Effects of Psilocybin in Concussion Headache

Study Overview
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Brief Summary
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The purpose of this study is to investigate the effects of oral psilocybin in post-traumatic headache. Subjects will be randomized to receive placebo, low dose psilocybin, or high dose psilocybin on two separate test days approximately 14 days apart. Subjects will maintain a headache diary prior to, during, and after the treatments in order to document headache frequency and intensity, as well as associated symptoms. Blood samples will be drawn at various timepoints to measure levels of inflammatory peptides.

Official Title
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Safety and Efficacy of Psilocybin for the Treatment of Headache Disorders: Sub-Study II

Conditions
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Post-Traumatic Headache

Intervention / Treatment
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* Drug: Placebo oral capsule
* Drug: Low Dose Psilocybin
* Drug: High Dose Psilocybin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of post-traumatic headache Typical pattern of headache attacks with approximately two attacks or more weekly Attacks are managed by means involving no more than twice weekly triptan use Exclusion Criteria: Axis I psychotic disorder (e.g. schizophrenia, bipolar I, depression with psychosis) Axis I psychotic 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, LSD, or related compounds Drug or alcohol abuse within the past 3 months (excluding tobacco) Urine toxicology positive to drugs of abuse 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

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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo/Low Dose Psilocybin<br>Subjects in this arm receive placebo in the first session and low dose psilocybin in the second session. | Drug: Placebo oral capsule<br>* microcrystalline cellulose capsule<br>Drug: Low Dose Psilocybin<br>* 0.0143 mg/kg psilocybin capsule (weight-based option) or 1 mg psilocybin capsule (fixed-dose option)<br>|
| Experimental: Placebo/High Dose Psilocybin<br>Subjects in this arm receive placebo in the first session and high dose psilocybin in the second session. | Drug: Placebo oral capsule<br>* microcrystalline cellulose capsule<br>Drug: High Dose Psilocybin<br>* 0.143 mg/kg psilocybin capsule (weight-based option) or 10 mg psilocybin capsule (fixed-dose option)<br>|
| Experimental: Low Dose Psilocybin/Placebo<br>Subjects in this arm receive low dose psilocybin in the first session and placebo in the second session. | Drug: Placebo oral capsule<br>* microcrystalline cellulose capsule<br>Drug: Low Dose Psilocybin<br>* 0.0143 mg/kg psilocybin capsule (weight-based option) or 1 mg psilocybin capsule (fixed-dose option)<br>|
| Experimental: High Dose Psilocybin/Placebo<br>Subjects in this arm receive high dose psilocybin in the first session and placebo in the second session. | Drug: Placebo oral capsule<br>* microcrystalline cellulose capsule<br>Drug: High Dose Psilocybin<br>* 0.143 mg/kg psilocybin capsule (weight-based option) or 10 mg psilocybin capsule (fixed-dose option)<br>|
| Experimental: High Dose Psilocybin/Low Dose Psilocybin<br>Subjects in this arm receive high dose psilocybin in the first session and low dose psilocybin in the second session. | Drug: Low Dose Psilocybin<br>* 0.0143 mg/kg psilocybin capsule (weight-based option) or 1 mg psilocybin capsule (fixed-dose option)<br>Drug: High Dose Psilocybin<br>* 0.143 mg/kg psilocybin capsule (weight-based option) or 10 mg psilocybin capsule (fixed-dose option)<br>|
| Experimental: Low Dose Psilocybin/High Dose Psilocybin<br>Subjects in this arm receive low dose psilocybin in the first session and high dose psilocybin in the second session. | Drug: Low Dose Psilocybin<br>* 0.0143 mg/kg psilocybin capsule (weight-based option) or 1 mg psilocybin capsule (fixed-dose option)<br>Drug: High Dose Psilocybin<br>* 0.143 mg/kg psilocybin capsule (weight-based option) or 10 mg psilocybin capsule (fixed-dose option)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute change in pain intensity | 4-tiered pain score (0=none, 1=mild, 2=moderate, 3=severe) | Measured at 0, 1, 2, 4, and 24 hours after drug administration | 
| Acute change in nausea/vomiting | 4-tiered pain score (0=none, 1=mild, 2=moderate, 3=severe) | Measured at 0, 1, 2, 4, and 24 hours after drug administration | 
| Acute change in photophobia | 4-tiered pain score (0=none, 1=mild, 2=moderate, 3=severe) | Measured at 0, 1, 2, 4, and 24 hours after drug administration | 
| Acute change in phonophobia | 4-tiered pain score (0=none, 1=mild, 2=moderate, 3=severe) | Measured at 0, 1, 2, 4, and 24 hours after drug administration | 
| Acute change in functional disability | 4-tiered pain score (0=none, 1=mild, 2=moderate, 3=severe) | Measured at 0, 1, 2, 4, and 24 hours after drug administration | 
| Time to first headache attack | Measured in days | Two weeks following each test session | 
| Time to last headache attack | Measured in days | Two weeks following each test session | 
| Change in headache attack frequency | Average number (number per week) | From two weeks before first session to two weeks after second session using a headache diary | 
| Change in headache attack duration | Average duration (measured in hours) | From two weeks before first session to two weeks after second session using a headache diary | 
| Change in pain intensity of headache attacks | Average pain intensity (4-tiered pain score; 0=none, 1=mild, 2=moderate, 3=severe) | From two weeks before first session to two weeks after second session using a headache diary | 
| Change in intensity of nausea/vomiting during headache attacks | Average intensity of nausea/vomiting (4-tiered pain score; 0=none, 1=mild, 2=moderate, 3=severe) | From two weeks before first session to two weeks after second session using a headache diary | 
| Change in intensity of photophobia during headache attacks | Average intensity of photophobia (4-tiered pain score; 0=none, 1=mild, 2=moderate, 3=severe) | From two weeks before first session to two weeks after second session using a headache diary | 
| Change in intensity of phonophobia during headache attacks | Average intensity of phonophobia (4-tiered pain score; 0=none, 1=mild, 2=moderate, 3=severe) | From two weeks before first session to two weeks after second session using a headache diary | 
| Change in intensity of functional disability during headache attacks | Average intensity of functional disability (4-tiered pain score; 0=none, 1=mild, 2=moderate, 3=severe) | From two weeks before first session to two weeks 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 first session to two weeks after second session using a headache diary | 
| Headache attack-free time | Number of 24 hour days (may be non-consecutive) | From two weeks before first session to two weeks 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, and (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 first session to two weeks after second session using a headache diary | 
| Depression using Patient Health Questionnaire 9 (PHQ-9) | 9 question self-report questionnaire to assess the presence of depression-related symptoms. Each question is rated on a scale of 0-3 (0 = Not at all; 1 = Several days; 2 = More than half the days; 3 = Nearly every day). Higher scores indicate greater presence of depression-related symptoms. Total score is calculated. Total score 5-9 = minimal symptoms; total score 10-14 = Major Depression, mild; total score 15-19 = Major Depression, moderately severe; total score >20 = Major Depression severe. | From two weeks before first session to two weeks after second session using a headache diary | 
| Suicide risk using the Columbia Suicide Severity Rating Scale (CSSRS) | A 10-category assessment of suicidal ideation and behavior. 5 categories (scored yes/no) relate to the presence of suicidal ideation. 5 categories (scored yes/no) relate to the presence of suicidal behavior. A yes to any of the suicidal ideation categories indicates the presence of suicidal ideation; a yes to any of the suicidal behavior categories indicates the presence of suicidal behavior. | From two weeks before first session to two weeks 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. | Taken on each test day approximately 6 hours after drug administration | 
| Change in blood pressure | Maximum change from baseline during each test day (mmHg) | Measured during each test session prior to drug administration, every 15 min in the first hour, every 30 min in the second hour, and then hourly for 4 hours or until resolution of psychedelic effects ( 6 hours post drug) | 
| Change in heart rate | Maximum change from baseline during each test day (beats per minute) | Measured during each test session prior to drug administration, every 15 min in the first hour, every 30 min in the second hour, and then hourly for 4 hours or until resolution of psychedelic effects ( 6 hours post drug) | 
| Change in peripheral oxygenation | Maximum change from baseline during each test day (SpO2) | Measured during each test session prior to drug administration, every 15 min in the first hour, every 30 min in the second hour, and then hourly for 4 hours or until resolution of psychedelic effects ( 6 hours post drug) | 
| Change in peripheral levels of calcitonin gene-related peptide (CGRP) | Change from baseline during each test day (pg/mg protein) | Measured during each test session prior to drug administration, and at 2 and 4 hours after drug administration | 
| Change in peripheral levels of pituitary adenylate cyclase-activating peptide (PACAP) | Change from baseline during each test day (pg/mg protein) | Measured during each test session prior to drug administration, and at 2 and 4 hours after drug administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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psilocybin