The role of the psychedelic experience in psilocybin treatment for treatment-resistant depression.
Guy M. Goodwin, Scott T Aaronson, Oscar Alvarez, Robin Carhart-Harris, Jamie Chai-Rees, Megan Croal, Charles DeBattista, Boadie W Dunlop, David Feifel, David J Hellerstein, Muhammad I Husain, John R. Kelly, Namik Kirlic, Rasmus W Licht, Lindsey Marwood, Thomas D Meyer, Sunil Mistry, Ania Nowakowska, Tomáš Páleníček, Dimitris Repantis, Robert A Schoevers, Hollie Simmons, Metten Somers, Emma Teoh, Joyce Tsai, Mourad Wahba, Sam Williams, Allan H. Young, Matthew B Young, Sidney Zisook, Ekaterina Malievskaia
Journal of Affective Disorders March 1, 2025 DOI: 10.1016/j.jad.2024.12.061 (opens in new tab)
The journal has published a correction to this paper. Read the correction (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Peer reviewed |
|---|---|
| Sample size | 233 |
| Population | Adults with treatment-resistant depression |
| Intervention | COMP360 psilocybin |
| Dose | 25, 10, or 1 mg |
| Duration | Single dose, outcome measured at 3 weeks post-administration |
| Topics | Depression Psilocybin |
| Keywords | Psychedelics psilocybin Hallucinogens Mental health depression Mood disorders Dose-response dosage Therapeutic dose Drug effects Mystical experiences Psychedelic experience Randomized-control trial |
| Citations | 35 |
| Key findings | At the 25 mg psilocybin dose, the psychedelic experience dimensions of oceanic boundlessness, visual restructuralization, and emotional breakthrough showed the strongest correlations with reduced depression scores three weeks after administration. |
Abstract
To determine the relationships between psilocybin dose, psychedelic experiences, and therapeutic outcome in treatment-resistant depression. For treatment-resistant depression, 233 participants received a single dose of 25, 10, or 1 mg of COMP360 psilocybin (a proprietary, pharmaceutical-grade synthesized psilocybin formulation, developed by the sponsor, Compass Pathfinder Ltd.) with psychological support. The resulting psychedelic experience (Five-Dimensional Altered States of Consciousness questionnaire [5D-ASC] and Emotional Breakthrough Inventory [EBI]) were measured. These proximal variables and outcome 3 weeks post-administration (change in Montgomery-Åsberg Depression Rating Scale [MADRS]) were explored using correlation analysis. The mean intensity of psychedelic effects was dose-related, but distributions of scores for different doses overlapped considerably. Depression response correlated with select aspects of the psychedelic experience overall and for individual doses. At the 25 mg dose, 5D-ASC dimensions Oceanic Boundlessness (Pearson correlation coefficient r = -0.508) and Visual Restructuralization (r = -0.516), and EBI (r = -0·637) were the variables with the strongest correlation to the Week 3 change from Baseline in MADRS score. The existence of correlation does not establish causation and exploratory findings require further replication, preferably in larger independent samples. The intensity of psychedelic experience overlaps widely across doses and mitigates the risk of unblinding to dose. Correlations between psychedelic experience and outcome suggest specificity in psilocybin's mechanism of action. Quality and intensity of psychedelic experience may be a measure of pharmacodynamic effect and reveal an effective dose response phenomenon for single oral doses.
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 |