MDMA-assisted therapy for major depressive disorder: A seven-month follow-up proof of principle trial

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; Jan Ivar Røssberg; Ingmar Clausen; Ole A Andreassen

doi:10.1016/j.jpsychires.2025.11.030

MDMA-assisted therapy for major depressive disorder: A seven-month follow-up proof of principle trial

J Psychiatr Res. 2026 Feb:193:302-308. doi: 10.1016/j.jpsychires.2025.11.030. Epub 2025 Nov 27.

Affiliations

¹ Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Nordre Østfold DPS, Østfold Hospital Trust, Grålum, Norway. Electronic address: tor-morten.kvam@so-hf.no.
² Nordre Østfold DPS, Østfold Hospital Trust, Grålum, Norway.
³ Nordre Østfold DPS, Østfold Hospital Trust, Grålum, Norway; Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway.
⁴ Department of Psychiatry, Østfold Hospital Trust, Grålum, Norway; Department of Clinical Research, Østfold Hospital Trust, Grålum, Norway.
⁵ Department of Clinical Research, Østfold Hospital Trust, Grålum, Norway.
⁶ Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Oslo University Hospital, Division of Mental Health and Addiction, Oslo, Norway.

PMID: 41344230
DOI: 10.1016/j.jpsychires.2025.11.030

Abstract

Background: Major depressive disorder (MDD) is a leading cause of global disability, and current treatments often fail to provide sustained effectiveness. MDMA-assisted therapy (MDMA-AT) is a promising treatment for MDD. However, the long-term effects are not known.

Objectives: To examine the long-term effects of MDMA-AT for MDD.

Methods: Twelve participants with MDD and an ongoing moderate to severe depressive episode received MDMA-AT in two MDMA dosing sessions one month apart, integrated with nine psychotherapy sessions. Clinical assessments were done before MDMA-AT (baseline), after the final psychotherapy session (post-treatment), and at follow-up seven months after baseline. The primary and secondary outcome measures were the Montgomery-Asberg Depression Rating Scale (MADRS) and Sheehan Disability Scale (SDS), respectively. Suicidality was tracked with the Columbia-Suicide Severity Rating Scale. Exploratory outcomes included self-reported assessments of functional impairment, depression, generalized anxiety, insomnia, and PTSD symptoms. We used a mixed-effects model and multinomial logistic regression for analysis of repeated measures.

Results: All twelve participants attended the follow-up visit. At follow-up, there was a significant reduction of MADRS (p < 0.001) and SDS (p = 0.001) scores compared with baseline, along with significant improvements in all exploratory outcome measures. There were no significant changes in any measures from the post-treatment visit. Neither the mean suicidal ideation (SI) score nor the SI intensity rating exceeded pre-study levels.

Conclusion: This long-term follow-up study of MDMA-AT provides preliminary evidence supporting sustained treatment effects and long-term safety in MDD. However, further validation in larger, controlled trials is needed.

Clinical trial identification: EudraCT number 2021-000805-26.

Keywords: Long-term follow-up; MDMA; MDMA-Assisted therapy; Major depressive disorder.

MeSH terms

Adult
Combined Modality Therapy
Female
Follow-Up Studies
Humans
Major Depressive Disorder* / drug therapy
Major Depressive Disorder* / therapy
Male
Middle Aged
N-Methyl-3,4-methylenedioxyamphetamine* / administration & dosage
N-Methyl-3,4-methylenedioxyamphetamine* / pharmacology
Outcome Assessment, Health Care*
Proof of Concept Study
Psychiatric Status Rating Scales
Psychotherapy* / methods

Substances

N-Methyl-3,4-methylenedioxyamphetamine