Repeat Dosing of Psilocybin in Migraine Headache

• ClinicalTrials.gov Identifier: NCT04218539
• Recruitment Status: Recruiting
• First Posted: January 6, 2020
• Last Update Posted: August 8, 2022
• Sponsor: Yale University
• Collaborator: Wallace Research Foundation
• Information provided by (Responsible Party): Yale University

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Migraine Headache	Drug: Psilocybin; Drug: Placebo	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Repeat Dosing of Psilocybin in Headache Disorders
• Actual Study Start Date: August 10, 2021
• Estimated Primary Completion Date: July 15, 2023
• Estimated Study Completion Date: July 15, 2024

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. 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)
2. 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)
3. 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)
4. 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)
5. 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)
6. 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)
7. 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)

Secondary Outcome Measures :

1. Use of abortive/rescue medication [ Time Frame: From two weeks before the first session to two months after second session using a headache diary ]
   number of times per week
2. Time to first migraine attack [ Time Frame: From the second session until two months after second session using a headache diary ]
   Measured in days
3. Migraine attack-free time [ Time Frame: From two weeks before the first session to two months after second session using a headache diary ]
   Number of 24-hour days (may be non-consecutive)
4. 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 ]

   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

5. 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 ]
   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.
6. 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) ]
   Maximum change from baseline during each test day (mm Hg)
7. 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) ]
   Maximum change from baseline during each test day (mm Hg)
8. 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) ]
   Maximum change from baseline during each test day (beats per minute)
9. 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) ]
   Maximum change from baseline during each test day (SpO2)
10. 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 peripheral neuropeptide levels
11. 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) ]
    Change in peripheral neuropeptide levels

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Contacts

Contact: Carly Hewes; 203-932-5711 ext 7411; carly.hewes@yale.edu

Contact: Emmanuelle Schindler, MD PhD; 203-932-5711 ext 4335; emmanuelle.schindler@yale.edu

Locations

United States, Connecticut

VA Connecticut Healthcare System; Recruiting

West Haven, Connecticut, United States, 06516

Contact: Carly Hewes 203-932-5711 ext 7411 carly.hewes@yale.edu

Contact: Christina Luddy, BS 203-932-5711 ext 4549 christina.luddy@yale.edu

Principal Investigator: Emmanuelle Schindler, MD, PhD

Sponsors and Collaborators

Yale University

Wallace Research Foundation

More Information

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT04218539
• Other Study ID Numbers: 2000026974
• First Posted: January 6, 2020
• Last Update Posted: August 8, 2022
• Last Verified: August 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Yale University:

psilocybin; inflammation; calcitonin gene-related peptide (CGRP); pituitary adenylate cyclase-activating peptide (PACAP)

Additional relevant MeSH terms:

Migraine Disorders; Headache; Headache Disorders, Primary; Headache Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Psilocybin; Hallucinogens; Physiological Effects of Drugs; Psychotropic Drugs