Exploratory Controlled Study of the Migraine-Suppressing Effects of Psilocybin

Abstract

While anecdotal evidence suggests that select 5-hydroxytryptamine 2A (5-HT_2A) receptor ligands, including psilocybin, may have long-lasting therapeutic effects after limited dosing in headache disorders, controlled investigations are lacking. In an exploratory double-blind, placebo-controlled, cross-over study, adults with migraine received oral placebo and psilocybin (0.143 mg/kg) in 2 test sessions spaced 2 weeks apart. Subjects maintained headache diaries starting 2 weeks before the first session until 2 weeks after the second session. Physiological and psychological drug effects were monitored during sessions and several follow-up contacts with subjects were carried out to assure safety of study procedures. Ten subjects were included in the final analysis. Over the 2-week period measured after single administration, the reduction in weekly migraine days from baseline was significantly greater after psilocybin (mean, - 1.65 (95% CI: - 2.53 to - 0.77) days/week) than after placebo (- 0.15 (- 1.13 to 0.83) days/week; p = 0.003, t(9) = 4.11). Changes in migraine frequency in the 2 weeks after psilocybin were not correlated with the intensity of acute psychotropic effects during drug administration. Psilocybin was well-tolerated; there were no unexpected or serious adverse events or withdrawals due to adverse events. This exploratory study suggests there is an enduring therapeutic effect in migraine headache after a single administration of psilocybin. The separation of acute psychotropic effects and lasting therapeutic effects is an important finding, urging further investigation into the mechanism underlying the clinical effects of select 5-HT_2A receptor compounds in migraine, as well as other neuropsychiatric conditions. Clinicaltrials.gov : NCT03341689.

Keywords: Migraine; headache; preventive treatment; psilocybin; psychedelics.

Fig. 1

Subject screening and enrollment

Fig. 2

Change in migraine frequency. The average reduction in weekly migraine days from baseline in the 2 weeks following the single administration of drug was significantly greater after psilocybin than after placebo (n = 10, paired t test). Error bars represent standard error about the mean

Fig. 3

Time to the next migraine attacks. The average number of days to the first and second migraine attacks after drug administration is shown. The time to the second attack was significantly greater after psilocybin than after placebo (n = 10, paired t test). Error bars represent standard error about the mean