Mechanistic Studies of Psilocybin in Headache Disorders

NCT06464367 | Recruiting Early Phase 1 DMC FDA Drug

• 2 other identifiers: 2000034634ES0006
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Migraine

Keywords

psilocybin; resting state functional connectivity; synaptic density; synaptic vessel glycoprotein 2A (SV2A); circadian rhythm; sleep; inflammation

Outcome Measures

Primary Outcomes (4)

• Baseline SV2A PET

  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

  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

  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

  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 Outcomes (13)

• Change in TNF-alpha

  from screening to 7 days after drug administration

• Change in IL-1beta

  from screening to 7 days after drug administration

• Change in IL-6

  from screening to 7 days after drug administration

• Change in calcitonin gene-related peptide (CGRP)

  from screening to 7 days after drug administration

• Change in pituitary adenylate cyclase activating polypeptide (PACAP)

  from screening to 7 days after drug administration

Other Outcomes (10)

• Acute change in TNF-alpha during drug administration

  0, 120, and 240 minutes after drug administration

• Acute change in IL-1beta during drug administration

  0, 120, and 240 minutes after drug administration

• Acute change in IL-6 during drug administration

  0, 120, and 240 minutes after drug administration

Study Arms (4)

Migraine psilocybin

EXPERIMENTAL

Migraine participants randomized to receive 10 mg psilocybin (oral)

Drug: Psilocybin

Migraine placebo

PLACEBO COMPARATOR

Migraine participants randomized to receive 2.5 mg THC (oral)

Drug: Placebo

Healthy control psilocybin

EXPERIMENTAL

Healthy control participants randomized to receive 10 mg psilocybin (oral)

Drug: Psilocybin

Healthy control placebo

PLACEBO COMPARATOR

Healthy control participants randomized to receive 2.5 mg THC

Drug: Placebo

Interventions

Psilocybin DRUG

synthetic psilocybin 10 mg (oral)

Healthy control psilocybin; Migraine psilocybin

Placebo DRUG

synthetic THC 2.5 mg (oral)

Healthy control placebo; Migraine placebo

Eligibility Criteria

• Age: 21 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 21 to 70 (inclusive)
• Migraine disease per ICHD-3 criteria (for migraine participants) OR Healthy control patient
• 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.

Sponsors & Collaborators

• Yale University: lead
• The Wallace Foundation: collaborator

Study Sites (1)

VA Connecticut Healthcare System

West Haven, Connecticut, 06516, United States

RECRUITING

MeSH Terms

Conditions

Migraine Disorders; Inflammation

Interventions

Psilocybin

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Tryptamines; Indolizidines; Indolizines

Central Study Contacts

Sarah Anthony, MSc

CONTACT

203-932-5711; sarah.anthony@yale.edu

Emmanuelle Schindler, MD, PhD

CONTACT

203-932-5711; emmanuelle.schindler@yale.edu

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Neurology

Study Record Dates

• First Submitted: June 8, 2024
• First Posted: June 18, 2024
• Study Start: May 19, 2025
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: July 24, 2025

Record last verified: 2025-07

Locations

US (1)