Psilocybin versus active placebo for migraine prevention: small trial finds no clear difference

The question

Does psilocybin reduce how often migraines happen, and does giving two doses a week apart work better than one dose or an active placebo?

What they did

Eighteen adults who had at least two migraine days per week took part in a randomized, double-blind trial between September 2021 and August 2023. Each person attended two drug sessions seven days apart and received zero, one, or two doses of psilocybin (10 mg). When psilocybin was not given, participants received diphenhydramine (25 mg), an antihistamine used as an “active placebo” to mimic some noticeable drug effects and help keep people unaware of their group. Participants kept headache diaries from two weeks before until eight weeks after the second session.

What they found

In the two weeks after the second session, the change in migraine days per week was not statistically different between groups: -0.7 (95% confidence interval -1.5 to 0.2) for placebo twice, -2.0 (-3.0 to -1.0) for one psilocybin dose, and -1.7 (-4.1 to 0.7) for two doses (p = 0.102), although effect sizes against placebo were large (d = 1.66 for one dose, d = 0.69 for two). Over the full eight weeks, all three groups showed similar reductions of roughly 50%. The share of people whose migraine days dropped by at least half over two weeks was 17% for placebo, 80% for one psilocybin dose and 80% for two doses, a difference that only approached significance (p = 0.087). Ratings of which drug people thought they received suggested diphenhydramine partly imitated psilocybin’s acute effects, and no serious or unexpected adverse events occurred.

The fine print

Only 18 people took part, which is far too few to detect modest differences reliably, and the authors call the study exploratory. Blinding was incomplete, since the active placebo partly mimicked psilocybin, and the placebo group also improved substantially, making it hard to separate drug effects from expectation. Follow-up was eight weeks, and this summary is based on the abstract alone.

What it means

In this small trial, psilocybin did not clearly outperform an active placebo for preventing migraine, and the strong placebo response highlights how hard it is to tell drug effects from expectation in psychedelic research.

Evidence grade: Very low. A randomized, double-blind trial, but described by the authors as exploratory, with only 18 participants and incomplete blinding.

This summary is based on the study’s published abstract.