Effects of Psilocybin in Concussion Headache

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

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.

Study Overview

• Status: Terminated
• Conditions: Post-Traumatic Headache
• Intervention / Treatment: Drug: Placebo oral capsule; Drug: Low Dose Psilocybin; Drug: High Dose Psilocybin

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Mackenzie Creighton, BS; Phone Number: 2526 203-932-5711; Email: mackenzie.creighton@yale.edu
• Study Contact Backup: Name: Emmanuelle Schindler, MD, PhD; Phone Number: 4335 203-932-5711; Email: emmanuelle.schindler@yale.edu

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 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

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

What is the study measuring?

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
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 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)
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
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 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

Collaborators and Investigators

• Sponsor: Yale University

Study record dates

Study Major Dates

• Study Start (Actual): March 28, 2019
• Primary Completion (Actual): June 27, 2023
• Study Completion (Actual): June 27, 2023

Study Registration Dates

• First Submitted: January 14, 2019
• First Submitted That Met QC Criteria: January 14, 2019
• First Posted (Actual): January 16, 2019

Study Record Updates

• Last Update Posted (Actual): October 12, 2023
• Last Update Submitted That Met QC Criteria: October 11, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: psilocybin
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Headache Disorders; Headache Disorders, Secondary; Headache; Post-Traumatic Headache; Physiological Effects of Drugs; Psychotropic Drugs; Hallucinogens; Psilocybin
• Other Study ID Numbers: 1607018057.B

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No