Psilocybin-induced reduction in chronic cluster headache attack frequency correlates with changes in hypothalamic functional connectivity

Chronic cluster headache (CCH) is an excruciating disorder of unknown pathophysiology, but hypothalamic dysfunction has been implicated. CCH is difficult to treat but on a case-basis, the psychedelic compound psilocybin is said to have beneficial effects. In this first-ever clinical trial ([NCT04280055][1]), we evaluate in a small open-label study of CCH patients the feasibility and prophylactic effect of three low-to-moderate doses of psilocybin as well as effects on hypothalamic functional connectivity (FC), using functional magnetic resonance imaging. The treatment was well-tolerated and without serious adverse reactions. Attack frequency was on average reduced by 30% from baseline to follow-up (PFWER=0.008). One patient experienced 21 weeks of complete remission. Changes in hypothalamic-diencephalic FC correlated negatively with relative reduction in attack frequency, implicating this neural pathway in treatment response. Further clinical studies are warranted to confirm the safety and prophylactic efficacy of psilocybin for CCH and hypothalamic involvement in treatment response. ### Competing Interest Statement MKM has received an honorarium as a speaker for Lundbeck Pharma and the Lundbeck Foundation. DSS has received an honorarium as a speaker for the Lundbeck Foundation. GMK has received honoraria as a consultant for Sanos and as a speaker for Sage-Biogen. RHJ has given lectures for Pfizer, Eli-Lilly, Merck, TEVA, Novartis, Lundbeck and Allergan and is or has been primary investigator in clinical trials funded by Eli-Lilly, Novartis and Lundbeck. RHJ has received research funding from University of Copenhagen, Rigshospitalet, Lundbeck Foundation, The Medical Society in Copenhagen, NovoNordisk Foundation and Tryg Foundation. ### Clinical Trial NCT04280055 ### Funding Statement The study was sponsored by Augustinusfonden (grant number: 18-0317), Rigshospitalets Research Council (grant numbers: R130-A5324 and R214-A9447), Innovation Fund Denmark (NeuroPharm, grant number: 4108-00004B), and Lundbeck Foundation through Danish Neurological Society (no grant number available). COMPASS Pathways Ltd, UK, kindly provided the study drug. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was conducted at the Copenhagen University Hospital Rigshospitalet Blegdamsvej-Glostrup and was approved by the Ethics Committee of the Capital Region of Copenhagen and by the Danish Medicines Agency. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04280055&atom=%2Fmedrxiv%2Fearly%2F2022%2F07%2F10%2F2022.07.10.22277414.atom