CCH attack frequency reduction after psilocybin correlates with hypothalamic functional connectivity

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.