Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial
In a within-subject, placebo-controlled fixed-order trial in moderate–severe major depressive disorder, both placebo and a single 0.3 mg/kg psilocybin dose delivered within psychotherapy produced significant improvements, but psilocybin showed larger effect sizes and high response (66.7%) and remission (46.7%) rates with benefits persisting about two months. The findings support the antidepressant promise of psilocybin while emphasising the strong influence of expectancy and psychotherapeutic context—and the need for trials that better mitigate and measure these effects.
Authors
- Deepak Cyril D’Souza
- Brian Pittman
- Jordan Sloshower
Published
Abstract
Background
Several early phase studies have demonstrated that psilocybin-assisted therapy has rapid-acting and persisting antidepressant effects from just one or two doses. However, methodological limitations (e.g., placebo-control, blinding) limit interpretability of the existing literature.
Methods
In an exploratory placebo-controlled, within-subject, fixed-order study, individuals with moderate to severe major depressive disorder were administered placebo ( n = 19) followed by psilocybin (0.3 mg/kg) ( n = 15) 4 weeks later. Dosing sessions were embedded within an manualized course of psychotherapy. Enhanced blinding procedures were used. Depression, anxiety, and quality of life were measured over a 16-week study period.
Results
Depression and anxiety significantly improved following both placebo and psilocybin with no significant difference in the degree of change between the two conditions. However, antidepressant effect sizes were larger after psilocybin ( d′ = 1.02–2.27) than after placebo ( d′ = 0.65–0.99) and there were high rates of response (66.7%) and remission (46.7%) following psilocybin administration. Antidepressant effects following psilocybin persisted, on average, for 2 months and there were persisting improvements in mood-related quality of life domains. The strength of mystical-type experience during psilocybin dosing was not correlated with subsequent antidepressant effects.
Conclusions
The results of this exploratory study highlight the complex interplay between expectancy, therapy effects, and drug/placebo effects in psychedelic-assisted psychotherapy studies. Nonetheless, the acute and persisting clinical improvements observed following psilocybin support further study of its potential in the treatment of major depression. Future studies should more explicitly mitigate and measure expectancy effects and assess the impact of repeated dosing and different forms of psychotherapeutic support.
Research Summary of 'Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial'
Introduction
Earlier clinical work has reported rapid and sometimes durable antidepressant effects after one or two doses of psilocybin given with psychological support, but many of those studies lacked placebo control, had limited measures to preserve blinding, used heterogeneous psychotherapeutic approaches, and in some cases assessed long-term outcomes after crossover or delayed-treatment periods that complicate interpretation. In particular, uncertainty remains about how much of observed clinical benefit is attributable to the pharmacological effects of psilocybin versus expectancy, nonspecific “set and setting” influences, or the psychosocial elements of therapy. Sloshower and colleagues designed an exploratory trial to address some of these gaps by combining a placebo-controlled design with enhanced blinding procedures and a manualised psychotherapeutic framework that incorporated elements of Acceptance and Commitment Therapy (ACT). Although the study was powered primarily to investigate electrophysiological markers of neural plasticity, the current report presents the clinical outcomes from that trial, focusing on depressive symptoms, anxiety, quality of life, acute subjective effects, blinding success, and safety following placebo and a single moderate dose of psilocybin administered within a structured therapy protocol.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
Sloshower, J., Skosnik, P. D., Safi-Aghdam, H., Pathania, S., Syed, S., Pittman, B., & D’Souza, D. C. (2023). Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial. Journal of Psychopharmacology, 37(7), 698-706. https://doi.org/10.1177/02698811231154852
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