Mechanistic Studies of Psilocybin in Headache Disorders

July 21, 2025 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

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
50

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • 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

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

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

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
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

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
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

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
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

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Yale University

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
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)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
May 19, 2025

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 31, 2026

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 31, 2026

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
June 8, 2024

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 12, 2024

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
June 18, 2024

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
July 24, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 21, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
July 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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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