CCH attack frequency reduction after psilocybin correlates with hypothalamic functional connectivity

Martin K Madsen, Anja Sofie Petersen, Dea S Stenbaek, Inger Marie Sørensen, Harald Schiønning, Tobias Fjeld, Charlotte H Nykjaer, Sara Marie Ulv Larsen, Maria Grzywacz, Tobias Mathiesen, Ida L Klausen, Oliver Overgaard-Hansen, Kristoffer Brendstrup-Brix, Kristian Linnet, Sys S Johansen, Patrick M Fisher, Rigmor H Jensen, Gitte M Knudsen*

*Corresponding author for this work


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 (pFWER  = 0.008). One patient experienced 21 weeks of complete remission. Changes in hypothalamic-diencephalic FC correlated negatively with a percent change in attack frequency (pFWER  = 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.

Original languageEnglish
Issue number1
Pages (from-to)55-67
Number of pages13
Publication statusPublished - Jan 2024


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