Efficacy and safety of psilocybin-assisted treatment for major depressive disorder : Prospective 12-month follow-up, Natalie Gukasyan et al., 2022

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

Natalie Gukasyan, Alan K Davis, Frederick S Barrett, Mary P Cosimano, Nathan D Sepeda, Matthew W Johnson and Roland R Griffiths

Journal of Psychopharmacology, 2022, Vol. 36(2) 151–158.

Doi : 10.1177/02698811211073759



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


Major depressive disorder (MDD) affects over 260 million people worldwide and is a leading cause of disability and healthcare expenditures (James et al., 2018). First-line treatments, including pharmacotherapy and psychotherapy, may take weeks or months to produce clinically meaningful symptom reduction, and patients can have difficulty with treatment adherence (Cuijpers et al., 2008; Kolovos et al., 2017; Lam, 2012). At least 30% of patients ultimately meet criteria for treatment-resistant depressive illness after failing to respond to multiple attempts at treatment (Nemeroff, 2007). MDD also has a highly recurrent course, with 40–60% of those diagnosed with a single episode eventually relapsing, and rate of relapse increasing with each subsequent episode (Richards, 2011; Solomon et al., 2000). Novel interventions are needed that can act rapidly and produce sustained remission.

Several preliminary studies suggest that psilocybin-assisted treatment may have substantial antidepressant effects in patients with MDD, with treatment response occurring within a week of administration of just one or two doses in the context of psychotherapy (Carhart-Harris et al., 2018, 2021; Davis et al., 2021). In an initial report of primary outcomes following two doses of psilocybin using a randomized waitlist-control study design, we reported a large effect size (Cohen d = 2.3) and high rates of treatment response and remission (71% and 54%) at 1 month following intervention (Davis et al., 2021). Treatment-resistant patients also appear to have a favorable response rate (Carhart-Harris et al., 2018). A more recent study used a double-blind double dummy design to compare high-dose psilocybin plus 6 weeks of placebo with very low dose psilocybin plus 6 weeks of escitalopram (Carhart-Harris et al., 2021). The authors failed to show a significant difference between the two groups at 6 weeks in their designated primary outcome measure (Quick Inventory of Depressive Symptoms). The majority of results for secondary outcome measures including other depression severity scores favored the high-dose psilocybin group, though analyses were not corrected for multiple comparisons.

Although psilocybin treatment of MDD appears promising, little is known about long-term efficacy and safety. The three studies conducted to date demonstrated efficacy at their longest follow-up assessments of 4 weeks (Davis et al., 2021), 6 weeks (Carhart-Harris et al., 2021), and 6 months (Carhart-Harris et al., 2018), although depression severity scores were trending upward at 3- and 6-month follow-up timepoints. Carhart-Harris et al. (2018), with the longest period of follow-up, had an open-label design. Given the chronicity and relapsing disease course of MDD (Richards, 2011), the present study represents a significant extension of these previous findings by assessing efficacy and safety of a psilocybin intervention throughout a 12-month follow- up period.