MDMA-assisted therapy as a treatment for major depressive disorder: proof of principle study
In an open‑label proof‑of‑principle study of 12 participants with moderate–severe major depressive disorder, two MDMA‑assisted therapy sessions plus psychotherapy were feasible, well tolerated and produced large, statistically significant reductions in depressive symptoms (mean MADRS change −19.3) and functional impairment. No unexpected or serious adverse events occurred, and the authors conclude that randomised trials are needed to confirm efficacy.
Authors
- Kvam, T. M.
- Goksøyr, I. W.
- Rog, J.
Published
Abstract
Background 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy (MDMA-AT) has shown promising safety and efficacy in phase 3 studies of post-traumatic stress disorder, but has not been investigated for a primary diagnosis of major depressive disorder (MDD).
Aim
We aimed to explore the proof of principle and safety as a first study with MDMA-AT for MDD, and to provide preliminary efficacy data.
Method
Twelve participants (7 women, 5 men) with moderate to severe MDD received MDMA in 2 open-label sessions 1 month apart, along with psychotherapy before, during and after the MDMA sessions, between January 2023 and May 2024. The primary outcome measure was mean change in Montgomery–Asberg Depression Rating Scale (MADRS), and the secondary outcome measure was mean change in functional impairment as measured with the Sheehan Disability Scale (SDS), both from baseline to 8 weeks following the second MDMA session. We used descriptive statistics and the two-tailed Wilcoxon signed-rank test to compare baseline and outcome scores. Repeated measures were analysed by a mixed-effects model.
Results
Baseline MADRS was 29.6 (s.d. 4.9). Feasibility was demonstrated with sufficient recruitment and retention. MADRS scores were significantly reduced post treatment compared with baseline (mean difference –19.3, s.e. 2.4, CI –14.8 to –23.8, P < 0.001). SDS scores significantly decreased from baseline (mean difference –11.7, s.e. 2.2, CI –7.5 to –15.9, P = 0.001). There were no adverse events of special interest, and no unexpected or serious adverse events.
Conclusion
The study met the primary objectives of safety and feasibility, and provided indications of efficacy for MDMA-AT for MDD. Further studies with a randomised design are required to confirm these findings. Trial registration EudraCT no. 2021-000805-26.
Research Summary of 'MDMA-assisted therapy as a treatment for major depressive disorder: proof of principle study'
Introduction
Major depressive disorder (MDD) is highly prevalent and a leading cause of disability, with many people deriving limited benefit from existing treatments and experiencing high relapse rates. 3,4-methylenedioxymethamphetamine (MDMA) has monoamine-releasing and reuptake inhibitor properties and may promote neuroplasticity; when combined with psychotherapy (MDMA-assisted therapy, MDMA-AT) it is hypothesised to facilitate therapeutic processes by reducing anxiety and enhancing trust, insight and emotion regulation. Clinical research to date has focused primarily on post-traumatic stress disorder (PTSD), where randomised phase 3 trials have shown safety and efficacy; MDMA-AT has not previously been studied for a primary diagnosis of MDD. This study aimed to provide a proof-of-principle assessment of MDMA-AT for people with moderate to severe MDD, focusing on feasibility and safety and providing preliminary efficacy data. Kvam and colleagues set out an open-label design to explore whether MDMA-AT can be safely delivered to this population and whether changes in depressive symptoms and functioning warrant further randomised controlled trials. The study therefore serves as an initial, exploratory investigation rather than a definitive test of efficacy.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- APA Citation
Kvam, T., Goksøyr, I. W., Rog, J., van de Vooren, I. J., Stewart, L. H., Autran, I., Berthold-Losleben, M., Mørch-Johnsen, L., Holst, R., Clausen, I., & Andreassen, O. A. (2025). MDMA-assisted therapy as a treatment for major depressive disorder: proof of principle study. The British Journal of Psychiatry, 227(5), 783-789. https://doi.org/10.1192/bjp.2025.10320
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Gründer, G., Brand, M., Mertens, L. J. et al. · Lancet Psychiatry (2024)
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