Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial

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. Metho...

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Published in:Journal of psychopharmacology (Oxford) 2023-07, Vol.37 (7), p.698-706
Main Authors: Sloshower, Jordan, Skosnik, Patrick D., Safi-Aghdam, Hamideh, Pathania, Surbhi, Syed, Shariful, Pittman, Brian, D’Souza, Deepak Cyril
Format: Article
Language:English
Subjects:
Antidepressants
Antidepressive Agents - pharmacology
Antidepressive Agents - therapeutic use
Anxiety
Depressive Disorder, Major - drug therapy
Dosage
Expectancy
Hallucinogens - pharmacology
Hallucinogens - therapeutic use
Humans
Mental depression
Placebos
Psilocybin
Psilocybin - pharmacology
Psilocybin - therapeutic use
Psychedelic drugs
Psychotherapy
Quality of Life
Remission
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Summary: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.
ISSN:0269-8811
1461-7285
DOI:10.1177/02698811231154852