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 via PubMed
Summary
AI-generated from the abstractIn treatment-resistant depression, a single dose of 25 mg of psilocybin produced stronger correlations between certain psychedelic experiences and depression improvement three weeks later than lower doses. The intensity of psychedelic effects was dose-related, but scores for different doses overlapped considerably. At the 25 mg dose, dimensions of oceanic boundlessness and visual restructuralization, along with emotional breakthrough, showed the strongest correlations with reduced depression scores. The study does not establish causation and requires replication. The overlap in experience intensity across doses suggests unblinding to dose is less likely. Correlations between psychedelic experience and outcome indicate specificity in psilocybin's mechanism of action.
Study at a glance
| 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 |
| Citations | 35 |
| Key finding | 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.