CCH attack frequency reduction after psilocybin correlates with hypothalamic functional connectivity
In a small open‑label trial of 10 patients with chronic cluster headache, three oral doses of psilocybin (0.14 mg/kg) were well tolerated and produced a mean 31 per cent reduction in attack frequency, with one patient achieving 21 weeks' remission. Changes in hypothalamic–diencephalic functional connectivity on fMRI correlated strongly with attack reduction (R = −0.81), implicating hypothalamic circuits in the therapeutic response and supporting further clinical study.
Authors
- Gitte Knudsen
- Patrick Fisher
- Dea Stenbæk
Published
Abstract
Objective
To evaluate the feasibility and prophylactic effect of psilocybin as well as its effects on hypothalamic functional connectivity (FC) in patients with chronic cluster headache (CCH).
Background
CCH is an excruciating and difficult‐to‐treat disorder with incompletely understood pathophysiology, although hypothalamic dysfunction has been implicated. Psilocybin may have beneficial prophylactic effects, but clinical evidence is limited.
Methods
In this small open‐label clinical trial, 10 patients with CCH were included and maintained headache diaries for 10 weeks. Patients received three doses of peroral psilocybin (0.14 mg/kg) on the first day of weeks five, six, and seven. The first 4 weeks served as baseline and the last 4 weeks as follow‐up. Hypothalamic FC was determined using functional magnetic resonance imaging the day before the first psilocybin dose and 1 week after the last dose.
Results
The treatment was well tolerated. Attack frequency was reduced by mean (standard deviation) 31% (31) from baseline to follow‐up ( p FWER = 0.008). One patient experienced 21 weeks of complete remission. Changes in hypothalamic–diencephalic FC correlated negatively with a percent change in attack frequency ( p FWER = 0.03, R = −0.81), implicating this neural pathway in treatment response.
Conclusion
Our results indicate that psilocybin may have prophylactic potential and implicates the hypothalamus in possible treatment response. Further clinical studies are warranted.
Research Summary of 'CCH attack frequency reduction after psilocybin correlates with hypothalamic functional connectivity'
Introduction
Cluster headache is described as one of the most painful conditions, affecting about 0.1% of the population, with chronic cluster headache (CCH) representing the more persistent form. Although established prophylactic options such as verapamil, lithium, CGRP antibodies, and transitional treatments can help many patients, these approaches may be insufficient or poorly tolerated in CCH. The paper notes that earlier observational reports and a recent clinical trial suggested that serotonin 2A receptor agonists, including psilocybin, might reduce cluster headache attacks, but prospective evidence on safety, efficacy, and mechanism remained limited. Hypothalamic dysfunction has also been implicated in cluster headache, but how it relates to treatment response is uncertain. Madsen and colleagues therefore set out to evaluate the feasibility and prophylactic effect of psilocybin in patients with CCH, and to examine whether any clinical response was associated with changes in hypothalamic functional connectivity measured with functional MRI. The researchers hypothesised that attack frequency would decrease after psilocybin and that this change would correlate with changes in hypothalamic connectivity. The study was also intended to explore whether hypothalamic-diencephalic pathways might be relevant to treatment response.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
Madsen, M. K., Petersen, A. S., Stenbæk, D. S., Sørensen, I. M., Schiønning, H., Fjeld, T., Nykjær, C. H., Larsen, S. M. U., Grzywacz, M., Mathiesen, T., Klausen, I. L., Overgaard‐Hansen, O., Brendstrup‐Brix, K., Linnet, K., Johansen, S. S., Fisher, P. M., Jensen, R. H., & Knudsen, G. M. (2024). CCH attack frequency reduction after psilocybin correlates with hypothalamic functional connectivity. Headache: The Journal of Head and Face Pain, 64(1), 55-67. https://doi.org/10.1111/head.14656
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Papers cited by this study that are also in Blossom
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Kaplan, A. L., Confair, D. N., Kim, K. et al. · Nature (2022)
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Cited By (4)
Papers in Blossom that reference this study
Garcia-Romeu, A., Naudé, G. P., Rebman, A. W. et al. · Scientific Reports (2026)
Schindler, E. A. D., Gottschalk, C. H., Pittman, B. P. et al. · Headache (2025)
Johansen, A., Plavén-Sigray, P., Madsen, M. K. et al. · Research Square (2025)
Rucker, J., Butler, M., Hambleton, S. et al. · Headache (2024)
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