NEWS FEATURE Cluster busters

Ignored by mainstream medicine, people who suffer bizarrely painful headaches are helping to test hallucinogenic drugs as a cure. Arran Frood talks to these citizen scientists.

It began the same way, every day at 3 p.m. First young children, had never even considered if untreated or if the medication fails. came the dull ache, then a sharp pain behind the taking mind-expanding drugs. But after trying The intense pain derives from stimulation right eye followed by debilitating agony. The only a veritable medicine chest of legal remedies, none of the trigeminal nerve, which is responsible difference was how long it would last—anywhere of which are designed to treat cluster headaches for sensation in the face. But the problem is not from 45 minutes to three hours on a bad day. and none of which worked, May was desperate local to the nerve, eye or face—it lies within the “It’s a hundred times worse than the worst pain for relief. brain. you’ve ever felt, but pulsating and persistent, like Like May, many individuals who suffer from Brain-imaging studies indicate the someone is trying to pull your eye out,” says Peter cluster headaches have found that the illegal hypothalamus as the area of pathogenesis, unlike May, who has suffered from cluster headaches drugs are their only choice. Neglected by the migraines where the brain stem is activated. Still, since 1999. scientific community and forced underground most prescribed medicines are those given for The headaches are so horrible that each year by the law, they have turned to the Internet to migraines, antidepressants or calcium channel people who endure them take their own lives, secretly find, research, promote and even sell the blockers designed to reduce blood pressure. earning the condition the gruesome moniker of treatments that work. There are no drugs specifically for cluster

http://www.nature.com/naturemedicine ‘suicide headaches’. In a classic example of ‘citizen science’, they headaches. “Really, you wouldn’t wish it on your worst have even roped in scientists to validate what Some migraine drugs such as sumatriptan enemy,” May says. “Once I was looking at a their experiences have shown and plan clinical (Imigran, Imitrex) are effective when inhaled pneumatic drill… wondering if drilling into trials and other research to take the treatments or injected, but May began to notice a worrying my head would relieve the pain. That’s when I forward. “I don’t believe that even any of the big increase in the frequency of his daily attacks after realized that things weren’t right and I had to get pharma companies would have got any further taking sumatriptan. it sorted somehow.” in the same period of time,” says May. The best abortive treatment isn’t even a drug. On the Internet, where many like May Inhaling pure oxygen works for about 80% of had begun to congregate, news had gained Periodic pain cluster headache sufferers, although the attack momentum that hallucinogenic drugs such as Often misdiagnosed as migraines, cluster must be caught within five minutes. Access to the LSD and psilocybin, the active ingredient in headaches were noted as early as 1745 by Gerhard bulky cylinder also isn’t always possible. ‘magic’ mushrooms, could provide sweet relief van Swieten, personal physician to the Austrian Frustrated with the poor functionality of from the headaches. Empress Maria Theresa. The doctor observed existing equipment, lifelong chronic sufferer Ben Nature Publishing Group Group 200 7 Nature Publishing May, a respectable middle-aged man with that a healthy, robust man of middle age suffered Khan invented the ‘Clustermasx’ which, Khan © from a “troublesome pain which came on every says, uses less oxygen, is more effective and can day at the same hour at the same spot above the abort an attack in five minutes. One reviewer of orbit of the left eye.” The man, the doctor said, his method raved that “a layer of pain is shaved “felt as if his eye was slowly forced out of its orbit off with every inhalation.”

Gary Carlson with so much pain that he nearly went mad.” About one in five sufferers is resistant to all More than 250 years on, doctors know little approved treatments, including oxygen. May, more about the condition, if they have heard of who had transitioned to chronic attacks in it at all. 2002, feared he’d soon be one of them. Then he Cluster headaches are a type of neurovascular stumbled on to a flurry of excited activity on the headache affecting about 1 in every 1,000 people. popular website www.clusterheadaches.com. Their hallmark is the curious periodicity of attacks, which occur at the same time each day Magic mushrooms and in the same spot, usually in otherwise healthy Typical posts on the website raved about middle-aged men. Only one in five sufferers is a mushrooms of the genus Psilocybe, which have woman. been used for centuries by traditional healers and The episodic forms of the headache, which shamans to commune with the spirit world. account for about 90% of the cases, are nothing Wary of experimenting with illegal drugs, May short of bizarre: one month of headaches in the researched them for six months before yielding in spring and one in the fall is typical. This semi- late 2002. The results were everything he’d hoped annual regularity based around the equinoxes for. “It worked immediately. I had ten pain-free defies explanation, but at least provides some days and I thought, ‘I’m cured’,” he says. The intense pain of cluster respite from the pain. Through trial and error, May discovered that a headaches derives from the The remaining 10% of sufferers live with the small dose—too small to cause hallucinations— trigeminal nerve. chronic form and are subjected to up to eight of the dried mushrooms taken every one or two attacks a day, each of which can last three hours months was enough to keep his daily attacks

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with rare disorders can band A controversial procedure called deep-brain together to become a more cohesive stimulation, used to treat Parkinson disease, force to advocate for themselves,” is another option. In that technique, doctors says Halpern, who knows of two implant electrodes in the hypothalamus to people at his institution who have stimulate an area associated with the attacks. The committed suicide because of cluster exact mechanism of action is unknown and may headaches. “I feel like we have a moral be complex, but the high-frequency stimulation obligation to pursue this because may inhibit or modulate the nerve cells that treatment-resistant people are killing initiate the pain. themselves,” he says. Massimo Leone of Milan-based Istituto Nazionale Neurologico Carlo Besta and his Citizen science team have treated 19 chronic, treatment-resistant Halpern and his colleague Andrew patients. “About 70% show a very good clinical Sewell began collecting the medical response and are mainly pain free,” says Leone, records of those who were using adding that some individuals seem to respond hallucinogens to relieve cluster better to conventional medicines after the headaches, and set up interviews procedure. and online surveys for a retrospective Unfortunately, some individuals appear analysis. to become tolerant to the treatment. The Their results show that psilocybin technique is not without risk, either. Of six cases is better at aborting acute attacks at a different institution, one individual died of than either oxygen or sumatriptan, a brain hemorrhage after the operation. “At this

http://www.nature.com/naturemedicine and LSD and psilocybin are both stage the surgery is the last resort,” says Leone. better at triggering and extending In another technique, doctors implant remission than are standard drugs electrodes under the scalp to stimulate the Psychedelic cure: Many with cluster headaches have (Neurology 66, 1920–1922; 2006). occipital nerve, which runs from deep inside the turned to LSD and magic mushrooms. The researchers are planning clinical brain to the spine, to override the pain. “Occipital trials using LSD and psilocybin. nerve stimulation is going to open up a whole at bay. If a headache did force its way through, The hallucinogens may be effective new chapter in treating medically intractable small doses of mushroom tucked under the because they are similar in structure to the headache,” says Peter Goadsby, an expert in tongue could sometimes abort an attack in just neurotransmitter serotonin and each affects a cluster headaches at the Institute of Neurology, 15 minutes. different suite of serotonin receptors in the brain. University College London. As the clusterheads collated their experiences, LSD and psilocybin, for example, both bind to His results, due to be published in The Lancet, chronic sufferer Bob Wold set up a new site, the same receptors as sumatriptan, but also bind suggest that the technique does not work for www.clusterbusters.com, specifically to spread to serotonin receptors that may be involved in everyone but the benefits accrue over time. Nature Publishing Group Group 200 7 Nature Publishing the message about the psychedelic drugs. “The the circadian response to light, which suggests an Goadsby says a controlled study of © first order of business is to let people know this effect on the biological clock to break the cluster hallucinogens is needed, as are follow-ups of life-changing treatment is out there,” says Wold. cycle. people already using them. “Only with that data “The second is to do what needs to be done to Although these drugs can be dangerous, could you make a sensible comparison between get clinical trials underway.” there are models in place for their distribution. intervention methods,” he says. Anecdotal evidence is all very well, but only a For instance, the infamous drug thalidomide In the meantime, the clusterheads are few were brave enough to try the hallucinogens. is prescribed for treatment-resistant stomach continuing with their attempts at citizen science. Most others were sceptical, or scared of breaking ulcers and for leprosy, but its makers have May and others began using seeds that contain the law. patented a system to ensure it never reaches a lysergic acid amide, a less potent precursor to One group, the evocatively named OUCH, for pregnant woman. Xyrem, a drug prescribed LSD, when the UK banned the sale of magic Organisation for the Understanding of Cluster for narcolepsy, contains as its active ingredient mushrooms in 2005. The seeds seem to work too, Headaches, banned discussion of the alternative gamma-hydroxybutyrate or GHB, a date-rape but data on correct dosage are sparse, so users treatments from their message boards. The drug that appeared in the 1990s. are saving batches of seeds from different plant highly charged arguments quickly devolved A national registry to monitor the drugs’ use species for a rigorous chemical analysis. into personal attacks, eventually forcing the and distribution could minimize the risk of May says despite the legal risks his self- resignations of many of the group’s members. misuse, Halpern says. “If we can do that for GHB medication poses, it is less scary than brain It was clear that the community needed real and thalidomide, then I believe we can for LSD surgery, and he is determined to get the treatment scientists to give their results some credibility. and psilocybin.” validated by scientists. He also has more reason Most scientists they approached baulked at the than some others to find a treatment that tricky legal situation. Then they found John Last resort works—he is worried because the headaches are Halpern, assistant professor of psychiatry at Choosing a treatment can often come down thought to have a genetic component. Harvard Medical School, who had experienced to the best of the worst. Psychosis aside, LSD is “My biggest fear is that I might pass on the the bureaucratic quagmire of trying to work with known to affect the expression of at least seven condition to my children,” he says. “There’s hallucinogenic drugs. genes. And almost nothing is known about no way you could give them the alternative “It’s unbelievable that they came to me. It the long-term effects in humans of ingesting treatment.” shows the power of the Internet that people psilocybin, especially in small doses. Arran Frood is Nature’s web editor.

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