Cluster Headache Defined

Cluster headache (CH) has the dubious distinction of being the most painful disorder known to humankind: topping cancer, broken bones, childbirth and third-degree burns1 and has been referred to as the suicide headache because suicidal ideation occurs in 55% of patients (Case).2 The International Clasification of Headache Disorders, 3rd edition (ICHD-3) describes CH as side-locked, periorbital pain lasting 15 to 180 minutes, with autonomic features such as ptosis, nasal congestion, and a bloodshot eye.3 Fortunately, CH is uncommon, striking an estimated 0.1% of persons in the US.4 Approximately 17% of patients with CH (~1 in 6) have the chronic variant, with no break in the unrelenting attacks. To say that chronic cluster is the worst version of the most painful condition known only begins to hint at the agony.

Treatments Approved and Being Studied

There is high-quality evidence for use of sumatriptan injection, zolmitriptan nasal spray, and high-flow oxygen inhalation to treat patients with acute CH. For preventive treatment, there is less evidence. Although ipsilateral occipital nerve block alone is an American Headache Society (AHS) level A recommendation,5 high-dose verapamil is the most commonly used preventive; lithium and topiramate remain mainstays, despite inadequate evidence. Newer therapeutic options include neurostimulators (eg, noninvasive vagal nerve stimulator [VNS] [Gammacore; Electrocore, Basking Ridge, NJ] shown effective for episodic CH or an investigational implanted sphenopalatine ganglion [SPG] stimulator [Pulsante; Autonomic Technology, Mountain View, CA] for acute treatment of chronic CH). Monoclonal antibodies to calcitonin gene-related peptide (CGRP) are also being studied for the treatment of patients with CH and may have efficacy in prevention of episodic but not chronic CH.

The Alternative Some Patients Use and May Not Speak About

More than 25% of patients with CH find that neither medicines, nerve blocks, oxygen, nor neurostimulators work for the crushing, unrelenting agony of this most painful of all maladies. A sizable subset of these patients, driven to the brink of suicide, will go to any length, including taking an illegal substance that may risk their health, job, and freedom, to break free of the torment that is CH.

Increasingly, patients with CH are turning to psychedelics (eg, lysergic acid diethylamine [LSD] or psilocybin), and treating themselves with hallucinogenic substances, although often in subhallucinogenic doses. For a variety of reasons, they may not be forthcoming with their headache specialist about this. It is therefore incumbent upon neurologists and others who treat patients with CH to know that what is termed busting, treating CH with psychedelics, is widely known, well-accepted, and frequently practiced by those with CH for whom all else has failed.

Lysergic Acid Diethylamide and Psilocybin-A Brief History

The first recorded neuropsychiatric effects of LSD were reported in 1943 by Albert Hoffmann, a young chemist at Swiss pharmaceutical giant Sandoz, who tested hundreds of serotonin-based compounds, determined to discover a safe and effective circulatory and respiratory stimulant. After ingesting a 0.25-mcg dose, he had an experience many consider the world's first acid trip of, “unprecedented colors and plays of shapes. . . kaleidoscopic, fantastic images alternating, variegated, opening and then closing themselves in circles and spirals, exploding in colored fountains, rearranging and hybridizing themselves in constant flux.”6

Psilocybin is a naturally occurring hallucinogenic tryptamine similar to LSD, found in over 180 species of small, nondescript mushrooms in the psilocybe family.7 For millennia, indigenous people throughout Mexico and Central America have consumed these in religious ceremonies. Albert Hoffmann isolated pure psilocin (the active metabolite of the prodrug psilocybin) in 1963.

Both LSD and psilocybin were studied for treatment of people with a number of psychiatric conditions, including severe depression, alcoholism, and posttraumatic stress disorder throughout the 1950s and 1960s.8 Then came the Age of Aquarius, counter-culture, and Timothy Leary, a Harvard psychologist who encouraged widespread recreational use of psychedelics, urging his followers to “turn on, tune in, and drop out.” Federal authorities, reacting to a perceived drug epidemic, outlawed both psilocybin and LSD, designating each a schedule 1 substance: meaning high abuse potential and no proven medical value.

Biochemistry of Psychedelics

Psychedelics like LSD and psilocybin stimulate serotoninergic and dopaminergic receptors (Table),9 and have varying routes of administration and pharmacokinetics with half-lives ranging from seconds to hours. At sufficient doses, psychedelics disrupt the default mode network (DMN), a collection of neural structures discovered by Raichle and colleagues in 2001.10 The DMN, which switches on when the brain is resting and not attending to external stimuli, is believed to be the seat of our ego, or sense of self. Hallucinogens dissolve the line between self and nonself and distort concepts of linear time. It has been theorized that psychedelics allow the user to see, hear, smell, and taste a far richer palette of sensory input than the brain would normally allow. Functional magnetic resonance imaging (fMRI) studies of volunteers who have ingested LSD or psilocybin show greatly enhanced functional connectivity that seemingly allows brain areas to signal to other areas that they normally wouldn't, accounting for such effects of audiovisual synesthesia, derealization, and depersonalization known as tripping.11

The ring structure of LSD is similar to ergotamine-based headache-relieving compounds such as methylergonovine and methysergide, and psilocin is chemically nearly identical to serotonin.12 Sumatriptan, a sulphonated indole, is structurally similar to the hallucinogen dimethyl tryptamine (DMT). Like psilocybin, DMT has been used in religious ceremonies for centuries; when DMT is combined with a plant-based monoamine oxidase inhibitor (MAOI), it is called ayahuasca. Because DMT is often inhaled rather than ingested, peak plasma concentrations are reached in seconds.

Psychedelics and Cluster Headache

The similarities in biochemistry make it unsurprising that indolamines (eg, ayahuasca, DMT, D-lysergic acid amide [LSA], LSD, psilocybin, and the nonhallucinogenic 2-bromo-LSD [bol-148]) are anecdotally reported to have efficacy for treating people with CH.13 Social media has raised awareness of this and even somewhat of a rush of desperation by patients with CH toward psychedelics for relief. Bob Wold, who had CH for 30 years, experimented on himself with great success and founded the nonprofit Cluster Busters in 2002 with the goals of spreading the psychedelic gospel.

In a study of 53 patients who practiced busting with LSD or psilocybin, colloquially termed clusterheads, investigators concluded that use of either compound appeared to stop attacks, extend breaks between cycles, and even stop cluster cycles in a majority of users (Case Resolution). When taken at microdoses, side effects were almost nonexistent.14

The Need for Adequate Research

The major drawback of self-treatment of CH with psychedelics is that most are illegal to possess, and the DEA schedule 1 status makes research nearly impossible, although there is 1 ongoing double-blind study of psilocybin in patients with CH.a By legal necessity, patients treat themselves in the shadows, often without guidance from their headache doctor, who likely has no idea what their patient is doing. In recent years, there has been a loosening of attitudes toward these substances, perhaps in part due to the widespread acceptance of medical marijuana, now legal in 30 states and the District of Columbia.15

I recently gave a lecture to the Cluster Headache Support Group at their annual conference in Philadelphia. In addition to covering neuromodulation and CGRP-related treatments, I spoke about psychedelics. I asked attendees to chat with me afterwards and heard story after story of heart-breaking pain dramatically reduced or eliminated by psychedelic compounds. I left convinced that there is just no good reason why these treatments remain illegal for those with CH. To deprive someone suffering this degree of pain a treatment that, while clearly inadequately studied, appears safe and effective, seems cruel.

As with all medicines, when discussing hallucinogens as treatment modalities, caveats abound, and these substances are not for everyone. I would include on a no-fly list: children, pregnant or lactating women, and those with pre-existing significant medical or psychiatric disease, pending further studies if we are ever allowed to do them. As is also true of typical medicines, psychedelics are neither panacea nor cure. Anecdotally, some patients with CH report no benefit, while a small group appears to feel worse.16 Clearly, there is much work to be done. We need, on behalf of all those suffering from the suicide headache, rigorous double-blind, placebo-controlled studies to properly determine efficacy, dosing, side effects, and safety.


Patients experiencing the excruciating pain of chronic CH are often desperate, and the lack of well-designed clinical studies is not enough to stop them from trying something—anything—that might end the pain. The patient we describe here has all the evidence for efficacy he needs: walking his daughter down the aisle.

For the countless other patients out there, let's hope (and advocate) for loosening of restrictions on research into psychedelics, by demoting them to a DEA schedule that will better allow proper research. Then, armed with knowledge derived from rigorous study, and legal access to psychedelics in microdoses, we may one day finally tame the beast, and the suicide headache will be no more.

1. Cicero K. The 10 most painful medical conditions. Published Dec. 12, 2014. Accessed September 4, 2018.

2. Rozen TD, Fishman RS. Cluster headache in the United States of America: demographics, clinical characteristics, triggers, suicidality, and personal burden. Headache. 2012; 52(1):99-113.

3. Headache Classification Committee of the International Headache Society. International classification of headache disorders. Celphalgia. 2018;3(1):1-211.

4. Fischera M, Marzinak M, Gralow I, Evers S. The incidence and prevalence of cluster headache: a meta-analysis of population-based studies. Cephalalgia. 2008;28(6):614-618.

5. Robbins MS, Starling AJ, Pringsheim TM, Becker WJ, Schwedt TJ. Treatment of cluster headache: the American Headache Society evidence-based guidelines. Headache. 2016;56(7):1093-1106.

6. Hagenbach D, Werthmueller L. Mystic chemist: the life of Albert Hoffman and his discovery of LSD. Santa Fe, NM; Synergetic Press: 2013.

7. Wasser S. Species diversity of the genus psilocybe (basidiomycotina, agaricales, strophariaceae) in the world mycobiota, with special attention to hallucinogenic properties. Int J Med Mushrooms. 2005;16(1):305-332.

8. Szalavitz S. LSD may help treat alcoholism. Time. Published March 09, 2012. Accessed September 4, 2018.

9. Nichols D. Hallucinogens. Pharmacol Rev. 2014;101(2):131-181.

10. Raichle M, MacLeod AM, Snyder AZ, et. al. A default mode of brain function. Proc Natl Acad Sci USA. 2001; 98(2):676-682.

11. Carhart-Harris R, Muthukmaraswamy S, Roseman L, et. al. Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proc Natl Acad Sci USA. 2016;113(17):4853-4858.

12. Furst PE. Mushrooms: Psychedelic Fungi. In Snyder SH. The Encyclopedia of Psychoactive Drugs (series). New York, NY: Chelsea House Publishers; 1986.

13. Ginzel KH, Mayer-Gross W. Prevention of psychological effects of d-lysergic acid diethylamide (LSD 25) by its 2-brom derivative (BOL 148). Nature. 1956;178(4526):210.

14. Sewell RA, Halpern JH. Response of cluster headache to psilocybin and LSD. Neurology. 2006;66(12):1920-1922.

15. 30 Legal medical marijuana states and DC: laws, fees, and possession limits. Updated July 28, 2018. Accessed Septemer 4,2018.

16. Persson M, Kjellgren A. Psychoactive substances as a last resort—a qualitative study of self-treatment of migraine and cluster headaches. Harm Reduct J. 2017;14:60.