November 1, 2023

Can Psilocybin Suppress Cluster Headaches?

Trial of low-dose psilocybin
An exploratory trial of psilocybin for cluster headaches found no significant reduction in headaches.


Schindler EAD, Sewell RA, Gottschalk CH, et al. Exploratory investigation of a patient-informed low-dose psilocybin pulse regimen in the suppression of cluster headaches: results from a randomized, double-blind, placebo-controlled trial. Heachache. 2022;62:1383-1394. 

Study Objective

To determine the effect of low-dose psilocybin in 3 pulsed doses vs placebo in patients with cluster headaches

Key Takeaway

A small, exploratory, randomized, double-blind, placebo-controlled trial of pharmaceutical psilocybin (0.413 mg/kg) did not significantly alter cluster headaches over 3 successive doses in 14 males and females who completed the trial. Outcomes point to the need for a larger trial and an improved understanding of both the mechanisms behind and the treatment of cluster headaches.


Randomized, double-blind, placebo-controlled trial for patients who met criteria in the International Classification of Headache Disorders, 3rd Edition, 2013, for cluster headaches


Of 238 participants screened, 20 received secondary screening, 16 were inducted into the study, and 2 violated study protocol and were excluded from the final analysis, leaving 14 in the final analysis. Participants were classified as having either episodic cluster headaches that occurred every 2 months or longer (n=6) or chronic cluster headaches that occurred about once per day. Prior exposure to psilocybin was permitted if it took place more than 3 months in the past. Caffeine and nicotine were not restricted. Use of selective serotonin reuptake inhibitors (SSRIs) in the previous 6 weeks was not permitted. Triptans were permitted, but no more than twice per week and none within 5 half-lives of the respective triptan and receiving the treatment or placebo. Written consent was obtained from all participants. None of the participants was satisfied with their current cluster-headache treatment at baseline.


Synthetic psilocybin was prepared under Drug Enforcement Agency (DEA) Schedule 1 registration at the University of Wisconsin–Madison, Usona Institute, by coauthor Nicholas V Cozzi using Shirota’s method with slight modifications. Chemical analysis confirmed its 98.6%-to-100% purity via multiple methods including GC-MS (gas chromatography and mass spectrometry).1 

The treatment dose was 0.143 mg/kg or 10 mg for a 70-kg adult, equivalent to approximately 1.6 g dried Psilocybe cubensis. Placebo was microcrystalline cellulose (Fagron, St, Paul, Minnesota). Treatment and placebo were placed in the same blue gelatin capsules. Three doses were given approximately 5 days apart over 3 weeks to reduce the frequency of cluster headaches based on anecdotal reports of similar regimens.

Study Parameters Assessed

Each subject kept a headache diary noting frequency, duration, pain intensity, side of headache, autonomic symptoms, circadian pattern, attack triggers, and family history of cluster headaches. Psychedelic effects were measured on the 5D-ASC Scale (5-Dimensional Altered States of Consciousness Scale). 

Statistics included histograms, descriptive statistics, multiway interactions, best-fitting variance-covariance structure, least-squares means, and Fisher’s exact test. Significance was set at P<0.05. SAS version 9.4 and GraphPad Prism were used for data analysis.

Primary and Secondary Outcomes

No single primary outcome was defined a priori, as this was deemed an exploratory trial. According to the authors, “To capture a clinically relevant duration that would also allow the inclusion of episodic participants, the change in weekly attacks compared to baseline in the 3-week period after the start of the pulse regimen was used as the primary outcome measure. Other primary outcomes included such measures as change in attack duration (min) and pain intensity (0–10 numerical scale) in the 3-week period after start of the pulse.” 

Secondary outcomes were a comparison of episodic vs chronic cluster-headache patients assessed for vital sign changes, drug effects, psychedelic ratings, and adverse events.

Key Findings

Mean amount of psilocybin was 2.0 mg. 

Five participants had used psilocybin mushrooms in the past (from 2 years to more than 20 years prior to the study).

Baseline headache attack duration was significantly higher in the psilocybin group than placebo (P=0.022). The frequency of attacks was lower in the psilocybin group, but the difference was not statistically significant. Psilocybin increased mean arterial pressure 60 to 90 minutes after the treatment dose, but no significant interactions were found for heart rate, oxygen saturation, and drug-day interactions. 

Drug-over-time interactions were observed for sleepiness, anxiety, and joy/intense happiness but not for nausea or peace/harmony. The total for the 5D-ASC score was higher in the psilocybin group (P<0.0001). The mean 5D-ASC score after psilocybin was 20.6% vs 0.9% after placebo (P<0.0001). These results are not surprising given the nature of the active treatment.

Adverse events in the psilocybin group included nausea, anxiety, and fatigue, but they were self-limiting. Nausea was significantly higher in the psilocybin group (P=0.031). One subject experienced paranoia during their second psilocybin exposure. It was resolved with staff support, their cluster-headache cycle rapidly terminated, they indicated they would choose this treatment again, and at 6 months they reported no lasting physical or neuropsychological changes.


Author contributions to the trial and paper are noted, and it was dedicated to the late Dr R Andrew Sewell, assistant professor, Psychiatry Department, Yale University, a young rising star in the realm of clinical practice and research into brain chemistry, substances, schizophrenia, and mental illnesses. Funding was provided by the Heffter Research Institute and Ceruvia Lifesciences. Conflicts were noted, and the trial was registered as NCT02981173. 

Practice Implications and Limitations

Cluster headaches affect about 0.1% of the population, mostly males aged over 30 years, with possible triggers including alcohol, history of brain surgery or trauma, family history, television viewing, hot weather, stress, nitroglycerine use, solar glare, and sexual activity.2 Acute treatments include 100% oxygen, which can provide relief in about two-thirds of patients in 10 minutes; subcutaneous sumatriptan 20 mg; or nasal zolmitriptan 5 mg. The response rate to the latter 2 is much lower, and the response takes place over a significantly longer time frame.2 Avoidance of triggers, if identified, can also be beneficial, with alcohol considered the No 1 trigger.2 The possible addition of psilocybin to the therapeutic list poses some interesting questions: Who will benefit? How long will it take to act? What are the psychedelic consequences? How can those consequences be effectively supported? And how does one access it easily and when needed in the acute scenario? In Ontario, psilocybin is available only through a few medical doctors in a controlled setting if the diagnosis is depression or posttraumatic stress disorder (PTSD). Psilocybin can be obtained on the street, but that has considerable safety concerns.

Adverse events in the psilocybin group included nausea, anxiety, and fatigue, but they were self-limiting.

This research group did a small (N=10), double-blind, placebo-controlled, crossover trial using the same dose (0.413 mg/kg) in migraine headache patients 2 weeks apart and observed a significant reduction in weekly migraines (P=0.003).1 The effect was found to be enduring. Psilocybin affects 5-hydroxytryptamine 2A (5-HT2A) receptor ligands, which may be a factor in migraine headaches. Further research is required to confirm the benefits of psilocybin in various headache types.

This is the first reported trial of psilocybin for cluster headaches. Headache reduction in the treatment group was not statistically significant in this small trial, but the treatment was safe and well-tolerated. Expectations and blinding are at risk in a psychedelic study, and the significant 5D-ASC scores in the psilocybin group confirmed this reality. An active control that will not affect clinical outcomes should be considered in future trials to enhance blinding. Mechanisms were not studied in this trial, but the hypothalamus is currently considered a key structure in cluster headaches; psilocybin can reduce cerebral blood flow in the hypothalamus. 

Unfortunately, until more positive and larger studies are published, access will likely be very limited. Research on cluster headaches does point to the role of the hypothalamus and its effect on circulation.


A small, exploratory, randomized, double-blind, placebo-controlled trial of pharmaceutical psilocybin (0.413mg/kg) did not significantly alter cluster headaches over 3 successive doses in 14 individuals who completed the trial. Outcomes point to the need for a larger trial and an improved understanding of both the mechanisms and the treatment of cluster headaches.

Conflict of Interest

This author has no ties to the authors of this trial or access to psilocybin. He is in private practice, faculty at CCNM and NUHS , and consults for the Vitazan Medical Advisory Panel.

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  1. Schindler EAD, Sewell RA, Gottschalk CH, et al. Exploratory controlled study of the migraine suppressing effects of psilocybin. Neurotherapeutics. 2021;18:534-543. 
  2. Kandel SA, Mandiga P. Cluster Headache. Treasure Island, Florida: StatPearls Publishing; 2023.