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Review
. 2025 Jan 1;182(1):79-103.
doi: 10.1176/appi.ajp.20230681.

MDMA and MDMA-Assisted Therapy

Aaron S Wolfgang  1 , Gregory A Fonzo  1 , Joshua C Gray  1 , John H Krystal  1 , Adrienne Grzenda  1 , Alik S Widge  1 , Nina V Kraguljac  1 , William M McDonald  1 , Carolyn I Rodriguez  1 , Charles B Nemeroff  1
Affiliations
Review

MDMA and MDMA-Assisted Therapy

Aaron S Wolfgang et al. Am J Psychiatry. .

Abstract

MDMA (i.e., 3,4-methylenedixoymethamphetamine), commonly known as "Ecstasy" or "Molly," has been used since the 1970s both in recreational and therapeutic settings. The Food and Drug Administration (FDA) designated MDMA-Assisted Therapy (MDMA-AT) as a Breakthrough Therapy for posttraumatic stress disorder (PTSD) in 2017, and the FDA is requiring an additional phase 3 trial after rejecting the initial New Drug Application in 2024. Unlike other psychedelics, MDMA uniquely induces prosocial subjective effects of heightened trust and self-compassion while maintaining ego functioning as well as cognitive and perceptual lucidity. While recreational use in nonmedical settings may still cause harm, especially due to adulterants or when used without proper precautions, conclusions that can be drawn from studies of recreational use are limited by many confounds. This especially limits the extent to which evidence related to recreational use can be extrapolated to therapeutic use. A considerable body of preliminary evidence suggests that MDMA-AT delivered in a controlled clinical setting is a safe and efficacious treatment for PTSD. After a course of MDMA-AT involving three MDMA administrations supported by psychotherapy, 67%-71% of individuals with PTSD no longer meet diagnostic criteria after MDMA-AT versus 32%-48% with placebo-assisted therapy, and effects endure at long-term follow-up. This review primarily aims to distinguish evidence of recreational use in nonclinical settings versus MDMA-AT using pharmaceutical-grade MDMA in controlled clinical settings. This review further describes the putative neurobiological mechanisms of MDMA underlying its therapeutic effects, the clinical evidence of MDMA-AT, considerations at the level of public health and policy, and future research directions.

Keywords: Clinical Drug Studies; Depressive Disorders; MDMA; Major Depressive Disorder; PTSD.

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Conflict of interest statement

Dr. Fonzo reports consulting for SynapseBio AI and Alto Neuroscience; stock ownership in Alto Neuroscience; and a U.S. Provisional Patent Application 16/981,822 filed on March 15, 2019 by Leland Stanford Junior University and the University of Texas System for treatment of depression. Dr. Krystal reports editorial compensation as Editor of Biological Psychiatry; he is the co-founder of Freedom Biosciences, Inc.; he reports consulting for Aptinyx, Inc., Biogen, Idec, MA, Bionomics, Limited (Australia), Boehringer Ingelheim International, Epiodyne, Inc., EpiVario, Inc., Janssen Research & Development, Jazz Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc., Spring Care, Inc., Sunovion Pharmaceuticals, Inc.; he has received research support (drug supply) from AstraZeneca Pharmaceuticals, Cerevel, and Novartis; he has served on scientific advisory boards for Biohaven Pharmaceuticals, BioXcel Therapeutics, Inc. (Clinical Advisory Board), Cerevel Therapeutics, LLC, Delix Therapeutics, Inc., Eisai, Inc., EpiVario, Inc., Jazz Pharmaceuticals, Inc., Neumora Therapeutics, Inc., Neurocrine Biosciences, Inc., Novartis Pharmaceuticals Corporation, PsychoGenics, Inc., Takeda Pharmaceuticals, Tempero Bio, Inc., Terran Biosciences, Inc. Stock: Biohaven Pharmaceuticals, Freedom Biosciences, Spring Health, Inc. Stock Options: Biohaven Pharmaceuticals Medical Sciences, Cartego Therapeutics, Damona Pharmaceuticals, Delix Therapeutics, EpiVario, Inc., Neumora Therapeutics, Inc., Rest Therapeutics, Tempero Bio, Inc., Terran Biosciences, Inc., Tetricus, Inc.; and he holds the following patents: 1) Seibyl JP, Krystal JH, Charney DS: Dopamine and Noradrenergic Reuptake Inhibitors in Treatment of Schizophrenia (U.S. Patent #:5,447,948. September 5, 1995), 2) Vladimir C, Krystal, JH, Sanacora G: Glutamate Modulating Agents in the Treatment of Mental Disorders (U.S. Patent No. 8,778,979 B2 Patent Issue Date: July 15, 2014. US Patent Application No. 15/695,164: Filing Date: 09/05/2017), 3) Charney D, Krystal JH, Manji H, Matthew S, Zarate C: Intranasal Administration of Ketamine to Treat Depression (U.S. Patent Number: 9592207, Issue date: 3/14/2017. Licensed to Janssen Research & Development), 4) Zarate C, Charney DS, Manji HK, Mathew SJ, Krystal JH, Yale University: Methods for Treating Suicidal Ideation (Patent Application No. 15/379,013 filed on December 14, 2016 by Yale University Office of Cooperative Research), 5) Arias A, Petrakis I, Krystal JH: Composition and Methods to Treat Addiction (Provisional Use Patent Application no.61/973/961. April 2, 2014. Filed by Yale University Office of Cooperative Research), 6) Chekroud A, Gueorguieva R, Krystal, JH: Treatment Selection for Major Depressive Disorder (filing date June 3, 2016, USPTO docket number Y0087.70116US00. Provisional patent submission by Yale University, 7) Gihyun Y, Petrakis I, Krystal JH: Compounds, Compositions and Methods for Treating or Preventing Depression and Other Diseases (U.S. Provisional Patent Application No. 62/444,552, filed on January 10, 2017 by Yale University Office of Cooperative Research OCR 7088 US01), 8) Abdallah C, Krystal JH, Duman R, Sanacora G: Combination Therapy for Treating or Preventing Depression or Other Mood Diseases. (U.S. Provisional Patent Application No. 62/719,935 filed on August 20, 2018 by Yale University Office of Cooperative Research OCR 7451 US01), 9) Krystal J, Pearlson G, O’Malley S, Potenza M, Gasparini F, Gomez-Mancilla B, Malaterre V: Mavoglurant in Treating Gambling and Gaming Disorders (U.S. Provisional Patent Application No. 63/125,181, filed on December 14, 2020 by Yale University Office of Cooperative Research OCR 8065 US00). Dr. Widge reports research support (non-Federal) from MnDRIVE Brain Conditions Initiative, Minnesota Medical Discovery Team on Addictions. Dr. Nemeroff reports a compensated board membership with Lucy Scientific Discovery, Inc.; serving as a consultant for Abbvie, ANeuroTech (division of Anima BV), Signant Health, Intra-Cellular Therapies, Inc., EMA Wellness, Sage, Silo Pharma, Engrail Therapeutics, GoodCap Pharmaceuticals, Inc., Senseye, Clexio, EmbarkNeuro, SynapseBio, BioXcel Therapeutics, Galen Mental Health; serving on scientific advisory boards for ANeuroTech (division of Anima BV), Brain and Behavior Research Foundation (BBRF), Anxiety and Depression Association of America (ADAA), Skyland Trail, Signant Health, Laureate Institute for Brain Research (LIBR), Sage; owning stock or stock options in Seattle Genetics, Corcept Therapeutics Pharmaceuticals Company, EMA Wellness, Relmada Therapeutics, Galen Mental Health; and holds the following patents: 1) Method and Devices for Transdermal Delivery of Lithium (U.S. 6,375,990B1) and 2) Method of Assessing Antidepressant Drug Therapy via Transport Inhibition of Monoamine Neurotransmitters by Ex Vivo Assay (U.S. 7,148,027B2). Disclosures of Editors’ financial relationships (McDonald, Rodriguez) appear in the April 2024 issue of the Journal. All other authors report no financial relationships with commercial interests.

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