Assessment of Kratom under the CSA Eight Factors and Scheduling Recommendation November 28, 2016 Page 1 of 126 Contents List of In-Text Tables....................................................................................................... 4 List of Abbreviations........................................................................................................ 5 1 Summary, Interpretation, and Discussion of Abuse Potential Data........................ 13 2 Analysis of Kratom under the CSA 8 Factors......................................................... 21 3 Review of the Eight Factors of the Controlled Substances Act ..............................21 3.1 Factor 1: Its actual or relative potential for abuse............................................. 21 3.1.1 Animal Data on Drug Discrimination and Reinforcement........................... 23 3.1.2 Summary of Factor 1 ................................................................................. 30 3.2 Factor 2: Scientific evidence of its pharmacological effect, if known ................ 30 3.3 Factor 3: The state of current scientific knowledge regarding the drug or other substance .................................................................................................................. 33 3.4 Factor 4: Its history and current pattern of abuse............................................. 35 3.4.1 History ....................................................................................................... 35 3.4.2 Federal Surveys ........................................................................................ 37 3.4.3 Other Federal Data Sources...................................................................... 38 3.5 Factor 5: The scope, duration, and significance of abuse................................ 40 3.5.1 Internet monitoring..................................................................................... 41 3.5.2 Dr. Oliver Grundmann Preliminary Report on Kratom Use and the Health Impact of Kratom Consumption – An online anonymous survey............................ 44 3.5.3 Testimonials Regarding Benefits............................................................... 46 3.6 Factor 6: What, if any, risk there is to the public health....................................46 3.6.1 American Association of Poison Control Centers’ National Poison Data System (AAPCC-NPDS) ........................................................................................ 48 3.6.2 Pediatric/Child (less than 6 years of age) exposure related adverse events and deaths. ............................................................................................................ 48 3.6.3 Ex-US Safety/Toxicity Data ....................................................................... 51 3.6.4 Deaths Possibly Involving Kratom ............................................................. 52 3.7 Factor 7: Its psychic or physiological dependence liability ............................... 55 3.8 Factor 8: Whether the substance is an immediate precursor of a substance already controlled under this subchapter................................................................... 56 4 Recommendation................................................................................................... 56 5 Conclusion ............................................................................................................. 64 6 References............................................................................................................. 65 Attachment A: Testimonies of Kratom Consumers........................................................ 75 Page 2 of 126 Page 3 of 126 List of In-Text Tables Table 1. Number of units that would be required to achieve discrimination and reinforcement from several over-the-counter products................................... 26 Table 2. Number of Unweighted Cases of Kratom, Aspirin and Diphenhydramine Reported to the National Survey on Drug Use and Health, 2010-2014..........38 Table 3. National Semiannual Estimates of Selected Opiate and Related Drug Reports in NFLIS, 2009-2014. ..................................................................................... 40 Table 4. Verbatim accounts from Internet reports from a website that typically attracts people with histories of diverse substance use and abuse to describe their experiences .................................................................................................... 41 Page 4 of 126 List of Abbreviations Abbreviation Definition 7-OH-MG 7-Hydroxymitragynine 8FA Summary Analysis of the 8 Factors AAPCC-NPDS American Association of Poison Control Centers’ National Poison Data System AKA American Kratom Association APA American Psychiatric Association CA2+ Calcium CDC CentersforDiseaseControlandPrevention CFR Code of Federal Regulations CNS Central Nervous System CPP Conditioned Place Preference CSA ControlledSubstancesAct DAWN Drug Abuse Warning Network DEA Drug Enforcement Administration DHHS Department of Health and Human Services DSM-5 The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition EC50 Median Effective Concentration Emax Maximal Efficacy EMCDDA European Monitoring Centre for Drugs and Drug Addiction FDA Food and Drug Administration FDCA Federal Food, Drug, and Cosmetic Act FOIA Freedom of Information Act g Gram GI Gastrointestinal Page 5 of 126 Abbreviation Definition h Hour i.p. Intraperitoneal IC50 Inhibitory Concentration of 50% kg Kilogram MeOH Methanol mg Milligram MG Mitragynine MTF Monitoring the Future N Number N/A Not Applicable NEISS-CADES National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance NFLIS National Forensic Laboratory Information System NIDA NationalInstituteonDrugAbuse nM Nanomolar NSAIDS Nonsteroidal Anti-Inflammatory Drugs NSDUH National Survey on Drug Use and Health p.o. ByMouth,Orally s.c. Subcutaneously SAE SeriousAdverseEvent SE Southeast SG SurgeonGeneral SR Sustained Release TEDS Treatment Episode Datasets THC Tetrahydrocannabinol USorU.S. UnitedStates Page 6 of 126 Abbreviation Definition USC United States Code δ Delta κ Kappa μ Mu μM Micromolar Page 7 of 126 Definitions Term Definition Abuse potential Abuse potential, often referred to as abuse liability, is the term (liability) used to describe the risk that a substance carries for sustaining self-administration due to central nervous system effects that are typically reinforcing and often pleasant, yet associated with harm. From a regulatory perspective abuse potential is evaluated by 8 factors listed in the Controlled Substances Act (CSA) for the purpose of determining if a substance or drug meets criteria for placement in the CSA and regulation as a controlled substance. In that case, the level or severity of abuse potential is a factor in determining how restrictively a substance or new drug should be regulated. Many substances that are not placed in the CSA have noteworthy levels of abuse potential, e.g. caffeine, nicotine, nutmeg, various antihistamines, glues, whipped-cream aerosols, salvia, and dextromethorphan (active ingredient in many cough suppressants) (Hanson, 2014; See discussion in FDA 2010b and NIDA, https://www.drugabuse.gov/publications/finder/t/160/ DrugFacts). Addiction Addiction is often used interchangeably with terms such as dependence and substance use disorder (see further on in definitions). Addiction is generally defined as a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. This definition of addiction has been accepted by the American Academy of Pain Medicine, the American Pain Society and the American Society of Addiction Medicine. See also O’Brien, 2011. The National Institute on Drug Abuse (NIDA) focuses more on the research and mechanisms of addiction in its definition. It defines addiction as a chronic, relapsing brain disease that is characterized by compulsive drug seeking and use, despite harmful consequences. It is considered a brain disease because drugs change the brain—they change its structure and function. These brain changes can be long-lasting, and can lead to the harmful behaviors seen in people who abuse drugs. Page 8 of 126 Term Definition NIDA, and many others, consider addiction to be equivalent to a severe substance use disorder as defined in the APA DSM-5 (see https://www.drugabuse.gov/publications/media-guide/ science-drug-abuse-addiction-basics). Eight Factors of the (1) Actual and relative potential for abuse CSA which must be (2) Scientific evidence of its pharmacological effects analyzed for (3) State of the current scientific knowledge regarding the drug scheduling (4) History and current pattern of abuse recommendations (5) Scope, duration, and significance of abuse (6) Public health risk (7) Psychic or physiologic dependence potential (8) Whether the drug is an immediate precursor of a controlled substance Controlled Placement of a substance in the CSA is often referred to as Substances Act being “scheduled” because it must be placed in one of the five Drug Schedules drug schedules based on the 8-Factor Analysis of the CSA. Schedule I (C-I): Substances that do not have an accepted medical use and have a high abuse potential and/or were designated for C-I in the 1970 CSA, e.g., heroin, LSD, GHB, “bath