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

Psilocybin for Major Depressive Disorder (MDD)

130 papers and 67 clinical trials exploring psilocybin as a treatment for major depressive disorder (mdd).

CompoundClassic Psychedelic

Psilocybin

Psilocybin is a naturally occurring tryptamine psychedelic that acts as a prodrug to psilocin, a potent 5-HT2A receptor agonist. It is the furthest advanced psychedelic in clinical development, with two positive Phase III trials in treatment-resistant depression and expanding regulated access in Australia, Germany, and US states.

Full Psilocybin 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

130 papers
Open Accessindividual

Real-World Psilocybin Therapy for Treatment-Resistant Depression: a Retrospective Observational Study

In a retrospective case series (n=19) of treatment‑resistant depression patients treated with psilocybin (20–35 mg) in routine clinical practice, depressive symptoms decreased significantly with large effect sizes on MADRS and BDI, though response and remission rates were lower than in controlled trials and no additive benefit of multiple doses was found.

Published
June 1, 2026
Journal
The Lancet Regional Health – Europe
Authors
Jungwirth, J., Westenhöfer, S., Aicher, H., Provaznikova, B., Kronenberg, G., Seifritz, E., Prinz, S., Olbrich, S.
Paywallindividual

An Open-Label Study of Single-Dose Psilocybin for Borderline Personality Disorder With Co-Occurring Major Depressive Disorder

This open-label pilot study (n=9) tested a single dose of psilocybin in adults with borderline personality disorder and major depressive disorder. Depressive symptoms improved over four weeks, but borderline personality disorder symptoms did not change significantly.

Published
April 1, 2026
Journal
Journal of Clinical Psychopharmacology
Authors
Grant, J. E., Boutouis, S., O’Brien, M., Avila, L., Neelapu, M., Ehsan, D.
Paywallindividual

Psilocybin-assisted therapy for demoralisation in hospice patients: feasibility, safety and preliminary efficacy

In an open‑label pilot where 10 hospice patients received a single 25 mg psilocybin‑assisted therapy session, the intervention was feasible and well tolerated with no serious psilocybin‑related adverse events and produced a significant reduction in demoralisation at three weeks (mean reduction 8.8 points, p=0.0196). Acceptability varied because of the intervention’s emotional intensity, indicating PAT can be integrated into hospice care but requires optimisation and larger controlled trials.

Published
November 3, 2025
Journal
BMJ Open
Authors
Beaussant, Y., Sager, Z., Brennan, C., Kristan, I., Ljuslin, M., Mazzola, E., Macdonald, D., Murphy, M. E., Nigam, K., Rinaldi, A. D., Sanders, J., Schaefer, K. G., Sholevar, R., Summer, L., Waliji-Banglawala, A., Yudilevich-Espinoza, S., Tulsky, J. A.
Paywallindividual

Long-term outcomes of single-dose psilocybin for U.S. military Veterans with severe treatment-resistant depression - 12-month data from an open-label pilot study

This open-label follow-up study (n=10) of Veterans with severe treatment-resistant depression (TRD) found that a single dose of psilocybin (25mg) significantly reduced depression for up to 12 months, though effects began to wane after 6 months, with 40% maintaining response and 30% maintaining remission at the 12-month follow-up.

Published
November 1, 2025
Journal
Journal of Affective Disorders
Authors
Ellis, S., Bostian, C., Donnelly, A., Feng, W., Eisen, K., Lean, M., Conlan, E., Ostacher, M., Aaronson, S., Suppes, T.
Open Accessindividual

Set and setting in psilocybin-assisted therapy: A qualitative study of patients with cancer and depression

This qualitative study (n=28 interviews) of participants in a psilocybin-assisted therapy trial for cancer-related depression found that therapeutic benefits were closely tied to participants' ability to surrender (accepting and remaining open to the experience's intensity and unpredictability), with a safe, supportive, and ethical environment critical to fostering trust and engagement, and preparation and integration key to maximizing benefit, whilst music played a significant but variable role and ceremonial elements added meaning for many despite the clinical setting providing safety.

Published
November 1, 2025
Journal
General Hospital Psychiatry
Authors
Beaussant, Y., Tarbi, E., Nigam, K. B., Miner, S., Sager, Z., Sanders, J. J., Ljuslin, M., Guérin, B., Sholevar, R., Roddy, K., Tulsky, J., Agrawal, M.
Open Accessindividual

A novel psychedelic 5-HT2A receptor agonist GM-2505: The pharmacokinetic, safety, and pharmacodynamic profile from a randomized trial healthy volunteer

In a randomized, placebo‑controlled ascending‑dose study in 48 healthy volunteers, single IV doses of GM‑2505 up to 20 mg were well tolerated and showed dose‑proportional pharmacokinetics (t1/2 40–50 min) with dose‑dependent neuroendocrine, neurophysiological and subjective psychedelic effects, including decreased theta/alpha and increased gamma EEG power. The duration of cardiovascular and subjective effects was intermediate between psilocybin and DMT, indicating a practical 10–15 mg IV dose range for supervised clinical use.

Published
October 16, 2025
Journal
Journal of Psychopharmacology
Authors
Marek, G. J., Makai-Bölöni, S., Umbricht, D., Christian, E. P., Winters, J., Dvorak, D., Raines, S., Hughes, Z. A., Austin, E. W., Klein, A. K., Leong, W., Krol, F. J., Van Der Graaf, A. J., Juachon, M. J., Otto, M. E., Borghans, L. G. J. M., Jacobs, G., Kruegel, A. C., Sporn, J.

Clinical Trials

67 trials
Not yet recruitingPhase II

Group PACBT for Depression

This Phase II, single-group trial (n=30) will assess group psilocybin-assisted cognitive behavioural therapy for adults with major depressive disorder, with a focus on acceptability and feasibility, while also exploring effects on depressive symptoms and psychosocial functioning. Participants aged 21 to 60 years with current or past major depressive episodes and active depressive symptoms will receive manualised group cognitive behavioural therapy alongside oral psilocybin. The intervention consists of 12 group PA-CBT sessions and two oral psilocybin administrations, given as a 10mg dose followed by a 25mg dose one month later, with all treatments delivered together in a group format. Primary outcomes include treatment acceptability from baseline to post-treatment, feasibility measured by participant retention, and change on the Hamilton Depression Rating Scale from baseline to the end of the study.

Started
January 1, 2027
Type
interventional
Blinding
none
Randomized
No
Registry ID
NCT07566104
Not yet recruitingPhase I

Psilocybin as a Novel Therapy for Residual Anhedonia

This Phase I, randomised, triple-masked, parallel-group trial (n=90) will evaluate whether a single oral dose of psilocybin 25 mg can improve residual anhedonia and emotional blunting in adults with major depressive disorder who remain symptomatic despite ongoing SSRI or SNRI treatment. The study will compare psilocybin with placebo and will assess whether treatment can restore fronto-striatal reward circuit function and reduce anhedonia. Participants in both arms will complete six MRI sessions, with two scans before the administration day and four afterwards. The psilocybin group will receive a supervised one-time 25 mg capsule dose, while the control group will receive a matching placebo capsule containing 25 mg of inert filler. Key outcomes include change in Dimensional Anhedonia Rating Scale score and change in fronto-striatal connectivity (pgACC-NAcc functional connectivity) from baseline to end of study, with assessments planned from week -3 to week 8.

Started
July 1, 2026
Type
interventional
Blinding
triple
Randomized
Yes
Registry ID
NCT07607938
Not yet recruitingPhase II

Psilocybin-Assisted Therapy as a Treatment for Depression

This Phase 2b open-label, single-arm pilot mechanistic trial (n=50) evaluates psilocybin-assisted therapy (PAT) for adults with mild-to-moderate depression at Washington University in St. Louis. Each participant receives the Usona Institute PAT protocol: 2 preparation sessions (~8 hours total), one Dosing Day with a single 25 mg oral psilocybin capsule, and 3 integration sessions at Trial Days 2, 8 and 15 (~80 min each) with two trained facilitators. Participants on a stable antidepressant monotherapy may continue their medication, and those with a MADRS score ≥7 at Trial Day 30 are eligible for one optional re-administration. Primary endpoints are change in depression severity (MADRS) and psychological flexibility (MPFI) at ~1 week (Trial Day 8) and ~30 days after dosing. Exploratory aims characterise neural mechanisms via up to 10 fMRI sessions per participant (including imaging during dosing using precision functional brain mapping), proteomic blood biomarkers (the senescence-associated secretory phenotype, SASP), and cognitive functioning via the NIH Toolbox. The study is designed to estimate feasibility, effect sizes and operational parameters — it is not powered for confirmatory hypothesis testing — to inform a subsequent adequately-powered trial.

Started
June 1, 2026
Type
interventional
Blinding
none
Randomized
No
Registry ID
NCT07582120
Not yet recruitingPhase II

The Efficacy of Psilocybin Therapy for Depression in Parkinson's Disease

This Phase II, randomised, quadruple-masked, parallel-group trial (n=40) will evaluate oral psilocybin therapy for depression in people with Parkinson’s disease. The study will assess whether two psilocybin administration sessions, delivered in a monitored setting with psychotherapeutic support, improve depressive symptoms and other clinical outcomes in participants with early to moderate Parkinson’s disease and moderate or greater depression. Participants with Hoehn and Yahr stage 1–3 Parkinson’s disease and a baseline Beck Depression Inventory-2 score of at least 20 will receive one dose of psilocybin ranging from low (“microdose”) to high in each of two drug administration sessions, with preparation psychotherapy before and integration sessions after. Outcomes will include change in depression measured by the Montgomery-Asberg Depression Rating Scale from baseline to 30 days after the first dose, as well as safety, tolerability, non-motor and motor symptoms of Parkinson’s disease, cognitive performance, and quality of life, with follow-up continuing for 3 months after the second session.

Started
May 1, 2026
Type
interventional
Blinding
quadruple
Randomized
Yes
Registry ID
NCT07610369
Not yet recruitingPhase I

A Phase 1, Open-label, Single-arm Basket Trial of the Intravenously Administered Psilocin (TRP-8803): Safety, Anxiety, and Quality of Life Across Health Conditions Characterised by Cognitive Inflexibility, Emotional Distress, and Persistent Bodily Symptom Burden

This Phase 1, open‑label, single‑arm basket trial (N=66) tests the safety and early clinical effects of intravenous psilocin (TRP‑8803) administered in two dosing sessions alongside psychotherapy over a 6‑week treatment period, with a 12‑week follow‑up. Conducted in Australia and sponsored by Tryp Therapeutics, the study enrols participants across ten diagnostic cohorts — anorexia nervosa, body dysmorphic disorder, chronic fatigue, fibromyalgia, generalised anxiety disorder, irritable bowel syndrome, long COVID, major depressive disorder, obsessive–compulsive disorder and post‑traumatic stress disorder — to evaluate tolerability and signals of benefit in anxiety and quality of life. As a Phase 1 trial the primary outcomes focus on safety and tolerability (adverse events, vital signs and treatment‑emergent effects), with secondary or exploratory outcomes assessing changes in anxiety symptoms and health‑related quality of life using standardised, validated instruments. The single‑arm, open‑label design means there is no placebo or active comparator, and efficacy assessments are intended to generate preliminary, hypothesis‑generating data to inform the design of subsequent controlled studies. The study began recruitment in November 2025.

Started
November 3, 2025
Type
interventional
Blinding
none
Randomized
Yes
Registry ID
ACTRN12625000949482
Not yet recruitingPhase II

Mindfulness-based Psilocybin Therapy for PTSD

Phase II, assessor-blinded, randomised controlled trial (n=30) of a single 25 mg oral synthetic psilocybin dose given with either standard psychological support or psychological support plus MBCT in adults with PTSD.

Started
November 1, 2025
Type
interventional
Blinding
single
Randomized
Yes
Registry ID
NCT07104916

Explore further

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