Psychedelic Outlaws
How people with cluster headaches became unexpected psychedelic pioneers.
Below is an excerpt of my book Psychedelic Outlaws: The Movement Revolutionizing Modern Medicine, which explains the rise of psychedelic medicine through the lens of an unexpected group of pioneers: people desperate to find a treatment for cluster headache, one of the most excruciating diseases in the world.
Tracing the story of Clusterbusters allowed me to uncover the fascinating history of psychedelics as a pain medicine, while also offering an inside view into the backstage politics shaping the second wave of psychedelic medicine. Their epic journey raises important questions about who gets labeled as an outlaw, a criminal, or an expert, and how these labels influence our understanding of society and science.
Clusterbusters traces its origins to a pivotal moment in July 1998 when a guy named "Flash" posted a remarkable message to an online support group for cluster headaches. Flash claimed that using LSD and magic mushrooms had completely prevented his cluster headache cycles. Most everyone ignored him. But Flash kept posting research to support his claim.
Eventually, a member of the discussion board named Derek Garlin* decided to reach out to neurologist Dr. Ethan Russo, who Garlin told the discussion board “had done some research about how ‘other plants’ might treat headache disorders, but ‘the frigging research bucks and federal laws’ were stopping it.”
The following excerpt begins with Russo’s response.
Dr. Ethan Russo, board-certified neurologist, psychopharmacology researcher, and sometime ethnobotanist, sent Garlin an encouraging reply. After the usual caveats about how he “obviously” couldn’t recommend a risky, illegal drug, Russo explained that he’d been studying for a decade how indigenous people use plant medicine and had noticed a pattern: every psychoactive organism that produced a psychedelic effect in a high dosage treated headache at a low dosage.
He ticked off the examples: cannabis, peyote (mescaline), ergot alkaloids (which give us LSD, methysergide, and others), and Psilocybe mushrooms. Indigenous people in the Amazon used several plant medicines that did the same.
The efficacy of these drugs, Russo explained, could almost certainly be explained by neurochemistry—specifically, the affinity of psychedelics for certain serotonin receptors. A broad range of evidence supported his hypothesis: he’d heard that indigenous cultures in Mexico aborted migraine by putting small pieces of mushroom under their tongue, and there’d been reports about peyote as a treatment for migraine as early as the nineteenth century. Biomedical research identifying the ideal serotonin receptors for treating migraine and cluster headache only underscored the point. Flash had stumbled on an idea that was old and new at the same time, echoing ancient practice, even as it jutted against modern medical dogmas. So Russo, frustrated with barriers to continuing his studies, asked Garlin to share a call to action with as many patients as he could: “What is needed in this country is for groups like yours to rally politically so that work in this area can proceed to provide safe and effective treatments for cluster and other diseases.”
Ethan Russo had spent years slogging around the Amazon to bring back countless promising species of psychoactive plants. He knew better than almost anyone how much knowledge could be lost if we didn’t ask the right questions of the right people.
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We often think about scientists as people who “discover” new drugs—or at least “discover” new uses for drugs we already know about. But every drug has a backstory. These histories can be difficult to see—but those tiny little pills that the doctor prescribes have so many stories to tell about power, inequality, and deceit.
In the sixteenth and seventeenth centuries, colonial explorers opened an exchange between an Old and New World that would radically transform the global biome. The indigenous people in the New World were decidedly shortchanged in the deal. Christopher Columbus and his contemporaries might have brought domesticated animals like horses, cattle, pigs, and chickens to the Americas, but their expeditions unleashed a devastating wave of infectious diseases like smallpox, malaria, and measles that decimated indigenous populations.1
European explorers eyed the New World’s exotic flora from their initial voyages, but by the eighteenth century, the lure of botanical “green gold” exceeded even the appeal of precious metals. Along with significant cash crops—sugar, potatoes, tomatoes, cacao—the Western world also discovered potent medicinal plants, including quinine, coca, sassafras, ginger, aloe, and tobacco.
Then, as now, bioprospecting often came in the form of ethnobotany, a term coined in 1896 to describe the study of an indigenous people’s plant lore. Many commonly prescribed drugs in contemporary life come from plants or fungi, their discovery made possible because scientists noticed indigenous populations using them as medicine. Pharmaceuticals derived from plant medicines have rarely, if ever, produced value for the indigenous peoples who taught us their worth.
The same is true of the magic mushrooms used by Clusterbusters. Psychedelic mushrooms are native in regions across North America, Europe, and Russia, but as Andy Letcher describes in his excellent history of magic mushrooms, Shroom: A Cultural History of the Magic Mushroom, nearly all Western cultures considered these fungi toxic until the early to mid-twentieth century. Those who ate hallucinogenic mushrooms by accident, by and large, considered the aftereffects to be undesirable poisonings.2
Spanish colonists who observed Aztecs consuming a psychedelic mushroom as early as the sixteenth century considered the practice to be blasphemous. Locals called this fungus teonanácatl, a word, colonists noted with disgust, that translated to “God’s flesh.” The Spanish prohibited its use given the obvious conclusion that this mushroom assisted the idolatrous in witchcraft. Westerners’ knowledge of these fungi faded so much that by the twentieth century, academics questioned whether teonanácatl had ever existed. This otherwise obscure academic debate only came to a conclusion when ethnobotanist Richard Evans Schultes’s research identified teonanácatl as a mushroom called Panaeolus sphinctrinus still used by indigenous healers in Oaxaca.3-4 But put a pin in that story, because the next mycelial thread passes through Peru before it stops off in Mexico.
***
I called Dr. Russo to learn more about the indigenous people he studied. Who knew what other connections he’d point me toward?
Russo remembered receiving that email from Derek Garlin, the Clusterhead who had contacted him to ask if Flash’s theory about psychedelics might have merit. It helps that he saves every email he receives from people who get relief from plant medicines.
Plant medicines, Russo told me, had always interested him, but it took him seven years of practicing neurology before he decided to study their therapeutic use. Prescribing “increasingly toxic drugs . . . with less and less benefit” was burning him out. His migraine patients seemed to bear the brunt of it.
There had to be an alternative. So he started by digging into ethnobotanists’ research on headache. This is when he first noticed that psychedelic drugs, taken in a low dose, could treat headache disorders. His first article on the topic, published in 1992, offered a review of potential headache treatments used by indigenous people in the Ecuadorian Amazon.5 His next step would be to learn from the people themselves.
In 1995, Russo spent several months living with the Machiguenga, an indigenous tribe residing in the middle of Parque Nacional del Manú, a reserve in the Amazon famous for its biological diversity. Peru keeps it that way by forbidding access to everyone but its indigenous denizens and a few researchers who must apply for permission to enter.
Russo left Peru with a deep appreciation for the Machiguenga, whom he called “geniuses.” Following the “ancient ways of their culture” seemed to keep people in excellent health. So far as he could tell, the biggest risk to the community came from contact with Westerners who brought infectious diseases.6
As for plant medicine, the Parque Nacional del Manú might be famous for its biological diversity, but the real opportunity for an ethnobotanist like Russo wasn’t in the flora or fauna but in the people. The Machiguenga knew how to use the plants in the jungle, and one of their practices that really caught his attention involved a plant called Psychotria sp. (Rubiaceae). He learned that hunters would drip juice of the leaves into their eyes. The liquid stung, but it sharpened their senses: sight, sound, and smell became more acute. Russo thought the plant contained dimethyltryptamine (DMT), the hallucinogen in ayahuasca. But using it as an eye drop didn’t cause a psychedelic effect—the experiences included no hallucinations at all. Intriguingly, the Machiguenga used the same plant when they had a migraine. The process was simple: wrap the leaves in a banana leaf and squeeze, filtering the liquid through cotton. The resulting drops could go straight into the eye. It would sting, but the headache and all its symptoms—nausea, sensitivity to light—would disappear in about ten to fifteen minutes.
Did it really work? Russo has migraine, and a self-experiment gave him confidence that, yes, it’s a great way to abort an attack. But he wanted to learn whether a DMT-containing plant medicine could offer a useful preventive medicine for migraine or cluster headache.
He collected five hundred different plants while in the Peruvian Amazon with the help of medical anthropologist Glenn Shepherd, who was fluent in the Matsigenka language. When they returned to Montana, they screened each one. Nearly all exhibited serotonin-receptor activity. The experiment made him realize that DMT is not available just in that little corner of the Amazon, either. Rather, he concluded, it’s pretty widespread in nature. “If there’s some grand design to all this, there’s quite a trickster involved.”
Was he onto something big? Something that might help his patients? He knew the right person to ask.
***
In 1997, Ethan Russo sent a handwritten letter to Basel, Switzerland, via airmail. Did the recipient, Dr. Hofmann, think it possible that a subhallucinogenic dose of LSD could prevent migraine? Russo received a reply a few months later.
Dr. Hofmann’s hand-typed letter, dated May 19, 1997, apologized for his delayed response. 7
“Your idea, that LSD in low doses may be effective in migraine prophylaxis, seems to me very reasonable.” He too once wanted to study the “effects of daily use of low, no hallucinations producing doses of LSD, but only came to very preliminary studies.” Hofmann—a company man—had stopped his formal investigations of LSD once Sandoz Pharmaceuticals abandoned its production in 1965. Nevertheless, he was “very interested in [Russo’s] upcoming investigation.”
Russo was ecstatic to receive Hofmann’s “ringing endorsement of the idea.” (He still had it, of course—a keepsake like that is something to preserve.)
Russo might not have managed to get his research on psychedelics and headaches off the ground, but he never gave up on plant medicine. He shifted his attention toward medical marijuana. Rick Doblin’s Multidisciplinary Association for Psychedelic Studies supported Russo’s early efforts to obtain National Institutes of Health funding for a clinical trial testing smoked marijuana as a treatment for migraine and, when that failed, a subsequent safety study of prolonged marijuana use.8-9 Between 2003 and 2017, he worked as senior medical advisor, medical monitor, and study physician at GW Pharmaceuticals, where he played a pivotal role in developing cannabis-derived treatments for cancer-related pain and intractable epilepsy. Every position he has held since has been on the same trajectory: transforming the cannabis therapeutics industry.
People with cluster headache, Russo assured me, were on the right track. But getting the FDA and the biomedical establishment to pay attention would be difficult. Clusterbusters’ method of self-experimentation with plants, he told me, should continue. “Ethnobotany doesn’t have to originate in the jungle; it can originate in the concrete jungle, too.”
*Derek Garlin is a pseudonym.
Adapted excerpt from PSYCHEDELIC OUTLAWS: The Movement Revolutionizing Modern Medicine by Joanna Kempner, PhD. Copyright © 2024. Available from Hachette Books, an imprint of Hachette Book Group, Inc
References
Benjamin Breen, The Age of Intoxication: Origins of the Global Drug Trade (Philadelphia: University of Pennsylvania Press, 2019).
Andy Letcher, Shroom: A Cultural History of the Magic Mushroom, 1st US ed. (New York: Ecco, 2007).
Richard Evans Schultes, “The Appeal of Peyote (Lophophora Williamsii) as a Medicine,” American Anthropologist 40, no. 4 (1938): 698–715.
For a history of the debate, see Gaston Guzman, “Hallucinogenic Mushrooms in Mexico: An Overview,” Economic Botany 62, no. 3 (2008): 404–412.
Ethan B. Russo, “Headache Treatments by Native Peoples of the Ecuadorian Amazon: A Preliminary Cross-Disciplinary Assessment,” Journal of Ethnopharmacology 36, no. 3 (June 1, 1992): 193–206, https://doi.org/10.1016/0378-8741(92)90044-r.
Ethan B. Russo, “Machiguenga: Peruvian Hunter-Gatherers,” Weston A. Price Foundation, September 7, 2002, https://www.westonaprice.org/health-topics/in-his-footsteps/machiguenga-peruvian-hunter-gatherers/#gsc.tab=0.
Albert Hofmann to Ethan Russo, in Psychedelic Outlaws: The Movement Revolutionizing Modern Medicine, by Joanna Kempner (New York: Hachette Books, 2024), Appendix.
“MAPS, MPP and Dr. Ethan Russo Filed an Updated Version,” Multidisciplinary Association for Psychedelic Studies, May 1, 2003, https://maps.org/2003/05/01/mmj-news-id1429.
Ethan B. Russo et al., “Chronic Cannabis Use in the Compassionate Investigational New Drug Program,” Journal of Cannabis Therapeutics 2, no. 1 (2002): 3–57, https://doi.org/10.1300/j175v02n01_02.
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