Mechanistic Studies of Psilocybin in Headache Disorders
NCT Number: NCT06464367
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: EARLY_PHASE1
Conditions: Migraine
Interventions: DRUG: Psilocybin|DRUG: Placebo
Sponsor: Yale University
Collaborators: Wallace Research Foundation
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 50
Study Design: Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: QUADRUPLE (PARTICIPANT, CARE_PROVIDER, INVESTIGATOR, OUTCOMES_ASSESSOR)|Primary Purpose: OTHER
Start Date: 2024-09-01
Completion Date: 2026-12-31
Locations: VA Connecticut Healthcare System, West Haven, Connecticut, 06516, United States

Summary:
In previous clinical trial work, the investigators observed lasting reductions in headache burden after limited dosing of psilocybin. This purpose of this study is to examine potential sources for this observed effect. This study will measure brain resting state functional connectivity (fMRI), central synaptic density (SV2A PET), peripheral markers of inflammation, circadian rhythm (actigraphy), and sleep (sleep EEG) in both migraine and healthy control participants before and one week after the administration of psilocybin or an active control agent.

Primary Outcome Measures: Baseline SV2A PET, Comparing initial SV2A PET between migraine and HC, from date of randomization until the date of first PET scan, assessed up to 6 months|Baseline RSFC, Comparing initial RSFC between migraine and HC, from date of randomization until the date of first MRI, assessed up to 6 months|Change in SV2A PET after drug administration, Comparing change in SV2A PET after drug between psilocybin/THC and migraine/HC, from date of first PET scan to the date of second PET scan, assessed up to 6 months|Change in resting state functional connectivity (RSFC) after drug administration, Comparing change in RSFC after drug between psilocybin/THC and migraine/HC, from date of first MRI to the date of second MRI, assessed up to 6 months
Secondary Outcome Measures: Change in TNF-alpha, Comparing change in TNF-alpha levels after drug between psilocybin/THC and migraine/HC, from screening to 7 days after drug administration|Change in IL-1beta, Comparing change in IL-1beta levels after drug between psilocybin/THC and migraine/HC, from screening to 7 days after drug administration|Change in IL-6, Comparing change in IL-6 levels after drug between psilocybin/THC and migraine/HC, from screening to 7 days after drug administration|Change in calcitonin gene-related peptide (CGRP), Comparing change in CGRP levels after drug between psilocybin/THC and migraine/HC, from screening to 7 days after drug administration|Change in pituitary adenylate cyclase activating polypeptide (PACAP), Comparing change in PACAP levels after drug between psilocybin/THC and migraine/HC, from screening to 7 days after drug administration|Change in bedtime (via actigraphy), Comparing change in bedtime (time) after drug between psilocybin/THC and migraine/HC, from screening through 14 days after drug administration|Change in get-up time (via actigraphy), Comparing change in get-up time (time) after drug between psilocybin/THC and migraine/HC, from screening through 14 days after drug administration|Change in daily active period (via actigraphy), Comparing change in daily active period (hours) after drug between psilocybin/THC and migraine/HC, from screening through 14 days after drug administration|Change in daily rest period (via actigraphy), Comparing change in daily rest period (hours) after drug between psilocybin/THC and migraine/HC, from screening through 14 days after drug administration|Change in REM latency (via sleep electroencephalography), Comparing change in REM latency (minutes) after drug between psilocybin/THC and migraine/HC, from screening to 7 days after drug administration|Change in percent REM (via sleep electroencephalography), Comparing change in percent REM (%) after drug between psilocybin/THC and migraine/HC, from screening to 7 days after drug administration|Change in sleep efficiency (via sleep electroencephalography), Comparing change in sleep efficiency (%) after drug between psilocybin/THC and migraine/HC, from screening to 7 days after drug administration|Adverse events, Adverse events from any procedure or drug administration, from screening through 3 months after drug administration
Other Outcome Measures: Acute change in TNF-alpha during drug administration, Comparing change in TNF-alpha between psilocybin/THC and migraine/HC, 0, 120, and 240 minutes after drug administration|Acute change in IL-1beta during drug administration, Comparing change in IL-1beta between psilocybin/THC and migraine/HC, 0, 120, and 240 minutes after drug administration|Acute change in IL-6 during drug administration, Comparing change in IL-6 between psilocybin/THC and migraine/HC, 0, 120, and 240 minutes after drug administration|Acute change in calcitonin gene related peptide (CGRP) during drug administration, Comparing change in CGRP between psilocybin/THC and migraine/HC, 0, 120, and 240 minutes after drug administration|Acute change in pituitary adenylate cyclase activating polypeptide (PACAP) during drug administration, Comparing change in PACAP between psilocybin/THC and migraine/HC, 0, 120, and 240 minutes after drug administration|Acute change in mean arterial pressure (MAP) during drug administration, Comparing change in MAP (mmHg) between psilocybin/THC and migraine/HC, 0, 30, 60, 120, 180, 240, 300, and 360 minutes after drug administration|Acute change in heart rate during drug administration, Comparing change in heart rate (beats per minute) between psilocybin/THC and migraine/HC, 0, 30, 60, 120, 180, 240, 300, and 360 minutes after drug administration|Acute change in SpO2 during drug administration, Comparing change in SpO2 (%) between psilocybin/THC and migraine/HC, 0, 30, 60, 120, 180, 240, 300, and 360 minutes after drug administration|Acute change in general drug effects during drug administration, Comparing "overall," "anxiety/fear," "sleepiness/sedation," "nausea," "joy/intense happiness,""peace/harmony" between psilocybin/THC and migraine/HC, 0, 30, 60, 120, 180, 240, 300, and 360 minutes after drug administration|Acute psychedelic effects during drug administration, Comparing 5-Dimensional Altered States of Consciousness scale scores (0-100; higher score being more psychedelic) between psilocybin/THC and migraine/HC, up to 8 hours after drug administration