A single psilocybin session for major depression, tested against a placebo
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The question
Earlier psilocybin studies for depression were small, and many had no proper placebo. This trial asked: when adults with major depressive disorder (ongoing low mood and loss of interest that affects daily life) get one dose of psilocybin with psychological support, do they improve more than people who get a placebo with the same support? And does any effect last for six weeks?
Who took part and what happened
The study was a phase 2 randomized clinical trial (a mid-stage test where people are assigned to groups by chance). It ran at 11 sites in the United States between December 2019 and June 2022. It included 104 adults aged 21 to 65 with moderate or severe depression. Their average age was 41, and half were women. People with recent active suicidal thoughts or behavior were not included.
- 51 people were assigned to a single 25 mg dose of psilocybin.
- 53 people were assigned to 100 mg of niacin, a B vitamin that causes skin flushing. It was used as an "active placebo," so that people would feel something and find it harder to guess their group.
Both groups got the same support: about 6–8 hours of preparation, a dosing day of 7–10 hours with two facilitators, and about 4 hours of integration (talking through the experience afterward). Participants, site staff, the sponsor and the raters were all blinded. Depression was measured with the MADRS (a 60-point clinician rating scale; higher means worse). Raters scored people by phone without knowing their group. Follow-up lasted six weeks.
What they found
- After six weeks (the main outcome), depression scores fell by about 19 points in the psilocybin group and about 7 points in the niacin group. The difference was 12.3 points.
- After one week, the drop was already clear: about 18 points versus about 6 points.
- Improvement held at every check between day 8 and day 43.
- About 42% of the psilocybin group had a sustained response (symptoms cut by at least half and staying that way), compared with about 11% in the niacin group.
- Sustained remission (very low symptoms) was 25% versus 9%. The authors did not count this as a clear, statistically significant difference.
- Participants in the psilocybin group also reported less disability in work, social life and family life.
Safety. No serious treatment-emergent adverse events (serious problems caused by the treatment) were reported. But side effects were much more common with psilocybin. Headache affected 66% of the psilocybin group versus 24% with niacin. Nausea affected 48% versus 6%. Most side effects were mild or moderate and passed within a day or two. A small number of people had severe side effects, and these were more common in the psilocybin group.
What this study does not tell us
- Six weeks is short. We don't know how long the benefit lasts. A planned long-term follow-up stopped early because too few people signed up.
- Niacin does not cause psychedelic effects, so many people probably knew which group they were in. The study did not ask them to guess.
- The sample was small and not very diverse: about 89% of participants were white.
- People with recent suicidal thoughts, psychosis risk and some other conditions were excluded, so results may not apply to them.
- Many people did not respond. Psilocybin did not help everyone.
- The trial was funded by the Usona Institute, a nonprofit that develops psilocybin.
Why it matters
This was one of the better-designed early trials: an active placebo, blinded remote raters, and identical support for both groups. It found that one supported psilocybin session was linked to a meaningful drop in depression symptoms that lasted through six weeks, with no serious adverse events but plenty of short-term side effects. The authors describe psilocybin as a possible new approach that still needs larger and longer studies. It is a careful step, not the last word.
This is a summary of published research for general information. It is not medical advice. The study took place in a clinical research setting with medical screening and professional support.
Source: Raison CL, Sanacora G, Woolley J, et al. (2023). Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial. JAMA, 330(9), 843–853. doi:10.1001/jama.2023.14530 · PubMed · Full text
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