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

In a small exploratory study, 19 adults with moderate-to-severe major depression received placebo first, then 4 weeks later a single dose of psilocybin (0.3 mg/kg), both embedded in psychotherapy. Depression and anxiety improved after both placebo and psilocybin, with no statistically significant difference 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 66.7% of participants responded and 46.7% remitted following psilocybin. Improvements lasted about 2 months on average. The intensity of mystical-type experience during psilocybin did not correlate with antidepressant effects. The authors conclude that expectancy and therapy effects complicate interpretation but support further study of psilocybin for depression.

Study at a glance

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.