Repeat Dosing of Psilocybin in Migraine Headache

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Repeat Dosing of Psilocybin in Headache Disorders

Conditions
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Migraine Headache

Intervention / Treatment
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* Drug: Psilocybin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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psilocybin, inflammation, calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating peptide (PACAP)