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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Exploring Psychedelics and Entactogens as Treatments for Psychiatric Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26648.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Exploring Psychedelics and Entactogens as Treatments for Psychiatric Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26648.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Exploring Psychedelics and Entactogens as Treatments for Psychiatric Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26648.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Exploring Psychedelics and Entactogens as Treatments for Psychiatric Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26648.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Exploring Psychedelics and Entactogens as Treatments for Psychiatric Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26648.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Exploring Psychedelics and Entactogens as Treatments for Psychiatric Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26648.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Exploring Psychedelics and Entactogens as Treatments for Psychiatric Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26648.
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Page viii Cite
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Exploring Psychedelics and Entactogens as Treatments for Psychiatric Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26648.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Exploring Psychedelics and Entactogens as Treatments for Psychiatric Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26648.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Exploring Psychedelics and Entactogens as Treatments for Psychiatric Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26648.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Exploring Psychedelics and Entactogens as Treatments for Psychiatric Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26648.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Exploring Psychedelics and Entactogens as Treatments for Psychiatric Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26648.
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PageR12
Page xiii Cite
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Exploring Psychedelics and Entactogens as Treatments for Psychiatric Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26648.
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PageR13
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2022. Exploring Psychedelics and Entactogens as Treatments for Psychiatric Disorders: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/26648.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Exploring Psychedelics and Entactogens as Treatments for Psychiatric Disorders Lisa Bain, Chanel Matney, Sheena M. Posey Norris, and Clare Stroud, Rapporteurs Forum on Neuroscience and Nervous System Disorders Board on Health Sciences Policy Health and Medicine Division PREPUBLICATION COPY—Uncorrected Proofs Proceedings of a Workshop

THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 This activity was supported by contracts between the National Academy of Sciences and the Alzheimer’s Association; California Institute for Regenerative Medicine; Cerevel Therapeutics; Cohen Veterans Bioscience; Department of Health and Human Services’ Food and Drug Administration (R13FD005362) and National Institutes of Health (NIH) (75N98019F00769 [Under Master Base HHSN263201800029I]) through the National Center for Complementary and Integrative Health, National Eye Institute, National Institute of Environmental Health Sciences, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute on Aging, National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse, and NIH BRAIN Initiative; Department of Veterans Affairs (36C24E20C0009); Eisai Inc.; Eli Lilly and Company; Foundation for the National Institutes of Health; Gatsby Charitable Foundation; Janssen Research & Development, LLC; Karuna Therapeutics; Lundbeck Research USA; Merck Research Laboratories; The Michael J. Fox Foundation for Parkinson’s Research; National Multiple Sclerosis Society; National Science Foundation (DBI-1839674); One Mind; Simons Foundation Autism Research Initiative; Takeda Pharmaceuticals International, Inc.; and Wellcome Trust. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project. International Standard Book Number-13: 978-0-309-XXXXX-X International Standard Book Number-10: 0-309-XXXXX-X Digital Object Identifier: https://doi.org/10.17226/26648 This publication is available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. Copyright 2022 by the National Academy of Sciences. National Academies of Sciences, Engineering, and Medicine and National Academies Press and the graphical logos for each are all trademarks of the National Academy of Sciences. All rights reserved. Printed in the United States of America. Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2022. Exploring psychedelics and entactogens as treatments for psychiatric disorders: Proceedings of a workshop. Washington, DC: The National Academies Press. https://doi.org/10.17226/26648. PREPUBLICATION COPY—Uncorrected Proofs

The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president. The National Academy of Engineering was established in 1964 under the charter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. John L. Anderson is president. The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president. The three Academies work together as the National Academies of Sciences, Engineering, and Medicine to provide independent, objective analysis and advice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine. Learn more about the National Academies of Sciences, Engineering, and Medicine at www.nationalacademies.org. PREPUBLICATION COPY—Uncorrected Proofs

Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the study’s statement of task by an authoring committee of experts. Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and the committee’s deliberations. Each report has been subjected to a rigorous and independent peer-review process and it represents the position of the National Academies on the statement of task. Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies. Rapid Expert Consultations published by the National Academies of Sciences, Engineering, and Medicine are authored by subject-matter experts on narrowly focused topics that can be supported by a body of evidence. The discussions contained in rapid expert consultations are considered those of the authors and do not contain policy recommendations. Rapid expert consultations are reviewed by the institution before release. For information about other products and activities of the National Academies, please visit www.nationalacademies.org/about/whatwedo. PREPUBLICATION COPY—Uncorrected Proofs

EXPLORING PSYCHEDELICS AND ENTACTOGENS AS TREATMENTS FOR PSYCHIATRIC DISORDERS1 SARAH H. LISANBY (Co-Chair), National Institute of Mental Health GERARD SANACORA (Co-Chair), Yale University PAUL APPELBAUM, Columbia University CHARMA DUDLEY, National Alliance on Mental Illness ALLYSON GAGE, Cohen Veterans Bioscience JAVIER GONZALEZ-MAÉSO, Virginia Commonwealth University ROLAND GRIFFITHS, Johns Hopkins University VICTORIA HALE, Sacred Medicines JOHN KRYSTAL, Yale University TRISTAN McCLURE-BEGLEY, Defense Advanced Research Projects Agency JAVIER MUÑIZ, Food and Drug Administration SRINIVAS RAO, atai Life Sciences RITA VALENTINO, National Institute on Drug Abuse Health and Medicine Division Staff CHANEL MATNEY, Program Officer (until June 2022) EDEN NELEMAN, Senior Program Assistant SHEENA M. POSEY NORRIS, Director, Forum on Neuroscience and Nervous System Disorders CLARE STROUD, Senior Board Director, Board on Health Sciences Policy 1 The National Academies of Sciences, Engineering, and Medicine’s planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published Proceedings of a Workshop rests with the workshop rap- porteurs and the institution. v PREPUBLICATION COPY—Uncorrected Proofs

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FORUM ON NEUROSCIENCE AND NERVOUS SYSTEM DISORDERS1 FRANCES JENSEN (Co-Chair), University of Pennsylvania JOHN KRYSTAL (Co-Chair), Yale University SUSAN AMARA, National Institute of Mental Health ELINE APPELMANS, Foundation for the National Institutes of Health KATJA BROSE, Chan Zuckerberg Initiative EMERY BROWN, Harvard Medical School and Massachusetts Institute of Technology JOSEPH BUXBAUM, Icahn School of Medicine at Mount Sinai SARAH CADDICK, Gatsby Charitable Foundation ROSA CANET-AVILÉS, California Institute for Regenerative Medicine MARIA CARRILLO, Alzheimer’s Association EDWARD CHANG, University of California, San Francisco (until July 2022) MICHAEL CHIANG, National Eye Institute TIMOTHY COETZEE, National Multiple Sclerosis Society JONATHAN COHEN, Princeton University BEVERLY DAVIDSON, University of Pennsylvania (from August 2022) BILLY DUNN, Food and Drug Administration MICHAEL EGAN, Merck Research Laboratories MICHELLE ELEKONICH, National Science Foundation NITA FARAHANY, Duke University EVA FELDMAN, University of Michigan (from August 2022) BRIAN FISKE, The Michael J. Fox Foundation for Parkinson’s Research JOSHUA A. GORDON, National Institute of Mental Health MAGALI HAAS, Cohen Veterans Bioscience RICHARD HODES, National Institute on Aging STUART HOFFMAN, Department of Veterans Affairs YASMIN HURD, Icahn School of Medicine at Mount Sinai STEVEN HYMAN, Broad Institute of Massachusetts Institute of Technology and Harvard University MICHAEL IRIZARRY, Eisai Inc. PUSHKAR JOSHI, One Mind GEORGE KOOB, National Institute on Alcohol Abuse and Alcoholism WALTER KOROSHETZ, National Institute of Neurological Disorders and Stroke HUSSEINI MANJI, Johnson & Johnson (until June 2022) BILL MARTIN, Johnson & Johnson (from July 2022) 1 The National Academies of Sciences, Engineering, and Medicine’s forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution. vii PREPUBLICATION COPY—Uncorrected Proofs

GEORGINA MacKENZIE, Wellcome Trust (from August 2022) JOHN NGAI, National Institutes of Health BRAIN Initiative STEVE PAUL, Karuna Therapeutics RAYMOND SANCHEZ, Cerevel Therapeutics SARAH SHEIKH, Takeda Pharmaceuticals International DAVID SHURTLEFF, National Center for Complementary and Integrative Health JOHN SIMS, Eli Lilly and Company JOHN SPIRO, Simons Foundation Autism Research Initiative NORA VOLKOW, National Institute on Drug Abuse DOUG WILLIAMSON, Lundbeck RICHARD WOYCHIK, National Institute of Environmental Health Sciences Health and Medicine Division Staff SHEENA M. POSEY NORRIS, Director, Forum on Neuroscience and Nervous System Disorders CHANEL MATNEY, Program Officer (until June 2022) EDEN NELEMAN, Senior Program Assistant CHRISTIE BELL, Senior Finance Business Partner CLARE STROUD, Senior Board Director, Board on Health Sciences Policy viii PREPUBLICATION COPY—Uncorrected Proofs

Reviewers This Proceedings of a Workshop was reviewed in draft form by indi- viduals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical com- ments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published proceedings as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the charge. The review comments and draft manuscript remain confidential to protect the integrity of the process. We thank the following individuals for their review of this proceedings: PAUL APPELBAUM, Columbia University GÜL DÖLEN, Johns Hopkins University CAROLINE DORSEN, Rutgers University School of Nursing WALTER DUNN, University of California, Los Angeles KATRIN PRELLER, University of Zurich CARLOS ZARATE, The George Washington University Although the reviewers listed above provided many constructive com- ments and suggestions, they were not asked to endorse the content of the proceedings nor did they see the final draft before its release. The review of this proceedings was overseen by LESLIE Z. BENET, University of California, San Francisco. He was responsible for making certain that an independent examination of this proceedings was carried out in accordance with standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the rapporteurs and the National Academies. ix PREPUBLICATION COPY—Uncorrected Proofs

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Contents 1 INTRODUCTION AND BACKGROUND 1 The National Institutes of Health Examines Research Opportunities and Gaps, 2 Workshop Objectives, 4 Organization of the Proceedings, 6 2 HISTORY AND CURRENT STATUS OF PSYCHEDELICS AND ENTACTOGENS FOR THE TREATMENT OF PSYCHIATRIC DISORDERS 7 The Psychedelic Psychopharmacology Paradigm, 9 Personal Experiences of Psychedelic Treatment, 10 3 MECHANISMS OF ACTION AND KEY RESEARCH GAPS FOR PSYCHEDELICS AND ENTACTOGENS 15 Molecular Mechanisms, 16 Psychosocial Contexts as Essential Treatment Elements, 22 Linking Biological, Psychological, and Clinical Effects of Psychedelics: Research Gaps and Opportunities, 25 4 ADVANCING CLINICAL DEVELOPMENT: CHALLENGES AND OPPORTUNITIES 31 Confounders to Efficacy Assessments, 33 Clinical Efficacy: Recent Trials with MDMA and Psilocybin, 38 xi PREPUBLICATION COPY—Uncorrected Proofs

xii CONTENTS 5 ANTICIPATING IMPLEMENTATION TO GUIDE CLINICAL RESEARCH AND DEVELOPMENT 45 Frameworks for Accessible and Equitable Implementation, 47 Building Trust with Marginalized Communities, 49 Ensuring Safe and Ethical Research and Care Practices, 50 Navigating the Legal Complexity of Medicalizing Schedule 1 Substances, 53 6 REFLECTING ON THE ROAD AHEAD 55 Clinical Challenges for Psychedelic Therapy, 56 Perspectives from a Diverse Group of Stakeholders, 59 Concluding Remarks, 63 APPENDIXES A References 65 B Workshop Agenda 71 PREPUBLICATION COPY—Uncorrected Proofs

Acronyms and Abbreviations 5-HT1A Serotonin 1A receptor 5-HT2A Serotonin 2A receptor ACE Accept, Connect, Embody ACT Acceptance Commitment Therapy BDNF brain derived neurotrophic factor CAPS-IV Clinician-Administered PTSD Scale for DSM-IV CPT Current Procedural Terminology DARPA Defense Advanced Research Projects Agency DEA Drug Enforcement Administration DMT dimethyl tryptamine DSM Diagnostic and Statistical Manual of Mental Disorders FDA Food and Drug Administration fMRI functional magnetic resonance imagining GMP Good Manufacturing Practice LGBTQIA+ lesbian, gay, bisexual, transgender, queer, intersex, asexual LSD lysergic acid diethylamide MADRS Montgomery-Åsperg Depression Rating Scale xiii PREPUBLICATION COPY—Uncorrected Proofs

xiv ACRONYMS AND ABBREVIATIONS MAPS Multidisciplinary Association for Psychedelic Studies MDMA methylenedioxymethamphetamine mPEC medial prefrontal cortex MRI magnetic resonance imagine mTOR mammalian/mechanistic target of rapamycin NDA New Drug Application NIDA National Institute on Drug Abuse NIH National Institutes of Health NIMH National Institute of Mental Health OCD obsessive-compulsive disorder PBC Public Benefit Corporation PCP phencyclidine PET positron emission tomography PFC prefrontal cortex PTSD posttraumatic stress disorder REMS risk evaluation and mitigation strategy RTN reticular thalamic nuclei SAMHSA Substance Abuse and Mental Health Services Administration SNRI selective noradrenaline reuptake inhibitors SSRI serotonin reuptake inhibitors SV2A synaptic vesicle protein 2A TBG tabernanthalog TRD treatment-resistant depression VA Department of Veterans Affairs VEH vehicle control PREPUBLICATION COPY—Uncorrected Proofs

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Psychiatric illnesses - such as major depressive disorder, anxiety disorder, substance use disorder, and posttraumatic stress disorder (PTSD) - are widely prevalent and represent a substantial health burden worldwide. Yet, conventional medications for mental illnesses often fail to provide relief to patients' disruptive and disabling symptoms. Existing and emerging evidence that psychedelics (e.g., LSD and psilocybin) and entactogens (e.g., MDMA) may be useful as tools to alleviate mental illness has sparked a renaissance of interest by investigators, clinicians, drug developers, and patient advocates in recent years. While promising data on therapeutic efficacy has energized research and development, resolving the mechanisms of action will be important for optimizing the efficacy and safety of these medicines. Further, evaluating the effect of psychedelics and entactogens on mood and behavior comes with unique challenges still in need of resolution. These include unresolved questions relating to blinding, placebo and nocebo effects, and the impact of psychosocial contexts.

In response to this renewed interest, the National Academies of Sciences, Engineering, and Medicine's Forum on Neuroscience and Nervous System Disorders convened a workshop on March 29-30, 2022. The workshop brought together a diverse group of stakeholders to explore the use of psychedelics and entactogens as treatments for psychiatric disorders. This Proceedings of a Workshop summarizes the presentations and discussions of the workshop.

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