Psilocybin for the Treatment of Cluster Headache

Safety and Efficacy of Psilocybin for the Treatment of Headache Disorders

The purpose of this study is to investigate the effects of an oral psilocybin pulse regimen in cluster headache. Subjects will be randomized to receive oral placebo, low dose psilocybin, or high dose psilocybin in three experimental sessions, each separated by 5 days. Subjects will maintain a headache diary prior to, during, and after the pulse regimen in order to document headache frequency and intensity before, during, and after the pulse regimen. After at least 6 months from the last experimental session, subjects may be invited for a second round, in which they will be randomized to receive either low dose or high dose psilocybin.

Study Overview

• Status: Completed
• Conditions: Cluster Headache
• Intervention / Treatment: Drug: 0.143 mg/kg Psilocybin or 10 mg Psilocybin; Drug: 0.0143 mg/kg Psilocybin or 1 mg Psilocybin; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 25
• 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:

• Chronic cluster headache with at least one attack daily
• Episodic cluster headache with periods that are predictable and have a duration of approximately 2 months
• Attacks are managed by means involving no more than twice weekly triptan use (e.g., high-flow oxygen, heat/cold pack)

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, lysergic acid diethylamide (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 five half-lives of test days
• Use of serotonergic antiemetics (i.e. ondansetron) in the past 2 weeks
• Use of antidepressant medications (i.e. amitriptyline, isocarboxazid, fluoxetine, citalopram) 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: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Microcrystalline cellulose capsule ingested on each of three test days (5 days apart +/- 1-2 days)
Active Comparator: Psilocybin High Dose	Drug: 0.143 mg/kg Psilocybin or 10 mg Psilocybin; 0.143 mg/kg psilocybin capsule (weight-based option) or 10 mg psilocybin capsule (fixed-dose option) ingested on each of three test days (5 days apart +/- 1-2 days)
Active Comparator: Psilocybin Low Dose	Drug: 0.0143 mg/kg Psilocybin or 1 mg Psilocybin; 0.0143 mg/kg psilocybin capsule (weight-based option) or 1 mg psilocybin (fixed-dose option) ingested on each of three test days (5 days apart +/- 1-2 days)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to first attack after completion of pulse regimen	Measured in days	Two months following the completion of pulse regimen (after completion of experimental sessions 1, 2, and 3)
Time to last attack after completion of pulse regimen	Measured in days	Six months following the completion of pulse regimen (after completion of experimental sessions 1, 2, and 3)
Change in frequency of attacks	Average number of attacks (number per week)	Measured from 2 weeks before to 2 months after completion of pulse regimen using a headache diary
Change in intensity of attacks	Average intensity of attacks (1-10 on visual analog scale)	Measured from 2 weeks before to 2 months after completion of pulse regimen using a headache diary
Change in duration of attacks	Average duration of attacks (minutes)	Measured from 2 weeks before to 2 months after completion of pulse regimen using a headache diary
Change in cluster period duration compared to typical cluster period (episodic subjects only)	Duration of cluster period after intervention (days)	Measured from 2 weeks before pulse regimen to 6 months following the completion of pulse regimen, then comparing to historical average duration of cluster periods
Difference in the change in cluster attack frequency between 1st and 2nd round	Average number of attacks (number per week); only in those subjects who return for 2nd round	Measured from 2 weeks before to 2 months after completion for each of the two pulse regimens using a headache diary
Difference in the change in cluster attack intensity between 1st and 2nd round	Average intensity of attacks (1-10 on visual analog scale); only in those subjects who return for 2nd round	Measured from 2 weeks before to 2 months after completion for each of the two pulse regimens using a headache diary
Difference in the change in the duration of attacks between 1st and 2nd round	Average duration of attacks (minutes); only in those subjects who return for 2nd round	Measured from 2 weeks before to 2 months after completion for each of the two pulse regimens using a headache diary

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Use of abortive/rescue medication	Number of times per week	Measured from 2 weeks before to 2 months after completion of pulse regimen using a headache diary
Attack-free time	Number of 24 hour days (may be nonconsecutive)	Measured from 2 weeks before to 2 months after completion of pulse regimen using a headache diary
Health-Related Quality of life	Using the CDC's Health-Related Quality of Life (HRQOL) scale	Measured from 2 weeks before to 2 months after completion of pulse regimen using a headache diary
Psychedelic effects	Using the 5-Dimensional Altered States of Consciousness (5D-ASC) scale	Taken daily on each experimental day after the resolution of psychedelic effects, approximately 6 hours after drug administration
Change in blood pressure	Maximum change from baseline during each experimental session (mmHg)	Measured during each experimental session prior to drug administration, every 15 min in the first hour after drug administration, 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 experimental session (beats per minute)	Measured during each experimental session prior to drug administration, every 15 min in the first hour after drug administration, 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 experimental session (SpO2)	Measured during each experimental session prior to drug administration, every 15 min in the first hour after drug administration, every 30 min in the second hour, and then hourly for 4 hours or until resolution of psychedelic effects (~6 hours post drug)

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: Heffter Research Institute; Ceruvia Lifesciences; CH TAC LLC

Study record dates

Study Major Dates

• Study Start (Actual): December 5, 2016
• Primary Completion (Actual): June 30, 2022
• Study Completion (Actual): October 21, 2022

Study Registration Dates

• First Submitted: November 11, 2016
• First Submitted That Met QC Criteria: November 30, 2016
• First Posted (Estimated): December 5, 2016

Study Record Updates

• Last Update Posted (Actual): December 15, 2023
• Last Update Submitted That Met QC Criteria: December 8, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Headache Disorders, Primary; Headache Disorders; Trigeminal Autonomic Cephalalgias; Headache; Cluster Headache; Physiological Effects of Drugs; Psychotropic Drugs; Hallucinogens; Psilocybin
• Other Study ID Numbers: 1607018057

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No