CCH attack frequency reduction after psilocybin correlates with hypothalamic functional connectivity

This open-label study (n=10) finds that three moderate doses of psilocybin (10mg/70kg) significantly reduced the frequency of chronic cluster headaches (CCH). On average, the frequency was reduced by 30%. One participant was free from CCHs for 21 weeks.

Abstract of CCH attack frequency reduction after psilocybin correlates with hypothalamic functional connectivity

“Objective To evaluate the feasibility and prophylactic effect of psilocybin as well as its effects on hypothalamic functional connectivity (FC) in patients with chronic cluster headache (CCH).

Background CCH is an excruciating and difficult-to-treat disorder with incompletely understood pathophysiology, although hypothalamic dysfunction has been implicated. Psilocybin may have beneficial prophylactic effects, but clinical evidence is limited.

Methods In this small open-label clinical trial, 10 patients with CCH were included and maintained headache diaries for 10 weeks. Patients received three doses of peroral psilocybin (0.14 mg/kg) on the first day of weeks five, six, and seven. The first 4 weeks served as baseline and the last 4 weeks as follow-up. Hypothalamic FC was determined using functional magnetic resonance imaging the day before the first psilocybin dose and 1 week after the last dose.

Results The treatment was well tolerated. Attack frequency was reduced by mean (standard deviation) 31% (31) from baseline to follow-up (pFWER = 0.008). One patient experienced 21 weeks of complete remission. Changes in hypothalamic–diencephalic FC correlated negatively with a percent change in attack frequency (pFWER = 0.03, R = −0.81), implicating this neural pathway in treatment response.

Conclusion Our results indicate that psilocybin may have prophylactic potential and implicates the hypothalamus in possible treatment response. Further clinical studies are warranted.”

Authors: Martin K. Madsen, Anja Sofie Petersen, Dea S. Stenbæk, Inger Marie Sørensen, Harald Schiønning, Tobias Fjeld, Charlotte H. Nykjær, Sara Marie Ulv Larsen, Maria Grzywacz, Tobias Mathiesen, Ida L. Klausen, Oliver Overgaard-Hansen, Kristoffer Brendstrup-Brix, Kristian Linnet, Sys S. Johansen, Patrick M. Fisher, Rigmor H. Jensen & Gitte M. Knudsen

Summary pf CCH attack frequency reduction after psilocybin correlates with hypothalamic functional connectivity

In a small open-label study, three low-to-moderate doses of psilocybin were administered to patients with chronic cluster headache. The treatment was well-tolerated and without serious adverse reactions, and attack frequency was reduced by 30% from baseline to follow-up.

Cluster headache (CH) is one of the most painful conditions known, and affects 0.1% of the population. A small open-label study evaluated the feasibility and prophylactic effects of psilocybin in patients with CCH, and assessed the association of treatment response with hypothalamic functional connectivity.

Ten patients with a verified diagnosis of CCH received a moderate dose of peroral psilocybin, spaced by seven days. They reported daily headache attacks and average pain intensity, and were followed up three and six months after the study.

Nine patients completed all three psilocybin treatments, and one patient reported complete absence of psychoactive effects of psilocybin. Psilocybin induced variable acute subjective psychoactive effects, but was not associated with changes in blood pressure.

We observed a statistically significant reduction in headache frequency and self-rated pain intensity after psilocybin treatment, and the patients used acute therapy for their attacks at the overall same rate during follow-up and baseline.

We investigated effects on hypothalamic functional connectivity (FC) by analyzing MRI data from baseline and follow-up. We found no significant associations for the remaining three FC estimates, and no significant change in FC from baseline to follow-up.

We observed substantial interindividual variability in psilocybin concentration and area under the curve, and no significant associations between psilocybin concentration and change in attack frequency or pain intensity. Psilocybin therapy may constitute a valuable therapeutic option in some patients with chronic cluster headache.

Previous studies on psilocybin CH have not specifically reported on reduced pain intensity. Our study observed a 13% reduction in pain intensity.

One patient reported no subjective psychoactive effects of psilocybin, but still reported a reduction in headache frequency of 22% from baseline to the follow-up, indicating a possible prophylactic effect even in the absence of psychoactive effects.

Psilocybin has a favorable safety profile, but serious negative health-related outcomes have been observed in non-clinical settings.

Our study is not without limitations, including that we only included ten patients and did not employ a placebo-control condition. Further, the included patients were relatively treatment refractory to standard prophylactic treatment.

Psilocybin treatment decreased attack frequency and pain intensity in patients with chronic headache. Changes in hypothalamic-diencephalic functional connectivity correlated negatively with percent change in attack frequency.

Ten patients with a verified diagnosis of CCH were recruited from Danish Headache Center, Glostrup Hospital, Denmark, and completed the study.

Inclusion criteria were: age 18-65 years, diagnosis of CCH according to IHCD-III, ability to separate cluster headache attacks from other types of headache, history of at least 4 attacks per week in the last 4 weeks before inclusion, and no history of using a serotonergic hallucinogen for CH. All patients were thoroughly informed about the study and underwent a medical examination. Eleven patients were included in the study.

After study inclusion, patients completed an online headache logbook daily for ten weeks. They underwent three psilocybin treatments spaced by one week, and were contacted by phone after three and six months to obtain information of potential remission duration and perception of the psilocybin treatment. Psilocybin dose was determined based on body weight at inclusion (0.14 mg psilocybin per kg bodyweight), and patients were asked to limit food and caffeine on the morning of all treatment days. Psilocybin produced high psilocin occupancy at cerebral 5-HT2ARs while still having limited psychoactive effects.

Plasma psilocin concentration was determined using ultra high performance liquid chromatography and tandem mass spectrometry. The internal standard was psilocin-d10, and the reconstitution mixture contained 1 mM ascorbic acid.

Magnetic resonance imaging (MRI) data was acquired using a 32-channel head coil on a 3T Siemens Prisma scanner. BOLD fMRI data was acquired using a T2*-weighted gradient echo-planar imaging (EPI) sequence and a high-resolution, T1-weighted 3D structural MP-RAGE image was also acquired during each scan session.

Image preprocessing included unwarping, realignment, co-registration, segmentation of structural image and normalization to Montreal Neurological Institute (MNI) space. 15 regions were selected for structural regional analysis, and cortical thickness and grey matter volume were extracted for each region.

Functional connectivity analysis was performed on BOLD images using CONN (v17c). Seven networks were identified using FC estimates within and between the posterior hypothalamus, default mode, ventral attention, dorsal attention, fronto-parietal control, visual, limbic, and somatomotor.

The primary outcome was change in CH attack frequency per week and the secondary outcome was change in average pain intensity. Statistical analyses were conducted using the Wilcoxon-signed-rank test.

Psilocybin effects on brain structure and function were evaluated by evaluating change from baseline to follow-up and by evaluating the correlation between percent change in attack frequency and change in neuroimaging outcome.

We explored the dose-response relation between psilocin and percent change in attack frequency and pain intensity, using linear regression.

Study details

Compounds studied

Topics studied
Pain Headache Disorders

Study characteristics
Original Open-Label

10 Humans


Authors associated with this publication with profiles on Blossom

Martin Madsen
Martin Korsbak Madsen is a medical doctor, whose research utilizes PET and fMRI to gain a better understanding of psilocybin brain effects. His main research areas involve multimodal neuroimaging using PET and fMRI to investigate the effects of 5-HT2AR modulation using the classic psychedelic psilocybin and the antagonist ketanserin.

Gitte Knudsen
Gitte Moos Knudsen is the Chair Professor at the Neurology and Neurobiology Research Unit, Copenhagen University Hospital, and director of the Center for Experimental Medicine Neuropharmacology (NeuroPharm).

Compound Details

The psychedelics given at which dose and how many times

Psilocybin 10 - 10
mg | 3x

Linked Clinical Trial

Prophylactic Effects of Psilocybin on Chronic Cluster Headache
This study aims to investigate the prophylactic effects of psilocybin in chronic cluster headaches. Subjects will receive a low dose of psilocybin during three sessions spaced over one week. Subjects will maintain a headache diary prior to, during, and after the administrations to document headache frequency, intensity and duration. Subjects will undergo an fMRI scanning before the first and after the last psilocybin session.

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