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Cited by 359Psychedelics and Drug StudiesPosttraumatic Stress Disorder ResearchPsychotherapy Techniques and Applications

RETRACTED ARTICLE: MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled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 access
Mithoefer, Michael C., Feduccia, Allison A., Jerome, Lisa, Mithoefer, Anne, Wagner, Mark, Walsh, Zach, Hamilton, Scott, Yazar-Klosinski, Berra +2 more·2019·Psychopharmacology
DOI 10.1007/s00213-019-05249-5PMC PMC6695343
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Abstract

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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Crossref · 10.1007/s00213-019-05249-5This paper is marked retracted.

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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 (pooled pre- to post-treatment effect in six phase 2 RCTs of approximately d = 1.20).

    “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

    The Introduction identifies six phase 2 randomized trials, so the cited paper is an appropriate source for the pooled PTSD treatment results. But the Results (Secondary outcomes; page unavailable) report a pooled within-participant pre- to post-treatment Cohen’s d of 1.4 after two sessions, rising to 1.9 after three—not approximately 1.20. The pilot study’s comparison is the citing authors’ own conclusion, not a finding attributed to this source. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • MDMA-AT has been most extensively tested in the treatment of PTSD and has shown large effect size differences compared to placebo controls in Phase II and Phase 3 trials.

    “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]

    The Discussion reports a large between-group effect in the pooled phase 2 PTSD trials (Cohen’s d = 0.8). It says phase 3 trials were planned, not that they had produced effect-size results. The reported comparison was against control doses, which included inactive placebo and low-dose MDMA; this paper also does not establish that PTSD was the most extensively tested indication. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • MDMA has been used to facilitate an individual therapy for PTSD.

    “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

  • Both Phase II and the existing Phase 3 study suggest excellent safety and low abuse potential when MDMA is used under controlled conditions.

    “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.”

    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]

  • Pooled analysis of six phase 2 trials of MDMA-assisted therapy for PTSD has shown promising safety and efficacy findings.

    “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]

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1 of the 39 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Kadel R & Kip K (2012). A SAS macro to compute effect size (Cohen’s d) and its confidence interval from raw survey data. In Proceedings of the Annual Southeast SAS Users Group Conference

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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.
ORCID
Venue
Psychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2019-05-07
Volume
236
Issue
9
Pages
2735-2745
ISSN
  • 0033-3158 (ISSN-L)
  • 1432-2072
DOI
10.1007/s00213-019-05249-5
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
Licence
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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