Silencing the Storm: Could Psychedelics Change How We Treat Migraine and Cluster Headache?

Ainslie Course’s first reckoning with cluster headache began with a violent pain that seared through her head in the hours before dawn. “I was convinced that I was dying,” she says. “I thought I must have a brain tumor, or something seriously wrong in my head to cause this level of extreme, agonizing pain.”

Course, then 19, was enduring an experience said to be more painful than being shot or giving birth. More than 30 years later, she has persevered through misdiagnosis, failing treatments and countless bouts of lightning-sharp cluster attacks, which arrive in predictable, seasonal patterns. At their worst, the attacks persist daily for up to eight months, despite regular dosing with the limited therapies available.

But now, she has a new tool in her fight against clusters. When she feels an attack coming on, she puts on a jacket, steps out into the woodlands near her house in central Scotland with her two dogs, Lhasa Apso Poppy and Chihuahua Coco, and ingests a dose of psychedelic mushrooms.

Categorizing clusters

When Course first started having attacks, appointments with physicians proved fruitless. “Because of my age, and the fact that I was female, they were convinced that what I had was a migraine,” she explains. Course’s clusters went misdiagnosed for 15 years.

Why did these medical professionals jump to the wrong conclusion? The answer may lie in the epidemiology of Course’s condition. Cluster headaches affect just 0.1% of the population, while migraine affects nearly 1 in 5 US women. “Migraine is more common than many people realize,” says Sara Crystal, medical director at Cove, a private health service set up to offer migraine-focused treatments.

Now, emerging clinical trial data suggest that the same psychedelic compounds that Course has self-medicated with could also benefit both the millions of migraineurs and thousands of “clusterheads” who find limited benefit from even gold-standard treatments.

Migraine and cluster headaches are both grouped under an umbrella of headache disorders, but upon closer inspection, they have little in common. Once you look more carefully at how these two conditions affect our bodies, it’s a surprise they even share treatment options. “Migraine and cluster headaches are very different animals,” says Emmanuelle Schindler, a researcher at Yale University. Schindler is a co-author of trials investigating the efficacy of psychedelics for both conditions.

The miserable history of headache

Migraine has a long and storied history of inflicting misery on humanity. In his 1970 book Migraine, neurologist Oliver Sacks writes that “the major clinical characteristics of migraine … had all been clearly recognized by the second century of our era.” Aretaeus of Cappadocia, a famed Greek physician, described migraine under the name heterocrania, which he called “a disease by no means mild … it occasions unseemly and dreadful symptoms.” Aretaeus correctly noted that migraine has a pathology much broader than its primary feature – a pounding, throbbing ache usually affecting one side of the head – on sufferers. Nausea, diarrhea and cognitive symptoms are all noted as sequelae of the condition. Aretaeus also wrote of the condition’s photophobic effect on migraineurs. “For they flee the light, the darkness soothes their disease.”

Migraine patients often only find relief in quiet, dark settings – sometimes sleep can alleviate symptoms. Paul Durham, director of cell biology at the Center for Biomedical and Life Sciences at Missouri State University, says that a popular theory of migraine suggests its origin lies in the flow of blood to the head, pointing to genome-wide association studies that have implicated cardiovascular genes in migraine risk. This is a hotly debated area, however, as some researchers say that the efficacy of newer therapies instead positions migraine as a condition that begins in the brain rather than the blood vessels outside it.  

Cluster headache, by comparison, manifests around the ophthalmic zone near the eye. Attacks can last anywhere from 15 to 180 minutes per day and often appear rapidly, but in predictable patterns that are circadian or circannual. Course’s clusters appear seasonally, with the change into spring and autumn heralding the attacks. The uniquely excruciating quality of cluster pain has seen them dubbed “suicide headaches” – a 2019 study found that nearly 65% of cluster patients had thoughts of killing themselves during attacks. While migraine patients find comfort in stillness when in a cluster, many patients rock themselves or pace constantly during attacks. While most cluster patients have episodic disease with significant periods of remission, 15–20% of patients have chronic cluster headaches where attacks can recur for over a year with little relief. 

How to treat a headache disorder

Despite these very different disease features, modern medicine offers migraineurs and cluster patients similar pharmacological options. Triptans are the current leading class of headache drug. First introduced in the 1990s, these compounds are taken after an attack has come on with the aim of shortening its duration – an abortive treatment – rather than preventing their onset altogether. The class includes the current gold-standard headache treatment sumatriptan, which can bestow relief in as little as 10 minutes. Interestingly, triptans do not relieve other types of pain.   

Triptans’ exact mechanism of action in migraine isn’t certain – which has caused much gnashing of teeth among competing academic theory proponents – but likely lies in how they affect blood flow in the brain. These compounds bind to serotonin receptors that line blood vessels leading to the head. This binding constricts the vessels which dilate during a migraine. They are also thought to tamp down the release of protein molecules, called peptides, that induce dilation. One of those peptides is called calcitonin gene related peptide (CGRP), which is the target of some of the newest treatments for migraine, called anti-CGRP therapies. Triptans also bind to serotonin receptors across the nervous system, both within and outwith the brain and spinal cord.

While migraine pain typically occurs on one side of the head, cluster pain is centered around one eye. Credit: Technology Networks

As for other treatments, Durham keeps an open mind; for those taking triptans already, he points to lifestyle modifications: “When I talk to migraineurs, I want to know how they are sleeping, I want to know if they are exercising and what they are eating,” he says. Crystal additionally mentions that some patients have found relief with Botox injections, while solutions on the market have involved glasses that screen out certain types of light, herbal supplements and even acupuncture. The reason for this proliferation of options is that for up to a third of migraine patients, triptans fail to reduce attacks or produce side effects that make the drugs intolerable.

There’s a similar need among the cluster community. A survey study of over 2,000 cluster patients rated the efficacy of various treatments, putting triptans, alongside oxygen therapy, at the top of the pile. Nevertheless, even these options were only rated as completely or very effective by 54% of patients. Some patients, including Course, find that compounds that are initially helpful start to lose their efficacy over time. By the turn of the century, she found her medication no longer brought relief. That’s when she met Bob Wold, the founder of the cluster headache non-profit Clusterbusters, and when she first started taking psychedelics.

Psychedelics’ links with headache

The recent explosion of interest in psychedelics has been centered around psychiatry. Using them to treat headaches is even counterintuitive – after all, these drugs can cause headaches in healthy users that get stronger the more drug is taken. But the entangled relationship between psychedelics and headache relief goes back more than 50 years. Harold Wolff, a professor of medicine at Cornell University, developed one of the first targeted migraine treatments, methysergide, in the 1950s. This drug had an excellent clinical effect but had the unexpected side effect of causing fibrous tissue to form inside the abdomen, which led to it being withdrawn from the US market just five years after it was introduced. Nevertheless, methysergide is also synthesized from lysergic acid, which can be tweaked to produce LSD.

Despite the immense pain of her attacks, Course wasn’t initially an enthusiastic convert to mind-altering compounds. “It took me probably close to 18 months before I was ready,” she says. “I'm just the kind of person who likes to know everything before I try something.” Worried about engaging with yet another kind of medication, Course talked to others in the cluster community who had dabbled with psychedelic treatments. One of those was Wold, who started an online forum to share what he felt were the miraculous effects of psychedelics on his clusters. At this time, the stigma against psychedelics was overwhelming. Roland Griffiths and colleagues at Johns Hopkins University had only just begun to receive small amounts of funding for psychedelic treatments, after a period of the mid-1990s where such research efforts almost dried up entirely. There was little public acceptance of the idea that psychedelics could be anything other than harmful. For Course and her fellow cluster patients, this meant sharing treatment ideas almost entirely underground.

When she eventually did decide to engage with a psilocybin-based treatment, Course used an approach that has become standard across the clusterbusters community – a body weight-adjusted dose every five days until the cluster breaks. For Course, the results have been transformative.  Attacks that used to persist for months now usually subside after 20 days. Course also credits psilocybin with a current two-year remission she has enjoyed, which is in sharp contrast to the regular biannual clusters she withstood for the last few decades. “That’s a huge difference for me,” she says.

Seeing through the psychedelic hype

However, if the value of psychedelics was purely accounted for in terms of anecdotal evidence, they would be the most-prescribed drug on Earth. In the midst of the current psychedelic research boom, internet discussions are awash with users attesting to the compounds’ utility in treating every malady imaginable. But for many people with treatment-resistant headache disorders, the barriers to accessing psychedelics, which remain illegal in most countries, are too great. “People are frightened to embark on this kind of treatment,” Course says. It’s only through the regulatory approval and licensing process that the full benefits of psychedelics for headache disorders can be assessed and realized. Schindler is leading the charge in this area.

A pair of small clinical trials released in 2021 and 2022 represents the first steps towards scientifically quantifying psychedelics for migraine and cluster headache respectively. Schindler, co-author on both studies, says that their initial evidence “supports the anecdotal findings” that Course and her fellow clusterbusters have crowed about for decades. In both populations, there was a reduction in disease burden. Migraineurs taking psilocybin saw an average reduction of 1.65 weekly migraine days after a single dose of psilocybin in comparison to placebo patients, who saw only a 0.15 days/week change. Cluster patients, who in Schindler’s study recorded roughly 9 cluster attacks per week, had a reduction of 3.2 attacks/week after taking the psychedelic and no change after taking placebo.

These initial results, while promising, must be taken in the context of the tiny sample sizes involved in the trials – just 16 and 10 participants completed the protocols in the migraine and cluster studies respectively – and the performance of currently available treatments for these conditions.

Recent trials for cluster headaches include those for the anti-CGRP antibody galcanezumab and vagus nerve stimulation (VNS), which applies an electrical current to one of the key nerves linking the body to the brain. These two treatments produced improvements in cluster symptoms comparable to that of psilocybin. Galcanuzumab game patients 3.7 fewer attacks per week on average, while VNS stimulation cut the figure by 3.9 attacks. But galcanezumab’s figure was taken from a far larger phase III trial of 106 patients, and both the galcanezumab and VNS trials featured patient cohorts who reported higher cluster burdens, averaging 17 attacks per week at baseline. Importantly, the primary improvement seen in Schindler’s cluster study results was not significant, which the authors attribute to a lack of statistical power, a common problem in small, exploratory studies. Furthermore, neither galcanezumab nor VNS produce hallucinations, which are significant barriers to home use of psychedelic treatments. Will the availability of strong rival treatment options and a broad side effect profile limit psychedelics’ usefulness?

Schindler says there are two pieces of compelling evidence that suggest otherwise. Firstly, psychedelics, at least for migraine, stand alone as the only available treatment option that can have an enduring effect after a single short-acting dose. “Current preventive medications have to be taken every day or they're injected but stay in your body for a whole month,” says Schindler. This hints at a completely novel therapeutic mechanism for psychedelic headache relief. Furthermore, in both trials, Schindler’s data made clear that patients didn’t have to undergo a deep hallucinatory experience to receive a clinical benefit. This finding stands in contrast to the research zeitgeist in psychedelic psychiatry, where mind-altering trips are largely thought to assist in any therapeutic benefit.

This latter finding opens up the possibility that serotonergic compounds that share psychedelics’ mechanism of action but have no hallucinatory effect (compounds dubbed psychoplastogens), could prove useful at-home headache relief options.

The next steps to beat headache

But that possibility can only be explored by conducting larger, more robust studies. Psychedelics – and the hallucinations they produce – remain problematic compounds to test in clinical trials, in which patients are meant to be unaware of whether they have received an active treatment or a placebo. Psychoplastogens could avoid this limitation but have never been tested in humans. Combine these difficulties with the challenges of testing on headache patients, who can have attacks irregularly or go through long periods with no symptoms, and traditional approval for these medications is likely to be a drawn-out process.

Course says she will continue Clusterbusters’ campaigning work to accelerate approval for psychedelic compounds in the context of headache trials. Her organization is supported by the cross-party Conservative Drug Policy Reform group, which pushes for political movement on the issue. Major UK political parties appear some distance from embracing reform in this area.

“Clusterbusters saved my life,” she says. “Am I still terrified of cluster headaches? Yes, absolutely. I will never be complacent about them. However, am I in a better place? Absolutely. I know that I am in control now. They used to control me.”