Exploratory investigation of a patient-informed low-dose psilocybin pulse regimen in the suppression of cluster headache: Results from a randomized, double-blind, placebo-controlled trial

This double-blind placebo-controlled study (n=14) finds that psilocybin (10mg/70kg, 3x) reduced the frequency of cluster headaches by 3 (from a baseline of 10), but this effect was not significant. The intensity of the acute experience didn’t impact the outcome. A study with more participants might find a significant treatment effect.


Objective Using a patient-informed regimen, we conducted an exploratory randomized, double-blind, placebo-controlled study to systematically investigate the effects of psilocybin in cluster headache.

Background Sustained reductions in cluster headache burden after limited quantities of psilocybin-containing mushrooms are anecdotally reported, although to date there are no controlled studies investigating these effects.

Methods Participants were randomized to receive psilocybin (0.143 mg/kg) or placebo (microcrystalline cellulose) in a pulse of three doses, each ~5 days apart. Participants maintained headache diaries starting 2 weeks before and continuing through 8 weeks after the first drug session. A total of 16 participants were randomized to receive experimental drug and 14 were included in the final analysis.

Results In the 3 weeks after the start of the pulse regimen, the change in cluster attack frequency was 0.03 (95% confidence interval [CI] −2.6 to 2.6) attacks/week with placebo (baseline 8.9 [95% CI 3.8 to 14.0]) and −3.2 (95% CI −8.3 to 1.9) attacks/week with psilocybin (baseline 9.6 [95% CI 5.6 to 13.6]; p = 0.251). Group difference in change from baseline had a moderate effect size (d = 0.69). The effect size was small in episodic participants (d = 0.35) but large in chronic participants (d = 1.25), which remained over the entire 8-week period measured (d = 0.81). Changes in cluster attack frequency were not correlated with the intensity of acute psychotropic effects during psilocybin administration. Psilocybin was well-tolerated without any unexpected or serious adverse events.

Conclusions Findings from this initial, exploratory study provide valuable information for the development of larger, more definitive studies. Efficacy outcomes were negative, owing in part to the small number of participants. The separation of acute psychotropic effects and lasting therapeutic effects underscores the need for further investigation into the mechanism(s) of action of psilocybin in headache disorders.

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

Summary of Exploratory investigation of a patient-informed low-dose psilocybin pulse regimen in the suppression of cluster headache

Cluster headache is a relatively rare headache disorder characterized by distinctive autonomic, circadian, and circannual features. Psychedelic compounds have been reported to produce lasting reductions in headache burden after a single or a few doses, suggesting a mechanism of action independent from these namesake effects.

A low dose of psilocybin taken three times, 5 days apart each, was found to be effective in suppressing several measures of cluster headache burden and was safe when administered under experimental conditions.

Study details

Compounds studied

Topics studied
Headache Disorders

Study characteristics
Original Placebo-Controlled Double-Blind Randomized

14 Humans


Institutes associated with this publication

Yale University
The Yale Psychedelic Science Group was established in 2016.

Compound Details

The psychedelics given at which dose and how many times

Psilocybin 10 mg | 3x

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