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NCT Number: NCT06464367

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.

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Key information

Conditions

Migraine Brain Diseases Central Nervous System Diseases Headache Disorders Headache Disorders, Primary Inflammation Migraine Disorders Nervous System Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms

Age range

21 year–70 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Early Phase 1

Primary location

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Psilocybin

Drug

synthetic psilocybin 10 mg (oral)

Placebo

Drug

synthetic THC 2.5 mg (oral)

Primary outcomes

  1. 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

  2. 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

  3. 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

  4. 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

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. Adverse events

    Time frame: from screening through 3 months after drug administration

    Adverse events from any procedure or drug administration

Other outcomes

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

Study contacts

Contact information is provided by the study sponsor or research team.

Emmanuelle Schindler, MD, PhD

CONTACT

[email protected]

203-932-5711 ext. 14335

Erik Zorrilla, PhD

CONTACT

[email protected]

203-932-5711 ext. 14335

Sponsors and collaborators

Lead sponsor

Yale University

Other

Collaborators

  • The Wallace Foundation

Registry information

Important dates

Study start
2025
Primary completion
2027
Study completion
2027
First posted
Jun 18, 2024
Registry last updated
Jul 13, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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