Single-Dose Psilocybin for Treatment-Resistant Major Depression


Is psilocybin a viable treatment for MDD? Researchers performed a phase 2, double blind trial of single-dose psilocybin in patients with treatment resistant depression.




“Mr Mora” is a 39-year-old African American male with a history of recurrent, severe major depressive disorder (MDD) without psychosis. The onset of his depression was in early adolescence. Mr Mora previously failed trials of sertraline, bupropion, venlafaxine, nortriptyline, lithium, aripiprazole, and perphenazine. He also sees a psychotherapist for monthly cognitive-behavioral therapy. His current regimen includes fluoxetine 80 mg daily and amphetamine-dextroamphetamine extended-release 20 mg daily, to which he has had a partial response.

At his most recent outpatient clinic visit, Mr Mora asks whether he is a candidate for treatment with adjunctive psychedelics, and specifically asks about psilocybin. As his psychiatrist, how would you respond?

Treatment-resistant depression (TRD) has been defined as failure of 2 different courses of treatment. Patients with TRD have greater duration of illness, illness severity, disability, physical illness, suicide risk, and economic costs than patients with treatment-responsive depression. Psilocybin has demonstrated antidepressant properties in patients with MDD and TRD.1-3

The Current Study

Goodwin and colleagues4 conducted a phase 2 double-blind, dose-finding, parallel group, randomized controlled trial. The study sponsor, COMPASS Pathfinder, designed and funded the trial and provided a proprietary pharmaceutical-grade synthetic form of psilocybin (COMP360).

An independent contract research organization (MedAvante-ProPhase) was responsible for assessment of participants using the Montgomery-Åsberg Rating Scale (MADRS), performed by trained, blinded, remote raters, as well as the statistical analyses. The sponsor performed data interpretation and post-hoc statistical analyses and paid for professional writing assistance for the first draft of the manuscript.

The authors recruited adults aged 18 years or older with TRD, defined as a depressive episode without psychotic features, with failure to respond to an adequate dose and duration (≥ 8 weeks) of 2 to 4 pharmacological treatments for the current episode. The trial was conducted at 22 sites in Europe and North America between March 2019 and September 2021. Eligible participants completed a 3- to 6-week run-in period, during which antidepressants and medications affecting the central nervous system (CNS) were tapered and discontinued at least 2 weeks before the baseline visit. During this period, the participants met at least 3 times with a study therapist.

Patients were randomized 1:1:1 to a single dose of psilocybin 25 mg, 10 mg, or 1 mg (control). The administration session lasted 6 to 8 hours and was accompanied by a lead therapist. Blood pressure was continuously monitored. Participants wore eyeshades and headphones with a specifically designed music playlist. The trial followed participants for 12 weeks after treatment, including 2 post-treatment integration sessions.

The primary efficacy endpoint was the change in MADRS from baseline (day -1) to week 3 in the 25 mg- and 10 mg-dose groups compared to the 1-mg dose. Secondary endpoints were the proportion of responders (≥ 50% improvement in MADRS total score) and remitters (MADRS total score ≤ 10) at week 3, and sustained response (week 3 response maintained through week 12). Safety assessments included evaluation of adverse events, the Columbia Suicide Severity Rating Scale, vitals signs, clinical laboratory tests, and electrocardiogram (ECG).

The authors calculated that a sample of 216 participants (72/group) would have 90% power to detect a 6-point difference in the mean change in the MADRS total score from baseline to week 3. Efficacy analyses were performed in the modified intention-to-treat analysis set. The primary efficacy endpoint (change in MADRS total score) was evaluated using mixed model for repeated measures analysis. Response and remission were analyzed using generalized linear mixed models, and sustained response was analyzed using binary logistic regression.

A total of 428 participants were screened, and 233 were randomized and received psilocybin treatment (79 25-mg, 75 10-mg, 79 1-mg). The mean participant age was 40 years, 52% of participants were female, and 92% were white. Two-thirds of participants were receiving antidepressant treatment, and mean MADRS scores were 32 to 33 at baseline.

The least-squares mean change from baseline to week 3 in the MADRS total score was -12.0 in the 25-mg group, -7.9 in the 10-mg group, and -5.4 in the 1-mg group. This change was statistically significant for the 25- versus 1-mg, but not the 10- versus 1-mg groups. The incidence of response was 37% in the 25-mg group, 19% in the 10-mg group, and 18% in the 1-mg group, corresponding to a 2.9-fold increased odds of response in the 25- versus 1-mg groups.

The incidence of remission was 29% in the 25-mg group, 9% in the 10-mg group, and 8% in the 1-mg group, corresponding to a 4.8-fold increased odds of response in the 25- versus 1-mg groups. The incidence of sustained remission was 20% in the 25-mg group, 5% in the 10-mg group, and 10% in the 1-mg group, which was not statistically significant between groups.

Adverse events occurred in 84% in the 25-mg group, 75% in the 10-mg group, and 72% in the 1-mg group, which was not statistically significant between groups. The most frequent adverse events on the day of administration were headache, nausea, dizziness, and fatigue. Serious adverse events from day 2 to week 3 in the 25- and 10-mg groups included suicidal ideation (n=4), non-suicidal self-injurious behaviors (n=3), and hospitalization for depression (n=1). There were no serious adverse events in the 1-mg group during this period. There were no clinically significant changes in vital signs, clinical laboratory tests, or ECG.

Study Conclusions

The authors concluded that the trial showed the feasibility of psilocybin monotherapy for up to 12 weeks in patients with TRD. The change from baseline to week 3 in MADRS total score was significantly better with 25-mg, but not 10-mg, versus the 1-mg dose. Reported adverse effects included headache, nausea, dizziness, and fatigue, as well as numerically higher suicidal ideation and self-injurious behavior in the 25- and 10-mg groups.

Study limitations include the lack of an active comparator, the lack of an ethnically diverse participant sample, and the exclusion of participants at clinically significant risk for suicide. The intensity of the acute subjective effects of 25- and 10-mg psilocybin may have reduced the effective of trial blinding, although the ability of participants to guess their dose assignment was not assessed.

The Bottom Line

A single dose of 25 mg versus 1 mg psilocybin significantly reduced depression scores over 3 weeks in patients with TRD. Larger and longer trials, including comparisons with existing treatments, are required to determine the efficacy and safety of psilocybin in this patient population.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times®. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.


1. Davis AK, Barrett FS, May DG, et al. Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial [published correction appears in JAMA Psychiatry. 2021 Feb 10;:]. JAMA Psychiatry. 2021;78(5):481-489.

2. Carhart-Harris R, Giribaldi B, Watts R, et al. Trial of psilocybin versus escitalopram for depression. N Engl J Med. 2021;384(15):1402-1411.

3. Carhart-Harris RL, Bolstridge M, Day CMJ, et al. Psilocybin with psychological support for treatment-resistant depression: six-month follow-upPsychopharmacology (Berl). 2018;235(2):399-408.

4. Goodwin GM, Aaronson ST, Alvarez O, et al. Single-dose psilocybin for a treatment-resistant episode of major depressionN Engl J Med. 2022;387(18):1637-1648.

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