MDMA-Assisted Therapy for Severe PTSD: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study

Jennifer M Mitchell¹, Michael Bogenschutz¹, Alia Lilienstein¹, Charlotte Harrison¹, Sarah Kleiman¹, Kelly Parker-Guilbert¹, Marcela Ot'alora G¹, Wael Garas¹, Casey Paleos¹, Ingmar Gorman¹, Christopher Nicholas¹, Michael Mithoefer¹, Shannon Carlin¹, Bruce Poulter¹, Ann Mithoefer¹, Sylvestre Quevedo¹, Gregory Wells¹, Sukhpreet S Klaire¹, Bessel van der Kolk¹, Keren Tzarfaty¹, Revital Amiaz¹, Ray Worthy¹, Scott Shannon¹, Joshua D Woolley¹, Cole Marta¹, Yevgeniy Gelfand¹, Emma Hapke¹, Simon Amar¹, Yair Wallach¹, Randall Brown¹, Scott Hamilton¹, Julie B Wang¹, Allison Coker¹, Rebecca Matthews¹, Alberdina de Boer¹, Berra Yazar-Klosinski¹, Amy Emerson¹, Rick Doblin¹

Affiliations

Affiliation

¹ Department of Neurology, University of California San Francisco, San Francisco, CA, USA. Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, CA, USA. Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, USA. Multidisciplinary Association for Psychedelic Studies (MAPS), San Jose, CA, USA. MAPS Public Benefit Corporation (MAPS PBC), San Jose, CA, USA. Kleiman Consulting and Psychological Services, Sayreville, NJ, USA. KPG Psychological Services LLC, Brunswick, ME, USA. Aguazul-Bluewater Inc., Boulder, CO, USA. MDMA Therapy Training Program, MAPS Public Benefit Corporation, San Jose, CA, USA. Nautilus Sanctuary, New York, NY, USA. Fluence, Woodstock, NY, USA. Department of Family Medicine and Community Health, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. Medical University of South Carolina, Charleston, SC, USA. San Francisco Insight and Integration Center, San Francisco, CA, USA. British Columbia Centre on Substance Use, Vancouver, British Columbia, Canada. Boston University School of Medicine, Boston, MA, USA. Chaim Sheba Medical Center, Tel HaShomer, Israel. Ray Worthy Psychiatry LLC, New Orleans, LA, USA. Wholeness Center, Fort Collins, CO, USA. New School Research LLC, North Hollywood, CA, USA. Zen Therapeutic Solutions, Mt Pleasant, SC, USA. University of Toronto, Toronto, Ontario, Canada. Dr Simon Amar Inc., Montreal, Quebec, Canada. Be'er Ya'akov Ness Ziona Mental Health Center, Be'er Ya'akov, Israel. Stanford School of Medicine, Stanford, CA, USA. e-mail: jennifer.mitchell@ucsf.edu.

PMID: 37404971
PMCID: PMC10316215
DOI: 10.1176/appi.focus.23021011

MDMA-Assisted Therapy for Severe PTSD: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study

Jennifer M Mitchell et al. Focus (Am Psychiatr Publ). 2023 Jul.

. 2023 Jul;21(3):315-328.

doi: 10.1176/appi.focus.23021011. Epub 2023 Jun 28.

Authors

Affiliation

¹ Department of Neurology, University of California San Francisco, San Francisco, CA, USA. Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, CA, USA. Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, USA. Multidisciplinary Association for Psychedelic Studies (MAPS), San Jose, CA, USA. MAPS Public Benefit Corporation (MAPS PBC), San Jose, CA, USA. Kleiman Consulting and Psychological Services, Sayreville, NJ, USA. KPG Psychological Services LLC, Brunswick, ME, USA. Aguazul-Bluewater Inc., Boulder, CO, USA. MDMA Therapy Training Program, MAPS Public Benefit Corporation, San Jose, CA, USA. Nautilus Sanctuary, New York, NY, USA. Fluence, Woodstock, NY, USA. Department of Family Medicine and Community Health, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. Medical University of South Carolina, Charleston, SC, USA. San Francisco Insight and Integration Center, San Francisco, CA, USA. British Columbia Centre on Substance Use, Vancouver, British Columbia, Canada. Boston University School of Medicine, Boston, MA, USA. Chaim Sheba Medical Center, Tel HaShomer, Israel. Ray Worthy Psychiatry LLC, New Orleans, LA, USA. Wholeness Center, Fort Collins, CO, USA. New School Research LLC, North Hollywood, CA, USA. Zen Therapeutic Solutions, Mt Pleasant, SC, USA. University of Toronto, Toronto, Ontario, Canada. Dr Simon Amar Inc., Montreal, Quebec, Canada. Be'er Ya'akov Ness Ziona Mental Health Center, Be'er Ya'akov, Israel. Stanford School of Medicine, Stanford, CA, USA. e-mail: jennifer.mitchell@ucsf.edu.

PMID: 37404971
PMCID: PMC10316215
DOI: 10.1176/appi.focus.23021011

Abstract

Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P < 0.0001, d = 0.91) and to significantly decrease the SDS total score (P = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was -24.4 (s.d. 11.6) in the MDMA group and -13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation. Appeared originally in Nat Med 2021; 27:1025-1033.

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MDMA-Based Psychotherapy in Treatment-Resistant Post-Traumatic Stress Disorder (PTSD): A Brief Narrative Overview of Current Evidence.
Riaz K, Suneel S, Hamza Bin Abdul Malik M, Kashif T, Ullah I, Waris A, Di Nicola M, Mazza M, Sani G, Martinotti G, De Berardis D. Riaz K, et al. Diseases. 2023 Nov 3;11(4):159. doi: 10.3390/diseases11040159. Diseases. 2023. PMID: 37987270 Free PMC article. Review.

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MDMA-Assisted Therapy for Severe PTSD: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study

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MDMA-Assisted Therapy for Severe PTSD: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study

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