Psilocybin pulse regimen reduces cluster headache attack frequency in the blinded extension phase of a randomized controlled trial
This double-blind, placebo-controlled study (n=10) assesses the safety and efficacy of repeated pulse administration of psilocybin (10mg/70kg, 3x in 15 days) in cluster headache patients. Following the initial trial, eligible participants received a psilocybin pulse at least 6 months later and kept headache diaries for 8 weeks. Results indicate a significant reduction in cluster attack frequency following the psilocybin pulse, suggesting potential therapeutic benefits.
Authors
- Nicholas Cozzi
- Deepak Cyril D’Souza
- Emmanuelle Schindler
Published
Abstract
Background
In a recent randomized, double-blind, placebo-controlled study, we observed a nonsignificant reduction of attack frequency in cluster headache after pulse administration of psilocybin (10 mg/70 kg, 3 doses, 5 days apart each). We carried out a blinded extension phase to consider the safety and efficacy of repeating the pulse regimen.
Methods
Eligible participants returned to receive a psilocybin pulse at least 6 months after their first round of study participation. Participants kept headache diaries starting two weeks before and continuing through eight weeks after the first drug session. Ten participants completed the extension phase and all ten were included in the final analysis.
Results
In the three weeks after the start of the pulse, cluster attack frequency was significantly reduced from baseline (18.4 [95% confidence interval 8.4 to 28.4] to 9.8 [4.3 to 15.2] attacks/week; p = 0.013, d’ = 0.97). A reduction of approximately 50% was seen regardless of individual response to psilocybin in the first round. Psilocybin was well-tolerated without any unexpected or serious adverse events.
Discussion
This study shows a significant reduction in cluster attack frequency in a repeat round of pulse psilocybin administration and suggests that prior response may not predict the effect of repeated treatment. To gauge the full potential of psilocybin as a viable medicine in cluster headache, future work should investigate the safety and therapeutic efficacy in larger, more representative samples over a longer time period, including repeating the treatment.
Research Summary of 'Psilocybin pulse regimen reduces cluster headache attack frequency in the blinded extension phase of a randomized controlled trial'
Introduction
Cluster headache (CH) is an intensely painful primary headache disorder that affects roughly 0.1% of the population and exists in episodic and chronic forms; chronic cluster headache (CCH) denotes attacks that persist with less than three months without attacks per year and is associated with anxiety, depression and suicidal ideation. Standard prophylactic drugs such as verapamil or lithium reduce attack frequency in many patients but can produce unacceptable side-effects or inadequate benefit, such that novel prophylactic options are needed. Observational reports and case series have suggested that serotonergic psychedelics, in particular psilocybin, may reduce CH frequency, but these effects had not been prospectively evaluated in a clinical trial setting. Madsen and colleagues set out to assess feasibility, safety and preliminary prophylactic efficacy of a short course "pulse" regimen of moderate-dose oral psilocybin in people with CCH, and to explore whether treatment response relates to changes in hypothalamic functional connectivity (FC) measured with fMRI. The study therefore combines clinical diary-based outcomes (attack frequency and self-rated pain intensity) with plasma psilocin pharmacokinetics and resting-state neuroimaging to probe potential neural correlates of any clinical effect.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
Schindler, E. A., Sewell, R. A., Gottschalk, C. H., Flynn, L. T., Zhu, Y., Pittman, B. P., Cozzi, N. V., & D'Souza, D. C. (2024). Psilocybin pulse regimen reduces cluster headache attack frequency in the blinded extension phase of a randomized controlled trial. Journal of the Neurological Sciences, 460, 122993. https://doi.org/10.1016/j.jns.2024.122993
References (11)
Papers cited by this study that are also in Blossom
Schindler, E. A. D., Gottschalk, C. H., Weil, M. J. et al. · Journal of Psychoactive Drugs (2015)
Kraehenmann, R., Preller, K. H., Scheidegger, M. et al. · Biological Psychiatry (2015)
Madsen, M. K., Stenbaek, D. S., Arvidsson, A. et al. · European Neuropsychopharmacology (2021)
Ly, C., Greb, A. C., Cameron, L. P. et al. · Cell Reports (2018)
De Coo, I. F., Naber, W. C., Wilbrink, L. A. et al. · Cephalalgia (2018)
Di Lorenzo, C., Di Lorenzo, G., Coppola, G. et al. · Cephalalgia (2015)
Madsen, M. K., Fisher, P. M., Burmester, D. et al. · Neuropsychopharmacology (2019)
Nichols, C. D., Nichols, D. E., Johnson, M. W. · Clinical Pharmacology and Therapeutics (2016)
Madsen, M. K., Fisher, P. M., Stenbæk, D. S. et al. · European Neuropsychopharmacology (2020)
Van Amsterdam, J., Opperhuizen, A., Van Den Brink, W. · Regulatory Toxicology and Pharmacology (2011)
Show all 11 referencesShow fewer
Studerus, E., Gamma, A., Vollenweider, F. X. · PLOS ONE (2010)
Cited By (3)
Papers in Blossom that reference this study
Garcia-Romeu, A., Naudé, G. P., Rebman, A. W. et al. · Scientific Reports (2026)
Jacobs, E., Zahid, Z., Hinkle, J. et al. · BMJ (2026)
Schindler, E. A. D., Gottschalk, C. H., Pittman, B. P. et al. · Headache (2025)
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