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Clinical Trial
. 2025 Jan 1;182(1):104-113.
doi: 10.1176/appi.ajp.20231063.

Single-Dose Psilocybin for Depression With Severe Treatment Resistance: An Open-Label Trial

Scott T Aaronson  1 , Andrew van der Vaart  1 , Tammy Miller  1 , Jeffrey LaPratt  1 , Kimberly Swartz  1 , Audrey Shoultz  1 , Margo Lauterbach  1 , Trisha Suppes  1 , Harold A Sackeim  1
Affiliations
Clinical Trial

Single-Dose Psilocybin for Depression With Severe Treatment Resistance: An Open-Label Trial

Scott T Aaronson et al. Am J Psychiatry. .

Abstract

Objective: Depression varies along a difficulty-to-treat spectrum. Patients whose illness fails to respond to at least five treatments may be considered to have severely treatment-resistant depression (TRD). The objective of this study was to document the safety and efficacy of psilocybin in patients with severe TRD.

Methods: This was a 12-week, open-label trial conducted at Sheppard Pratt Hospital. Participants were 18-65 years of age, in a major depressive episode with documented insufficient benefit from at least five treatments during the current episode. A single dose of synthetic psilocybin (25 mg) was administered. Psychotropic medications were discontinued at least 2 weeks prior to dosing through at least 3 weeks post-dosing. Therapists met with patients for three sessions during pretreatment, during the 8-hour dosing day, and for three integration sessions posttreatment. The primary outcome measure was change in Montgomery-Åsberg Depression Rating scale (MADRS) at 3 weeks posttreatment. Secondary measures including MADRS scores up to 12 weeks posttreatment, and subject-rated scales capturing depression and level of function were completed at baseline and all subsequent visits.

Results: Twelve participants (six male, six female; mean age=40.6 years [SD=9.6]) with severe TRD were followed over the study period. Depressive symptoms were significantly decreased at week 3 (MADRS least-squares mean change=-15.8, 95% CI=-25.4 to -6.3) and Week 12 (MADRS least-squares mean change=-17.2, 95% CI=-25.2 to -9.1). In exploratory analyses, the Oceanic Boundlessness (OB) dimension of the psychedelic experience correlated with post-dosing antidepressant responses. Patients with comorbid PTSD (N=5) showed significantly less antidepressant effect of psilocybin.

Conclusions: This open-label study suggests efficacy and safety of psilocybin in severe TRD and supports further study of psychedelics in this population, including consideration of PTSD interaction effects.

Keywords: Clinical Drug Studies; Depressive Disorders; Drug/Psychotherapy Combination; Major Depressive Disorder; Psychedelics; Psychopharmacology.

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Conflict of interest statement

Dr. Aaronson reports grants and nonfinancial support (supply of drug) from COMPASS Pathways during the conduct of the study and personal fees from Genomind, LivaNova, Neuronetics, and Sage Therapeutics outside the submitted work. Dr. Miller reports personal fees from COMPASS Pathways during the conduct of the study. Dr. LaPratt reports grants from COMPASS Pathways during the conduct of the study. Dr. Lauterbach reports study support from Sheppard Pratt/COMPASS Pathways and one-third ownership of Brain Educators outside the submitted work. Dr. Suppes reports stock options with Psilotec and one-time service on an advisory board for MindMed outside the submitted work. Dr. Sackeim serves as a consultant to Cerebral Therapeutics Inc., Holmusk Inc, LivaNova PLC, MECTA Corporation, Neurolief LTD, NeuroInsights Inc, Neuronetics Inc, Parow Entheobiosciences LLC, and SigmaStim LLC; he serves on the advisory boards of LivaNova PLC, Neuronetics Inc, and SigmaStim LLC; he receives honoraria and royalties from Elsevier, Inc. and Oxford University Press; he is the inventor on nonremunerative U.S. patents for Focal Electrically-Administered Seizure Therapy (FEAST) (US8712532), titration in the current domain in ECT (US9789310), and the adjustment of current in ECT devices (US10583288), each held by SigmaStim LLC; he is also the originator of magnetic seizure therapy (MST). The remaining authors report no financial relationships with commercial interests.

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