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Home/Research/MDMA/Major Depressive Disorder (MDD)

MDMA for Major Depressive Disorder (MDD)

22 papers and 1 clinical trial exploring mdma as a treatment for major depressive disorder (mdd).

Compoundempathogen

MDMA

MDMA is a synthetic empathogen that enhances monoamine release, producing prosocial and anxiolytic effects without frank hallucinosis. Two Phase III trials demonstrated significant PTSD symptom reductions, though FDA review raised concerns about blinding, durability, and safety characterisation.

Full MDMA profile
IndicationOver 264 million worldwide.

Major Depressive Disorder (MDD)

Major Depressive Disorder (MDD) represents a significant mental health challenge, with emerging research into the efficacy of psychedelics like psilocybin and ketamine offering new avenues for treatment. Recent studies have demonstrated the potential of these compounds to alleviate symptoms, particularly in treatment-resistant cases of MDD.

Full Major Depressive Disorder (MDD) profile

Academic Research

22 papers
Paywallindividual

MDMA-Assisted Therapy for Major Depressive Disorder: A Seven-Month Follow-Up Proof of Principle Trial

This long-term follow-up (n=12) of participants with moderate-to-severe major depressive disorder who received MDMA-assisted therapy (two dosing sessions integrated with nine psychotherapy sessions) found significant reductions in depression severity and functional impairment at seven months compared to baseline, with improvements maintained from the post-treatment assessment and no increases in suicidal ideation.

Published
February 1, 2026
Journal
Journal of Psychiatric Research
Authors
Kvam, T. M., Goksøyr, I. W., Rog, J., van de Vooren, I. T. J., Stewart, L. H., Autran, I., Berthold-Losleben, M., Mørch-Johnsen, L., Holst, R., Røssberg, J. I., Clausen, I., Andreassen, O. A.
Open Accessindividual

Psilocybin with psychotherapeutic support for treatment-resistant depression: a pilot clinical trial

An open‑label pilot trial of two 25 mg psilocybin sessions with preparatory and integration psychotherapy for treatment‑resistant depression produced a clinically meaningful reduction in self‑rated depressive symptoms at three weeks (Hedges’ g = −1.27) that was maintained at 20 weeks, although individual responses varied (two sustained responders, three relapses, two non‑responders). Exploratory analyses linked pre‑dosing mindset, spiritual experiences and perceptual shifts to outcome trajectories, with adverse events consistent with prior studies and no serious adverse events.

Published
October 2, 2025
Journal
Therapeutic Advances in Psychopharmacology
Authors
Meikle, S., Carter, O., Liknaitzky, P., Johansen, L., Iyer, R., Strauss, N., Williams, M., Castle, D., Rossell, S. L., Ids, O.
Open Accessindividual

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.

Published
July 11, 2025
Journal
British Journal of Psychiatry
Authors
Kvam, T. M., Goksøyr, I. W., Rog, J., Jentoft Van De Vooren, I. T., Stewart, H., Autran, I., Berthold-Losleben, M., Mørch-Johnsen, L., Holst, R., Clausen, I., Andreassen, O. A.
Open Accessindividual

Self-compassion mediates treatment effects in MDMA-assisted therapy for posttraumatic stress disorder

This secondary analysis (n=82) of a Phase III RCT of MDMA-assisted therapy found significant improvements in both uncompassionate self-responding and compassionate self-responding across all six Self-Compassion Scale subscales, most with large effect sizes. Changes in self-compassion fully mediated the reductions in PTSD severity and depressive symptoms observed with MDMA-AT versus placebo plus therapy, though no significant effects were seen for alcohol or substance use outcomes.

Published
May 7, 2025
Journal
European Journal of Psychotraumatology
Authors
Agin-Liebes, G. I., Zeifman, R. J., Mitchell, J.
Open Accessindividual

Negative Affect Circuit Subtypes and Neural, Behavioral, and Affective Responses to MDMA: A Randomized Clinical Trial

In a double‑blind, placebo‑controlled within‑participant randomised trial of 16 adults stratified by baseline nonconscious‑threat–evoked amygdala activity, 120 mg MDMA acutely reduced amygdala and subgenual ACC activity, increased sgACC–amygdala connectivity, and raised likability of threat expressions in the high‑reactivity subgroup (NTNA+) versus the low‑reactivity subgroup. These results indicate that baseline neuroimaging of negative affect circuitry can identify biomarkers to personalise MDMA‑based therapies.

Published
April 30, 2025
Journal
JAMA Network Open
Authors
Zhang, X., Hack, L. M., Bertrand, C., Hilton, R., Gray, N. J., Boyar, L., Laudie, J., Heifets, B. D., Suppes, T., Van Roessel, P. J., Rodriguez, C. I., Deisseroth, K., Knutson, B., Williams, L. M.
Open Accessmeta

Implementing psychedelic-assisted therapy: History and characteristics of the Swiss limited medical use program

This review (2025) of the Swiss limited access scheme describes how approximately 100 physicians treated 723 patients with MDMA, LSD, or psilocybin in 2024, with patients typically receiving 2-4 psychedelic-assisted therapy sessions within 12 months for treatment-resistant conditions.

Published
January 1, 2025
Journal
Neuroscience Applied
Authors
Mueller, F., Hawrot, T., Schmid, Y.

Clinical Trials

1 trial
CompletedPhase II

An Open-Label, Phase 2, Feasibility Study of Manualized MDMA-Assisted Psychotherapy in Subjects with Major Depressive Disorder

This open-label Phase II feasibility study (n=12) of manualized MDMA-assisted psychotherapy for moderate-to-severe depression (MDD) included up to two experimental oral MDMA sessions (supplemental dose allowed) and used clinician-rated MADRS change at ~12 weeks as the primary outcome.

Started
November 19, 2021
Type
interventional
Blinding
none
Randomized
No
Registry ID
2021-000805-26

Explore further

Search all MDMA papers Search all Major Depressive Disorder (MDD) trials Full MDMA profile Full Major Depressive Disorder (MDD) profile