TY - JOUR
T1 - Effects of psilocybin on sleep quality and brain microstructure in chronic cluster headache
AU - Brendstrup-Brix, Kristoffer
AU - Ozenne, Brice
AU - Fisher, Patrick M.
AU - Stenbæk, Dea S.
AU - Petersen, Anja S.
AU - Armand, Sophia
AU - McCulloch, Drummond E.Wen
AU - Marstrand-Joergensen, Maja Rou
AU - Ulv Larsen, Sara M.
AU - Johansen, Annette
AU - Jensen, Rigmor H.
AU - Knudsen, Gitte M.
AU - Madsen, Martin K.
N1 - Publisher Copyright:
© The Author(s) 2026
PY - 2026/5/29
Y1 - 2026/5/29
N2 - Background: 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. Aims: To investigate the effects of psilocybin on sleep, brain water diffusivity, and microstructure in CCH. Methods: 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. Results: 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. Conclusion: Subjective sleep quality improved in CCH patients after psilocybin and showed some evidence of an association with measures of brain microstructure and water diffusivity. ClinicalTrials.gov identifiers: Prophylactic Effects of Psilocybin on Chronic Cluster Headache (EPOCH; NCT04280055) and The Neurobiological Effect of 5-HT2AR Modulation (NeuroPharm2; NCT03289949).
AB - Background: 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. Aims: To investigate the effects of psilocybin on sleep, brain water diffusivity, and microstructure in CCH. Methods: 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. Results: 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. Conclusion: Subjective sleep quality improved in CCH patients after psilocybin and showed some evidence of an association with measures of brain microstructure and water diffusivity. ClinicalTrials.gov identifiers: Prophylactic Effects of Psilocybin on Chronic Cluster Headache (EPOCH; NCT04280055) and The Neurobiological Effect of 5-HT2AR Modulation (NeuroPharm2; NCT03289949).
KW - brain microstructure
KW - brain water diffusivity
KW - cluster headache
KW - psilocybin
KW - sleep quality
UR - https://www.scopus.com/pages/publications/105040354703
U2 - 10.1177/02698811261449380
DO - 10.1177/02698811261449380
M3 - Journal article
C2 - 42212900
AN - SCOPUS:105040354703
SN - 0269-8811
JO - Journal of psychopharmacology
JF - Journal of psychopharmacology
ER -