Comparing single‐ and repeat‐dose psilocybin with active placebo for migraine prevention in an exploratory randomized controlled clinical trial

Abstract Objective The goals of this study were to examine the therapeutic effects and safety of psilocybin given as a pulsed regimen for the prevention of migraine and to consider the blinding integrity of an active control agent.

Background: The administration of a single low dose of psilocybin was observed to have lasting therapeutic effects in one small pilot trial in migraine, although the ability of a pulse dose regimen, as practiced by patients with cluster headache, to potentially improve magnitude and/or duration of transitional preventive effects has not been studied. Furthermore, comparison to an active placebo agent that adequately mimics the acute subjective effects of psilocybin is required to improve blinding integrity and measure placebo effects.

Methods: In an exploratory randomized, double‐blind, placebo‐controlled, parallel group study, adults with migraine having at least two weekly migraine days at baseline ( n = 18) participated in two drug administration sessions separated by 7 days during which they received zero, one, or two doses of psilocybin (10 mg; psi). Whenever participants did not receive psilocybin, they received diphenhydramine (25 mg; diph). Participant recruitment took place between September 2021 and August 2023. The primary outcome measure was a change in migraine frequency using headache diary data collected starting 2 weeks before and continuing through 8 weeks after the second drug session.

Results: In the 2 weeks after completion of the two drug administration sessions, the change from baseline in migraine days/week was not significantly different among groups [diph‐diph: −0.7 (95% confidence interval, −1.5 to 0.2); diph‐psi: −2.0 (−3.0 to −1.0); psi‐psi: −1.7 (−4.1 to 0.7); Χ 2 (2) = 4.56, p = 0.102], despite large effect sizes against the placebo group in the those receiving one (diph‐psi; d = 1.66) or two (psi‐psi; d = 0.69) doses of psilocybin. Similar reductions in migraine frequency approximating 50% were seen in all groups over the 8 weeks measured. The difference in 50% response rate among groups over 2 weeks, however, approached significance (diph‐diph: 17%; diph‐psi: 80%; psi‐psi: 80%; p = 0.087). Drug confidence ratings (i.e., blinding integrity) suggested that diphenhydramine partially substituted for the acute effects of psilocybin. No correlations were observed between changes in migraine frequency after psilocybin and drug confidence, acute general drug effects, or acute psychedelic effects. No serious or unexpected adverse events occurred.

Conclusion: This exploratory study found similar reductions in migraine frequency with single‐dose psilocybin, a two‐dose pulse of psilocybin, or diphenhydramine placebo. Whereas blinding was incomplete in this study, this important topic is highlighted in the study design and findings. The potential for psilocybin to serve as a transitional treatment in migraine remains but will require careful planning in future studies to separate drug and non‐drug effects. Furthermore, the inclusion of headache specialists in the design and execution of these future studies is necessary to preserve the viability of psilocybin treatment in headache medicine.