Mechanistic Studies of Psilocybin in Headache Disorders

July 9, 2026 updated by: Emmanuelle Schindler, Yale University
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

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

50

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

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
Time Frame: from date of randomization until the date of first PET scan, assessed up to 6 months
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
Time Frame: from date of randomization until the date of first MRI, assessed up to 6 months
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
Time Frame: from date of first PET scan to the date of second PET scan, assessed up to 6 months
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
Time Frame: from date of first MRI to the date of second MRI, assessed up to 6 months
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
Time Frame: from screening to 7 days after drug administration
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
Time Frame: from screening to 7 days after drug administration
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
Time Frame: from screening to 7 days after drug administration
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)
Time Frame: from screening to 7 days after drug administration
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)
Time Frame: from screening to 7 days after drug administration
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)
Time Frame: from screening through 14 days after drug administration
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)
Time Frame: from screening through 14 days after drug administration
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)
Time Frame: from screening through 14 days after drug administration
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)
Time Frame: from screening through 14 days after drug administration
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)
Time Frame: from screening to 7 days after drug administration
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)
Time Frame: from screening to 7 days after drug administration
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)
Time Frame: from screening to 7 days after drug administration
Comparing change in sleep efficiency (%) after drug between psilocybin/THC and migraine/HC
from screening to 7 days after drug administration
Adverse events
Time Frame: from screening through 3 months after drug administration
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
Time Frame: 0, 120, and 240 minutes after 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
Time Frame: 0, 120, and 240 minutes after 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
Time Frame: 0, 120, and 240 minutes after 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
Time Frame: 0, 120, and 240 minutes after 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
Time Frame: 0, 120, and 240 minutes after 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
Time Frame: 0, 30, 60, 120, 180, 240, 300, and 360 minutes after 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
Time Frame: 0, 30, 60, 120, 180, 240, 300, and 360 minutes after 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
Time Frame: 0, 30, 60, 120, 180, 240, 300, and 360 minutes after 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
Time Frame: 0, 30, 60, 120, 180, 240, 300, and 360 minutes after 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
Time Frame: up to 8 hours after 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

This is where you will find people and organizations involved with this study.

Sponsor

Yale University

Collaborators

The Wallace Foundation

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 19, 2025

Primary Completion (Estimated)

December 31, 2027

Study Completion (Estimated)

December 31, 2027

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 13, 2026

Last Update Submitted That Met QC Criteria

July 9, 2026

Last Verified

July 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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