S. and Childers, S.R. (2000). and no controlled, large scale, clinical trials Murray R., Caspi. A., and Moffitt, T.E. have been conducted with marijuana on its Cannabinoid agonist signal transduction in (2002). Cannabis use in adolescence and rat brain: comparison of cannabinoid efficacy for any indications or its safety. risk for adult psychosis: longitudinal agonists in receptor binding, G-protein 3. There is a lack of accepted safety for use prospective study. British Medical Journal. activation, and adenylate cyclase of marijuana under medical supervision 325 (7374):1212–1213. inhibition. Journal of Pharmacology and Azorlosa, J., Heishman, S., Stitzer, M., and Experimental Therapeutics. 295(1):328– At present, there are no FDA-approved Mahaffey, J.M. (1992). Marijuana smoking: marijuana products, nor is marijuana under 336. effect of varying delta-9- Breivogel, C.S., Griffin, G., Di Marzo, V., NDA evaluation at the FDA for any tetrahydrocannabinol content and number Martin, B.R. (2001). Evidence for a new G indication. Marijuana does not have a of puffs. Journal of Pharmacology and protein-coupled cannabinoid receptor in currently accepted medical use in treatment Experimental Therapeutics. 261:114–122. mouse brain. Molecular Pharmacology. in the United States or a currently accepted Baldwin, G.C., Tashkin, D.P., Buckley, D.M., 60(1):155–63. medical use with severe restrictions. The Park, A.N., Dubinett, S.M., and Roth, M.D. Breivogel, C.S., Scates, S.M., Beletskaya, I.O., Center for Medicinal Cannabis Research in (1997). Marijuana and cocaine impair Lowery, O.B., Aceto, M.D., and Martin, California, among others, is conducting alveolar macrophage function and cytokine B.R. (2003). The effects of delta9- research with marijuana at the IND level, but production. American Journal of tetrahydrocannabinol physical dependence these studies have not yet progressed to the Respiratory and Critical Care Medicine. on brain cannabinoid receptors. European stage of submitting an NDA. Current data 156:1606–1613. Journal of Pharmacology. 459(2–3):139– suggest that marijuana use produces adverse Balster, R.L. and Prescott, W.R. (1992). D9- 150. effects on the respiratory system, memory tetrahydrocannabinol discrimination in Browne, R.G., and Weissman, A. (1981). and learning. Marijuana use is associated rats as a model for cannabis intoxication. Discriminative stimulus properties of D9- with dependence and addiction. In addition, Neuroscience and Biobehavioral Reviews. tetrahydrocannabinol: Mechanistic studies. very large epidemiological studies indicate 16: 55–62. Journal of Clinical Pharmacology. 21: that marijuana use may be a causal factor for Barrett, R.L., Wiley, J.L., Balster, R.L. and 227S–234S. the development of psychosis in individuals Martin, B.R. (1995). Pharmacological Budney, A.J., Hughes, J.R., Moore, B.A., and predisposed to develop psychosis and may specificity of D9-tetrahydrocannabinol Vandrey, R. (2004). Review of the validity exacerbate psychotic symptoms in discrimination in rats. and significance of cannabis withdrawal individuals with schizophrenia. Thus, at this Psychopharmacology. 118: 419–424. syndrome. American Journal of Psychiatry. time, the known risks of marijuana use have Bedard, M., Dubois, S., Weaver, B. (2007). 161(11):1967–1977. not been shown to be outweighed by specific The impact of cannabis on driving. Budney, A.J., Novy, P.L., and Hughes, J.R. benefits in well-controlled clinical trials that Canadian Journal of Public Health. (1999). Marijuana withdrawal among scientifically evaluate safety and efficacy. In 98(1):6–11. adults seeking treatment for marijuana sum, at present, marijuana lacks an Benowitz, N.L. and Jones, R T. (1975). dependence. Addiction. 94:1311–1322. acceptable level of safety even under medical Cardiovascular effects of prolonged delta- Cabral, G.A. and Dove-Pettit, D.A. (1998). supervision. tetrahydrocannabinol ingestion. Clinical Drugs and immunity: cannabinoids and

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their role in decreased resistance to Croxford, J.L. and Yamamura, T. (2005). contingencies and low probability infectious disease. Journal of Cannabinoids and the immune system: activities. Journal of the Experiment Neuroimmunology. 83(1–2):116–123. potential for the treatment of inflammatory Analysis of Behavior. 53:5–19. Cabral, G.A. and Staab, A. (2005). Effects on diseases? Journal of Neuroimmunology. Fried, P. A. and Watkinson, B. (1990). 36- the immune system. Handbook of 166(1–2): 3–18. and 48-month neurobehavioral follow-up Experimental Pharmacology. 168:385–423. Dax, E.M., Pilotte, N.S., Adler, W.H., Nagel, of children prenatally exposed to Capriotti, RM., Foltin, R.W., Brady, J.V. and J.E., and Lange, W.R. (1989). The effects of marijuana, cigarettes and alcohol. Journal Fischman, M.W. (1988). Effects of 9-ene-tetrahydrocannabinol on hormone of Developmental and Behavioral marijuana on the task elicited release and immune function. Journal of Pediatrics. 11:49–58. physiological response. Drug and Alcohol Steroid Biochemistry. 34:263–70. Fried, P. A., Watkinson, B., and Gray, R. Dependence. 21(3): 183–7. Degenhardt, L., Hall, W., Lynskey, M. (2003). (1992). A follow-up study of attentional Caspi, A., Moffitt, T.E., Cannon, M., McClay, Testing hypotheses about the relationship behavior in 6-year-old children exposed J., Murray, R., Harrington, H., Taylor, A., between cannabis use and psychosis. Drug prenatally to marihuana, cigarettes and Arseneault, L., Williams, B., Braithwaite, and Alcohol Dependence. 71(1): 37–48. alcohol. Neurotoxicology and Teratology. A., Poulton, R., and Craig, I.W. (2005). Department of Health and Human Services 14:299–311. Moderation of the effect of adolescent- (2006). Basis For The Recommendation For Fried, P. A., Watkinson, B., Gray, R. (1998). onset cannabis use on adult psychosis by Maintaining Marijuana In Schedule I Of Differential effects on cognitive functioning a functional polymorphism in the catechol- The Controlled Substances Act. in 9- to 12-year olds prenatally exposed to O-methyltransferase gene: longitudinal Department of Health and Human Services. cigarettes and marihuana. Neurotoxicology evidence of a gene X environment Announcement of the Department of and Teratology. 20(3):293–306. interaction. Biological Psychiatry. Health and Human Services Guidance on Fried, P., Watkinson, B., James, D., and Gray, 57(10):1117–1127. Procedures for the Provision of Marijuana R. (2002). Current and former marijuana Centers for Disease Control (CDC). (1981). for Medical Research. May 21, 1999. use: preliminary findings of a longitudinal Salmonellosis traced to marijuana— (http://grants.nih.gov/grants/guide/notice- study of effects on IQ in young adults. Ohio, Michigan. Morbidity and Mortality files/not99-091.html). Canadian Medical Association Journal. Weekly Report. 30(7):77–9. Dewey, W.L., Martin, B.R., and May, E.L. 166(7):887–891. Chait L.D. and Burke, K.A. (1994). Preference (1984). Cannabinoid stereoisomers: Fung, M., Gallagher, C., and Machtay, M. for ‘‘high’’ versus low-potency marijuana. pharmacological effects. In Smith, D.F. (1999). Lung and aeo-digestive cancers in Pharmacology, Biochemistry, and (Ed.) CRC Handbook of Stereoisomers: young marijuana smokers. Tumori. 85 (2): Behavior. 49:643–646. Drugs in Psychopharmacology, 317–326 140–142. Chait, L.D. and Pierri, J. (1992). Effects of (Boca Raton, FL, CRC Press). Galiegue, S., Mary, S., Marchand, J., smoked marijuana on human performance. Ehrenreich, H., Rinn, T., Kunert, H.J., Dussossoy, D., Carriere, D., Carayon, P., In: Marijuana/Cannabinoids. Neurobiology Moeller, M.R., Poser, W., Schilling, L., Bouaboula, M., Shire, D., Le Fur, G., and and Neurophysiology. Murphy, L., and Gigerenzer, G., and Hoehe, M.R. (1999). Casellas, P. (1995). Expression of central Bartke, A. (Eds). CRC Press, Boca Raton, Specific attentional dysfunction in adults and peripheral cannabinoid receptors in FL. Pp. 387–423. following early start of cannabis use. human immune tissues and leukocyte Chait, L.D. and Zacny, J.P. (1992). Psychopharmacology (Berl). 142(3):295– subpopulations. European Journal of Reinforcing and subjective effects of oral 301. Biochemistry. 232(1):54–61. D9-THC and smoked marijuana in humans. Gerard, C.M., Mollereau, C., Vassart, G., and Psychopharmacology. 107:255–262. Eldridge, J.C., Murphy, L.L., and Landfield, Chait, L.D., Evans, S.M., Grant, K.A., Kamien, P.W. (1991). Cannabinoids and the Parmentier, M. (1991). Molecular cloning J.B., Johanson, C.E., and Schuster, C.R. hippocampal glucocorticoid receptor: of a human cannabinoid receptor which is (1988). Discriminative stimulus and recent findings and possible significance. also expressed in testis. Biochemistry subjective effects of smoked marijuana in Steroids. 56(5): 226–231. Journal. 279:129–134. humans. Psychopharmacology. 94: 206– Fant, R.V., Heishman, S.J., Bunker, E.B., and Glass, M. and Felder, C.C. (1997). Concurrent 212. Pickworth, W.B. (1998). Acute and residual stimulation of cannabinoid CB1 and Charuvastra, A., Friedmann, P.D., Stein, M.D. effects of marijuana in humans. dopamine D2 receptors augments cAMP (2005). Physician attitudes regarding the Pharmacology Biochemistry and Behavior. accumulation in striatal neurons: Evidence prescription of medical marijuana. Journal 60(4):777–784. for a Gs linkage to the CB1 receptor. of Addiction Diseases. 24(3):87–93. Felder, C.C., Joyce, K.E., Briley, E.M., Glass, Journal of Neuroscience. 17: 5327–5333 Cocchetto, D.M., Owens, S.M., Perez-Reyes, M., Mackie, K.P., Fahey, K.J., Cullinan, Gold, L.H., Balster, R.L., Barrett, R.L., Britt, M., DiGuiseppi, S., and Miller, L.L. (1981). G.J., Hunden, D.C., Johnson, D.W., Chaney, D.T., and Martin, B.R. (1992). A Relationship between delta-9- M.O., Koppel, G.A. and Brownstein, M. comparison of the discriminative stimulus tetrahydrocannabinol concentration and (1998). LY320135, a novel cannabinoid properties of delta 9-tetrahydrocannabinol pharmacologic effects in man. CB1 receptor antagonist, unmasks coupling and CP 55,940 in rats and rhesus monkeys. Psychopharmacology. 75:158–164. of the CB1 receptor to stimulation of cAMP Journal of Pharmacology and Experimental Collins, R.J., Weeks, J.R., Cooper, M.M., accumulation. Journal of Pharmacology Therapeutics. 262(2):479–486. Good, P.I., and Russell, R.R. (1984). and Experimental Therapeutics. 284: 291– Gong, H. Jr., Tashkin, D.P., Simmons, M.S., Prediction of abuse liability of drugs using 297 Calvarese, B., and Shapiro, B.J. (1984). IV self-administration by rats. Fergusson, D.M., Horwood, L.J., and Ridder, Acute and subacute bronchial effects of Psychopharmacology, 82: 6–13. E.M. (2005). Tests of causal linkages oral cannabinoids. Clinical Cone, E.J., Johnson, R.E., Moore, J.D., and between cannabis use and psychotic Pharmacalology and Therapeutics. 35(1): Roache, J.D. (1986). Acute effects of symptoms. Addiction. 100(3):354–366. 26–32. smoking marijuana on hormones, Fergusson, D.M., Poulton, R., Smith, P.F., Gong, J.P., Onaivi, E.S., Ishiguro, H., Liu, subjective effects and performance in male Boden, J.M. (2006). Cannabis and Q.R., Tagliaferro, P.A., Brusco, A., and Uhl, human subjects. Pharmacology, psychosis. British Medical Journal. G.R. (2006). Cannabinoid CB2 receptors: Biochemistry and Behavior. 24(6):1749– 332(7534):172–5. Immunohistochemical localization in rat 1754. Fligiel, S.E., Roth, M.D., Kleerup, E.C., brain. Brain Research. 1071(1):10–23. Cone, E.J., Johnson, R.E., Paul, B.D., Mell, Barsky, S.H., Simmons, M., and Tashkin, Gonsiorek, W., Lunn, C., Fan, X., Narula, S., L.D., and Mitchell, J. (1988). Marijuana- D.P. (1997). Tracheobronchial Lundell, D., and Hipkin, R.W. (2000). laced brownies: Behavioral effects, histopathology in habitual smokers of Endocannabinoid 2-arachidonyl glycerol is physiological effects and urinalysis in cocaine, marijuana, and/or tobacco. Chest. a full agonist through human type 2 humans following ingestion. Journal of 112:319–326. cannabinoid receptor: antagonism by Analytical Toxicology. 12:169–175. Foltin, R.W., Fischman M.W., Brady J.V., anandamide. Molecular Pharmacology. Crider, R. (1986). Phencyclidine: changing Bernstein D.J., Capriotti, R.M., Nellis, M.J., 57(5): 1045–1050 abuse patterns. NIDA Research and Kelly, T.H. (1990). Motivational effects Graham, J.D.P., ed. (1976). Cannabis and Monograph. 64:163–173. of smoked marijuana: behavioral Health. New York: Academic Press. Green,

VerDate Mar<15>2010 17:58 Jul 07, 2011 Jkt 223001 PO 00000 Frm 00036 Fmt 4701 Sfmt 4702 E:\FR\FM\08JYP3.SGM 08JYP3 jlentini on DSK4TPTVN1PROD with PROPOSALS3 Ex. C-36 Case Federal2:11-cr-00449-KJM Register / Vol. 76, Document No. 131 / Friday,324-3 July Filed 8, 07/29/142011 / Proposed Page Rules 38 of 40 40587

B., Young, R., and Kavanagh, D. (2005). young people. British Medical Journal. Kagen, S.L., Kurup, V.P., Sohnle, P.G., Fink, Cannabis use and misuse prevalence 330(7481):11. J.N. (1983). Marijuana smoking and fungal among people with psychosis. British Herkenham, M. (1992). Cannabinoid receptor sensitization. The Journal of Allergy and Journal of Psychiatry. 187:306–313. localization in brain: Relationship to motor Clinical Immunology. 71(4):389–93. Griffith, D.R., Azuma, S.D., and Chasnoff, I.J. and reward systems. Annals of the New Kamien, J.B., Bickel, W.K., Higgins, S.T., and (1994). Three-year outcome of children York Academy of Sciences. 654:19–32. Hughes, J.R. (1994). The effects of D9- exposed prenatally to drugs. Journal of the Herkenham, M., Lynn, A. B., Little, M. D., tetrahydrocannabinol on repeated American Academy of Child and Johnson, M. R., Melvin, L. S., de Costa, B. acquisition and performance of response Adolescent Psychiatry. 33:20–27. R., and Rice, K. C. (1990). Cannabinoid sequences and on self-reports in humans. Griffiths, R.R., Bigelow, G.E. and receptor localization in Brain. Proceedings Behavioural Pharmacology. 5: 71–78. Henningfield, J.E. (1980). Similarities in of the National Academy of Sciences USA. Kandel, D.B. and Chen, K. (2000). Types of animal and human drug-taking behavior. 87:1932–1936. marijuana users by longitudinal course. In: ‘‘Advances in substance abuse, vol 1’’. Hollister, L.E. (1986). Health aspects of Journal on Studies on Alcohol. 61(3): 367– (Ed. N.K. Mello). pp. 1–90. JAI Press, cannabis. Pharmacological Reviews. 3:1– 378. Greenwich, CT. 20. Kelly, T.H., Foltin, R.W., and Fischman, Grotenhermen, F. (2003). Pharmacokinetics Hollister, L.E. (1988). Cannabis—1988 M.W. (1993). Effects of smoked marijuana and pharmacodynamics of cannabinoids. (Literature Review). Acta Psychiatrica on heart rate, drug ratings and task Clinical Pharmacokinetics. 42(4):327–60 Scandinavica. 78:108–118. performance by humans. Behavioural Hall, W., Degenhardt, L., Teesson, M. (2004). Howlett, A.C., Breivogel, C.S., Childers, S.R., Pharmacology. 4:167–178. Cannabis use and psychotic disorders: an Deadwyler, S.A., Hampson, R.E., and Kelly, T.H., Foltin, R.W., Mayr, M.T., and D update. Drug and Alcohol Reviews. Porrino, L.J. (2004). Cannabinoid Fischman, M.W. (1994). Effects of 9- 23(4):433–43. physiology and pharmacology: 30 years of tetrahydrocannabinol and social context on Haney, M., Ward, A.S., Comer, S.D., Foltin, progress. Neuropharmacology. 47 (Suppl marijuana self-administration by humans. R.W., and Fischman, M.W. (1999). 1):345–358. Pharmacology, Biochemistry and Behavior. Abstinence symptoms following smoked Idanpaan-Heikkila, J., Fritchie, G.E., Englert, 49:763–768. marijuana in humans. L.F., Ho, B.T. and McIsaac, W.M. (1969). Kirk, J.M. and de Wit, H. (1999). Responses Psychopharmacology. 141:395–404. Placental transfer of tritiated-1-delta-9- to oral delta9-tetrahydrocannabinol in Hanus, L. and Subiva´, D. (1989). The amount tetrhydrocannabinol. New England Journal frequent and infrequent marijuana users. of main cannabinoid substances in hemp of Medicine. 281(6):330. Pharmacology, Biochemistry and Behavior. cultivated for industrial fibre production Institute of Medicine, Division of 63(1):137–142. Klein, T.W., Lane, B., Newton, C.A. and and their changes in the course of one Neuroscience and Behavioral Health. (1999). Marijuana and Medicine: Assessing Friedman, H. (2000). The cannabinoid vegetation period. Acta Universitatis the Science Base. National Academy Press. system and cytokine network. Proceedings Palackianae Olomucensis Facultatis Washington D.C. of the Society for Experimental Biology and Medicae. 122:11–23. Ja¨rbe, T.U., Lamb, R.J., Lin, S., and Medicine. 225(1):1–8. Hanus, L., Breuer, A., Tchilibon, S., Shiloah, Makriyannis, A. (2001). (R)-methandamide Kurup, V.P., Resnick, A., Kagen, S.L., Cohen, S., Goldenberg, D., Horowitz, M., Pertwee, and delta-9–THC as discriminative stimuli S.H., Fink, J.N. (1983). Allergenic fungi and R.G., Roos, R.A., Mechoulam, R., and in rats: tests with the cannabinoid actinomycetes in smoking materials and Fride, E. (1999). HU–308: a specific agonist antagonist SR–141716 and the endogenous their health implications. Mycopathologia. for CB (2), a peripheral Cannabinoid ligand anandamide. Psychopharmacology. 82(1):61–4. receptor. Proceedings of the National 156(4):369–380. Kurzthaler, I., Hummer, M., Miller, C., Academy of Science. 96:14228–14233. Johanson, C.E. and Balster, R.L. (1978). A Spemer-Unterweger, R, Gunther, V., Hanus, L., Yoshida, T., and Kreji. (1975). summary of the results of a drug self- Wechdom, H., Battista, H.J., and D9 Production of -tetrahydrocannabinol administration study using substitution Fleischhacker, W.W. (1999). Effect of from hemp cultivated in climatic procedures in rhesus monkeys. Bulletin of cannabis use on cognitive functions and conditions of Czechoslovakia. Acta Narcotics, 30:43–54. driving ability. Journal of Clinical Universitatis Palackianae Olomucensis Jones, R.T. (1980). Human Effects: An Psychiatry. 60(6): 395–9. Facultatis Medicae. 74:173–180. Overview. In NIDA Research Monograph Lane, J.D. and Phillips-Bute, R.G. (1998). Harder, S. and Rietbrock, S. (1997). 31, Marijuana Research Findings: 1980. Caffeine deprivation affects vigilance Concentration-effect relationship of delta- 31:54–80. performance and mood. Physiology and 9-tetrahydrocannabinol and prediction of Jones, R.T. (2002). Cardiovascular system Behaviour, 65: 171–5. psychotropic effects after smoking effects of marijuana. The Journal of Clinical Lemberger, L., Crabtree, R.E., and Rowe, H.M. marijuana. International Journal of Clinical Pharmacology. 42:58S–63S. (1972). 11-hydroxy-9- Pharmacology and Therapeutics. Justinova, Z., Goldberg, S.R., Heishman, S.J., tetrahydrocannabinol: pharmacology, 35(4):155–159. Tanda, G. (2005). Self-administration of disposition, and metabolism of a major Heishman, S.J., Huestis, M.A., Henningfield, cannabinoids by experimental animals and metabolite of marihuana in man. Science. J.E., and Cone, E.J. (1990). Acute and human marijuana smokers. Pharmacology 177(43):62–64. residual effects of marijuana: profiles of Biochemistry and Behavior. 81(2):285–99. Liguori, A., Gatto, C.P., and Robinson, J.H. plasma THC levels, physiological, Justinova, Z., Munzar, P., Panlilio, L.V., (1998). Effects of marijuana on equilibrium, subjective, and performance measures. Yasar, S., Redhi, G.H., Tanda, G., Goldberg, psychomotor performance, and simulated Pharmacology, Biochemistry and Behavior. S.R. (2008). Blockade of THC-seeking driving. Behavioral Pharmacology. 37(3):561–565. behavior and relapse in monkeys by the 9(7):599–609. Heishman, S.J., Singleton, E.G., and Ligouri, cannabinoid CB(1)-receptor antagonist Lile, J.A. (2006). Pharmacological A. (2001). Marijuana craving questionnaire: rimonabant. Neuropsychopharmacology. determinants of the reinforcing effects of development and initial validation of a 33(12):2870–7. psychostimulants: relation to agonist self-report instrument. Addiction. Justinova, Z., Tanda, G., Munzar, P., substitution treatment. Experimental 96(7):1023–1034. Goldberg, S.R. (2004). The opioid Clinical Psychopharmacology. 14(1):20–33. Heishman, S.J., Stitzer, M.L., and Bigelow, antagonist naltrexone reduces the Lukas, S.E., Mendelson, J.H., and Benedikt, G.E. (1988). Alcohol and marijuana: reinforcing effects of Delta 9 R. (1995). Electroencephalographic Comparative dose effect profiles in tetrahydrocannabinol (THC) in squirrel correlates of marijuana-induced euphoria. humans. Pharmacology, Biochemistry and monkeys. Psychopharmacology (Berl). Drug and Alcohol Dependence. 37:131– Behavior. 31:649–655. 173(1–2):186–94. 140. Henquet, C., Krabbendam, L., Spauwen, J., Justinova, Z., Tanda, G., Redhi, G.H., and Lyketsos, C.G., Garrett, E., Liang, K.Y., and Kaplan, C., Lieb, R., Wittchen, H.U., and Goldberg, S.R. (2003). Self-administration Anthony, J.C. (1999). Cannabis use and van Os, J. (2005). Prospective cohort study of delta9-tetrahydrocannabinol (THC) by cognitive decline in persons under 65 years of cannabis use, predisposition for drug naive squirrel monkeys. of age. American Journal of Epidemiology. psychosis, and psychotic symptoms in Psychopharmacology. 169(2):135–140. 149(9):794–800.

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Lyons, M.J., Bar, J.L., Panizzon, M.S., Cannabis and cannabinoids. CB1 antagonist, SR 141716A. Toomey, R., Eisen, S., Xian, H., and Pharmacology, toxicology, and Behavioural Pharmacology. 7: 65–71. Tsuang, M.T. (2004). Neuropsychological therapeutic potential. Binghamton (NY): Piomelli, D. (2005). The endocannabinoid consequences of regular marijuana use: a Haworth Press. system: a drug discovery perspective. twin study. Psychological Medicine. Mechoulam, R. (1973). Marijuana: Chemistry, Current Opinion in Investigational 34(7):1239–1250. pharmacology, metabolism, and clinical Drugs. 6(7): 672–9. Mackie, K., Lai, Y., Westenbroek, R., and effects. NY: Academic Press. Pope, G.H. Jr., Gruber, A.J., Hudson, J.I., Mitchell, R. (1995). Cannabinoids Medina, K.L., Hanson, K.L., Schweinsburg, Huestis, M.A., and Yurgelun-Todd, D. activate an inwardly rectifying A.D., Cohen-Zion, M., Nagel, B.J., Tapert, (2002). Cognitive measures in long-term potassium conductance and inhibit Q- S.F. (2007). Neuropsychological cannabis users. Journal of Clinical type calcium currents in AtT20 cells functioning in adolescent marijuana Pharmacology. 42(11 Suppl):41S–47S. transfected with rat brain cannabinoid users: subtle deficits detectable after a Pope, G.H. Jr., Gruber, A.J., Hudson, J.I., receptor. Journal of Neuroscience. month of abstinence. Journal of the Cohane, G., Huestis, M.A., and Yurgelun- 15(10):6552–6561. International Neuropsychology Society. Todd, D. (2003). Early-onset cannabis Maldonado, R. (2002). Study of cannabinoid 13(5):807–20. use and cognitive deficits: what is the dependence in animals. Pharmacology Mello, N. K. (1983). A behavioral analysis of nature of the association? Drug and and Therapeutics. 95(2):153–64. the reinforcing properties of alcohol and Alcohol Dependence. 69(3):303–310. Maneuf, Y.P., and Brotchie, J.M. (1997). other drugs in man. In B. Kissin & H. Ramaekers, J.G., Berghaus, G., van Laar, M., Paradoxical action of the cannabinoid Begleiter (Eds.), The pathogenesis of Drummer, O.H. (2004). Dose related risk WIN 55212–2 in stimulated and basal alcoholism, biological factors (Vol. 7, pp. of motor vehicle crashes after cannabis cyclic AMP accumulation in rat globus 133–198). New York: Plenum Press. use. Drug and Alcohol Dependence. pallidus slices. British Journal of Mello, N.K. (1989). Drug self-administration 73(2):109–119. Pharmacology. 120: 1397–1398. procedures: Alcohol and marijuana. In Regier, D.A., Farmer, M.E., Rae, D.S., Locke, Mansbach, R.S., Rovetti, C.C., Winston, E.N., NIDA Research Monograph 92: Testing B.Z., Keith, S.J., Judd, L.L., and and Lowe J.A. (1996). Effects of the for Abuse Liability of Drugs in Humans. Goodwin, F.K. (1990). Comorbidity of cannabinoid CB1 receptor antagonist 92:147–170. mental disorders with alcohol and other SE14176A on the behavior of pigeons Mendelson, J.H. and Mello, N.K. (1984). drug abuse. Results from the and rats. Psychopharmacology. Reinforcing properties of oral D9- Epidemiologic Catchment Area (ECA) 124(4):315–322. tetrahydrocannabinol, smoked marijuana Study. Journal of the American Medical Martellotta, M.C., Cossu, G., Fattore, L., and nabilone: Influence of previous Association. 264(19):2511–2518. Gessa, G.L., and Fratta, W. (1998). Self- marijuana use. Psychopharmacology. Robbe, H.W.J., and O’Hanlon, J.F., (1999). Marijuana, alcohol and actual driving administration of the cannabinoid 83:351–356. performance. Dot HS 808 939. US receptor agonist WIN 55,212–2 in drug- Messinis, L., Kyprianidou, A., Malefaki, S., Department of Transportation National naive mice. Neuroscience. 85(2):327– and Papathanasopoulos, P. (2006). Highway Traffic Safety Administration, 330. Neuropsychological deficits in long-term Maastrict, The Netherlands. Martin, B.R. and Hall, W. (1997, 1998). The frequent cannabis users. Neurology. 66: Ross, S.A. and El Sohly, M.A. (1995). health effects of cannabis: key issues of 737–739. Constituents of Cannabis Sativa L. A policy relevance. Bulletin on Narcotics Moore, T.H., Zammit, S., Lingford-Hughes, review of the natural constituents: 1980– XLIX & L (1 &2): 85–116. A., Barnes, T.R., Jones, P.B., Burke, M., 1994. Zagazig Journal of Pharmaceutical Martin, B.R., Mechoulam, R., and Razdan, Lewis, G. (2007). Cannabis use and risk Sciences. 4 (2):1–10. R.K. (1999). Discovery and of psychotic or affective mental health Roth, M.D., Arora, A., Barsky, S.H., Kleerup, characterization of endogenous outcomes: a systematic review. Lancet. E.C., Simmons, M. and Tashkin, D.P. cannabinoids. Life Science. 65:573–595. 370(9584):319–28. (1998). Airway inflammation in young Mathers, D.C., Ghodse, A.H. (1992). Cannabis Murray, J.E., Bevins, R.A. (2010). marijuana and tobacco smokers. and psychotic illness. British Journal of Cannabinoid conditioned reward and American Journal of Respiratory and Psychiatry. 61:648–53. aversion: behavioral and neural Critical Care Medicine. 157:928–937. Mathew, R.J., Wilson, W.H., Davis, R. (2003). processes. ACS Chemical Neuroscience. Roth, M.D., Tashkin, D.P., Whittaker, K.M., Postural syncope after marijuana: a 1(4):265–278. Choi, R., and Baldwin, G.C. (2005). transcranial Doppler study of the National Institutes of Health (NIH). Tetrahydrocannabinol suppresses hemodynamics. Pharmacology, Workshop on the medical Utility of immune function and enhances HIV Biochemistry and Behavior. 75:309–318. Marijuana, February 19–20, 1997. replication in the huPBL–SCID mouse. Matsuda, L. A., Lolait, S. J., Brownstein, M. (www.nih.gov/news/medmarijuana/ Life Science. 77(14):1711–22. J., Young, A. C., and Bonner, T.I. (1990). MedicalMarijuana.htm) Russo, E., Mathre, M.L., Byrne, A., Velin, R., Structure of a cannabinoid receptor and Paris, M. and Nahas, G.G. (1984). Botany: the Bach, P.J., Sanchez-Ramos, J., Kirlin, functional expression of the cloned unstabilized species. In: Nahas G.G. (Ed.) K.A. (2002). Chronic Cannabis Use in the cDNA. Nature. 346:561–564. Marihuana in science and medicine. NY: Compassionate Investigational New Drug McGrath, J., Welham, J., Scott, J., Varghese, Raven Press, pp. 3–36. Program: An Examination of Benefits D., Degenhardt, L., Hayatbakhsh, M.R., Perez-Reyes, M., Simmons, J., Brine, D., Kiel, and Adverse Effects of Legal Clinical Alati, R., Williams, G.M., Bor, W., G.L., Davis, K.H., Wall, M.E. (1976). Rate Cannabis. Journal of Cannabis Najman, J.M. (2010). Association of penetration of delta- Therapeutics. 2(1):3–58. between cannabis use and psychosis- tetrahydrocannabinol to the brain of Sarfaraz, S., Afaq, F., Adhami, V.M., related outcomes using sibling pair mice. In: Nahas G, Paton WDM, Mukhtar, H. (2005). Cannabinoid analysis in a cohort of young adults. Ida¨npa¨a¨n-Heikkila¨ JE (Eds), Marihuana: receptor as a novel target for the Archives of General Psychiatry. Chemistry, biochemistry, and cellular treatment of prostate cancer. Cancer 67(5):440–7 effects. Springer-Verlag: New York, pp Research. 65(5):1635–41. McLaren, J., Swift, W., Dillon, P., Allsop, S. 179–185. Schiffman, J., Nakamura, B., Earleywine, M., (2008). Cannabis potency and Perez-Reyes, M., Timmons, M.C., Lipton, LaBrie, J. (2005). Symptoms of contamination: a review of the literature. M.A., Davis, K.H., and Wall, M.E. (1972). schizotypy precede cannabis use. Addiction. 103(7):1100–9. Intravenous injection in man of 9- Psychiatry Research. 134(1):37–42. McPartland, J.M. (1994). Microbiological tetrahydrocannabinol and 11-OH-9- Schuster, C.R. and Thompson, T. (1969). contaminants of marijuana. Journal of tetrahydrocannabinol. Science. Administration of and behavioral the International Hemp Association. 1: 177(49):633–635. dependence on drugs. Annual Review of 41–44. Pe´rio, A., Rinaldi-Carmona, M., Maruani, J., Pharmacology. 9: 483–502. McPartland, J.M. (2002). Contaminants and Barth, F., LeFur, G., and Soubrie´, P. Sidney, S. (2002). Cardiovascular adulterants in herbal cannabis. In In: (1996). Central mediation of the consequences of marijuana use. Journal Grotenhermen F, Russo E, editors. cannabinoid cue: activity of a selective of Clinical Pharmacology. 42:64S–70S.

VerDate Mar<15>2010 17:58 Jul 07, 2011 Jkt 223001 PO 00000 Frm 00038 Fmt 4701 Sfmt 4702 E:\FR\FM\08JYP3.SGM 08JYP3 jlentini on DSK4TPTVN1PROD with PROPOSALS3 Ex. C-38 Case Federal2:11-cr-00449-KJM Register / Vol. 76, Document No. 131 / Friday,324-3 July Filed 8, 07/29/142011 / Proposed Page Rules 40 of 40 40589

Solinas, M., Panlilio, L.V., Justinova, Z., Tashkin, D.P., Shapiro, B.J., and Frank, I.M. American Journal of Epidemiology. Yasar, S., Goldberg, S.R. (2006). Using (1974). Acute effects of smoked 156(4):319–327. drug-discrimination techniques to study marijuana and oral D9- Vandrey, R.G., Budney, A.J., Moore, B.A., the abuse-related effects of psychoactive tetrahydrocannabinol on specific airway and Hughes, J.R. (2005). A cross-study drugs in rats. Nature Protocols. conductance in asthmatic subjects. comparison of cannabis and tobacco 1(3):1194–206. American Review of Respiratory Disease. withdrawal. American Journal of Solowij, N., Stephens, R.S., Roffman, R.A., 109(4):420–428. Addiction. 14(1): 54–63. Babor, T., Kadden, R., Miller, M., Tashkin, D.P., Zhang, Z.F., Greenland, S., Wachtel, S.R., El Sohly, M.A., Ross, S.A., Christiansen, K., McRee, B. and Vendetti, Cozen, W., Mack, T.M., and Ambre, J., and de Wit, H. (2002). J. (2002). Marijuana Treatment Project Morgenstern, H. (2006). Marijuana use Comparison of the subjective effects of Research Group. Cognitive functioning of and lung cancer: results of a case-control long-term heavy cannabis users seeking delta (9)-tetrahydrocannabinol and study. Abstract #A777, American marijuana in humans. treatment. Journal of the American Thoracic Society. Psychopharmacology. 161(4):331–339. Medical Association, 287(9):1123–31. Taylor, D.N., Wachsmuth, I.K., Shangkuan, Wagner, J.A., Varga, K., and Kunos, G. (1998). Substance Abuse and Mental Health Services Y.H., Schmidt, E.V., Barrett, T.J., Cardiovascular actions of cannabinoids Administration, Office of Applied Schrader, J.S., Scherach, C.S., McGee, Studies (2009). Results from the 2008 H.B., Feldman, R.A., Brenner, D.J. (1982). and their generation during shock. National Survey on Drug Use and Health: Salmonellosis associated with marijuana: Journal of Molecular Medicine. National Findings (NSDUH Series: H–34, a multistate outbreak traced by plasmid 76(12):824–36. DHHS Publication No. SMA 08–4343). fingerprinting. New England Journal of Weil, A.T. (1970). Adverse reactions to Rockville, MD. Medicine. 306(21):1249–53. marihuana. Classification and suggested Substance Abuse and Mental Health Services Thomas, H. (1993). Psychiatric symptoms in treatment. New England Journal of Administration, Office of Applied Medicine. 282 (18):997–1000. Studies (2009). Treatment Episode Data cannabis users. British Journal of Wiley, J.L., Huffman, J.W., Balster, R.L., and Set (TEDS). Highlights—2007. National Psychiatry. 163:141–149. Admissions to Substance Abuse Thornicroft, G. (1990). Cannabis and Martin, B.R. (1995). Pharmacological Treatment Services, DASIS Series: S–45, psychosis. Is there epidemiological specificity of the discriminative stimulus D DHHS Publication No. (SMA) 09–4360, evidence for an association? British effects of 9-tetrahydrocannabinol in Rockville, MD. Journal of Psychiatry. 157:25–33. rhesus monkeys. Drug and Alcohol Tanda, G., Munzar, P., Goldberg, S.R. (2000). Twitchell, W., Brown, S., and Mackie, K. Dependence. 40:81–86. Self-administration behavior is (1997). Cannabinoids inhibit N- and P/Q- Yanagita, T. (1980). Self-administration maintained by the psychoactive type calcium channels in cultured rat studies on psychological dependence. ingredient of marijuana in squirrel hippocampal neurons. Journal of Trends in Pharmacological Sciences. monkeys. Nature Neuroscience. 3(11): Neurophysiology. 78(1):43–50. 1:161–164. 1073–1074. Ungerleider, J.T., Andrysiak, T., Tashkin, Zhang, Z.F., Morgenstern, H., Spitz, M.R, Tashkin, D.P., Coulson, A.H., Clark, V.A., D.P., Gale, R.P. (1982). Contamination of Tashkin, D.P., Yu, G.P., Marshall, J.R, Simmons, M., Bourque, L.B., Duann, S., marihuana cigarettes with pathogenic Hsu, T.C., and Schantz, S.P. (1999). Spivey, G.H., and Gong, H. (1987). bacteria-possible source of infection in Marijuana use and increased risk of cancer patients. Cancer Treatment Respiratory symptoms and lung function squamous cell carcinoma of the head and Reports. 66(3):589–91. in habitual, heavy smokers of marijuana neck. Cancer Epidemiology, Biomarkers alone, smokers of marijuana and tobacco, van Os, J., Bak, M., Hanssen, M., Bijl, R.V., and Prevention. 8(12): 1071–8. smokers of tobacco alone, and de Graaf, R., and Verdoux, H. (2002). nonsmokers. American Review of Cannabis use and psychosis: a [FR Doc. 2011–16994 Filed 7–7–11; 8:45 am] Respiratory Disease. 135:209–216. longitudinal population-based study. BILLING CODE 4410–09–P

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