Promising Signs for Psychedelic Use in Cluster Headache

By Lincoln Tracy | February 27, 2023 | Posted in

A small study finds that low-dose psilocybin was safe and had a moderate effect size, though results did not reach statistical significance.

Cluster headache is a rare disorder in which pain is so severe that the condition is sometimes referred to as “suicide headache.” Knowledge of cluster headache is inadequate, and treatment options are limited, driving patients to use untested and unapproved therapies. That includes psychedelics – the focus of a new clinical trial that now provides valuable information to help guide the development of larger trials in this area.

The study, led by Emmanuelle Schindler, VA Connecticut Healthcare System, West Haven, US, and Yale School of Medicine, New Haven, US, found that low-dose psilocybin, in 14 patients with cluster headache, resulted in an average of three fewer headache attacks per week, compared to placebo. Though the difference between groups was not significant, the small size of the study, along with a host of other factors, might explain that outcome.

The research – the first controlled investigation of psilocybin in cluster headache – also found that the psychedelic had a moderate effect size and appeared safe.

Martin Madsen, who studies the effects of psychedelics using brain imaging at Copenhagen University Hospital, Rigshospitalet, Denmark, but who was not involved in the current work, was unfazed that the results did not reach statistical significance and instead pointed toward several positives.

“It’s important to note that the psilocybin treatment seemed to be safe. There were no severe side effects or adverse reactions, and the side effects that were observed were mild and somewhat expected,” he said.

“It also seemed like there might be a real treatment effect, in terms of the effect size. This lends some credence to the notion that it would be sensible to go forward with a larger study.”

The research appeared in the November 2022 edition of Headache.

Rediscovering a long history
Cluster headache affects approximately 0.1% of the global population and is characterized by ipsilateral headache attacks that cause pain in the orbital, supraorbital, or temporal head regions. In most patients, the headaches come on in groups (clusters) at the same time every year, lasting several weeks or months; this is known as episodic cluster headache. Other patients have headaches year-round, which is referred to as chronic cluster headache.

Although there are several treatments for cluster headache, some patients report no benefit from them, and intolerable side effects are common. In the search for new and effective therapies, researchers, clinicians, and patients are turning to psychedelic substances such as psilocybin, a psychedelic found in certain types of mushrooms, and lysergic acid diethylamide (LSD).

Schindler began studying the pharmacology of psychedelics in animal and tissue models during graduate school before learning of their clinical effects in headache disorders while writing her thesis. As she progressed through medical school, she developed an interest in headache medicine, which would soon join up with her earlier interest in psychedelics.

It was the familiarity of the cluster headache community with the long-lasting effects of psychedelics that particularly piqued Schindler’s passion for further study of these substances in this patient cohort.

“For the past 25 years, cluster headache patients have been self-managing their disease with psychedelics and reporting long-lasting effects after very limited drug dosing. Until now, this knowledge has largely remained within the cluster headache community. More recently, as clinical psychedelic research has re-emerged and the media has spotlighted psychedelics, the long history of psychedelics in headache has been rediscovered,” she wrote to Migraine Science  Collaborative in an email.

Schindler and colleagues previously reported that psilocybin significantly reduced the number of self-reported weekly migraine days (a mean decrease of 1.65 days/week), compared to placebo (a mean decrease of 0.15 days/week). That small, exploratory, proof-of-concept study, which included 10 patients in its final analysis, also found that 80% of participants reported at least a 25% reduction in weekly migraine days after receiving psilocybin, and that the treatment was safe.

Putting psilocybin to the test in cluster headache
Building upon these promising early findings with migraine, Schindler and colleagues recruited people with episodic or chronic cluster headache who experienced at least one attack per day; 14 people (six placebo, eight psilocybin, with a mean age of 49.1 years) were included in the final analysis, including five females. Study participants could have previously used psilocybin or related products but not in the three months prior to the trial.

Participants kept a headache diary starting two weeks before the first of three experimental sessions (as a baseline) and continuing through eight weeks after the first session. They documented the date, duration, and pain intensity of each cluster attack.

In each session, participants received small, weight-based doses of psilocybin (0.143 mg/kg, eight participants) or a placebo (six participants) in identical blue gelatin capsules. On average, those in the active treatment group received 10.6 mg of psilocybin in each session, separated by three to seven days.

The investigators did not define any single outcome a priori, but placed emphasis on the frequency of cluster headache attacks, particularly the change in the number of weekly attacks during the three weeks after the start of psilocybin, compared to baseline levels. The team also collected information about changes in attack duration and pain intensity; general drug effects including anxiety, sleepiness, and nausea; psychedelic ratings including audiovisual synesthesia, disembodiment, and vigilance reduction; and adverse events.

Psilocybin reduced the frequency of headache attacks in the three weeks after treatment commenced (a mean change of 3.2 fewer attacks per week) compared to placebo (a mean change of 0.03 more attacks/week), though the difference was not statistically significant. The effect size was 0.69, which is considered moderate.

Delving a bit deeper, the researchers found a large effect size (1.25) in those with chronic cluster headache, and a small effect size (0.35) in people with episodic cluster headache. No significant differences were observed for attack duration or pain intensity.

Notably, no serious or unexpected adverse events were reported following psilocybin administration, although participants did report experiencing nausea, anxiety, and fatigue during the experimental sessions. And, importantly, the effects of psilocybin on attack frequency were not associated with the intensity of acute psychotropic effects on experimental test days.

“Despite not reaching a significant p-value, I was pleased to see an approximately 30% reduction in cluster attack frequency. When you dig deeper into the data, it wasn’t simply a 30% reduction across the board, but rather, some patients in the study responded while others did not. Those who were psilocybin responders had about a 75% reduction in cluster attack frequency. Just like any medicine out there for cluster headache, migraine, or any other headache disorder, nothing is going to work for everyone,” according to Schindler.

Consistency with another study
The current results are in some ways consistent with findings reported by Madsen and colleagues in a preprint published in medRxiv last year. In that small open-label study, 10 individuals with chronic cluster headache (with a mean age of 49.4 years, and including five females) reported a 30% reduction in attack frequency from baseline to follow-up, after a similar psilocybin dosing regimen.

That study also found, based on brain MRI findings, that the reduction in attack frequency correlated with changes in hypothalamic functional connectivity with other brain regions, suggesting a neural pathway that may be involved in the treatment response. Functional connectivity refers to how different regions of the brain interact with each other, with regard to functional properties.

“The preprint results are fantastic, particularly the change in functional connectivity in the hypothalamus, which is a key brain region in cluster headache,” Schindler wrote MSC.

“It was also nice to see that the overall reduction in attack frequency was similar to that in my study (about 30%). Even though our studies were designed differently, this replication supports the reliability of the research,” she added.

Reason for optimism
A number of factors, such as the small size of the current study, could account for the absence of a significant finding with regard to efficacy.

“As a researcher, I get the sense there is this media hype around psychedelic drugs, which seems to increase patients’ expectations of what might occur,” Madsen said. “In addition, you know whether you received psilocybin, because it’s psychedelic in nature; you have psychedelic effects, even with the relatively low dose used in the current study,” he explained.

“So, participants are unblinded to a large extent. If people know they’re getting psilocybin and have high expectations, then you might see a pronounced placebo or expectation effect. Similarly, the people who get placebo might be disappointed that they didn’t get psilocybin, so you might see a nocebo or disappointment effect,” according to Madsen.

Schindler continues to test the effects of psilocybin, with further studies in cluster headache, migraine, and post-traumatic headache underway. “There is a lot more work to be done,” she said.

“We’re currently wrapping up an extension phase of the cluster headache study where patients come back for a second round of treatment. Most headache preventives don’t work immediately when they are started; it takes time for them to work, and if they are dosed intermittently (e.g., galcanezumab [an anti-CGRP antibody]), it may take a couple of rounds before effects are seen. This could also be the case with psilocybin in cluster headache,” she wrote to MSC.

“I also have a migraine study looking at the difference between a single drug administration versus two administrations one week apart. This study seeks to understand whether this double dosing extends the long-lasting suppression of the disease,” she added.

Schindler is also exploring circadian rhythm, sleep, inflammation, and brain structure and function as potential mechanistic targets of psilocybin.

Madsen, who does not have additional studies planned at this time, agrees it is important for this relatively immature research field to continue to grow and develop.

“There’s ample room to go forward with research, in terms of brain mechanisms,” he said. “We can understand the differential treatment effect of psychedelics through neuroimaging methods to get a better understanding of the underlying mechanisms.”

Lincoln Tracy is a researcher and freelance writer from Melbourne, Australia. You can follow him on Twitter @lincolntracy.


Exploratory investigation of a patient-informed low-dose psilocybin pulse regimen in the suppression of cluster headache: Results from a randomized, double-blind, placebo-controlled trial.
Schindler et al.
Headache. 2022 Nov;62(10):1383-1394.

Exploratory controlled study of the migraine-suppressing effects of psilocybin.
Schindler et al.
Neurotherapeutics. 2021 Jan; 18(1): 534-43.

Psilocybin-induced reduction in chronic cluster headache attack frequency correlates with changes in hypothalamic functional connectivity.
Madsen et al.
medRxiv. 2022 Jul 10.


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Dr. Lincoln Tracy is a researcher and freelance writer from Melbourne, Australia. As a researcher, he uses data from an international clinical quality registry to explore burn injuries in Australia and New Zealand. As a freelance writer, he turns basic, translational, and clinical research into high-quality news, features, interviews, meeting reports, and podcasts. As a person, he is one half of one of two sets of twins in his family. Follow him on Twitter @lincolntracy.



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