A comparison of MDMA-assisted psychotherapy to non-assisted psychotherapy in treatment-resistant PTSD: A systematic review and meta-analysis
This systematic review and meta-analysis of four randomised, double‑blind trials found MDMA‑assisted psychotherapy produced significant reductions in PTSD severity (CAPS‑IV) at 75 mg and 125 mg versus active placebo, with mainly transient adverse effects and minimal neurocognitive or physical risk, but little consistent benefit on depressive symptoms (BDI); larger, better‑powered RCTs are required.
Authors
- James Rucker
- Luke Jelen
Published
Abstract
Rationale
Novel, evidence-based treatments are required for treatment-resistant post-traumatic stress disorder (PTSD). 3,4-Methylenedioxymethamphetamine (MDMA) has beneficially augmented psychotherapy in several small clinical trials.
Objective
To review the use of MDMA-assisted psychotherapy in treatment-resistant PTSD.
Methods
Systematic searches of four databases were conducted from inception to February 2020. A meta-analysis was performed on trials which were double-blinded, randomised, and compared MDMA-assisted psychotherapy to psychotherapy and placebo. The primary outcomes were the differences in Clinician Administered PTSD Scale (CAPS-IV) score and Beck’s Depression Inventory (BDI). Secondary outcome measures included neurocognitive and physical adverse effects, at the time, and within 7 days of intervention.
Results
Four randomised controlled trials (RCTs) met inclusion criteria. When compared to active placebo, intervention groups taking 75 mg (MD −46.90; 95% (confidence intervals) CI −58.78, −35.02), 125 mg (MD −20.98; 95% CI −34.35, −7.61) but not 100 mg (MD −12.90; 95% CI −36.09, 10.29) of MDMA with psychotherapy, had significant decreases in CAPS-IV scores, as did the inactive placebo arm (MD −33.20; 95% CI −40.53, −25.87). A significant decrease in BDI when compared to active placebo (MD −10.80; 95% CI −20.39, −1.21) was only observed at 75 mg. Compared to placebo, participants reported significantly more episodes of low mood, nausea and jaw-clenching during sessions and lack of appetite after 7 days.
Conclusion
These results demonstrate potential therapeutic benefit with minimal physical and neurocognitive risk for the use of MDMA-assisted psychotherapy in TR-PTSD, despite little effect on Beck’s Depression Inventory. Better powered RCTs are required to investigate further. International Prospective Register of Systematic Reviews: CRD42019109132 available online at www.crd.york.ac.uk/prospero .
Research Summary of 'A comparison of MDMA-assisted psychotherapy to non-assisted psychotherapy in treatment-resistant PTSD: A systematic review and meta-analysis'
Introduction
Post-traumatic stress disorder (PTSD) is a chronic and disabling condition characterised by intrusive memories, hyperarousal, avoidance and mood and cognitive changes following exposure to traumatic events. The disorder has a substantial individual and societal burden, lifetime prevalence estimates around 3.6–3.9% worldwide, and higher rates in conflict-affected populations. A sizeable proportion of patients do not remit with standard treatments; the authors note that definitions of treatment-resistance vary but often denote failure to respond to at least two evidence-based therapies. Against this background, Illingworth and colleagues set out to evaluate whether MDMA (3,4-methylenedioxymethamphetamine) administered in a supervised clinical setting as an adjunct to psychotherapy provides benefit for treatment-resistant PTSD (TR-PTSD). Earlier phase 1 and phase 2 work suggested MDMA can facilitate psychotherapy through pro-social, anxiolytic and fear-reducing effects, but trials are small and blinding is challenging. This systematic review and meta-analysis therefore aimed to identify double-blind randomised trials comparing MDMA-assisted psychotherapy to psychotherapy plus placebo and to quantify effects on clinician-rated PTSD severity (CAPS-IV), depressive symptoms (BDI) and adverse events, including session and 7-day follow-up events.
Expert Research Summaries
Go Pro to access AI-powered section-by-section summaries, editorial takes, and the full research toolkit.
Full Text PDF
Full Paper PDF
Create a free account to open full-text PDFs.
Study Details
- Study Typemeta
- Journal
- Compound
- Topics
- Authors
- APA Citation
Illingworth, B. J., Lewis, D. J., Lambarth, A. T., Stocking, K., Duffy, J. M., Jelen, L. A., & Rucker, J. J. (2021). A comparison of MDMA-assisted psychotherapy to non-assisted psychotherapy in treatment-resistant PTSD: A systematic review and meta-analysis. Journal of Psychopharmacology, 35(5), 501-511. https://doi.org/10.1177/0269881120965915
References (5)
Papers cited by this study that are also in Blossom
Amoroso, T., Workman, M. · Journal of Psychopharmacology (2016)
Bahji, A., Forsyth, A., Groll, D. et al. · Progress in Neuro-Psychopharmacology and Biological Psychiatry (2020)
Dumont, G., Sweep, F., van der Steen, R. et al. · Social Neuroscience (2009)
Liechti, M. E., Gamma, A., Vollenweider, F. X. · Psychopharmacology (2001)
Mithoefer, M. C., Feduccia, A. A., Jerome, L. et al. · Psychopharmacology (2019)
Cited By (9)
Papers in Blossom that reference this study
Sevchik, B. L., Singleton, S. P., Lahey, A. et al. · MedRvix (2026)
Kachmarik, J. E., Loftis, J. M., Stauffer, C. S. · Frontiers in Neuroscience (2026)
Van Dongen, N. N. N., Zijlmans, J., Vermetten, E. et al. · European Journal of Psychotraumatology (2024)
Colcott, J., Guerin, A. A., Carter, O. et al. · Neuropsychopharmacology (2024)
Van Vugt, A. S., Zijlmans, J., Lindauer, R. et al. · Drug Science Policy and Law (2023)
Green, W. M., Raut, S. B., James, F. L. J. et al. · MedRvix (2023)
Belser, A. B. · Frontiers in Psychology (2022)
Earleywine, M., Low, F., Lau, C. et al. · Journal of Humanistic Psychology (2022)
Bird, C. I. V., Modlin, N. L., Rucker, J. · International Review of Psychiatry (2021)
Your Personal Research Library
Go Pro to save papers, add notes, rate studies, and organize your research into custom shelves.