Migraine HeadachePhase 1NCT04218539

Repeat Dosing of Psilocybin in Migraine Headache

A Phase 1 study testing Psilocybin in people with Migraine Headache, run by Yale University at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Trial summary

In seeking to understand the capacity for psilocybin to reduce migraine headache burden, this study will investigate single and repeated dosing of psilocybin up to two doses. In seeking to identify an underlying mechanism in psilocybin's effects, neuroinflammatory markers for migraine headache will be measured. Read more about this study

Who is it for?: Ages 21 to 65 years
Conditions the study is for: Migraine Headache
What is being tested?: Psilocybin
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 18 participants
Where: 1 siteUnited States
Study dates: 10 Aug 2021to 5 Nov 2023
Phase: Phase 1
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 21 to 65 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Diagnosis of migraine headache per ICHD-3 criteria
Typical pattern of migraine attacks with approximately two migraines or more weekly
Attacks are managed by means involving no more than twice weekly triptan use

Who cannot join

Axis I psychotic or manic disorder (e.g., schizophrenia, bipolar I, depression with psychosis)
Axis I psychotic or manic disorder in first degree relative
Unstable medical condition; severe renal, cardiac, or hepatic disease; pacemaker; or serious central nervous system pathology
Pregnant, breastfeeding, lack of adequate birth control
History of intolerance to psilocybin, lysergic acid diethylamide (LSD), or related compounds
Drug abuse within the past 3 months (excluding tobacco)

Show all 14Show fewer

Urine toxicology positive to drugs of abuse
Alcohol use of >21 drinks per week (males); >14 drinks per week (females; NIAAA guidelines)
Use of alcohol in the week prior to the first test day
Use of vasoconstrictive medications (i.e., sumatriptan, pseudoephedrine, midodrine) within 5 half-lives of test days
Use of serotonergic antiemetics (i.e., ondansetron) in the past 2 weeks
Use of antidepressant medication (i.e., TCA, MAOI, SSRI) in the past 6 weeks
Use of steroids or certain other immunomodulatory agents (i.e., azathioprine) in the past 2 weeks
Use of migraine onabotulinum toxin (i.e., Botox) or monoclonal antibodies against CGRP or its receptor (i.e., erenumab) in the past month or while therapeutic effects are still present

Trial locations and contacts

1 site in 1 country.

United States1 site

VA Connecticut Healthcare System
West Haven, Connecticut, 06516

Other trials in United States

About this study

Official title: Repeat Dosing of Psilocybin in Headache Disorders

Read the detailed description

Migraine headache is a common medical condition and a top cause of disability worldwide. Treatment options for migraine headache are many and varied, though an approximated 10% of migraineurs is refractory to medication and thus, there is a need to develop alternative treatments. There is anecdotal evidence supporting lasting therapeutic effects after limited dosing of psilocybin and related compounds in headache disorders. The cause of this unique effect remains unknown, though the drug class has demonstrable anti-inflammatory activity, a biological process relevant to migraine and other headache disorders. In seeking to understand the capacity for psilocybin to reduce migraine headache burden, this study will investigate single and repeated dosing of psilocybin up to two doses. In seeking to identify an underlying mechanism in psilocybin's effects, neuroinflammatory markers for migraine headache will be measured. The results from this study will serve in the development of larger investigations seeking to understand the effects of psilocybin and related compounds in headache disorders.

Conditions: Migraine Headache
Being tested: Psilocybin, Placebo
Keywords: psilocybin, inflammation, calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating peptide (PACAP)
Medical subject headings: Migraine Disorders, Inflammation

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

PsilocybinDrug
10mg Psilocybin
PlaceboDrug
25mg Diphenhydramine

Study groups in NCT04218539
Study group	Role	What they receive
Placebo/Placebo	Experimental	Subjects will receive a dose of placebo, followed by a dose of placebo approximately 7 days later. Receives: Drug: Placebo
Placebo/Psilocybin	Experimental	Subjects will receive a dose of placebo, followed by a dose of psilocybin approximately 7 days later. Receives: Drug: Psilocybin; Drug: Placebo
Psilocybin/Placebo	Experimental	Subjects will receive a dose of psilocybin, followed by a dose of placebo approximately 7 days later. Receives: Drug: Psilocybin; Drug: Placebo
Psilocybin/Psilocybin	Experimental	Subjects will receive a dose of psilocybin, followed by a dose of psilocybin approximately 7 days later. Receives: Drug: Psilocybin

What is being measured

The primary outcome is the main question the study is designed to answer.

Change in migraine attack frequency
Average number (number per week)
Measured: From two weeks before the first session to two months after second session using a headache diary
Change in pain intensity of migraine attacks
Average pain intensity (4-tiered pain score; 0=none, 1=mild, 2=moderate, 3=severe)
Measured: From two weeks before the first session to two months after second session using a headache diary
Change in duration of migraine attacks
Average duration (measured in hours)
Measured: From two weeks before the first session to two months after second session using a headache diary
Change in intensity of photophobia (light sensitivity)
Average intensity (4-tiered pain score; 0=none, 1=mild, 2=moderate, 3=severe)
Measured: From two weeks before the first session to two months after second session using a headache diary
Change in intensity of phonophobia (noise sensitivity)
Average intensity (4-tiered pain score; 0=none, 1=mild, 2=moderate, 3=severe)
Measured: From two weeks before the first session to two months after second session using a headache diary
Average intensity of nausea/vomiting
Average intensity (4-tiered pain score; 0=none, 1=mild, 2=moderate, 3=severe)
Measured: From two weeks before the first session to two months after second session using a headache diary
Change in functional disability
Average disability (4-tiered pain score; 0=none, 1=mild, 2=moderate, 3=severe)
Measured: From two weeks before the first session to two months after second session using a headache diary

Secondary outcomes (11)

Use of abortive/rescue medication
number of times per week
Measured: From two weeks before the first session to two months after second session using a headache diary
Time to first migraine attack
Measured in days
Measured: From the second session until two months after second session using a headache diary
Migraine attack-free time
Number of 24-hour days (may be non-consecutive)
Measured: From two weeks before the first session to two months after second session using a headache diary
Quality of life using the Centers for Disease Control (CDC) Health-Related Quality of Life Scale: Healthy Days Symptoms Module
4 questions scored 0 to 30 each; higher numbers indicate worse quality of life.
(1) pain-related impairment, (2) mood symptoms, (3) anxiety symptoms, (4) lack of sleep. Percent change for each measure as well as total score (range 0 to 120) will be calculated
Measured: From two weeks before the first session to two months after second session using a headache diary
Psychedelic effects using the 5-Dimensional Altered States of Consciousness (5D-ASC) scale
94 questions scored 0 to 100 each; higher numbers indicate greater psychedelic effects. Questions address 5 dimensions: (1) Oceanic Boundlessness (score range 0-2700), (2) Dread of Ego Dissolution (score range 0-2100), (3) Visionary Restructuralization (score range 0-1800), (4) Auditory Alterations (score range 0-1600), and (5) Vigilance Reduction (score range 0-1200). Score for each dimension as well as total score (range 0 to 9400) will be measured.
Measured: Starting on the first test day until the second test day approximately one week later; taken both test days approximately 6 hours after drug administration
Change in blood pressure- Systolic
Maximum change from baseline during each test day (mm Hg)
Measured: Starting on the first test day until the second test day approximately one week later; measured both test sessions before drug administration, every 30 min in the first hour, then hourly for 4 hours or until resolution of drug effects (~6hrs after drug)
Change in blood pressure- Diastolic
Maximum change from baseline during each test day (mm Hg)
Measured: Starting on the first test day until the second test day approximately one week later; measured both test sessions before drug administration, every 30 min in the first hour, then hourly for 4 hours or until resolution of drug effects (~6hrs after drug)
Change in heart rate
Maximum change from baseline during each test day (beats per minute)
Measured: Starting on the first test day until the second test day approximately one week later; measured both test sessions before drug administration, every 30 min in the first hour, then hourly for 4 hours or until resolution of drug effects (~6hrs after drug)
Change in peripheral oxygenation
Maximum change from baseline during each test day (SpO2)
Measured: Starting on the first test day until the second test day approximately one week later; measured both test sessions before drug administration, every 30 min in the first hour, then hourly for 4 hours or until resolution of drug effects (~6hrs after drug)
Change in peripheral calcitonin gene-related peptide (CGRP) levels
Change in peripheral neuropeptide levels
Measured: Approximately 3 months; measured at screening, on both test days (0, 2, and 4 hours after drug administration), and follow-up (~2 months after second test day)
Change in pituitary adenylate cyclase-activating peptide (PACAP) levels
Change in peripheral neuropeptide levels
Measured: Approximately 3 months; measured at screening, on both test days (0, 2, and 4 hours after drug administration), and follow-up (~2 months after second test day)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

10 Aug 20215 Nov 2023

First posted6 Jan 2020
Study start10 Aug 2021
Primary completion5 Nov 2023
Study completion5 Nov 2023

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Migraine HeadacheStudies of the same condition, open and under way.
More trials run by Yale UniversityThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 18 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT04218539
Sponsor's protocol ID: 2000026974
Other IDs: 000
Status last verified: Feb 2024
First submitted: 20 Dec 2019
Last updated: 9 Feb 2024
Results posted: No
Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No

Publications

Schindler EAD, Gottschalk CH, Pittman BP, D'Souza DC. Comparing single- and repeat-dose psilocybin with active placebo for migraine prevention in an exploratory randomized controlled clinical trial. Headache. 2026 Apr;66(4):885-895. doi: 10.1111/head.70024. Epub 2025 Dec 29.
PubMed 41459830

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

RecruitingObservational study
Study of the Glymphatic System in Migraine
Migraine
Active, not recruiting
Clinical and Neurophysiological Effects of tDCS to Visual and Motor Cortex in Migraine
Migraine
Active, not recruiting
App-Based Migraine Treatment: The Health enSuite Study
Migraine, Migraine With Aura
Not yet recruiting
A Prospective Study of Rimegepant for Short-term Preventive Treatment of Night-shift-related Migraine in Healthcare Professionals
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Recruiting
Marine Lipids Ease Painful TMD
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All Migraine Headache trials

Study at a glance

From the registry record, last updated by the sponsor on 9 Feb 2024. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Repeat Dosing of Psilocybin in Headache Disorders
ClinicalTrials.gov ID: NCT04218539
Acronym / sponsor ID: 2000026974
Conditions: Migraine Headache
Keywords: psilocybin, inflammation, calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating peptide (PACAP)
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 18 participants (actual)
Lead sponsor: Yale UniversityUniversity, hospital or other
Collaborators: The Wallace Foundation
Study start: 10 Aug 2021 (actual)
Primary completion: 5 Nov 2023 (actual)
Study completion: 5 Nov 2023 (actual)
First posted: 6 Jan 2020 (actual)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 4

Arm	Type	Receives
Placebo/Placebo	Experimental	Drug: PlaceboSubjects will receive a dose of placebo, followed by a dose of placebo approximately 7 days later.
Placebo/Psilocybin	Experimental	Drug: Psilocybin, Drug: PlaceboSubjects will receive a dose of placebo, followed by a dose of psilocybin approximately 7 days later.
Psilocybin/Placebo	Experimental	Drug: Psilocybin, Drug: PlaceboSubjects will receive a dose of psilocybin, followed by a dose of placebo approximately 7 days later.
Psilocybin/Psilocybin	Experimental	Drug: PsilocybinSubjects will receive a dose of psilocybin, followed by a dose of psilocybin approximately 7 days later.

Who may qualify

Ages: 21 to 65 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (3 listed)

Diagnosis of migraine headache per ICHD-3 criteria
Typical pattern of migraine attacks with approximately two migraines or more weekly
Attacks are managed by means involving no more than twice weekly triptan use

Key exclusion criteria (14 listed)

Axis I psychotic or manic disorder (e.g., schizophrenia, bipolar I, depression with psychosis)
Axis I psychotic or manic disorder in first degree relative
Unstable medical condition; severe renal, cardiac, or hepatic disease; pacemaker; or serious central nervous system pathology
Pregnant, breastfeeding, lack of adequate birth control
History of intolerance to psilocybin, lysergic acid diethylamide (LSD), or related compounds

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Psilocybin10mg Psilocybin	Drug	Placebo/Psilocybin, Psilocybin/Placebo, Psilocybin/Psilocybin
Placebo25mg Diphenhydramine	Drug	Placebo/Placebo, Placebo/Psilocybin, Psilocybin/Placebo

Primary outcome

Change in migraine attack frequency
Time frame: From two weeks before the first session to two months after second session using a headache diary
Average number (number per week)
Change in pain intensity of migraine attacks
Time frame: From two weeks before the first session to two months after second session using a headache diary
Average pain intensity (4-tiered pain score; 0=none, 1=mild, 2=moderate, 3=severe)
Change in duration of migraine attacks
Time frame: From two weeks before the first session to two months after second session using a headache diary
Average duration (measured in hours)
Change in intensity of photophobia (light sensitivity)
Time frame: From two weeks before the first session to two months after second session using a headache diary
Average intensity (4-tiered pain score; 0=none, 1=mild, 2=moderate, 3=severe)
Change in intensity of phonophobia (noise sensitivity)
Time frame: From two weeks before the first session to two months after second session using a headache diary
Average intensity (4-tiered pain score; 0=none, 1=mild, 2=moderate, 3=severe)
Average intensity of nausea/vomiting
Time frame: From two weeks before the first session to two months after second session using a headache diary
Average intensity (4-tiered pain score; 0=none, 1=mild, 2=moderate, 3=severe)
Change in functional disability
Time frame: From two weeks before the first session to two months after second session using a headache diary
Average disability (4-tiered pain score; 0=none, 1=mild, 2=moderate, 3=severe)

11 secondary outcomes

Use of abortive/rescue medication
Time frame: From two weeks before the first session to two months after second session using a headache diary
Time to first migraine attack
Time frame: From the second session until two months after second session using a headache diary
Migraine attack-free time
Time frame: From two weeks before the first session to two months after second session using a headache diary
Quality of life using the Centers for Disease Control (CDC) Health-Related Quality of Life Scale: Healthy Days Symptoms Module
Time frame: From two weeks before the first session to two months after second session using a headache diary
Psychedelic effects using the 5-Dimensional Altered States of Consciousness (5D-ASC) scale
Time frame: Starting on the first test day until the second test day approximately one week later; taken both test days approximately 6 hours after drug administration
Change in blood pressure- Systolic
Time frame: Starting on the first test day until the second test day approximately one week later; measured both test sessions before drug administration, every 30 min in the first hour, then hourly for 4 hours or until resolution of drug effects (~6hrs after drug)
Change in blood pressure- Diastolic
Time frame: Starting on the first test day until the second test day approximately one week later; measured both test sessions before drug administration, every 30 min in the first hour, then hourly for 4 hours or until resolution of drug effects (~6hrs after drug)
Change in heart rate
Time frame: Starting on the first test day until the second test day approximately one week later; measured both test sessions before drug administration, every 30 min in the first hour, then hourly for 4 hours or until resolution of drug effects (~6hrs after drug)
Change in peripheral oxygenation
Time frame: Starting on the first test day until the second test day approximately one week later; measured both test sessions before drug administration, every 30 min in the first hour, then hourly for 4 hours or until resolution of drug effects (~6hrs after drug)
Change in peripheral calcitonin gene-related peptide (CGRP) levels
Time frame: Approximately 3 months; measured at screening, on both test days (0, 2, and 4 hours after drug administration), and follow-up (~2 months after second test day)
Change in pituitary adenylate cyclase-activating peptide (PACAP) levels
Time frame: Approximately 3 months; measured at screening, on both test days (0, 2, and 4 hours after drug administration), and follow-up (~2 months after second test day)

Results and safety

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 9 Feb 2024.
Derived from this study: PubMed 41459830Schindler EAD, Gottschalk CH, Pittman BP, D'Souza DC. Comparing single- and repeat-dose psilocybin with active placebo for migraine prevention in an exploratory randomized controlled clinical trial. Headache. 2026 Apr;66(4):885-895. doi: 10.1111/head.70024. Epub 2025 Dec 29.

Related trials for Migraine Headache

RecruitingObservational study
Study of the Glymphatic System in Migraine
Migraine
Active, not recruiting
Clinical and Neurophysiological Effects of tDCS to Visual and Motor Cortex in Migraine
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App-Based Migraine Treatment: The Health enSuite Study
Migraine, Migraine With Aura
Not yet recruiting
A Prospective Study of Rimegepant for Short-term Preventive Treatment of Night-shift-related Migraine in Healthcare Professionals
Migraine Disorders
Recruiting
Marine Lipids Ease Painful TMD
Temporomandibular Disorder (TMD)

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

The record lists no contact. Use the official record to reach the sponsor.

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Psilocybin in people with Migraine Headache, run by Yale University at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 9 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in migraine attack frequency (time frame: From two weeks before the first session to two months after second session using a headache diary). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04218539, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Feb 2024.