Prophylactic Effects of Psilocybin on Chronic Cluster Headache (EPOCH)

Prophylactic Effects of Psilocybin on Chronic Cluster Headache: an Open-label Clinical Trial and Neuroimaging Study

The purpose of this study is to investigate the prophylactic effects of psilocybin in chronic cluster headache. Subjects will receive a low dose of psilocybin during 3 sessions spaced by one week. Subjects will maintain a headache diary prior to, during, and after the administrations in order to document headache frequency, intensity and duration. Subjects will undergo a fMRI scanning before the first and after the last psilocybin session.

Study Overview

• Status: Terminated
• Conditions: Cluster Headache
• Intervention / Treatment: Drug: Psilocybin

Detailed Description

Cluster headache (CH) is one of the most painful conditions known. CH affects 1 out 1000 and exists in two well-defined forms: episodic (ECH) and chronic (CCH). Ten to fifteen percent of patients have CCH and have less than three months of pain-free time during a year. Medical treatment for CH is divided into acute abortive treatment for the single attack and a prophylactic treatment. The most commonly used prophylactic, verapamil, decreases attack frequency but does not induce remission and very high doses are needed. Although most therapeutic options ameliorate CH, they may be problematic due to major side effects, unsatisfactory treatment response or availability. Thus, novel treatment options are needed. According to several studies, patients that self-medicate with low doses of the serotonin 2A receptor (5-HT2AR) agonist and psychedelic psilocybin report that this is effective as CH prophylaxis or even to induce remission. So far, no clinical trials to confirm this have been conducted, nor is there any objective measures of brain function in association with psilocybin intake in CH. There is, however, already some evidence from functional magnetic resonance (fMRI) imaging studies suggesting that CH patients have abnormal functional connectivity patterns involving the hypothalamus and distributed brain networks, but the implication of these abnormalities is unknown.

The investigators are conducting a prospective pilot study, evaluating prophylactic effects of psilocybin in CCH using an open-label study design. They're also going to investigate psilocybin's active metabolite psilocin and brain function (fMRI) to identify possible brain mechanisms underlying CCH and treatment response, including the correlation of treatment response with psilocin levels and estimated 5-HT2AR occupancy and the extent to which brain network changes are affected by psilocybin and correlated with treatment response.

Effects of psilocybin on headache frequency, duration and intensity will be assessed in a sample of 20 patients with CCH. Participants will fill out headache logs during the entire study period, in total 10 weeks. Before study inclusion, participants taking prophylactic medication will first go through a 2-week wash-out period to allow for elimination of the medicine. Inclusion is followed by a baseline observation period lasting four weeks, after which patients will first undergo a baseline rs fMRI scanning followed by the first dose of 0.14 mg/kg psilocybin p.o. Blood samples will be collected during the first psilocybin intervention to establish psilocin plasma concentrations, which will be used for estimating receptor occupancy. Participants will then undergo two additional psilocybin administrations spaced by one-week. The last psilocybin dose will be followed by 4 weeks of observation. One week after the last administration of psilocybin, participants will undergo a follow-up MRI scan. Participants will be contacted 3, 6 and 12 months after the last psilocybin dose to gain information about the duration of potential remission periods. All regular acute treatments are permitted during the study period and a systematic record hereof has to be noted in the headache diary. No other prophylactic medication is allowed during the trial and at least a two-week washout period before inclusion is required. Prophylactics are allowed again after the 4 weeks follow-up, with dose and type carefully recorded. Participants will fill out questionnaires during the observation period, in conjunction with psilocybin interventions and at follow-up.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Neurobiology Research Unit, Rigshospitalet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age between 18 and 65
• A diagnosis of chronic cluster headache according to IHCD-III.
• Ability to separate cluster headache attacks from other types of headache.
• A history of at least 4 attacks/week in the last 4 weeks before inclusion

Exclusion Criteria:

• A history of using a serotonergic hallucinogen for CH.
• Participation in any clinical trials within 30 days preceding study enrollment.
• Use of other prophylactic CH medication within the last two weeks.
• Current use of drugs suspected to interfere with treatment (e.g. antipsychotic medication) or to be hazardous in combination with psilocybin.
• Presence of other trigeminal autonomic cephalalgias.
• Known hypersensitivity/allergy to multiple drugs (including psilocybin).
• A history or presence of any medical and psychiatric condition that might render patient unsuitable for participation.
• Present or previous manic or psychotic disorder or critical psychiatric disorder.
• Current drug or alcohol abuse.
• MRI Contraindications.
• Pregnancy or breastfeeding
• Not using safe contraception (if fertile woman)
• Stroke (<1 year from inclusion)
• Myocardial infarction (<1 year from inclusion)
• Hypertension (> 140/90 mmHg at inclusion)
• Clinically significant arrhythmia (<1 year from inclusion)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Psilocybin	Drug: Psilocybin; 0.14 mg/kg p.o. in three sessions spaced by one week

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Headache frequency	Change in headache frequency in number of attacks/week	Week 6-10 (post drug observation) compared to week 0-4 (baseline observation)
Resting state FC fMRI analyses	Resting state FC fMRI analyses, including hypothalamic FC, comparing baseline and rescan, comparison with healthy control sample, and evaluation of correlation between headache frequency changes and FC changes.	Day 1 of first psilocybin session to 1 week after last psilocybin session (3 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of reduced frequency	Proportion of patients with a 50% reduction in headache frequency	Week 6-10 (post drug observation) compared to week 0-4 (baseline observation)
Headache intensity	Change in average headache intensity of attacks (0-10 on Visual Analog Scale (VAS), where 0 is no pain and 10 is worst pain imaginable)	Week 6-10 (post drug observation) compared to week 0-4 (baseline observation)
Need of acute therapy	Number of attacks requiring acute therapy	Week 6-10 (post drug observation) compared to week 0-4 (baseline observation)
Sideeffects	Proportion of patients experiencing serious side effects	Whole observation period (10 weeks)
Remission	Proportion of patients with remission lasting more than 1 month	Day 1 after first psilocybin session until 12 month follow up (1 year).
Remission duration	Duration of induced remission (number of weeks)	Day 1 after first psilocybin session until 12 month follow up (1 year).
SF-36	Quality of life assessed by questionnaires: The Short Form (36) Health Survey. SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. A score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.	Week 6-10 (post drug observation) compared to week 0-4 (baseline observation)
Preferred treatment	Proportion of patients that prefers to continue with psilocybin if this was an option or want to return to usual prophylactics.	Whole observation period (10 weeks)
Mood	Changes in mood measured be the POMS questionaire.	Pre-psilocybin (week 1 and 5) vs post-psilocybin (week six and eight).
Sleep quality	Sleep quality measured by the PSQI questionaire.	Pre-psilocybin (week 1 and 5) vs post-psilocybin (week six and eight).
Depressive symptoms	Depressive symptoms measured by the MDI questionaire.	Pre-psilocybin (week 1 and 5) vs post-psilocybin (week six and eight).
Stress	Perceived stress measured by the PSS questionaire.	Pre-psilocybin (week 1 and 5) vs post-psilocybin (week six and eight).

Collaborators and Investigators

• Sponsor: Gitte Moos Knudsen
• Investigators: Study Chair: Gitte Moos Knudsen, MD, DMSc, Neurobiology Research Unit, Rigshospitalet

Publications and helpful links

Helpful Links

• Online preprint of the outcome of the study. Positive!

Study record dates

Study Major Dates

• Study Start (Actual): January 21, 2020
• Primary Completion (Actual): November 1, 2020
• Study Completion (Actual): June 1, 2022

Study Registration Dates

• First Submitted: February 12, 2020
• First Submitted That Met QC Criteria: February 19, 2020
• First Posted (Actual): February 21, 2020

Study Record Updates

• Last Update Posted (Actual): August 10, 2022
• Last Update Submitted That Met QC Criteria: August 8, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Treatment; Psilocybin; Hallucinogens; Cluster Headache; Prophylactic
• 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: H-18040896

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Via database of Center for integrated Molecular Brain Imaging (CIMBI) data will be available for neuroscience research community contingent on approval by scientific board.

Drug and device information, study documents

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