Investigator’s Brochure SPONSOR Multidisciplinary Association for Psychedelic Studies (MAPS) 3141 Stevens Creek Blvd #40563 San Jose, CA 95117 PRODUCT 3,4-methylenedioxymethamphetamine (MDMA) DATA CUT-OFF DATE 01 October 2020 VERSION DATE 22 March 2021 EFFECTIVE DATE 31 March 2021 EDITION 13th Edition REPLACES 12th Edition (dated 17 August 2020) MAPS MDMA Investigator’s Brochure U.S. 13th Ed: 22 March 2021 Table of Contents List of Tables .................................................................................................................................. 5 List of Appendix Tables................................................................................................................. 7 List of Figures ................................................................................................................................. 8 List of Abbreviations ..................................................................................................................... 9 1.0 Summary ................................................................................................................................. 11 2.0 Introduction ............................................................................................................................ 13 3.0 Physical, Chemical, and Pharmaceutical Properties and Formulation ............................ 15 4.0 Nonclinical Studies ................................................................................................................. 17 4.1 Nonclinical Pharmacology ....................................................................................................... 17 4.1.1 Primary Pharmacodynamics ......................................................................................... 20 4.1.2 Secondary Pharmacodynamics ..................................................................................... 22 4.1.3 Safety Pharmacology .................................................................................................... 23 4.1.4 Central Nervous System ............................................................................................... 23 4.1.4.1 Cardiovascular System ........................................................................................... 27 4.1.4.2 Respiratory System ................................................................................................ 28 4.1.4.3 Hepatic System ...................................................................................................... 29 4.1.4.4 Renal System ......................................................................................................... 29 4.1.5 Pharmacodynamic Drug Interactions ............................................................................ 30 4.2 Pharmacokinetics and Product Metabolism in Animals .......................................................... 30 4.2.1 Absorption..................................................................................................................... 31 4.2.2 Distribution ................................................................................................................... 31 4.2.3 Metabolism ................................................................................................................... 32 4.2.4 Elimination .................................................................................................................... 33 4.2.5 Pharmacokinetic Drug Interactions ............................................................................... 33 4.3 Toxicology ............................................................................................................................... 34 4.3.1 Single-Dose Toxicology Studies ................................................................................... 34 4.3.2 Repeat-Dose Toxicology Studies .................................................................................. 35 4.3.3 Genotoxicity .................................................................................................................. 37 4.3.4 Carcinogenicity ............................................................................................................. 38 4.3.5 Reproductive and Developmental Toxicity .................................................................. 38 4.3.6 Other Toxicity Studies .................................................................................................. 40 4.3.6.1 Immunological Effects ........................................................................................... 40 4.3.6.2 Mechanistic Studies ............................................................................................... 41 4.3.6.3 Abuse Potential ...................................................................................................... 42 5.0 Epidemiological and Naturalistic Evidence Summary ....................................................... 43 5.1 Serious Reports of Incidents, Mortality, and Morbidity .......................................................... 44 5.1.1 Thermoregulatory Disorders ......................................................................................... 47 5.1.2 Cardiac Disorders .......................................................................................................... 47 5.1.3 Metabolism and Nutrition Disorders ............................................................................. 48 5.1.4 Hepatobiliary Disorders ................................................................................................ 49 5.1.5 Blood and Lymphatic System Disorders ...................................................................... 49 5.1.6 Injuries, Poisonings, and Procedural Complications..................................................... 49 5.1.7 Gastrointestinal Disorders ............................................................................................. 49 5.1.8 Respiratory, Thoracic, and Mediastinal Disorders ........................................................ 50 5.1.9 Psychiatric Disorders .................................................................................................... 50 5.1.10 Nervous System Disorders .......................................................................................... 51 5.2 Cognitive Function and Performance ...................................................................................... 52 6.0 Effects in Humans in Clinical Settings ................................................................................. 54 6.1 History of Use in Clinical Settings .......................................................................................... 54 6.1.1 Phase 1 Studies ............................................................................................................. 59 Page 2 of 227 MAPS MDMA Investigator’s Brochure U.S. 13th Ed: 22 March 2021 6.1.2 Phase 2 Studies ............................................................................................................. 59 6.1.2.1 Study MP-1 ............................................................................................................ 60 6.1.2.2 Study MP-8 ............................................................................................................ 60 6.1.2.3 Study MP-12 .......................................................................................................... 60 6.1.2.4 Study MP16 ........................................................................................................... 61 6.1.2.5 Other Phase 2 Studies ............................................................................................ 61 6.1.3 Phase 3 Studies ............................................................................................................. 62 6.1.3.1 Study MAPP1 ........................................................................................................ 62 6.1.4 Non-PTSD Indication Phase 2 Studies ......................................................................... 63 6.2 Pharmacology in Humans ........................................................................................................ 63 6.2.1 Pharmacokinetics and Product Metabolism in Humans ................................................ 64 6.2.1.1 Absorption.............................................................................................................. 64 6.2.1.2 Distribution ............................................................................................................ 64 6.2.1.3 Metabolism ............................................................................................................ 64 6.2.1.4 Elimination ............................................................................................................. 66 6.2.1.5 Pharmacogenomics ................................................................................................ 66 6.2.1.6 Pharmacokinetic Drug Interactions ........................................................................ 67 6.2.2 Pharmacodynamics ....................................................................................................... 69 6.2.2.1 Primary Pharmacodynamics .................................................................................. 69 6.2.2.2 Secondary Pharmacodynamics .............................................................................. 70 6.2.3 Physiological Effects ...................................................................................................