Single-Dose Psilocybin Treatment Significantly Reduces Depressive Symptoms

A single 25-mg dose of psilocybin was associated with clinically significant reductions in depressive symptoms and functional disability in individuals with major depressive disorder.

A single dose of psilocybin in combination with psychologic support may reduce depressive symptoms in individuals with major depressive disorder (MDD), according to results of a phase 2 trial published in The Journal of the American Medical Association.

Researchers conducted a randomized, placebo-controlled, 6-week trial to assess the safety and efficacy of psilocybin for the treatment of MDD. Eligible participants were aged 21 to 65 years, met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for moderate to severe MDD, scored 28 and greater on the Montgomery-Asberg Depression Rating Scale (MADRS), and had a current depressive episode of at least 60 days. Participants receiving psychiatric agents were also eligible for inclusion following a 7- to 35-day medication taper. However, those with improvement of 30% and greater in total MADRS score during this period were excluded. Individuals with history of psychosis or mania, substance misuse, and suicidal ideation and behavior were also excluded.

A total of 104 participants were randomly assigned 1:1 to receive either a single 25-mg dose of psilocybin (n=51) or a single 100-mg dose of niacin as an active placebo (n=53) in a “set and setting” protocol. Both groups received psychotherapy during preparatory, dosing, and postdose integration sessions. Postdosing assessments were administered on days 2, 8, 15, 29, and 43. The primary outcome was the between-group difference in mean MADRS score change from baseline to day 43. The key secondary outcome was the MADRS score change from baseline to day 8. Additional secondary outcomes included change in Sheehan Disability Scale score from baseline to day 43 and the percentage of participants with sustained depressive symptom response (≥50% MADRS score reduction) and sustained depressive symptom remission (MADRS total score of ≤10) at days 8, 15, 29, and 43.

These findings add to evidence that psilocybin — when administered with psychological support — may hold promise as a novel intervention for MDD.

Results showed clinically significant greater reduction in total MADRS score between patients in the psilocybin vs niacin group at day 8 (mean difference [MD], -12.0; 95% CI, -16.6 to -7.4; P <.001) and 43 (MD, -12.3; 95% CI, -17.5 to -7.2; P <.001). Patients in the psilocybin group also were significantly more likely to experience sustained depressive symptom response (42%) than those in the placebo group (42% vs 11%, respectively; odds ratio, 5.6; 95% CI, 1.9-16.7; P =.002), with an adjusted absolute difference of 30.3 (95% CI, 13.5-47.1; P =.002).

Further, the reduction in Sheehan disability scale scores was more significant for patients in the psilocybin group (MD, -2.31; 95% CI, 3.50-1.11; P <.001), reflecting improved psychosocial functioning following psilocybin treatment.

Adverse events (AEs) were also documented to assess safety. Psilocybin was generally well-tolerated, as most drug-related AEs were mild (78%) to moderate (22%) and mainly occurred during the acute dosing period.

The researchers concluded, “These findings add to evidence that psilocybin — when administered with psychological support — may hold promise as a novel intervention for MDD.”

Key limitations in this study include the functional unblinding produced by the acute psychoactive effects of psilocybin and a homogeneous patient population.

Disclosure: Multiple study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Raison CL, Sanacora G, Woolley J, et al. Single-dose psilocybin treatment for major depressive disorder. JAMA. Published online, August 31, 2023. doi:10.1001/jama.2023.14530