Mechanistic Studies of Psilocybin in Headache Disorders

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.

Study Overview

• Status: Recruiting
• Conditions: Migraine
• Intervention / Treatment: Drug: Psilocybin; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Sarah Anthony, MSc; Phone Number: 14335 203-932-5711; Email: sarah.anthony@yale.edu
• Study Contact Backup: Name: Emmanuelle Schindler, MD, PhD; Phone Number: 14335 203-932-5711; Email: emmanuelle.schindler@yale.edu

Study Locations

• United States
  • Connecticut
    • West Haven, Connecticut, United States, 06516
      • Recruiting
      • VA Connecticut Healthcare System
      • Contact: Sarah Anthony, MSc; Phone Number: 14335 203-932-5711; Email: sarah.anthony@yale.edu
      • Contact: Emmanuelle Schindler, MD, PhD; Phone Number: 14335 203-932-5711; Email: emmanuelle.schindler@yale.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion criteria:

• Age 21 to 70 (inclusive)
• Migraine disease per ICHD-3 criteria (for migraine participants) OR Healthy control patient

Exclusion criterion

• Unstable medical condition or serious nervous system pathology
• Pregnant, breastfeeding, lack of adequate birth control
• Psychotic or manic disorder
• Substance abuse in the prior 3 months
• Use of classic psychedelics (e.g., psilocybin, LSD, mescaline) in the past 6 months
• Use of cannabis or other THC products in the prior 2 weeks
• Urine toxicology positive to drugs of abuse
• The use of triptans (e.g., sumatriptan) or ditans (e.g., lasmiditan) more than twice weekly on average
• Use of serotonergic preventive therapies (i.e., taken chronically; amitriptyline, fluoxetine, imipramine, cyproheptadine) in the past 6 weeks
• Use of preventive or transitional treatments that produce spikes and waning of symptom relief (e.g., botulinum toxin, calcitonin gene-related peptide system targeting antibodies, peripheral nerve or ganglion blocks, chiropractic manipulation)
• History of a bleeding disorder or are currently taking anticoagulants (e.g., warfarin, enoxaparin, dabigatran, apixaban).
• Use of non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen, naproxen) in the 7 days before PET scan and 7 days after PET scan.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Migraine psilocybin; Migraine participants randomized to receive 10 mg psilocybin (oral)	Drug: Psilocybin; synthetic psilocybin 10 mg (oral)
Placebo Comparator: Migraine placebo; Migraine participants randomized to receive 2.5 mg THC (oral)	Drug: Placebo; synthetic THC 2.5 mg (oral)
Experimental: Healthy control psilocybin; Healthy control participants randomized to receive 10 mg psilocybin (oral)	Drug: Psilocybin; synthetic psilocybin 10 mg (oral)
Placebo Comparator: Healthy control placebo; Healthy control participants randomized to receive 2.5 mg THC	Drug: Placebo; synthetic THC 2.5 mg (oral)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Outcome Measure	Measure Description	Time Frame
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

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: The Wallace Foundation

Study record dates

Study Major Dates

• Study Start (Actual): May 19, 2025
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: June 8, 2024
• First Submitted That Met QC Criteria: June 12, 2024
• First Posted (Actual): June 18, 2024

Study Record Updates

• Last Update Posted (Actual): July 24, 2025
• Last Update Submitted That Met QC Criteria: July 21, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: sleep; inflammation; psilocybin; circadian rhythm; resting state functional connectivity; synaptic density; synaptic vessel glycoprotein 2A (SV2A)
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders; Headache; Physiological Effects of Drugs; Psychotropic Drugs; Hallucinogens; Psilocybin
• Other Study ID Numbers: 2000034634; ES0006 (Other Identifier: VA Connecticut Healthcare System)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No