Effects of psilocybin on sleep quality and brain microstructure in chronic cluster headache.
Kristoffer Brendstrup‐brix, Brice Ozenne, Patrick M. Fisher, Dea S Stenbæk, Anja S Petersen, Sophia Armand, Drummond E-Wen Mcculloch, Maja Rou Marstrand-Joergensen, Sara M Ulv Larsen, Annette Johansen, Rigmor Jensen, Gitte M. Knudsen, Martin K Madsen
Journal of psychopharmacology (Oxford, England) May 29, 2026 DOI: 10.1177/02698811261449380 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort with before-after intervention Peer reviewed |
|---|---|
| Sample size | 11 |
| Population | Patients with chronic cluster headache |
| Intervention | Psilocybin |
| Dose | 0.14 mg/kg |
| Duration | Three administrations spaced 1 week apart, with assessments before and 1 week after the last dose |
| Topics | Psilocybin |
| Keywords | Brain microstructure Brain water diffusivity Cluster headache Sleep quality |
| Registration | NCT04280055 NCT03289949 |
| Key findings | Subjective sleep quality improved in CCH patients after psilocybin treatment, but no statistically significant changes in brain microstructure or water diffusivity were observed on average. |
Abstract
Patients with chronic cluster headache (CCH) suffer from poor sleep, which may impact their brain microstructure and parenchymal clearance of waste products. Psilocybin has shown promise for the treatment of CCH and has been linked to increased neuroplasticity with possible influences on brain microstructure. To investigate the effects of psilocybin on sleep, brain water diffusivity, and microstructure in CCH. Eleven CCH patients underwent diffusion-weighted MRI and subjective sleep quality assessment with the Pittsburgh Sleep Quality Index (PSQI) before and 1 week after three psilocybin administrations (0.14 mg/kg) spaced 1 week apart. Measures taken prior to intervention were also compared to 24 healthy controls, and subjective sleep quality was related to brain microstructure and diffusivity across groups. We found that sleep was poor in CCH patients, but improved after psilocybin treatment (CCH mean PSQI change (SD) = -2.50 (2.1), pFWER = 0.015). When analyzing brain microstructure and water diffusivity in conjunction, we found differences between CCH patients and controls, which were primarily driven by differences in grey matter. On average, psilocybin intervention in CCH patients was not associated with statistically significant changes in brain microstructure or water diffusivity. However, most patients exhibited lower white matter diffusivity and neurite volume after intervention. Subjective sleep quality showed borderline significant correlations of moderate effect size with brain microstructure and water diffusivity. Subjective sleep quality improved in CCH patients after psilocybin and showed some evidence of an association with measures of brain microstructure and water diffusivity. gov identifiers:Prophylactic Effects of Psilocybin on Chronic Cluster Headache (EPOCH; NCT04280055) and The Neurobiological Effect of 5-HT2AR Modulation (NeuroPharm2; NCT03289949).