The role of the psychedelic experience in psilocybin treatment for treatment-resistant depression
This re-analysis of the COMPASS Phase IIb trial (n=233) investigates the relationships between psilocybin dose, psychedelic experiences, and therapeutic outcomes in treatment-resistant depression. Participants received a single dose of 25, 10, or 1 mg of psilocybin (COMP360) with psychological support. Higher doses produced stronger psychedelic effects, and reductions in depression (MADRS scores) at Week 3 correlated most strongly with dimensions of Oceanic Boundlessness (r = −0.508), Visual Restructuralization (r = −0.516), and Emotional Breakthrough Inventory (r = −0.637). Findings suggest the quality and intensity of psychedelic experiences mediate therapeutic outcomes and support dose-response mechanisms.
Authors
- Robin Carhart-Harris
- Allan Young
- Tomáš Páleníček
Published
Abstract
Objective
To determine the relationships between psilocybin dose, psychedelic experiences, and therapeutic outcome in treatment-resistant depression.
Methods
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.
Results
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.
Limitations
The existence of correlation does not establish causation and exploratory findings require further replication, preferably in larger independent samples.
Conclusions
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.
Research Summary of 'The role of the psychedelic experience in psilocybin treatment for treatment-resistant depression'
Introduction
Previous exploratory trials have suggested that psilocybin, a serotonergic prodrug metabolised to psilocin and acting as a 5-HT2A receptor agonist, can reduce symptoms of major depressive disorder (MDD), including in patients who have not responded to conventional treatments. Neuroimaging and pharmacodynamic studies indicate that 5-HT2A receptor engagement and peak plasma psilocin levels correlate with intensity and timing of the acute psychedelic experience, and that the experience is accompanied by transient increases in brain connectivity. Prior small clinical studies have reported relationships between measures of subjective psychedelic experience (for example Oceanic Boundlessness on the Five-Dimensional Altered States of Consciousness questionnaire and scores on the Mystical Experience Questionnaire) and subsequent clinical outcomes, but those studies were limited in size and varied in blinding methods, leaving uncertainty about which experiential domains are most clinically relevant. Goodwin and colleagues reported analyses from COMP 001, a large, multi-centre, dose-ranging clinical trial designed to probe these questions. The trial compared single oral doses of COMP360 psilocybin at 25 mg, 10 mg and 1 mg given with psychological support in adults with treatment-resistant depression (TRD). Building on the primary finding that 25 mg—but not 10 mg—improved depressive symptoms versus 1 mg at three weeks, the study set out to examine pre-specified exploratory and post-hoc associations between psilocybin dose, the intensity and character of the acute psychedelic experience (measured by the 5D-ASC and the Emotional Breakthrough Inventory, EBI), and change in depression severity, with the hypothesis that greater acute psychedelic intensity would correlate with larger reductions in depressive symptoms.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
Goodwin, G. M., Aaronson, S. T., Alvarez, O., Carhart-Harris, R., Chai-Rees, J., Croal, M., DeBattista, C., Dunlop, B. W., Feifel, D., Hellerstein, D. J., Husain, M. I., Kelly, J. R., Kirlic, N., Licht, R. W., Marwood, L., Meyer, T. D., Mistry, S., Nowakowska, A., Páleníček, T., . . . Malievskaia, E. (2025). The role of the psychedelic experience in psilocybin treatment for treatment-resistant depression. Journal of Affective Disorders, 372, 523-532. https://doi.org/10.1016/j.jad.2024.12.061
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