Psilocybin-assisted therapy for treatment-resistant major depressive disorder in a public healthcare setting: a randomized controlled trial
James Rucker, Tim Mantingh, Jess Kerr-Gaffney, Catherine Bird, Petrina Chu, Nadav Liam Modlin, Kete Campbell‐coker, Sadie Hambleton, Paige Seath, Rebecca Hignett, Diede Fennema, Elliot Hampsey, Dimosthenis Tsapekos, Rebecca J. Thomas, Joseph Cattell, Hassan Jafari, Camilla Day, Anna Borissova, Miranda Lloyd, Theo Boardman-Pretty, Mathieu Seynaeve, Famia Askari, Michael Creed, Luke Baxter, Raphael Rifkin‐Zybutz, Matt Butler, Luke A. Jelen, Ben Carter, Allan H. Young
Nature Medicine August 6, 2026 DOI: 10.1038/s41591-026-04541-0 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial (feasibility trial) Placebo-controlled Double-blind Peer reviewed |
|---|---|
| Sample size | 60 |
| Population | Adults with treatment-resistant major depressive disorder (DSM-5 criteria, inadequate response to ≥2 antidepressants or ≥1 antidepressant plus ≥1 psychotherapy) at one NHS site in England |
| Interventions | Psilocybin Psychological support |
| Dose | 25 mg |
| Duration | 6 weeks of follow-up |
| Measures | Montgomery-Åsberg Depression Rating Scale (MADRS) |
| Topics | Depression Psilocybin |
| Citations | 1 |
| Key findings | A single 25-mg dose of psilocybin with psychological support reduced MADRS scores by 10.41 points more than placebo at week 3 (Cohen's d = -1.70), with the effect sustained at week 6. Recruitment and retention were feasible, supporting a future confirmatory trial. |
Abstract
Psilocybin-assisted therapy may be a promising new treatment for treatment-resistant depression. We examined the feasibility of administering a single 25-mg dose of psilocybin or placebo with psychological support in a randomized controlled trial design with 6 weeks of follow-up. A two-arm, double-blind, randomized, placebo-controlled feasibility trial was conducted at one National Health Service (NHS) site in England. Eligible participants met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for major depressive disorder and had an inadequate response to ≥2 antidepressant treatments or ≥1 antidepressant plus ≥1 psychotherapy. Participants received 25-mg psilocybin or placebo with preparation, dosing support and integration. Primary outcomes were recruitment, retention and estimation of the Montgomery-Åsberg Depression Rating Scale (MADRS) variance. A multilevel regression analysis with an intention-to-treat population was used. Sixty participants were randomized (1:1), balanced by age, sex and prior psilocybin exposure, and 59 of 60 participants completed the MADRS at all follow-up visits. The adjusted between-group difference at week 3 on the MADRS was -10.41 (95% confidence interval: -14.86 to -5.95; Cohen's d = -1.70), favoring psilocybin, which was sustained at week 6. In total, 123 and 164 nonserious adverse events occurred in the placebo and psilocybin arms, respectively. Findings support a future confirmatory trial. EudraCT no.: 2018-003573-97 .
Comparable studies
Other randomized controlled trials on psilocybin for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety | 2016 | Randomized controlled trial | n = 51 |
| Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Patients with cancer-related anxiety and depression | 2016 | Double-blind, placebo-controlled, crossover trial | n = 29 |
| Trial of Psilocybin versus Escitalopram for Depression Selected group of patients with depression | 2021 | Randomized controlled trial | |
| Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder Adults aged 21 to 75 years with major depressive disorder, not currently using... | 2020 | Randomized controlled trial | n = 24 |
| Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. Adults with treatment-resistant depression | 2022 | Phase 2 double-blind randomized controlled trial | n = 233 |