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RETRACTED ARTICLE: MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials
Open accessAbstract
BACKGROUND: Posttraumatic stress disorder is a prevalent mental health condition with substantial impact on daily functioning that lacks sufficient treatment options. Here we evaluate six phase 2 trials in a pooled analysis to determine the study design for phase 3 trials of MDMA-assisted psychotherapy for PTSD. METHODS: Six randomized, double-blind, controlled clinical trials at five study sites were conducted from April 2004 to February 2017. Active doses of MDMA (75-125 mg, n = 72) or placebo/control doses (0-40 mg, n = 31) were administered to individuals with PTSD during manualized psychotherapy sessions in two or three 8-h sessions spaced a month apart. Three non-drug 90-min therapy sessions preceded the first MDMA exposure, and three to four followed each experimental session. RESULTS: After two blinded experimental sessions, the active group had significantly greater reductions in CAPS-IV total scores from baseline than the control group [MMRM estimated mean difference (SE) between groups - 22.0 (5.17), P < 0.001]. The between-group Cohen's d effect size was 0.8, indicating a large treatment effect. After two experimental sessions, more participants in the active group (54.2%) did not meet CAPS-IV PTSD diagnostic criteria than the control group (22.6%). Depression symptom improvement on the BDI-II was greatest for the active group compared to the control group, although only trended towards significant group differences [MMRM, estimated mean difference (SE) between groups - 6.0 (3.03), P = 0.053]. All doses of MDMA were well tolerated, with some expected reactions occurring at greater frequency for the active MDMA group during experimental sessions and the 7 days following. CONCLUSIONS: MDMA-assisted psychotherapy was efficacious and well tolerated in a large sample of adults with PTSD. These studies supported expansion into phase 3 trials and led to FDA granting Breakthrough Therapy designation for this promising treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00090064, NCT00353938, NCT01958593, NCT01211405, NCT01689740, NCT01793610.
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“The effect sizes for improvements in PTSD and common co-occurring conditions in this pilot study were greater than those found with individually delivered MDMA-facilitated psychotherapy for PTSD (see Mithoefer et al., 2019 for pooled pre- to post-treatment effect in six phase 2 RCTs of approximately d = 1.20).”
From MDMA-facilitated cognitive-behavioural conjoint therapy for posttraumatic stress disorder: an uncontrolled trial (2020) · cites this paper as Mithoefer et al., 2019
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In the citing paper
“MDMA-AT has also been most extensively tested in the treatment of post-traumatic stress disorder (PTSD) and has shown to result in large effect size differences compared to placebo controls in Phase II and Phase 3 trials (18–21).”
From MDMA-Assisted Therapy as a Means to Alter Affective, Cognitive, Behavioral, and Neurological Systems Underlying Social Dysfunction in Social Anxiety Disorder (2021) · cites this paper as [20]
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In the citing paper
“MDMA (3,4-methylenedioxymethamphetamine) has been used to facilitate an individual therapy for PTSD.”
From MDMA-facilitated cognitive-behavioural conjoint therapy for posttraumatic stress disorder: an uncontrolled trial (2020) · cites this paper as Mithoefer et al., 2019
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“In addition, both phase II (19) and the existing phase 3 study (20) suggest excellent safety and low abuse potential when MDMA is used under controlled conditions.”
In the citing paper
“Pooled analysis of six phase 2 trials of MDMA-assisted therapy for PTSD have now shown promising safety and efficacy findings15.”
From MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study (2021) · cites this paper as [15]
In the citing paper
“Although low-dose MDMA improved blinding in phase 2 studies, it led to decreased effectiveness compared with an inactive placebo in a PTSD population, making it easier to detect a difference between the active and comparator groups15.”
From MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study (2021) · cites this paper as [15]
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Metadata
- Authors
- Mithoefer, M. C., Feduccia, A. A., Jerome, L., Mithoefer, A., Wagner, M., Walsh, Z., Hamilton, S., Yazar-Klosinski, B., Emerson, A., & Doblin, R.
- Affiliations
- Medical University of South Carolina (US)
- Multidisciplinary Association for Psychedelic Studies (US)
- University of British Columbia, Okanagan Campus (CA)
- Stanford Medicine (US)
- Corresponding author
- Feduccia, Allison A.
- Venue
- Psychopharmacology
- Published
- 2019-05-07
- Volume
- 236
- Issue
- 9
- Pages
- 2735-2745
- ISSN
- 0033-3158 (ISSN-L)
- 1432-2072
- PMC
- PMC6695343
- OpenAlex
- W2944263526
- Cited by
- 359
- References
- 39
- Citations by year
- 2026: 14 · 2025: 32 · 2024: 54 · 2023: 76 · 2022: 78 · 2021: 56 · 2020: 38 · 2019: 11
- FWCI
- 53.72
- Type
- journal article
- Language
- en
- Status
- Retracted
- Update notices
- retraction (2024-08-10)
- Open access
- hybrid
- doi.org
- Locations
- Psychopharmacology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Multidisciplinary Association for Psychedelic Studies (X)
- 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, post-traumatic stress disorder, phase 3 trial design, treatment efficacy, depression symptom improvement, tolerability, breakthrough therapy designation
- MeSH terms
- Adult, Combined Modality Therapy, Double-Blind Method, Female, Follow-Up Studies, Humans, Male, Middle Aged, Psychotherapy, Stress Disorders, Post-Traumatic, Multicenter Studies as Topic, Randomized Controlled Trials as Topic, Clinical Trials, Phase III as Topic, Serotonin Agents, N-Methyl-3,4-methylenedioxyamphetamine
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