Repeat Dosing of Psilocybin in Migraine Headache

Repeat Dosing of Psilocybin in 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.

Study Overview

• Status: Completed
• Conditions: Migraine Headache
• Intervention / Treatment: Drug: Placebo; Drug: Psilocybin

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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • West Haven, Connecticut, United States, 06516
      • VA Connecticut Healthcare System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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)
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Placebo/Placebo; Subjects will receive a dose of placebo, followed by a dose of placebo approximately 7 days later.	Drug: Placebo; 25mg Diphenhydramine
Experimental: Placebo/Psilocybin; Subjects will receive a dose of placebo, followed by a dose of psilocybin approximately 7 days later.	Drug: Placebo; 25mg Diphenhydramine; Drug: Psilocybin; 10mg Psilocybin
Experimental: Psilocybin/Placebo; Subjects will receive a dose of psilocybin, followed by a dose of placebo approximately 7 days later.	Drug: Placebo; 25mg Diphenhydramine; Drug: Psilocybin; 10mg Psilocybin
Experimental: Psilocybin/Psilocybin; Subjects will receive a dose of psilocybin, followed by a dose of psilocybin approximately 7 days later.	Drug: Psilocybin; 10mg Psilocybin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in migraine attack frequency	Average number (number per week)	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)	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)	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)	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)	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)	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)	From two weeks before the first session to two months after second session using a headache diary

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Use of abortive/rescue medication	number of times per week	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	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)	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	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.	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)	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)	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)	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)	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	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	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)

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: Wallace Research Foundation

Study record dates

Study Major Dates

• Study Start (Actual): August 10, 2021
• Primary Completion (Actual): November 5, 2023
• Study Completion (Actual): November 5, 2023

Study Registration Dates

• First Submitted: December 20, 2019
• First Submitted That Met QC Criteria: January 2, 2020
• First Posted (Actual): January 6, 2020

Study Record Updates

• Last Update Posted (Estimated): February 9, 2024
• Last Update Submitted That Met QC Criteria: February 7, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: inflammation; psilocybin; calcitonin gene-related peptide (CGRP); pituitary adenylate cyclase-activating peptide (PACAP)
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Headache Disorders, Primary; Headache Disorders; Migraine Disorders; Headache; Physiological Effects of Drugs; Psychotropic Drugs; Hallucinogens; Psilocybin
• Other Study ID Numbers: 2000026974; 000 (Other Identifier: YCTG)

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