BACKGROUND: COMP360 is a proprietary, synthetic formulation of psilocybin being developed for treatment-resistant depression (TRD), a burdensome, life-threatening illness with high global impact. Here, we expand upon the previous report of primary outcomes from a phase 2 study of COMP360 in individuals with TRD-the largest randomised controlled clinical trial of psilocybin-to discuss findings of the exploratory efficacy endpoints. METHODS: In this phase 2, double-blind trial, 233 participants with TRD were randomised to receive a single dose of psilocybin 25 mg, 10 mg, or 1 mg (control), administered alongside psychological support from trained therapists. Efficacy measures assessed patient-reported depression severity, anxiety, positive and negative affect, functioning and associated disability, quality of life, and cognitive function. RESULTS: At Week 3, psilocybin 25 mg, compared with 1 mg, was associated with greater improvements from Baseline total scores in all measures. The 10 mg dose produced smaller effects across these measures. LIMITATIONS: Interpretation of this trial is limited by the absence of an active comparator and the possibility of functional unblinding in participants who received a low dose of psilocybin. CONCLUSIONS: Three weeks after dosing, psilocybin 25 mg and, to a lesser degree, 10 mg improved measures of patient-reported depression severity, anxiety, affect, and functioning. These results extend the primary findings from the largest randomised clinical trial of psilocybin for TRD to examine other outcomes that are of importance to patients.

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

COMPASS Pathfinder Ltd London UK

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

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

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

Department of Psychiatry and Behavioral Sciences Stanford University Stanford CA USA

Department of Psychiatry and Neurosciences Charité Universitätsmedizin Berlin Campus Benjamin Franklin Berlin Germany

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

Department of Psychiatry University Medical Centre Groningen Groningen the Netherlands

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

Department of Psychiatry University of California San Diego San Diego CA USA

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

Kadima Neuropsychiatric Institute La Jolla CA USA

New York State Psychiatric Institute New York NY USA; Department of Psychiatry Vagelos College of Physicians and Surgeons Columbia University New York NY USA

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

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

The National Institute of Mental Health Klecany Czech Republic

UTHealth Harris County Psychiatric Center Houston TX USA; Department of Psychiatry and Behavioral Sciences UTHealth Center of Excellence on Mood Disorders UT Houston Medical School Houston TX USA

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