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.

Aalborg University Hospital Department of Psychiatry Aalborg Denmark; Aalborg University Department of Clinical Medicine Aalborg Denmark

Campbell Family Mental Health Research Institute Centre for Addiction and Mental Health Toronto Canada; Temerty Faculty of Medicine Department of Psychiatry University of Toronto Toronto Canada

Charité Universitätsmedizin Berlin Department of Psychiatry and Neurosciences Campus Charité Mitte Germany

Compass Pathfinder Ltd London UK

Compass Pathways Inc New York United States

Cumbria Northumberland Tyne and Wear NHS Foundation Trust UK; Newcastle University Newcastle upon Tyne UK

Department of Psychiatry University of California San Diego San Diego CA United States

Emory University School of Medicine Department of Psychiatry and Behavioral Sciences Atlanta GA United States

Faillace Department of Psychiatry and Behavioral Sciences McGovern Medical School University of Texas Health Science Center Houston Texas United States

Institute of Psychiatry Psychology and Neuroscience Department of Psychological Medicine King's College London and South London and Maudsley NHS Foundation Trust London UK

Kadima Neuropsychiatry Institute San Diego CA United States

New York State Psychiatric Institute Department of Psychiatry Vagelos College of Physicians and Surgeons Columbia University New York City New York United States

Parc Sanitari Sant Joan de Déu Barcelona Spain; Sant Joan de Déu Research Foundation Barcelona Spain

Stanford University Department of Psychiatry and Behavioral Sciences Stanford CA United States

The Institute for Advanced Diagnostics and Therapeutics Sheppard Pratt Baltimore Maryland United States; University of Maryland School of Medicine Department of Psychiatry Baltimore MD United States

The National Institute of Mental Health Klecany Czech Republic

Trinity Centre for Health Sciences Department of Psychiatry Tallaght University Hospital Dublin Ireland

University Medical Centre Groningen Department of Psychiatry Groningen the Netherlands

University Medical Centre Utrecht Brain Center Department of Psychiatry University Medical Center Utrecht Utrecht the Netherlands

Weill Institute for Neurosciences University of California San Francisco San Francisco CA United States

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