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Cited by 455Psychedelics and Drug StudiesPosttraumatic Stress Disorder ResearchPsychotherapy Techniques and Applications

MDMA-assisted therapy for moderate to severe PTSD: A randomized, placebo-controlled phase 3 trial

Open access
Mitchell, Jennifer M., Ot’alora G., Marcela, van der Kolk, Bessel, Shannon, Scott, Bogenschutz, Michael, Gelfand, Yevgeniy, Paleos, Casey, Nicholas, Christopher R. +26 more·2023·Nature Medicine
DOI 10.1038/s41591-023-02565-4PMC PMC10579091
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Abstract

This multi-site, randomized, double-blind, confirmatory phase 3 study evaluated the efficacy and safety of 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) versus placebo with identical therapy in participants with moderate to severe post-traumatic stress disorder (PTSD). Changes in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total severity score (primary endpoint) and Sheehan Disability Scale (SDS) functional impairment score (key secondary endpoint) were assessed by blinded independent assessors. Participants were randomized to MDMA-AT (n = 53) or placebo with therapy (n = 51). Overall, 26.9% (28/104) of participants had moderate PTSD, and 73.1% (76/104) of participants had severe PTSD. Participants were ethnoracially diverse: 28 of 104 (26.9%) identified as Hispanic/Latino, and 35 of 104 (33.7%) identified as other than White. Least squares (LS) mean change in CAPS-5 score (95% confidence interval (CI)) was -23.7 (-26.94, -20.44) for MDMA-AT versus -14.8 (-18.28, -11.28) for placebo with therapy (P < 0.001, d = 0.7). LS mean change in SDS score (95% CI) was -3.3 (-4.03, -2.60) for MDMA-AT versus -2.1 (-2.89, -1.33) for placebo with therapy (P = 0.03, d = 0.4). Seven participants had a severe treatment emergent adverse event (TEAE) (MDMA-AT, n = 5 (9.4%); placebo with therapy, n = 2 (3.9%)). There were no deaths or serious TEAEs. These data suggest that MDMA-AT reduced PTSD symptoms and functional impairment in a diverse population with moderate to severe PTSD and was generally well tolerated. ClinicalTrials.gov identifier: NCT04077437 .

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  • MDMA's pharmacological properties may facilitate alliance formation by increasing compassion, empathy, and emotional engagement.

    “MDMA’s unique pharmacological properties may facilitate alliance formation by increasing compassion, empathy, and emotional engagement, which contribute to deeper therapeutic work (6, 158).”

    From Psychoanalytically informed MDMA-assisted therapy for pathological narcissism: a novel theoretical approach (2025) · cites this paper as [6]

    The Discussion says MDMA induces prosocial feelings, may help people with PTSD benefit from psychotherapy, and appears to increase participant engagement. The Main section describes its pharmacological action. Neither passage says that MDMA increases compassion or facilitates therapeutic alliance formation, so those parts of the claim go beyond this paper’s account. (LLM, conf=0.84)

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  • MDMA-AT improves self-experience in patients with PTSD, including self-compassion and emotional regulation.

    “Recent studies have shown that MDMA-AT improves self-experience in patients with PTSD, including their self-compassion and emotional regulation (6).”

    From Psychoanalytically informed MDMA-assisted therapy for pathological narcissism: a novel theoretical approach (2025) · cites this paper as [6]

    The Discussion (page unavailable) says MDMA softens responses to emotionally challenging stimuli and may reduce fear and negative emotionality during psychotherapy. The trial’s Results report reduced PTSD symptoms, but our copy does not establish improvements in self-experience or self-compassion, or measure emotional regulation as an outcome. (LLM, conf=0.79)

    Experimental — accuracy not yet measured

  • Emerging research supports the safety and efficacy of psychedelic-assisted therapy (PAT) in a controlled clinical environment for several treatment-resistant psychiatric disorders including depression, PTSD, substance use disorders, social anxiety, and obsessive-compulsive disorder.

    “Emerging research supports the safety and efficacy of psychedelic-assisted therapy (PAT) when administered in a controlled clinical environment (1, 2) for several treatment-resistant psychiatric disorders including depression (3–5), post-traumatic stress disorder (PTSD) (6, 7), substance use disorders (8, 9), social anxiety (10), and obsessive-compulsive disorder (11).”

    From Psychoanalytically informed MDMA-assisted therapy for pathological narcissism: a novel theoretical approach (2025) · cites this paper as [6]

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Authors
Mitchell, J. M., Ot’alora G., M., van der Kolk, B., Shannon, S., Bogenschutz, M., Gelfand, Y., Paleos, C., Nicholas, C. R., Quevedo, S., Balliett, B., Hamilton, S., Mithoefer, M., Kleiman, S., Parker-Guilbert, K., Tzarfaty, K., Harrison, C., de Boer, A., Doblin, R., Yazar-Klosinski, B., MAPP2 Study Collaborator Group, Harrison, C., Yazar-Klosinski, B., Garas, W., May, D., Marta, C., Walker, S., Nielson, E., Wells, G., Brown, R., Amiaz, R., Wallach, Y., Worthy, R., Lilienstein, A., & Emerson, A.
Affiliations
  • San Francisco VA Medical Center (US)
  • New York University (US)
  • University of Wisconsin–Madison (US)
  • University of California, San Francisco (US)
  • Los Angeles Police Department (US)
  • Medical University of South Carolina (US)
  • University of Haifa (IL)
  • Multidisciplinary Association for Psychedelic Studies (US)
Corresponding author
Mitchell, Jennifer M.
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2023-09-14
Volume
29
Issue
10
Pages
2473-2480
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-023-02565-4
PMC
PMC10579091
OpenAlex
W4386740988
Cited by
455
References
39
Citations by year
2026: 139 · 2025: 160 · 2024: 145 · 2023: 10
FWCI
131.32
Type
journal article
Language
en
Update notices
correction (2024-10-07)
Open access
Licence
Locations
  • Nature Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
Funded by MAPS and Steven and Alexandra Cohen Foundation, Inc. and organized by MAPS PBC.
Topics
  • Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
  • Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
  • Social Sciences › Psychology › Clinical Psychology › Psychotherapy Techniques and Applications
Keywords
MDMA-assisted psychotherapy, MDMA, 3,4-methylenedioxymethamphetamine, post-traumatic stress disorder, psychedelic-assisted psychotherapy, PTSD symptom severity, functional disability, treatment-emergent adverse events, treatment safety, diverse populations
MeSH terms
Combined Modality Therapy, Double-Blind Method, Humans, Stress Disorders, Post-Traumatic, Treatment Outcome, N-Methyl-3,4-methylenedioxyamphetamine

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