This open-label pilot study (n=12) found that MDMA-assisted therapy (80-120mg; 2x) significantly reduced depression scores (MADRS) by 19.3 points and functional impairment (-11.7) in participants with moderate to severe major depressive disorder (MDD), with no serious adverse events reported over 8 weeks following treatment.
Abstract of MDMA-assisted therapy as a treatment for major depressive disorder
“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.“
Authors: Tor-Morten Kvam, Ivar W. Goksøyr, Justyna Rog, Inger-Tove Jentoft van de Vooren, Lowan Han Stewart, Ingrid Autran, Mark Berthold-Losleben, Lynn Mørch-Johnsen, René Holst, Ingmar Clausen & Ole A. Andreassen
Summary of MDMA-assisted therapy as a treatment for major depressive disorder
Major depressive disorder (MDD) remains a prevalent and disabling psychiatric condition, with existing treatments often providing limited effectiveness and tolerability. High relapse rates and treatment resistance, particularly to psychotherapy and pharmacotherapy, continue to pose challenges. Recent advances in psychedelic research have turned attention toward compounds like MDMA (3,4-methylenedioxymethamphetamine), which has shown significant promise in treating post-traumatic stress disorder (PTSD) during Phase III trials. However, no previous clinical trials have assessed MDMA-assisted therapy (MDMA-AT) as a primary treatment for MDD.
MDMA is a psychoactive compound known to enhance emotional processing by increasing monoamine neurotransmitter activity and inducing neuroplasticity. It facilitates reduced anxiety, enhanced self-compassion, and emotional openness. These properties make it particularly suitable as an adjunct to psychotherapy. Previous studies of MDMA-AT, mainly for PTSD, involve two or three extended MDMA sessions combined with preparatory and integration therapy. While these trials have shown substantial reductions in PTSD symptoms and associated depressive symptoms, MDMA-AT has not yet been studied for MDD as a standalone diagnosis.
This study, conducted by Kvam and colleagues, aimed to address this gap by assessing the safety, feasibility, and preliminary efficacy of MDMA-AT for participants with moderate to severe MDD. It represents a proof-of-concept investigation, with open-label administration of MDMA and accompanying therapy, focusing on both symptom reduction and functional improvement.
Method
Design
Find this paper
MDMA-assisted therapy as a treatment for major depressive disorder: proof of principle study
https://doi.org/10.1192/bjp.2025.10320
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Cite this paper (APA)
Kvam, T. M., Goksøyr, I. W., Rog, J., van de Vooren, I. T. J., Stewart, L. H., Autran, I., ... & Andreassen, O. A. MDMA-assisted therapy as a treatment for major depressive disorder: proof of principle study. The British Journal of Psychiatry: The Journal of Mental Science, 1-7.
Study details
Compounds studied
MDMA
Topics studied
Depression
PTSD
Addiction
Alcohol Use Disorder
Study characteristics
Original
Open-Label
Participants
12
Humans
Compound Details
The psychedelics given at which dose and how many times
MDMA 90 - 120mg | 2x
Linked Clinical Trial
An Open-Label, Phase 2, Feasibility Study of Manualized MDMA-Assisted Psychotherapy in Subjects with Major Depressive DisorderThe primary objective is to evaluate the effect of MDMA-assisted psychotherapy for MDD in clinician-rated depression scores, as measured by the mean change in MADRS scores from Visit 4 (Baseline) to Visit 13 (approximately 12 weeks post Baseline).