Last week the third annual Clusterbusters conference finished in Atlanta, Georgia. Clusterbusters? It’s an unconventional name for a patient group that espouses an unconventional treatment: using hallucinogenic drugs such as Lysergic Acid Diethylamide, better know as LSD, and psilocybin, the active ingredient in ‘magic’ mushrooms, to treat a type of headache so severe that many sufferers take their own lives, earning the condition – cluster headache – the gruesome name of the ‘suicide headache’.
And there is much to celebrate. New unpublished research supports their use of certain psychoactive seeds and a clinical trial protocol using the hallucinogens is under review, bolstered by the presence of a world authority on headaches.
Ten years ago the future looked bleak, but thanks to a chance discovery and a combination of patient power and citizen science, treatments devised and refined by the cluster community itself are steering the research agenda.
Cluster headaches affect up to 0.4% of any population and are often misdiagnosed as migraine. Unlike migraine, they are around four times more common in men than in women and follow an unexplained annual or daily cycle.
In the episodic form, debilitating attacks occur in certain months of the year, often when the seasons change. Those with the chronic form of the condition receive no respite and are plagued by six or more attacks every day. Untreated, each attack can last for hours. The pain of a cluster headache attack is compared to expelling kidney stones or giving birth without pain relief.
Ben Khan, a lifelong chronic sufferer says the pain comes on quickly and is all-encompassing. ‘I bang my head against the wall and flail my arms and body around, screaming,’ he says.
Khan is one of many sufferers drawn to using hallucinogens out of desperation. One sufferer, ‘Flash’, posted details on a cluster community internet message board explaining how he successfully treated his headaches with magic mushrooms using small doses that did not cause the wild hallucinations and sensory distortions normally associated with psychedelic drugs.
Khan says nothing happened until he tried a second dose. ‘When I woke up the next day, my headaches were pretty much gone.’ He adds that he takes a small maintenance dose every six to eight weeks, which keeps the headaches away without side effects.
The resurgent interest in using hallucinogenic drugs in a medical context (see Box) led John Halpern from Harvard Medical School, Massachusetts and his former colleague Andrew Sewell to methodically collect the anecdotal reports. Their paper (Neurology 2006, 66, 1920) showed that hallucinogens were more effective at preventing new cycles of future attacks than conventional medicines and psilocybin was better at aborting an attack than inhaling pure oxygen, which can terminate the pain in 15 minutes if administered at the right time. However, for the oxygen to be of any use, the user needs to be near the gas cylinder and it does nothing to prevent future bouts. Around 10% of people with the condition do not respond to any treatment.
By the time the paper was published, many users, afraid of the harsh penalties for possessing LSD or psilocybin, which are Schedule I substances in the US and Class A in the UK, had graduated on to using plant seeds that contain the LSDlike compound, lysergic acid amide (LSA). In the US, LSA seeds are a Schedule III substance and, although there are penalties for ingestion, there are none for possession. In the UK, many began using the seeds when a legal loophole allowing magic mushrooms to be legally sold was closed in 2005.
This gave Andrew Sewell, now based at Yale University School of Medicine, Connecticut, and colleagues the chance to invite seed users to send their specimens of Morning Glory (Ipomoea violacea), Hawaiian Baby Woodrose (Argyreia nervosa) and Ololuiqui (Rivea corymbosa) to analyse their LSA content and interview subjects about their experiences. Only subjects who agreed to have their medical records examined were included in the total sample of 53.
More than a third of subjects said the seeds were an effective abortive treatment and aborted the attack in less than 20 minutes. Nearly half of patients with episodic cluster headache reported termination of a cycle of attacks, and a further third reported partial success. Among the chronic sufferers, just over half reported between two and 120 pain-free days. The vast majority of respondents did not report psychedelic effects, providing more evidence that sub-hallucinogenic doses can be effective.
Sewell, who presented his preliminary results at the Clusterbusters conference, says that although the results have yet to be submitted to a journal, it’s strong enough evidence that a randomised clinical trial is warranted. ‘The seeds appear to be effective in some patients in terminating cluster attacks, ending cluster periods and extending remission periods in doses that don’t need to be hallucinogenic,’ says Sewell.
The results do not match those described with psilocybin or LSD, which may be due to the highly variable LSA content of the seeds. Some seeds contained no LSA at all, and varying concentrations of alkaloids in the three species’ seeds meant that the ingested dose ranged from 0-2.8mg; all users who ingested 1mg or less did not respond.
Bob Wold, who founded Clusterbusters to help fellow sufferers use hallucinogens as safely as possible, says people like the seeds because they are easy to get. ‘We’ve tracked over 100 people using the seeds and the results are very similar to psilocybin and LSD, although the percentages are slightly lower at breaking cycles.’ He adds that one person reported some stomach troubles, and others have reported feeling tired the next day.
This is because the chemistry of the seeds is not fully understood and ingesting them can cause nausea, vomiting and possibly other more serious side effects. Another alkaloid derived from ergot, the fungus of rye from which LSD and LSA were obtained, methysergide (Sansert), is hallucinogenic at high doses and was used to prevent migraine but is known to cause the autoimmune condition retroperitoneal fibrosis, and has now been withdrawn from the US market.
Kyle Reed, an industrial research chemist who analysed the seeds for the study, doubts whether LSA itself is hallucinogenic. ‘My general feeling is that the hallucinogenic effects of the seeds are caused by the combined effects of several alkaloids acting synergistically.’ He adds that it is unlikely that LSA is the only compound working to relieve the headaches. Albert Hoffman, who discovered LSD, ingested LSA but noted little more than a dreamy, sedative action.
The mechanism by which the hallucinogens ease headaches is also unclear. The hallucinogens are all tryptamine molecules and bind to the same receptors in the brain as naturally occurring neurotransmitters such as serotonin. This action is exploited by some migraine drugs, such as GSK’s sumatriptan (Imitrex, Imigran). But while it is the most effective remedy for many, regular use of tryptamine drugs can lead to medicine overuse headache, and can even make episodic cluster headache sufferers go chronic.
The distressing nature of the cluster attack and the lack of viable treatments has led Peter Goadsby, a neurologist at the University of California, San Francisco, US, to work with John Halpern to try and disentangle the issues. ‘There have been some important questions raised by patients in the terms of psilocybin/LSD and their possible effects in cluster headache,’ he says. In the late 1990s, Goadsby used PET scans and found abnormalities in sufferers’ ipsilateral posterior hypothalamus neurons, a region of the brain involved in regulating circadian rhythms and responses to light, which partly explains the strange patterns of attack. Torsten Passie of Hannover Medical School, Germany, is also utilising neuro-imaging, this time combined with open label bromo-LSD, which is nonhallucinogenic, to see if the medicinal effects can be uncoupled from the hallucinogenic effects.
Clinical trials often fail to replicate the success rates of earlier studies and there are safety issues attached to using such chemicals, albeit at small, infrequent doses. However, John Halpern, who has submitted an LSD/psilocybin clinical trial protocol to Harvard University’s Institutional Review Board, remains cautious but determined. ‘You don’t propose a study to not do it,’ he says.
Arran Frood is a science journalist based in the UK
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