Summary
Psilocybin has reached Preclinical as its most advanced recorded development stage across any indication, and the database holds no approval for Major Depressive Disorder. ClinicalTrials.gov lists 8 registered trials linking Psilocybin to Major Depressive Disorder: 1 is currently recruiting; 2 are active or not yet recruiting; 3 have completed; 2 are terminated, withdrawn, suspended or of unknown status. The most advanced is Phase 3 (NCT06308653). It plans or enrolled 238 participants. Registration activity spans 2017 to 2024. The literature layer holds 16 publications for this pair: 5 Cochrane reviews, 4 meta-analyses, 1 systematic review, 1 randomised controlled trial publication and 5 clinical trial publications. Publication years run from 2022 to 2026. Because at least one synthesis-level source exists (systematic review, meta-analysis or Cochrane review), this pair has been assessed beyond single studies, although the synthesis may concern a different indication.
The RepurpOS disease-intelligence file for Major Depressive Disorder ranks 580 candidate therapeutics from Open Targets, ChEMBL, DGIdb and PubMed; only a minority carry direct clinical evidence, and this page covers one of those. Spontaneous remission context recorded for the condition: Relapse in 19-45% within 1 year of antidepressant discontinuation after remission; relapse risk ratio (off-medication vs on) falls from 3.69x at 2 months to 1.34x at 5 years.
Evidence table
| Evidence tier | C · Preliminary |
|---|---|
| Evidence score | 60.0 (trials 25.0, literature 30.0, tier 5, approved bonus 0.0) |
| Registered trials | 8 total: 1 recruiting, 2 active / not yet recruiting, 3 completed, 2 other |
| Linked publications | 16 (5 Cochrane reviews, 5 clinical trial publications, 4 meta-analyses, 1 systematic review, 1 randomised controlled trial publication) |
| Agent type | Drug (Psychedelic) |
| Development stage (any indication) | Preclinical |
| Mechanism / class | Integrative interventions for improving outcomes in depression: a narrative review · Halma M, Plothe C, Marik PE · 2024 |
| Data sources | OSMF Chronic Disease Review |
How the evidence score is calculated
- Each registered trial scores by status (recruiting / active / enrolling 3, completed 2.5, not yet recruiting 2, unknown 1, terminated / withdrawn / suspended 0.5) plus a phase bonus (phase 3-4 +2, phase 2 +1, phase 1 +0.5). The trial component is capped at 30.
- Each literature item scores by design (Cochrane review 5, meta-analysis 4, systematic review 3, RCT 3, clinical trial publication 2, curated reference 1.5, other PubMed record 1). The literature component is capped at 30.
- The existing evidence tier adds 15 (A / Strong), 10 (B / Moderate), 5 (C / Preliminary) or 0 (D / Anecdotal).
- Agents approved for any indication (max clinical phase 4) add 5, because an approved agent has an established safety profile that lowers the barrier to repurposing trials.
- The score ranks what has been studied, not what works. It does not read effect sizes or directions of effect.
Registered clinical trials
| NCT ID | Title | Status | Phase | Enrolment |
|---|---|---|---|---|
| NCT06308653 | Psilocybin for Major Depressive Disorder (MDD) 2024 | active, not recruiting | Phase 3 | 238 |
| NCT05399498 | Psilocybin in Co-occuring Major Depressive Disorder and Borderline Personality Disorder 2023 | completed | Phase 2 | 9 |
| NCT05259943 | Microdosing Psychedelics to Improve Mood 2023 | completed | Phase 2 | 39 |
| NCT03181529 | Effects of Psilocybin in Major Depressive Disorder 2017 | completed | Phase 2 | 27 |
| NCT06141876 | Evaluation of Psilocybin-Assisted Psychotherapy in Treating Severe Depression in Patients With PTSD 2023 | status unknown | Phase 2 | 160 |
| NCT05381974 | The Effects of Psilocybin on Self-Focus and Self-Related Processing in Treatment Resistant MDD 2022 | withdrawn | Phase 2 | — |
| NCT05434156 | ELE-101 Safety & Tolerability Study in Healthy Participants and Patients With Depression 2022 | active, not recruiting | PHASE1, PHASE2 | 84 |
| NCT06624137 | Computer Game, Qualitative, and MEG/EEG Assessment of Serotonergic Psychedelics 2024 | recruiting | Not applicable | 200 |
Published literature
- Clinical trial publication Short-Term and Late-Term Effects of Psilocybin on Symptoms in Major Depression: A Randomized Clinical TrialYngwe H, Plavén-Sigray P, Ekman CJ et al. · JAMA network open · 2026 · PMID 42138922
- Clinical trial publication Evaluation of a facilitator training program in a randomized controlled trial of psilocybin treatment for depressionMorel NS, Stenbaek DS, Lundberg J et al. · BMC medical education · 2026 · PMID 41952163
- Clinical trial publication Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression: The EPISODE Randomized Clinical TrialMertens LJ, Koslowski M, Betzler F et al. · JAMA psychiatry · 2026 · PMID 41848690
- Clinical trial publication Psilocybin-assisted cognitive behavioral therapy for major depressive disorder: A pilot trialWeintraub MJ, Jeffrey JK, Ichinose MC et al. · Journal of affective disorders · 2026 · PMID 41707717
- Clinical trial publication Examining the effects of psilocybin-assisted psychotherapy on anhedonia in treatment-resistant depressionKaczmarek ES, Rodrigues NB, Chisamore N et al. · Journal of affective disorders · 2026 · PMID 41690631
- Cochrane review Therapeutic effects of psilocybin in major depressive disorder: a systematic review and meta-analysis exploring dose effectsHe Z, Wang Y, Chen J et al. · European archives of psychiatry and clinical neuroscience · 2026 · PMID 41677823
- Cochrane review Psilocybin for major depressive disorder: An updated systematic review and meta-analysis of randomized clinical trialsAghajanian S, Shafiee A, Parvizi Omran S et al. · Journal of psychopharmacology (Oxford, England) · 2026 · PMID 39480198
- Meta-analysis Psilocybin-assisted therapy for major depressive disorder: Perspective from meta-analysisKishi T, Sakuma K, Hatano M et al. · Journal of affective disorders · 2026 · PMID 41876058
- Meta-analysis Methodological moderators of psilocybin-assisted therapy in depression: A systematic review and meta-analysisSyed OA, Tsang B, Nestor SM et al. · Neuroscience and biobehavioral reviews · 2026 · PMID 41587629
- Meta-analysis Breaking the chains of depression: A systematic review and meta-analysis of psilocybin therapyKhan FA, Pandupuspitasari NS, Tencomnao T et al. · Journal of affective disorders · 2026 · PMID 41419063
- Randomized controlled trial A novel psychedelic 5-HT(2A) receptor agonist GM-2505: The pharmacokinetic, safety, and pharmacodynamic profile from a randomized trial healthy volunteerMarek GJ, Makai-Bölöni S, Umbricht D et al. · Journal of psychopharmacology (Oxford, England) · 2026 · PMID 41099491
- Systematic review Temporal dynamics in neuroimaging as correlates of therapeutic response to psilocybin in major depressive disorder: A systematic review and critical appraisalSabbah SG, Li S, Wong S et al. · Journal of affective disorders · 2026 · PMID 40962065
- Cochrane review Efficacy and safety of psilocybin in the treatment of Major Depressive Disorder (MDD): A dose-response network meta-analysis of randomized placebo-controlled clinical trialsSwieczkowski D, Kwaśny A, Pruc M et al. · Psychiatry research · 2025 · PMID 39754904
- Cochrane review Randomized Controlled Trials of Psilocybin-Assisted Therapy in the Treatment of Major Depressive Disorder: Systematic Review and Meta-AnalysisMenon V, Ramamurthy P, Venu S et al. · Acta psychiatrica Scandinavica · 2025 · PMID 39627679
- Meta-analysis Control Group Outcomes in Trials of Psilocybin, SSRIs, or Esketamine for Depression: A Meta-AnalysisHieronymus F, López E, Werin Sjögren H et al. · JAMA network open · 2025 · PMID 40736734
- Cochrane review [Treatment-resistant depression. From classification to new therapies.]Paganin W, Signorini S, Leccese V et al. · Rivista di psichiatria · 2022 · PMID 36503940
Mechanism and notes
Recorded mechanism or class: Integrative interventions for improving outcomes in depression: a narrative review · Halma M, Plothe C, Marik PE · 2024.
OSMF's existing evidence tier for this pair is C (Preliminary), derived from the strength of the disease association recorded in OSMF Chronic Disease Review. The tier describes how well the drug-disease link is documented, not how well the drug works.
Frequently asked questions
Is Psilocybin approved for Major Depressive Disorder?
Psilocybin has reached Preclinical as its most advanced recorded development stage across any indication, and the database holds no approval for Major Depressive Disorder. Approval status for the specific indication should always be confirmed with the relevant regulator and prescribing information.
Is Psilocybin in clinical trials for Major Depressive Disorder?
ClinicalTrials.gov lists 8 registered trials linking Psilocybin to Major Depressive Disorder: 1 is currently recruiting; 2 are active or not yet recruiting; 3 have completed; 2 are terminated, withdrawn, suspended or of unknown status. The most advanced is Phase 3 (NCT06308653). It plans or enrolled 238 participants. Registration activity spans 2017 to 2024.
What does the evidence show for Psilocybin in Major Depressive Disorder?
Psilocybin has both completed registered trials and synthesis-level publications linked to Major Depressive Disorder. That is the strongest profile in this database, but the summaries here do not extract effect sizes, so read the linked reviews for direction and magnitude of benefit. OSMF's existing evidence tier for this pair is C (Preliminary), derived from the strength of the disease association recorded in OSMF Chronic Disease Review. The tier describes how well the drug-disease link is documented, not how well the drug works.
Cite this page
Data: ClinicalTrials.gov, PubMed, Open Targets, ChEMBL, DGIdb and the OSMF therapeutic agent database. Last updated 2026-07-05. Page built 2026-10-07.