One dose of psilocybin for depression that other treatments didn't help
Photo: Robert Koorenny on Unsplash
The question
Some people with depression try two or more antidepressants and still don't feel better. Doctors call this treatment-resistant depression. This study asked a simple question: can one dose of psilocybin (the active compound in "magic mushrooms," here made as a pure synthetic drug called COMP360), given with psychological support, reduce depression in these people? And does the dose matter?
Who took part and what happened
The trial ran at multiple sites in Europe and North America and included 233 adults with treatment-resistant depression. Most had severe depression at the start. Before taking part, people stopped their antidepressants over several weeks.
Participants were randomly split into three groups:
- 25 mg of psilocybin (79 people)
- 10 mg of psilocybin (75 people)
- 1 mg of psilocybin (79 people), a dose too small to have much effect, used as the comparison
The study was double-blind (neither participants nor the people rating their symptoms were told which dose was given). Everyone had preparation sessions, a dosing session with trained therapists present, and follow-up sessions afterward. Depression was measured with the MADRS (a standard 60-point clinician rating scale; higher means worse). People were followed for 12 weeks.
What they found
The main result was the change in depression score after three weeks:
- The 25 mg group improved by about 12 points on average.
- The 10 mg group improved by about 8 points.
- The 1 mg group improved by about 5 points.
The difference between 25 mg and 1 mg was 6.6 points, and it was statistically significant. The 10 mg group was not clearly different from 1 mg.
At three weeks, 37% of the 25 mg group had a "response" (their score dropped by at least half), compared with 18% in the 1 mg group. About 29% of the 25 mg group were in remission (very low symptoms), compared with 8% in the 1 mg group.
The benefit did not hold up as well over time. By week 12, about 20% of the 25 mg group still had a lasting response, and this was not statistically different from the 1 mg group.
Safety. Side effects were common in all groups: about 77% of participants overall had at least one. The most frequent were headache, nausea and dizziness, mostly on the day of dosing. More serious concerns also appeared. In the weeks after dosing, suicidal thoughts, self-harm, or both were reported in the 25 mg and 10 mg groups (roughly 4–5% of people in each), and none in the 1 mg group. The authors noted that suicidal thoughts and behavior happened in all dose groups over the full study. This is an important signal and it needs careful study.
What this study does not tell us
- It does not show long-term benefit. The clear difference was at three weeks, and it faded by 12 weeks.
- There was no comparison with a standard antidepressant or with therapy alone.
- Strong effects at 25 mg may have made it easy for people to guess their dose, which can affect results.
- Most participants (over 90%) were white, which limits how widely the results apply.
- People at serious risk of suicide were excluded, so we don't know how such people would respond.
- The trial was funded by the company developing the drug.
Why it matters
This was the largest controlled psilocybin trial at the time. It showed that dose matters: a higher dose with support led to a bigger short-term drop in depression than a very low dose. It also showed, honestly, that the effect of one session may not last, and that some people may feel worse, including having suicidal thoughts. The authors called for larger and longer trials, including comparisons with existing treatments. The takeaway is cautious interest, not certainty.
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: Goodwin GM, Aaronson ST, Alvarez O, et al. (2022). Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine, 387(18), 1637–1648. doi:10.1056/NEJMoa2206443 · PubMed
More research
