INTERVENTIONALRECRUITINGNCT06464367

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.

Locally preserved from ClinicalTrials.govOpen ClinicalTrials.govlast source update 2026-07-13

What this record can show

Protocol only - no registry results posted

This locally preserved record separates the registered protocol from source-reported registry results. Neither is a treatment recommendation.

Registry facts

Study at a glance

Phase: EARLY PHASE1
Enrollment: 50 (ESTIMATED)
Start date: 2025-05-19
Sponsor: Yale University
Design: RANDOMIZED · PARALLEL · OTHER
Locations: 1
Results record: Not present in registry snapshot

Linked local records

Related local records

Local links use governed condition terms or exact source-reported intervention names. They are navigation candidates, not efficacy claims.

Conditions

Migraine Disorders

Cannabinoids and active compounds

No governed compound link was found.

Medicines

No exact medicine-name link was found.

Interventions

What was registered

DRUG

Psilocybin

synthetic psilocybin 10 mg (oral)

DRUG

Placebo

synthetic THC 2.5 mg (oral)

Eligibility

Population and criteria

Sex: ALL
Minimum age: 21 Years
Maximum age: 70 Years
Healthy volunteers: Accepted

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.

primary outcomes

primary measures

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

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

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

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

secondary outcomes

secondary measures

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

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

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

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

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

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

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

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

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

Change in REM latency (via sleep electroencephalography)

Time frame: from screening to 7 days after drug administration

other outcomes

other measures

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

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

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

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

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

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

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

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

Acute change in general drug effects during drug administration

Time frame: 0, 30, 60, 120, 180, 240, 300, and 360 minutes after drug administration

Publications

Locally readable linked articles

No exact PMID-linked public article is currently readable locally.

Snapshot provenance

Snapshot: 8c6ca547-5b69-4587-9ab0-8ab66f8bba9e
Retrieved: 11/09/2026, 14:54:28
SHA-256: 60a7adfa838c8f696e478f92920eda4eef150da4c1c0b5f2d434529852eef2fd

Protocol only - no registry results posted

Study at a glance

Related local records

Conditions

Cannabinoids and active compounds

Medicines

What was registered

Psilocybin

Placebo

Population and criteria

Inclusion criteria

primary measures

Baseline SV2A PET

Baseline RSFC

Change in SV2A PET after drug administration

Change in resting state functional connectivity (RSFC) after drug administration

secondary measures

Change in TNF-alpha

Change in IL-1beta

Change in IL-6

Change in calcitonin gene-related peptide (CGRP)

Change in pituitary adenylate cyclase activating polypeptide (PACAP)

Change in bedtime (via actigraphy)

Change in get-up time (via actigraphy)

Change in daily active period (via actigraphy)

Change in daily rest period (via actigraphy)

Change in REM latency (via sleep electroencephalography)

other measures

Acute change in TNF-alpha during drug administration

Acute change in IL-1beta during drug administration

Acute change in IL-6 during drug administration

Acute change in calcitonin gene related peptide (CGRP) during drug administration

Acute change in pituitary adenylate cyclase activating polypeptide (PACAP) during drug administration

Acute change in mean arterial pressure (MAP) during drug administration

Acute change in heart rate during drug administration

Acute change in SpO2 during drug administration

Acute change in general drug effects during drug administration

Locally readable linked articles

Change in percent REM (via sleep electroencephalography)

Change in sleep efficiency (via sleep electroencephalography)

Adverse events

Acute psychedelic effects during drug administration