Psilocybin for Depressive Disorders

390 papers and 145 clinical trials exploring psilocybin as a treatment for depressive disorders.

Blossom tracks 390 papers and 145 clinical trials examining psilocybin as a treatment for depressive disorders. Psilocybin acts primarily as a 5-ht2a agonist (prodrug to psilocin). The papers and trials below are sorted by recency, and reported adverse events and dosing protocols are summarised in the linked overviews.

Psilocybin Depressive Disorders Adverse events Dose summary Clinical guidelines

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

IndicationAround 280 million people live with depression worldwide

Depressive Disorders

Depression is the flagship indication for psychedelic and rapid-acting psychiatry, and the place where the field has gone furthest: an approved drug (esketamine), the first Phase 3 win for a classic psychedelic, and several striking trials of psilocybin for major depression. But it is also where the honest caveats bite hardest. The most rigorous recent analyses suggest much of psilocybin’s apparent edge comes from patients knowing they got the drug, and a head-to-head against a standard antidepressant was not significant on its main measure. This is the umbrella page for the depression family; the resistant, general and bipolar forms each have their own.

Full Depressive Disorders profile

Safety summary

Psilocybin for Depressive Disorders: adverse events

Psilocybin safety reports for Depressive Disorders most often include headache, nausea, anxiety, fatigue among the source-backed named adverse events currently normalized in Blossom.

22 source papers|188 named AE rows|Top events: headache, nausea, anxiety

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Dose summary

Psilocybin for Depressive Disorders: dose summaries

Psilocybin clinical studies for Depressive Disorders include 56 structured dose rows across 43 linked trials. Common source-reported dose patterns include 25 mg, 1 mg, 10 mg. Interpret these as descriptive trial protocols, not treatment recommendations.

113 source papers|56 dose rows|Patterns: 25 mg, 1 mg, 10 mg

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Clinical guidelines

Psilocybin clinical practice guidance

Blossom tracks 30 trial-anchored clinical guidelines for psilocybin, covering screening, dosing-session facilitation, safety, and integration competencies relevant to depressive disorders research.

30 guidelines|Psilocybin protocol family

View Psilocybin guidelines

Academic Research

390 papers

Open Accessindividual

Divergent changes in perturbation-induced brain reconfiguration following depression treatment with psilocybin and escitalopram

This brain imaging study examined resting-state fMRI from people with major depressive disorder before and after treatment with psilocybin or escitalopram, using computer models to test how the brain responded to artificial perturbations. It found that psilocybin increased brain reconfiguration under perturbation, while escitalopram decreased it, suggesting different effects on brain flexibility and stability.

Published: June 26, 2026
Journal: Biorxiv
Authors: Dagnino, P. C., Acero-Pousa, I., Carhart-Harris, R., Erritzoe, D., Nutt, D. J., Kringelbach, M. L., Sanz Perl, Y., Deco, G.

Paywallindividual

Blocking 5-HT2B receptors abolishes psilocybin’s efficacy in the rat forced swim test

This rat study examined whether blocking 5-HT2B receptors changes psilocybin’s effects in the forced swim test. In Wistar rats, a 5-HT2B blocker abolished psilocybin’s rapid and lasting antidepressant-like behaviour in the test, but did not affect the head-twitch response linked to psychedelic effects.

Published: June 23, 2026
Journal: Journal of Psychopharmacology
Authors: Seillier, L., Seillier, A., Zvolska, M. A., Šlamberová, R.

Open Accessindividual

Sex-Specific Effects of Psilocybin Versus Escitalopram on Anxiety and Anhedonia: A Bayesian Reanalysis of Antidepressant Treatment Outcomes

This reanalysis of a six-week double-blind randomised controlled trial compared psilocybin with escitalopram in adults with moderate-to-severe depression and found sex-specific patterns in response. Women given psilocybin had greater reductions in anxiety, while women given escitalopram had greater reductions in anhedonia; other differences were small and uncertain.

Published: June 19, 2026
Journal: Research Square
Authors: Frick, A., Blest-Hopley, G., Grin, M., Erritzoe, D., Nutt, D., Carhart-Harris, R.

Open Accessindividual

Distinct brain responses to psilocybin and escitalopram in depression captured by the Fluctuation-Dissipation Theorem

This double-blind randomised controlled trial studied brain scans from people with major depressive disorder treated with psilocybin or escitalopram and found that the two treatments caused opposite changes in brain organisation. Baseline brain measures also helped distinguish who responded to each treatment.

Published: June 16, 2026
Journal: Biorxiv
Authors: Dagnino, P. C., Acero-Pousa, I., Zamora-López, G., Escrichs, A., Erritzoe, D., Nutt, D. J., Carhart-Harris, R. L., Sanz Perl, Y., Kringelbach, M. L., Deco, G.

Paywallindividual

Psilocybin-assisted cognitive behavioral therapy for major depressive disorder: A pilot trial

This pilot trial (n=16) tested psilocybin-assisted cognitive behavioural therapy for adults with major depressive disorder, using 10 mg and 25 mg psilocybin doses alongside 12 therapy sessions. It was well accepted and feasible, with no serious adverse events, and most participants improved in depressive symptoms, with gains lasting three months after treatment.

Published: June 8, 2026
Journal: Journal of Affective Disorders
Authors: Weintraub, M. J., Jeffrey, J. K., Ichinose, M. C., Bergman, R. L., Shapiro, B., Barnett, G., Artin, H., Lynn, M., Salimian, A., Grody, S., Ramesh, R., Eales, L., Grob, C. S., Miklowitz, D. J.

Paywallindividual

Changes in anxiety, quality of life, and functioning following psilocybin-assisted therapy in veterans with treatment-resistant depression

This secondary analysis of an open-label trial (n=15) examined a single 25 mg dose of psilocybin with psychological support in veterans with treatment-resistant depression, focusing on anxiety, quality of life, functioning, and PTSD symptoms. Improvements were observed across these measures, but most were no longer significant after accounting for concurrent improvements in depression.

Published: June 4, 2026
Journal: Journal of Affective Disorders
Authors: Kelly, C. M., Fradet, M., Bostian, C. M., Donnelly, A., Ellis, S., Ostacher, M., Aaronson, S., Suppes, T.

Clinical Trials

145 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/II

Psilocybin Assisted Psychotherapy for Treatment Resistant Depression and Co-occurring Substance Use Disorder

This Phase I/Phase II, randomised, double-blind, quadruple-masked trial (n=50) will evaluate a single oral dose of psilocybin 5 mg, 10 mg or 25 mg, given alongside psychotherapy, in veterans and first responders with treatment-resistant depression (TRD) and co-occurring substance use disorder (SUD). The study will assess safety and tolerability, as well as whether psilocybin-assisted psychotherapy can reduce substance use severity and depressive symptoms. Participants will be assigned in parallel to one of three psilocybin dose groups and will complete two intake visits, three preparatory psychotherapy sessions, an 8 to 10 hour dosing session, and three weekly integrative psychotherapy sessions afterwards. Outcomes include adverse events, urine drug results, days of substance use, depression symptom ratings, plasma brain-derived neurotrophic factor (BDNF) during stress exposure, and resting brain functional connectivity on MRI, with repeated daily assessments across 6 weeks and follow-up through 12 weeks, including a 60-day follow-up.

Started: August 1, 2026
Type: interventional
Blinding: quadruple
Randomized: Yes
Registry ID: NCT07499583

Not yet recruitingPhase II

Anesthesia-Masked Psilocybin Therapy for Major Depression

This Phase II, randomised, double‑blind, crossover trial (n=10) will assess the safety, feasibility and effectiveness of masking psilocybin therapy with general anaesthesia in adults with major depressive disorder (age 25–65). Participants will receive oral psilocybin (10 mg and 25 mg) and placebo (0 mg) across repeated sessions administered under intravenous propofol anaesthesia so that both participants and outcome assessors remain blinded; the study will also collect preliminary data on changes in depressive symptoms. All participants complete four weekly dosing sessions (placebo, 10 mg, and two separate 25 mg sessions) in one of two counterbalanced sequences so every participant receives every dosing condition. Psilocybin or placebo capsules are given approximately 30 minutes before induction of general anaesthesia with propofol, with anaesthesia provided by a board‑certified anaesthesiologist at Stanford Hospital. Primary outcomes are blinding success measures (correct identification of psilocybin and accuracy of guessed dose) assessed 1 day after the final dosing session (Visit 21, Week 4); secondary data collection includes mood, sleep, wellbeing and anxiety questionnaires, optional consumer‑grade EEG sleep monitoring, and overall study duration per participant of about 7 weeks across ~25 visits.

Started: July 1, 2026
Type: interventional
Blinding: double
Randomized: Yes
Registry ID: NCT07479550

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 III

Psilocybin Intervention for Veterans Overcoming Treatment-Resistant Depression

This Phase III, randomised, quadruple‑masked, parallel trial (n=240) will evaluate the efficacy and risks of psilocybin for treatment‑resistant depression in U.S. military veterans with and without concurrent post‑traumatic stress disorder, with the primary outcome being change in the Montgomery‑Åsberg Depression Rating Scale (MADRS) at 2 weeks. This multi‑site study randomises participants to either a psilocybin intervention dose or a psilocybin comparator dose under blinded conditions. Consenting veterans will receive two psilocybin dosing sessions with psychological preparation, administration and integration support from a facilitator; participants are randomised at the first administration to one of the two doses and one month later all participants receive a 25 mg dose at the second session. Outcomes are measured by an independent evaluator masked to treatment at 2 and 4 weeks after each dosing session, with longer‑term follow‑up over 6 months, and both expected and unanticipated adverse events collected. Key eligibility includes English‑speaking U.S. veterans aged 18–75 years with a current major depressive episode (MADRS ≥20) who have not responded to ≥2 adequate antidepressant treatments.

Started: June 1, 2026
Type: interventional
Blinding: quadruple
Randomized: Yes
Registry ID: NCT07226232

Not yet recruitingPhase II

Group Retreat Psilocybin Therapy for Healthcare Clinicians With Loss of Meaning in Their Work and Symptoms of Depression

This Phase II, non-randomised, single-arm sequential dose-finding trial (n=72) will evaluate group retreat psilocybin therapy for healthcare clinicians with symptoms of depression and loss of meaning in their work. It will assess the feasibility, safety, and preliminary clinical effects of different preparation “doses” before a single psilocybin retreat session. Participants will be healthcare clinicians aged 25-70 years who are currently in clinical practice and have moderate or greater depressive symptoms. The study uses three sequential cohorts, each with 8 participants per retreat and 3 retreats per cohort, comparing 7 preparation sessions (6 virtual and 1 in-person), 4 preparation sessions (3 virtual and 1 in-person), and 2 preparation sessions (1 virtual and 1 in-person). The psilocybin dose depends on antidepressant use: 25 mg plus an optional 10 mg booster for those not taking an antidepressant, or 35 mg plus an optional 10 mg booster for those taking an antidepressant. The intervention includes preparation sessions, a single psilocybin session, and integration sessions, with outcomes collected at 1 week, 1 month, and 3 months after the retreat.

Started: June 1, 2026
Type: interventional
Blinding: none
Randomized: No
Registry ID: NCT07565909

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Search all Psilocybin papers Search all Depressive Disorders trials Full Psilocybin profile Full Depressive Disorders profile