While anecdotal evidence suggests that select 5-hydroxytryptamine 2A (5-HT2A) 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-HT2A receptor compounds in migraine, as well as other neuropsychiatric conditions. Clinicaltrials.gov: NCT03341689
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We thank CH-TAC, LLC, and the Schizophrenia Neuropharmacology Research Group at Yale (SNRGY) for their support of this project. This study was conducted with assistance from VACHS. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the Department of Veterans Affairs. The nurses of the NSU where this study was conducted, Ms. Angelina Genovese, Elizabeth O’Donnell, and Margaret Dion-Marovitz, as well as Rachel Galvan, PharmD, of the VACHS Investigational Research Pharmacy, are thanked for their excellent support. A vital force in the foundation of this research was the late Dr. Sewell, who was tragically lost to us in 2013 and whom we honor with the publication of this work.
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This exploratory study was registered on clinicaltrials.gov (NCT03341689) and received approvals from the Human Studies Subcommittee of Veterans Affairs Connecticut Healthcare System (VACHS) and the Human Investigations Committee of Yale University. In compliance with the Helsinki Declaration of 1975, as revised in 2000 , informed consent was obtained from every subject who participated in the study.
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R. Andrew Sewell, posthumous (RAS passed away in 2013)
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Schindler, E.A.D., Sewell, R.A., Gottschalk, C.H. et al. Exploratory Controlled Study of the Migraine-Suppressing Effects of Psilocybin. Neurotherapeutics 18, 534–543 (2021). https://doi.org/10.1007/s13311-020-00962-y
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