Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up

Abstract

Background: Preliminary data suggest that psilocybin-assisted treatment produces substantial and rapid antidepressant effects in patients with major depressive disorder (MDD), but little is known about long-term outcomes.

Aims: This study sought to examine the efficacy and safety of psilocybin through 12 months in participants with moderate to severe MDD who received psilocybin.

Methods: This randomized, waiting-list controlled study enrolled 27 patients aged 21-75 with moderate to severe unipolar depression (GRID-Hamilton Depression Rating Scale (GRID-HAMD) ⩾ 17). Participants were randomized to an immediate or delayed (8 weeks) treatment condition in which they received two doses of psilocybin with supportive psychotherapy. Twenty-four participants completed both psilocybin sessions and were followed through 12 months following their second dose.

Results: All 24 participants attended all follow-up visits through the 12-month timepoint. Large decreases from baseline in GRID-HAMD scores were observed at 1-, 3-, 6-, and 12-month follow-up (Cohen d = 2.3, 2.0, 2.6, and 2.4, respectively). Treatment response (⩾50% reduction in GRID-HAMD score from baseline) and remission were 75% and 58%, respectively, at 12 months. There were no serious adverse events judged to be related to psilocybin in the long-term follow-up period, and no participants reported psilocybin use outside of the context of the study. Participant ratings of personal meaning, spiritual experience, and mystical experience after sessions predicted increased well-being at 12 months, but did not predict improvement in depression.

Conclusions: These findings demonstrate that the substantial antidepressant effects of psilocybin-assisted therapy may be durable at least through 12 months following acute intervention in some patients.

Keywords: Insight; long-term effects; major depressive disorder; mystical experience; psilocybin.

Figure 1.

Decrease in GRID-HAMD depression scores over time from baseline through the 12-month follow-up (N = 24). Data points are means and brackets are ±1 SD; lower brackets are truncated at GRID-HAMD scores of 0. Mean GRID-HAMD was 22.8 (3.9) at baseline, 8.7 (7.6) at 1 week, 8.9 (7.4) at 4 weeks, 9.3 (8.8) at 3 months, 7.0 (7.7) at 6 months, and 7.7 (7.9) at 12 months post-treatment. All timepoints were significantly different from baseline (p < 0.001). Cohen d effect size is shown for each timepoint. Cohen d (95% CI) was 2.3 (1.5–3.1) at 1 week, 2.3 (1.5–3.1) at 4 weeks, 2.0 (1.3–2.7) at 3 months, 2.6 (1.7–3.4) at 6 months, and 2.4 (1.6–3.2) at 12 months.

Figure 2.

Depression scores (GRID-HAMD) for each of 24 study participants at baseline and each of 5 follow-up assessment timepoints. Individual participants are represented with different colors. Dashed lines indicate three participants who did not fulfill criteria for a treatment response at any post-treatment timepoint. Enlarged data points indicate participants who reported treatment with antidepressant medication, with the left-most enlarged data points showing the first follow-up timepoint at which medication use was reported.