Exploratory Controlled Study of the Migraine-Suppressing Effects of Psilocybin

This double-blind, placebo-controlled, cross-over study (n=10) finds that a medium dose of psilocybin (10mg/70kg) significantly reduced migraines (headaches) in the two weeks after dosing.

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 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 and other neuropsychiatric conditions.“

Authors: Emmanuelle A. D. Schindler, R. Andrew Sewell, Christopher H. Gottschalk, Christina Luddy, L. Taylor Flynn, Hayley Lindsey, Brian P. Pittman, Nicholas V. Cozzi & Deepak C. D’Souza

Summary

In an exploratory double-blind, placebo-controlled, cross-over study, adults with migraine received oral psilocybin (0.143 mg/kg) in 2 test sessions spaced 2 weeks apart. Psilocybin significantly reduced weekly migraine days from baseline, and the effect was not correlated with the intensity of acute psychotropic effects during drug administration.

Migraine, headache, psilocybin, psychedelics

Introduction

Select 5-HT2A receptor agonists, such as psilocybin and LSD, have been shown to produce long-lasting reductions in headache burden after a single or few oral doses, suggesting that this unique benefit of the drug class seen among different diseases is effected through a shared neurobiological mechanism(s).

This exploratory, proof-of-concept study investigated the effects of psilocybin on migraine in a double-blind, placebo-controlled, cross-over design.

Psilocybin

Synthetic psilocybin was prepared under DEA Schedule 1 registration at the University of Wisconsin – Madison and deemed 100% pure by HPLC. Weight-based capsules were compounded for each subject into identical blue gelatin capsules.

Subjects and Selection Criteria

Adults with migraine who were free from serious medical or psychiatric disease and had a frequency of migraine attacks of 2 per week or more were eligible to participate in this study. They were required to be free from serotonergic antidepressants, serotonergic antiemetics, and vasoconstrictive medications for at least five elimination half-lives of said medications.

Recruitment and Screening

Subjects were recruited from the local community, headache centers, online headache websites, and word of mouth. They underwent a medical history, physical examination, laboratory tests, structured mental health interview, personality assessment, and verbal intelligence quotient test to assess eligibility. During the multistage screening process, subjects were repeatedly reviewed the study procedures, the physiological and psychological effects of psilocybin, and emergency contacts. They were also quizzed on the study procedures and funding sources.

Study Design

This was a double-blind, placebo-controlled, crossover study in which subjects received an identically appearing oral psilocybin capsule in the first experimental session and an oral placebo capsule in the second experimental session.

Assessment of Migraine Burden

Subjects maintained a headache diary for 2 weeks prior to the first experimental session and 2 weeks after the second experimental session. They documented every headache attack, migraine or otherwise, as well as attack-related functional impairment.

Experimental Sessions

Subjects reported to the Neurobiological Studies Unit at 8:00 am, and baseline measures were collected at 15 min intervals for the first hour, 30 min intervals for the second hour, and then every hour thereafter.

Subjects self-reported their drug effects on a 0 – 3 VAS at baseline, every 30 min for the first 2 h, and then hourly thereafter. Psychedelic effects were self-reported at the end of experimental sessions using the validated 5-Dimensional Altered States of Consciousness scale.

Follow-up and Payment

Telephone follow-up was performed on all subjects the day after and weekly for 2 weeks after each experimental session and then at approximately 2 and 3 months.

Outcome Measures

This exploratory study measured change in migraine frequency, weekly migraine attacks, light sensitivity, sound sensitivity, nausea/ vomiting, and attack-related functional impairment in the 2 weeks after drug administration.

Statistical Analysis

We sought 12 subjects for this exploratory study, and found 10 with 80% statistical power to detect large effects.

Statistical analyses were performed using SAS, version 9.4 (SAS Institute Inc., Cary, NC), and figures were produced with GraphPad Prism. The effects of psilocybin on migraine burden and time to the first and second migraine attacks were compared using paired t tests.

The best-fitting variance – covariance structure was based on information criteria, and significant interactions were determined using least squares means. Psychotropic effects were calculated and compared using a linear mixed model.

Results

Ten subjects were included in the final analysis, 1 was excluded because of scheduling conflicts and 1 subject’s baseline period did not contain enough migraine attacks for qualification.

Demographics, Migraine Characteristics, and Substance Use (Table 1)

Seven females and 3 males with migraine were included in the final analysis. Two subjects had previously tried psilocybin (not specifically for migraine treatment).

Migraine Burden in the 2 Weeks After Drug Administration

The frequency of migraine days decreased significantly after psilocybin treatment compared to placebo, and the percentage of subjects who had at least 25% reduction was higher after psilocybin than after placebo.

The times to the first and second migraine attacks were measured, and the time to the second attack was significantly greater after psilocybin than after placebo.

Acute Effects of Drug Administration

During experimental sessions, psilocybin elicited overall drug effects and a feeling of peace/harmony, but no other interactions were observed. The maximum “overall drug effect” rating did not correlate with the percent change from baseline in weekly migraine days.

The percent possible score for the total scale was significantly higher after psilocybin than after placebo, but did not correlate with the percent change from baseline in weekly migraine days.

Adverse Events

There were no serious or unexpected AEs in this study. Both placebo and psilocybin administration were followed by tension/sore muscles, general headache attack, and migraine attack, but there was a significant drug – time interaction for MAP over the experimental test day.

Discussion

This study validates the previous anecdotal reports of therapeutic effects of psilocybin in migraine and complements previous research with psilocybin demonstrating lasting beneficial effects in treating depression, anxiety, alcohol addiction, and cigarette smoking.

This study reports that psilocybin has a therapeutic effect over 2 weeks after the single administration of an oral agent. This contrasts with existing preventive migraine therapies that require repeated, daily administration or include treatments that remain in the body long after administration.

In contrast to some previous psilocybin studies for other neuropsychiatric conditions, the current study did not find that psychotropic effects correlated with the migraine frequency change over 2 weeks. This suggests that the therapeutic effect of psilocybin in migraine may not require its namesake “psychedelic” effects.

Psilocybin has been shown to suppress migraine, but additional studies are needed to verify its full capacity and long-term safety. These studies should also investigate the effects of psilocybin on migraine, as well as its potential for drug development.

This study has several strengths and limitations. It is a double-blind, placebo-controlled, cross-over design with a small sample size, but strong statistical significance and large effect sizes validate the findings in this small sample.

There were no significant differences between chronic and episodic subjects, no obvious age or sex differences, and no correlation between migraine frequency reduction and psilocybin use. Further studies should use a control agent that has similar acute drug effects to psilocybin to reduce the risk of unblinding.

In the first controlled investigation of psilocybin in migraine, a low oral dose was shown to suppress migraine frequency in 2 weeks, independent from acute psychotropic effects.

Notes

This paper is included in our ‘Top 10 Articles on Psychedelics in the Year 2020‘