Psilocybin for Treatment-Resistant Depression (TRD)

95 papers and 41 clinical trials exploring psilocybin as a treatment for treatment-resistant depression (trd).

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

Indication30% of individuals with depression experience treatment-resistant depression.

Treatment-Resistant Depression (TRD)

Research into psychedelics as a treatment for Treatment-Resistant Depression (TRD) is advancing rapidly, with compounds like psilocybin showing particular promise. Approximately 30% of depression sufferers experience TRD, which reflects a significant unmet need in mental health treatment.

Full Treatment-Resistant Depression (TRD) profile

Academic Research

95 papers

Open Accessindividual

GH001 vs Placebo in Patients With Treatment-Resistant Depression A Randomized Clinical Trial

This randomised, double-blind, placebo-controlled Phase IIb trial (n=81) found that a single-day inhaled synthetic mebufotenin treatment (GH001; 5-MeO-DMT) reduced depression symptoms more than placebo in adults with treatment-resistant depression, with remission in over half of those treated. No severe or serious adverse events were reported during the placebo-controlled period.

Published: March 25, 2026
Journal: JAMA Psychiatry
Authors: Cubała, W. J., Bajbouj, M., Bauer, M., Baune, B. T., Cardoner, N., Devlin, F., Doolin, K., Dueñas Herrero, R. M., Elices, M., Feeney, A., Gałuszko-Węgielnik, M., Jakuszkowiak-Wojten, K., Janů, L., Kelly, J. R., Ledden, K., Maclsaac, R., Madero, S., McInerney, S. J., Montejo, A. L., Nawka, A., Páleníček, T., Pérez Solà, V., Ramaekers, J. G., Reif, A., Ritter, P., Ryan, F., Svendsen, C. B., Sweeney, C., Terwey, T. H., Trivedi, M. H., Valcheva, V., Vieta, E., Thase, M. E.

Paywallindividual

The role of therapeutic alliance in psilocybin treatment for treatment-resistant depression: A post hoc path analysis

This secondary analysis (n=79 of n=233) of a Phase II randomised trial examined whether therapeutic alliance or the psychedelic experience itself better predicted antidepressant outcomes in people with treatment-resistant depression (TRD) receiving psilocybin (25 mg), finding that measures of the psychedelic experience were more strongly associated with reduced depression scores than pre-dosing therapeutic alliance, though alliance did appear to modestly facilitate the quality of the psychedelic experience.

Published: March 23, 2026
Journal: Journal of Affective Disorders
Authors: Goodwin, G. M., Aaronson, S. T., Alvarez, O., Carhart-Harris, R., Croal, M., Feifel, D., Hellerstein, D. J., Husain, M. I., Kelly, J. R., Kirlic, N., Licht, R. W., Marwood, L., Nowakowska, A., Páleníček, T., Repantis, D., Schoevers, R. A., Simmons, H., Soares, J. C., Somers, M., Tsai, J., Wahba, M., Williams, E., Young, A. H., Young, M. B., Zisook, S., Malievskaia, E.

Open Accessindividual

Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression: The EPISODE Randomized Clinical Trial

In this triple‑blind, active placebo‑controlled randomised trial (n=144) of adults with treatment‑resistant depression, two 25 mg doses of psilocybin plus adjunct psychotherapy produced clinically meaningful reductions in depressive symptoms on exploratory secondary measures but did not significantly improve the pre‑second‑dose HAMD17 response rate versus nicotinamide.

Published: March 18, 2026
Journal: JAMA Psychiatry
Authors: Mertens, L. J., Koslowski, M., Betzler, F., Brand, M., Evens, R., Kärtner, L., Jungaberle, A., Jungaberle, H., Majić, T., Schmitz, C. N., Ströhle, A., Scharf, D., Spangemacher, M., Wolff, M., Assadi, Z., Bahri, S., Becher, L., Färber, L. V., Kirchen, N., Kulakova, E., Kunz, L., Meijer, A., Rohrmoser, B., Wellek, S., Berger, M. M., Gründer, G.

Open Accessmeta

Psychedelic medicine: mechanisms, evidence, and translation to practice

This review (2026) summarises the rapidly growing evidence for psychedelic-assisted therapies, finding the strongest support for psilocybin in treatment-resistant depression (TRD) and MDMA in post-traumatic stress disorder (PTSD). It also highlights that while these treatments are generally well tolerated in controlled settings, major challenges remain around unclear mechanisms, trial limitations, scalability, and translation into routine practice.

Published: February 23, 2026
Journal: BMJ
Authors: Jacobs, E., Zahid, Z., Hinkle, J., Nayak, S., Yaden, D. B.

Paywallindividual

A qualitative analysis of participant expectations and experiences of psilocybin-assisted psychotherapy for methamphetamine use disorder

Participants in a pilot study of psilocybin‑assisted psychotherapy for methamphetamine use disorder found the intervention acceptable and reported that confronting vividly challenging psychedelic experiences—described as “leaning into the obstacle”—fostered new self‑understandings and shifts in relationships that reduced the salience of methamphetamine. A strong therapeutic alliance, characterised by concentrated attention and intersubjective intimacy, was seen as critical to these positive changes.

Published: December 22, 2025
Journal: Addiction
Authors: Brett, J., Lea, T., Knock, E., Albert, S., Acheson, L., Siefried, K. J., Job, S.

Open Accessindividual

Effects of LSD and Psilocybin on Heart Rate in Patients Receiving Psychedelic Treatment for Depressive and Anxiety Disorders: A Retrospective Observational Study

In this retrospective study of 30 patients receiving LSD or psilocybin for treatment‑resistant depression or anxiety, LSD produced a delayed, sustained increase in heart rate peaking at 3–4 hours while psilocybin showed an earlier decline, with a significant time × substance interaction that persisted after adjusting for age and anxiety and no serious cardiovascular events observed. These preliminary findings suggest distinct temporal cardiovascular profiles for LSD versus psilocybin but should be interpreted cautiously given the retrospective design, small sample and dose imbalance.

Published: December 19, 2025
Journal: Psychology International
Authors: Cheng, M., Aboulafia-Brakha, T., Buchard, A., Boyanova Anastasova, R., Girani, L., Breitenmoser, A., Alaux, S., Mabilais, C., Amberger, C., Seragnoli, F., Furtado, L., Thorens, G., Zullino, D., Penzenstadler, L.

Clinical Trials

41 trials

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 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 III

Psilocybin-Assisted Therapy for Treatment-Resistant Depression in Bipolar II Disorder (PAT-BD-01)

This randomised, quadruple-blind, placebo-controlled Phase III trial (n=90) will study the effectiveness, safety, and tolerability of psilocybin (25 mg)–assisted therapy compared to an active placebo (1 mg psilocybin) in individuals with treatment-resistant depression associated with bipolar II disorder.

Started: June 1, 2025
Type: interventional
Blinding: quadruple
Randomized: Yes
Registry ID: NCT06943573

RecruitingPhase I

Psilocybin for Treatment-Resistant Depression in Autism With Pre-Post Brain and Cognitive Measurement to Understand Mechanisms (PAT-DA)

Open-label Phase I study (n=20) assessing feasibility, tolerability and safety of psilocybin (10 mg safety dose then 25 mg treatment dose) with manualised psilocybin-assisted therapy in autistic adults with treatment-resistant depression.

Started: December 1, 2024
Type: interventional
Blinding: none
Randomized: No
Registry ID: NCT06731621

Not yet recruitingPhase II

Psilocybin Medicine Open-Label Study (PMOS): a determination of the safety and efficacy of psilocybin-assisted psychotherapy for patients with Treatment Resistant Major Depressive Disorder (TRD) within an Australian clinical context

This open-label trial (n=50) will assess the safety and efficacy of psilocybin-assisted psychotherapy in patients with treatment-resistant major depressive disorder (TRD) in an Australian clinical setting. Participants will receive two doses of psilocybin (25mg each) alongside a structured programme of preparatory and integration psychotherapy sessions over approximately 16–18 weeks.

Started: November 20, 2024
Type: interventional
Blinding: none
Randomized: No
Registry ID: ACTRN12624001343594p

CompletedPhase NA

Effect of Psilocybin on the Positive Valence System in Treatment-resistant Depression (PSILODAC)

Single-group interventional study (n=10) testing a single 25 mg oral dose of psilocybin with pre/post MRI in patients with treatment-resistant depression to assess effects on the positive valence system.

Started: November 19, 2024
Type: interventional
Blinding: none
Randomized: No
Registry ID: NCT06650800

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Search all Psilocybin papers Search all Treatment-Resistant Depression (TRD) trials Full Psilocybin profile Full Treatment-Resistant Depression (TRD) profile

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Psilocybin for Treatment-Resistant Depression (TRD)

Psilocybin

Treatment-Resistant Depression (TRD)

Academic Research

GH001 vs Placebo in Patients With Treatment-Resistant Depression A Randomized Clinical Trial

The role of therapeutic alliance in psilocybin treatment for treatment-resistant depression: A post hoc path analysis

Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression: The EPISODE Randomized Clinical Trial

Psychedelic medicine: mechanisms, evidence, and translation to practice

A qualitative analysis of participant expectations and experiences of psilocybin-assisted psychotherapy for methamphetamine use disorder

Effects of LSD and Psilocybin on Heart Rate in Patients Receiving Psychedelic Treatment for Depressive and Anxiety Disorders: A Retrospective Observational Study

Clinical Trials

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

Psilocybin Intervention for Veterans Overcoming Treatment-Resistant Depression

Psilocybin-Assisted Therapy for Treatment-Resistant Depression in Bipolar II Disorder (PAT-BD-01)

Psilocybin for Treatment-Resistant Depression in Autism With Pre-Post Brain and Cognitive Measurement to Understand Mechanisms (PAT-DA)

Psilocybin Medicine Open-Label Study (PMOS): a determination of the safety and efficacy of psilocybin-assisted psychotherapy for patients with Treatment Resistant Major Depressive Disorder (TRD) within an Australian clinical context

Effect of Psilocybin on the Positive Valence System in Treatment-resistant Depression (PSILODAC)

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