Headache Horizons: The Study and Use of Psychedelics in Cluster Headache

Cluster headache (CH) is a rare primary headache disorder characterized by paroxysmal attacks of unilateral severe orbital or periorbital pain. Also known as suicide headache, CH is said to be the most intensely painful condition known to humankind.¹ CH affects up to 0.1% of the population, with a significant male predominance. CH refers to the disorder; cluster attacks, to the paroxysms of head pain. People with episodic CH have pain attacks during cluster periods or cycles, which last from weeks to months. People with chronic CH have attacks year-round without a remission period (an extended attack-free period) for longer than 3 months.² Cluster attacks occur up to 8 times per day, each lasting for 15 to 180 minutes. Because of its severity and propensity to occur overnight, CH has deleterious effects on sleep, as well as quality of life overall.

Abortive treatment in CH involves the inhalation of high-flow oxygen or use of parenteral triptan medication. The newest abortive therapy is noninvasive vagus nerve stimulation (gammaCore; electroCore, Rockaway, NJ). Preventive treatment, which suppresses attacks during cycles or in chronic CH, has included such medications as verapamil and lithium. The noninvasive vagus nerve stimulation device also can be used in preventive treatment, as can galcanezumab (Emgality; Eli Lilly, Indianapolis, IN), a monoclonal antibody against calcitonin gene-related peptide, for treatment of episodic CH. Transitional treatments in CH are short-term interventions that serve to suppress attack frequency or intensity, shorten cluster cycles, or induce temporary remission in chronic CH. Such treatments include pulse regimens with corticosteroid or dihydroergotamine, or anesthetic nerve blockade of occipital nerves or the sphenopalatine ganglion.

Whereas treatment options in CH have increased in recent years, their use often is limited by poor accessibility, low tolerability, or medical contraindications. Therefore, there is an ongoing need to identify other treatment options for CH. Emerging data suggest that psychedelic drugs possess therapeutic potential and do so in a novel way. In this brief narrative review, we explore the history of psychedelics in headache medicine and the existing evidence on their therapeutic benefits for CH.

Definition of a Psychedelic

In this review, we discuss classic psychedelics, which are a group of 5-hydoxytryptamine (5-HT) 2A receptor agonists that produce acute alterations in sensation, perception, mood, and consciousness. The most well-known classic psychedelics include psilocybin, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), and mescaline. Reports of therapeutic benefits of psychedelic drugs exist for several neuropsychiatric disorders, including depression, obsessive-compulsive disorder, and substance use disorders, as well as chronic pain disorders.³ Unlike conventional medications, psychedelics show long-lasting (ie, months) therapeutic effects after limited dosing (ie, 1 to 3 doses) based on existing clinical reports. However, because of their acute intoxicating effects and associated regulatory concerns, psychedelics are not available for routine clinical use.

Drugs such as ketamine and 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) also produce acute psychedelic-like effects; however, they are not classic psychedelics, because of their distinct pharmacology. Although ketamine has been suggested to have abortive effects in CH,⁴ the effects do not appear to be long-lasting after limited dosing, as occurs with the classic psychedelics. MDMA does not appear to have beneficial effects in CH. One survey study suggested that MDMA extended the duration of a CH attack.⁵

History of Psychedelics in Headache Medicine

Albert Hofmann, a Swiss chemist, created LSD in 1938 while seeking to identify a bronchoconstrictive and vasoconstrictive medicine. He first discovered the psychedelic effects of LSD in 1943 and later isolated psilocybin from Psilocybe mushrooms. Psychedelics were first investigated as treatments for headache disorders more than 60 years ago.⁶ Several medications routinely used in headache management share chemical or pharmacologic properties with psychedelic drugs. For example, triptans, dihydroergotamine (DHE), and methylsergide are all serotonergic compounds that share an indolamine structure with psilocybin, LSD, and DMT.

Scientific inquiry into the effects of psychedelics on CH remains limited, but a global community of people with CH has led the research initiative by sharing their experiences. The first documentation of disease self-management with a psychedelic was reported by an individual with episodic CH in the late 1990s, who posted on a CH website message board (https://clusterheadaches.com) about therapeutic effects after ingestion of LSD (which was taken for recreational purposes). Despite initial resistance, reports of success using LSD and psilocybin mushrooms in CH spread among the CH community. Now, scientists are studying these patient-informed treatment regimens; controlled studies on the safety and therapeutic effects of psychedelics are starting to emerge.

Descriptive Studies

What appears to set psychedelics apart from other headache medicines is their reported ability to produce lasting therapeutic effects after small, limited doses (1 to 3).^7-10 This is in stark contrast with conventional medications that are dosed daily (sometimes lifelong), and take weeks or months for the desired effects, and maximal effects, to occur. Although psychedelics have also been reported to abort CH attacks,^7,8 given the short duration and high frequency of attacks in the disorder, this method of treatment is not practical.

Several descriptive studies have supported the ability of psychedelics to induce and prolong remission periods with limited administration of low doses and subhallucinogenic doses^7-11 (Table 1). A small survey of people with CH in 2006 showed that 88% and 52% of respondents found LSD and psilocybin to be effective preventive agents, respectively.⁸ A more recent online survey of nearly 500 people with CH showed that psilocybin, LSD, and lysergic acid amide (LSA; a psychedelic found in morning glory seeds) were significantly more effective than verapamil and prednisone in preventing CH attacks.⁷ A review of CH survey studies identified consistency among reports of psilocybin and LSD preventive effectiveness.¹¹ Psilocybin is the most commonly tried psychedelic in these surveys¹¹ and individuals reported dosing from every few weeks to twice annually.⁷ Low and subpsychedelic doses of LSD and psilocybin are reported to be used,^7,8 and in a case series, a nonhallucinogenic congener of LSD, 2-bromo-LSD (BOL-148), was also shown to break a CH cycle, reduce attack frequency and intensity, and induce remission.¹²

Clinical Trials

Some small controlled clinical trials have evaluated the safety and efficacy of psilocybin. Studies of LSD in CH are ongoing or in preparation (Table 2). The first randomized controlled study of psilocybin in CH¹³ used a patient-informed, low-dose pulse regimen and demonstrated safety of psilocybin with no unexpected or serious adverse events (Table 2). The weekly attack frequency was moderately reduced in the experimental group in the first 3 weeks (Figure), and this was particularly notable among individuals with chronic CH. The change in attack frequency was not statistically significant (P=.251), likely because of the small sample size. The researchers also observed separation of therapeutic and acute psychotropic effects. An extension phase of this study has completed and will begin to inform on the safety and efficacy of repeating the psilocybin pulse regimen (Psilocybin for the Treatment of Cluster Headache, NCT02981173). A study with an open-label design, EPOCH (Prophylactic Effects of Psilocybin on Chronic Cluster Headache, NCT04280055), investigating the effects of the same low-dose psilocybin pulse in chronic CH showed that the treatment was safe, was well-tolerated, and reduced attack frequency by 30% (P=.008) (Table 2).¹⁴

The small number of participants in each study limits reliability and generalizability of the findings. Even with ongoing work, differences in dosing regimens and outcomes among studies will limit the consolidation of findings. Larger, more representative trials are required, although there are unique logistic and methodologic challenges associated with both CH and psychedelic trials, including recruitment difficulty because of rarity of the disease, timing of drug administration in episodic cases, and controlling for comorbidities and polypharmacy.

Whereas the acute psychedelic effects are believed to be relevant in the therapeutic use of psychedelics in psychiatric disease, research of psilocybin in CH and migraine has demonstrated that the transitional therapeutic effects are independent of the psychedelic effects.^13,15 This along with reports of the use of low and subpsychedelic doses by people with CH^7,8 and the therapeutic effects of the nonpsychedelic compound BOL-148 in CH¹² urge the consideration of an alternate mechanism of action. Researchers in the open-label EPOCH study performed functional MRI before and after psilocybin administration and found involvement of hypothalamic–diencephalic functional connectivity in treatment response.¹⁴ The relationship of treatment response to circadian and sleep systems is also being investigated in the Psilocybin for the Treatment of Cluster Headache clinical trial.

Conclusion

Psychedelics have emerged as a potential therapeutic drug class for CH. Their beneficial effects have been reported for decades, although the existing data from clinical trials are far from conclusive and must be interpreted with caution. Continued research on psychedelics is warranted, particularly as psychedelics may also offer a means to understand the pathogenesis of CH.