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.

Conflict of interest statement

Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AKD is a board member of Source Research Foundation. MWJ has received grant support from the Heffter Research Institute unrelated to this study and he is an advisor to the following companies: AJNA Labs LLC, AWAKN Life Sciences Inc., Beckley Psytech Ltd., Entheon Biomedical Corp., Field Trip Psychedelics Inc., Mind Medicine Inc., Otsuka Pharmaceutical Development & Commercialization Inc., and Silo Pharma, Inc. RRG is a board member of the Heffter Research Institute and has received grant support from the Heffter Research Institute unrelated to this study. RRG is site principal investigator, and MWJ and NG are co-investigators for a multi-site trial of psilocybin-assisted therapy for major depressive disorder sponsored by Usona Institute.

Figures

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 deffect 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.