Trial PaperPTSDSafety & Risk ManagementMDMA

3,4-Methylenedioxymethamphetamine-assisted psychotherapy for treatment of chronic posttraumatic stress dis - order: a randomized phase 2 controlled trial

In this randomised phase 2 dose‑response trial, two active MDMA doses (100 mg and 125 mg) given with eight‑hour psychotherapy sessions produced larger reductions in clinician‑rated PTSD severity than a low (40 mg) dose. Benefits were sustained at 12‑month follow‑up (76% no longer met PTSD criteria) and the treatment was well tolerated with no drug‑related serious adverse events.

Authors

  • Rick Doblin
  • Berra Yazar-Klosinski
  • Michael Mithoefer

Published

Journal of Psychopharmacology
individual Study

Abstract

Background

Posttraumatic stress disorder often does not resolve after conventional psychotherapies or pharmacotherapies. Pilot studies have reported that 3,4-methylenedioxymethamphetamine (MDMA) combined with psychotherapy reduces posttraumatic stress disorder symptoms.

Aims

This pilot dose response trial assessed efficacy and safety of MDMA-assisted psychotherapy across multiple therapy teams.

Methods

Twenty-eight people with chronic posttraumatic stress disorder were randomized in a double-blind dose response comparison of two active doses (100 and 125 mg) with a low dose (40 mg) of MDMA administered during eight-hour psychotherapy sessions. Change in the Clinician-Administered PTSD Scale total scores one month after two sessions of MDMA served as the primary outcome. Active dose groups had one additional open-label session; the low dose group crossed over for three open-label active dose sessions. A 12-month follow-up assessment occurred after the final MDMA session.

Results

In the intent-to-treat set, the active groups had the largest reduction in Clinician-Administered PTSD Scale total scores at the primary endpoint, with mean (standard deviation) changes of −26.3 (29.5) for 125 mg, −24.4 (24.2) for 100 mg, and −11.5 (21.2) for 40 mg, though statistical significance was reached only in the per protocol set ( p=0.03). Posttraumatic stress disorder symptoms remained lower than baseline at 12-month follow-up ( p<0.001) with 76% ( n=25) not meeting posttraumatic stress disorder criteria. There were no drug-related serious adverse events, and the treatment was well-tolerated.

Conclusions

Our findings support previous investigations of MDMA-assisted psychotherapy as an innovative, efficacious treatment for posttraumatic stress disorder.

Available with Blossom Pro

Research Summary of '3,4-Methylenedioxymethamphetamine-assisted psychotherapy for treatment of chronic posttraumatic stress dis - order: a randomized phase 2 controlled trial'

Expert Research Summaries

Go Pro to access AI-powered section-by-section summaries, editorial takes, and the full research toolkit.

See Pro PlansAlready have an account? Sign in

Full Text PDF

Full Paper PDF

Pro members can view the original manuscript directly in the browser.

See Pro PlansAlready have an account? Sign in
Open PDF in new tab

Study Details

References (24)

Papers cited by this study that are also in Blossom

Intimate insight: MDMA changes how people talk about significant others

Baggot, M. J., Kirkpatrick, M. G., Bedi, G. et al. · Journal of Psychopharmacology (2015)

53 cited
A window into the intoxicated mind? Speech as an index of psychoactive drug effects

Bedi, G., Cecchi, G. A., Slezak, D. F. et al. · Neuropsychopharmacology (2014)

89 cited
Is Ecstasy an “Empathogen”? Effects of ±3,4-Methylenedioxymethamphetamine on Prosocial Feelings and Identification of Emotional States in Others

Bedi, G., Hyman, D., De Wit, H. · Biological Psychiatry (2010)

213 cited
The effects of MDMA on socio-emotional processing: Does MDMA differ from other stimulants?

Bershad, A. K., Miller, M. A., Baggot, M. J. et al. · Journal of Psychopharmacology (2016)

MDMA-assisted psychotherapy using low doses in a small sample of women with chronic posttraumatic stress disorder

Bouso, J. C., Doblin, R., Farré, M. et al. · Journal of Psychoactive Drugs (2008)

Psilocybin with psychological support for treatment-resistant depression: six-month follow-up

Carhart-Harris, R. L., Bolstridge, &. M., Day, C. M. J. et al. · Psychopharmacology (2017)

The effects of acutely administered 3, 4-methylenedioxymethamphetamine on spontaneous brain function in healthy volunteers measured with arterial spin labeling and blood oxygen level-dependent resting state functional connectivity

Carhart-Harris, R. L., Murphy, K., Leech, R. et al. · Biological Psychiatry (2015)

151 cited
The effect of acutely administered MDMA on subjective and BOLD-fMRI responses to favourite and worst autobiographical memories

Carhart-Harris, R. L., Wall, M. B., Erritzoe, D. et al. · International Journal of Neuropsychopharmacology (2013)

90 cited
Direct comparison of the acute subjective, emotional, autonomic, and endocrine effects of MDMA, methylphenidate, and modafinil in healthy subjects

Dolder, P. C., Müller, F., Schmid, Y. et al. · Psychopharmacology (2017)

111 cited
MDMA-assisted psychotherapy for PTSD: are memory reconsolidation and fear extinction underlying mechanisms?

Feduccia, A. A., Mithoefer, M. C. · Progress in Neuro-Psychopharmacology and Biological Psychiatry (2018)

Show all 24 references
Subjective reports of the effects of MDMA in a clinical setting

Greer, G. R. · Journal of Psychoactive Drugs (1986)

423 cited
MDMA enhances emotional empathy and prosocial behavior

´dric, C., Hysek, M., Schmid, Y. et al. · Social Cognitive and Affective Neuroscience (2013)

The prosocial effects of 3, 4-methylenedioxymethamphetamine (MDMA): controlled studies in humans and laboratory animals

Kamilar-Britt, P., Bedi, G. · Neuroscience and Biobehavioral Reviews (2015)

Effects of MDMA and Intranasal oxytocin on social and emotional processing

Kirkpatrick, M. G., Lee, R., Wardle, M. C. et al. · Neuropsychopharmacology (2014)

Acute dose of MDMA (75 mg) impairs spatial memory for location but leaves contextual processing of visuospatial information unaffected

Kuypers, K. P. C., Ramaekers, J. G. · Psychopharmacology (2006)

68 cited
Gender differences in the subjective effects of MDMA

Liechti, M. E., Gamma, A., Vollenweider, F. X. · Psychopharmacology (2001)

349 cited
3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial

Mithoefer, A. T., Mithoefer, M. C., Feduccia, A. A. et al. · Lancet Psychiatry (2018)

274 cited
The safety and efficacy of ±3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study

Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T. et al. · Journal of Psychopharmacology (2010)

Durability of improvement in post-traumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study

Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T. et al. · Journal of Psychopharmacology (2012)

346 cited
A randomized, controlled pilot study of MDMA (±3,4-Methylenedioxymethamphetamine)- assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD)

Oehen, P., Traber, R., Widmer, V. et al. · Journal of Psychopharmacology (2012)

328 cited
Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression a SPECT study

Sanches, R. F., Osório, F. L., Dos Santos, R. G. et al. · Journal of Clinical Psychopharmacology (2016)

380 cited
Safety pharmacology of acute MDMA administration in healthy subjects

Vizeli, P., Liechti, M. E. · Journal of Psychopharmacology (2017)

Altered insula connectivity under MDMA

Walpola, I. C., Nest, T., Leor, R. et al. · Neuropsychopharmacology (2017)

Potential Psychiatric Uses for MDMA

Yazar-Klosinski, B., Mithoefer, M. C. · Clinical Pharmacology and Therapeutics (2016)

Cited By (21)

Papers in Blossom that reference this study

A living systematic review, meta-analysis, and open data resource of trials of MDMA-assisted therapy for PTSD

Sevchik, B. L., Singleton, S. P., Lahey, A. et al. · MedRvix (2026)

The conceptual framework for the therapeutic approach used in phase 3 trials of MDMA-assisted therapy for PTSD

O'Donnell, K., Okano, L., Alpert, M. et al. · Frontiers in Psychology (2024)

23 cited
Preliminary evidence for the importance of therapeutic alliance in MDMA-assisted psychotherapy for posttraumatic stress disorder

Zeifman, R. J., Kettner, H., Ross, S. et al. · European Journal of Psychotraumatology (2024)

27 cited
MDMA-assisted psychotherapy for PTSD: Growing evidence for memory effects mediating treatment efficacy

Sarmanlu, M., Kuypers, K. P. C., Vizeli, P. et al. · Progress in Neuro-Psychopharmacology and Biological Psychiatry (2023)

MDMA Assisted Psychotherapy Decreases PTSD Symptoms, Dissociation, Functional Disability, and Depression: A Systematic Review and Meta-Analysis

Green, W. M., Raut, S. B., James, F. L. J. et al. · MedRvix (2023)

Dark loops: contagion effects, consistency and chemosocial matrices in psychedelic-assisted therapy trials

Noorani, T. N., Bedi, G., Muthukumaraswamy, S. · Psychological Medicine (2023)

21 cited
Perceived key change phenomena of MDMA-assisted psychotherapy for the treatment of severe PTSD: an interpretative phenomenological analysis of clinical integration sessions

Godes, M., Lucas, J., Vermetten, E. · Frontiers in Psychiatry (2023)

Models of Psychedelic-Assisted Psychotherapy: A Contemporary Assessment and an Introduction to EMBARK, a Transdiagnostic, Trans-Drug Model

Belser, A. B. · Frontiers in Psychology (2022)

57 cited
MDMA and memory, addiction, and depression: dose-effect analysis

Pantoni, M. M., Kim, J. L., Van Alstyne, K. R. et al. · Psychopharmacology (2022)

Psychedelic treatment for co-occurring alcohol misuse and post-traumatic stress symptoms among United States Special Operations Forces Veterans

Mangini, P., Averill, L. A., Davis, A. K. · Journal of Psychedelic Studies (2022)

Show all 21 papers
The Need for Psychedelic-Assisted Therapy in the Black Community and the Burdens of its Provision

Smith, D., Faber, S., Buchanan, N. T. et al. · Frontiers in Psychiatry (2022)

Overcoming epistemic injustices in the biomedical study of ayahuasca: Towards ethical and sustainable regulation

Schenberg, E. E., Gerber, K. · Transcultural Psychiatry (2022)

Sleep Quality Improvements After MDMA-Assisted Psychotherapy for the Treatment of Posttraumatic Stress Disorder

Ponte, L., Jerome, L., Hamilton, S. et al. · Journal of Traumatic Stress (2021)

22 cited
People of color in North America report improvements in racial trauma and mental health symptoms following psychedelic experiences

Williams, T. M., Davis, A. K., Xin, Y. et al. · Drugs Education Prevention and Policy (2020)

MDMA-assisted psychotherapy for treatment of anxiety and other psychological distress related to life-threatening illnesses: a randomized pilot study

Wolfson, P. E., Andries, J., Feduccia, A. A. et al. · Scientific Reports (2020)

99 cited
Efficacy of Psychoactive Drugs for the Treatment of Posttraumatic Stress Disorder: A Systematic Review of MDMA, Ketamine, LSD and Psilocybin

Varker, T., Watson, L., Gibson, K. et al. · Journal of Psychoactive Drugs (2020)

Ethics and ego dissolution: the case of psilocybin

Smith, W. R., Sisti, D. · Journal of Medical Ethics (2020)

Posttraumatic Growth After MDMA-Assisted Psychotherapy for Posttraumatic Stress Disorder

Gorman, I., Belser, A. B., Jerome, L. et al. · Journal of Traumatic Stress (2020)

31 cited
Breakthrough for trauma treatment: safety and efficacy of MDMA-assisted psychotherapy compared to paroxetine and sertraline

Feduccia, A. A., Jerome, L., Yazar-Klosinski, B. et al. · Frontiers in Psychiatry (2019)

Perceived benefits of MDMA-assisted psychotherapy beyond symptom reduction: qualitative follow-up study of a clinical trial for individuals with treatment-resistant PTSD

Barone, W., Beck, J., Mitsunaga-Whitten, M. et al. · Journal of Psychoactive Drugs (2019)

46 cited
An exploratory study of experiences with conventional eating disorder treatment and ceremonial ayahuasca for the healing of eating disorders

Renelli, M., Fletcher, J., Tupper, K. W. et al. · Eating and Weight Disorders - Studies on Anorexia Bulimia and Obesity (2018)

68 cited

Your Personal Research Library

Go Pro to save papers, add notes, rate studies, and organize your research into custom shelves.

See Pro PlansSign in
3,4-Methylenedioxymethamphetamine-assisted... — Research Summary & Context | Blossom