Changes in self-related cognitive processes and depressive symptom severity following a single, moderate dose of psilocybin in depressed patients.
Lydia Belinger, Flora Moujaes, Robin von Rotz, Nathalie M. Rieser, Xaver Funk, Klemens Egger, Lena Meinhold, Maike Renkert, Philipp Stämpfli, Marcus Herdener, Franz X. Vollenweider, Katrin H. Preller
Philosophical transactions of the Royal Society of London. Series B, Biological sciences November 10, 2026 DOI: 10.1098/rstb.2025.0168 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized, double-blind, placebo-controlled clinical trial Peer reviewed |
|---|---|
| Sample size | 37 |
| Population | Individuals diagnosed with major depressive disorder |
| Interventions | Psilocybin psychological support |
| Dose | 0.215 mg kg-1 |
| Duration | Assessments two weeks after substance administration |
| Measures | Beck's depression inventory, Montgomery-Åsberg depression rating scale, Frankfurt self-concept scale, fMRI-based self-referential processing task |
| Topics | Depression Psilocybin Psychedelic-assisted therapy |
| Keywords | Self-concept Self-referential processing |
| Key findings | Two weeks after a single moderate dose of psilocybin (0.215 mg/kg) with psychological support, participants with major depressive disorder showed significant reductions in depressive symptoms and a significant increase in positive self-concept compared with placebo; self-concept changes correlated with decreased depressive scores. Neuroimaging showed psilocybin-associated modulation of caudate activation during externally oriented attention, contrasting with placebo-induced caudate changes during self-referential processing. |
Abstract
Psychedelic-assisted therapy, particularly with psilocybin, is increasingly proposed as a treatment for major depressive disorder, yet the neural and psychological mechanisms underlying its effects remain under investigation. In a randomized, double-blind, placebo-controlled clinical trial, individuals diagnosed with major depressive disorder received a single, moderate dose of psilocybin (0.215 mg kg-1) or placebo, with the same psychological support. We analysed N = 37 individuals with major depressive disorder undergoing assessments of depressive symptoms (Beck's depression inventory and Montgomery-Åsberg depression rating scale), self-concept (Frankfurt self-concept scale) and neural markers of self-referential processing using an fMRI-based task. Compared with placebo, the psilocybin group exhibited significant reductions in depressive symptoms and a significant increase in positive self-concept two weeks after substance administration. Changes in self-concept were significantly correlated with decreased depressive scores. Neuroimaging revealed psilocybin-associated modulation of caudate activation during externally oriented attention after two weeks, contrasting with placebo-induced caudate changes during self-referential processing. These findings extend prior evidence linking psychedelics to changes in self-referential processing and self-concept and demonstrate that such changes occur concurrently with reductions in depressive symptoms. Future research should aim to replicate and extend these results and refine therapy protocols targeting self-processing and self-concept in psychedelic-assisted therapy in major depressive disorder. This article is part of the discussion meeting issue 'From being to identity: analysis and synthesis of the self'.
Comparable studies
Other randomized controlled trials on psilocybin and psychedelic-assisted therapy, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects. Healthy adults, mostly hallucinogen-naïve | 2011 | Randomized controlled trial | n = 18 |
| Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder Adults aged 25–65 with DSM-IV alcohol dependence and at least 4 heavy drinking days in... | 2022 | Randomized controlled trial | n = 95 |
| Increased global integration in the brain after psilocybin therapy for depression. Patients with treatment-resistant depression and patients with major depressive disorder | 2022 | Open-label trial and double-blind phase II randomized controlled trial | |
| Single-dose psilocybin-assisted therapy in major depressive disorder: A placebo-controlled, double-blind, randomised clinical trial. Adults diagnosed with major depressive disorder and no unstable somatic conditions | 2023 | Double-blind, randomised clinical trial | n = 52 |
| Implications for psychedelic-assisted psychotherapy: functional magnetic resonance imaging study with psilocybin Healthy participants | 2012 | Randomized controlled trial | n = 10 |
Citations in the library
Cites 24
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Journal of Psychopharmacology November 30, 2016
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
- Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression Frontiers in Pharmacology January 17, 2018
and 19 more in the library