CCH attack frequency reduction after psilocybin correlates with hypothalamic functional connectivity

Headache. 2024 Jan;64(1):55-67. doi: 10.1111/head.14656.


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.

Keywords: cluster headache; functional connectivity; functional magnetic resonance imaging; hypothalamus; psilocin; psilocybin.

Publication types

  • Clinical Trial

MeSH terms

  • Cluster Headache* / drug therapy
  • Humans
  • Hypothalamus / diagnostic imaging
  • Magnetic Resonance Imaging / methods
  • Neural Pathways / diagnostic imaging
  • Psilocybin* / adverse effects


  • Psilocybin