They're known as "suicide headaches." Patients claim the pain from cluster headaches is far worse than anything else human beings typically encounter, including childbirth and gallstones.
Bernard Greenberg, a 76-year-old retired cancer doctor from West Chester, has had "the most painful headaches imaginable" for 15 years. They make him feel as if he has "an ice pick going through my temple to my brain."
Chris Hannah, 54, started having cluster headaches every day at 48. The Doylestown man describes his as feeling like a "severe electrical storm" with "erratic shards of pain" behind his left eye and from his ear to his jaw.
Yet these headaches have gotten surprisingly little research attention over the last 20 years. Their cause is unknown, and patients have had little choice but to try drugs meant for migraines or other conditions. Some patients have become so frustrated with their options that they have experimented with low doses of hallucinogenic mushrooms, which some claim are more effective than legal drugs.
"These people are in dire need of treatment," said Stephen Silberstein, director of the Jefferson Headache Center.
William Ratner, a pharmacist who is senior marketing director for migraine and headache for Eli Lilly, said companies have had trouble coming up with good treatments.
"It's not for lack of trying," he said. "The science just hasn't been there to help people in a major way."
Patient groups have lobbied for more clinical trials of treatments specifically for cluster headaches, and that is finally happening. Local doctors are testing a new monoclonal antibody from Lilly and a wand that stimulates a key nerve through a small implant in a patient's cheek. Doctors and patients are awaiting the Food and Drug Administration's decision on another type of electrical stimulation that targets the vagus nerve. A trial that will for the first time scientifically test whether magic mushrooms really do help - no small feat in the risk-averse research world - may start soon.
The question of whether illegal psychedelic drugs can help headache patients has been "radioactive," said Brian McGeeney, a Boston Medical Center neurologist who thinks the drugs deserve more study.
Sharp, one-sided pain
Cluster headaches are nothing like the tension headaches that almost everyone has experienced. Their intensity has more in common with migraines, but doctors say there are key differences. Migraines are sick headaches. Sufferers - there are more women than men - often feel nauseated and want to lie down in a dark room.
Cluster headaches have sharp, one-sided pain that leaves victims - there are more men than women - feeling "activated, like they want to run around the block or smack their head against the wall," said John Detre, a Penn Medicine neurologist. Eyes often turn red and water. Noses run. Cluster headaches tend to be shorter than migraines, about 15 minutes to an hour.
They're called cluster headaches because they tend to come in groups. Most sufferers have "episodic" headaches, or attacks that occur for two to three months out of a year, said William Young, a Jefferson headache specialist. About 20 percent of cluster sufferers have "chronic" headaches that happen every day like Hannah's.
Estimates of how many people have cluster headaches vary considerably, but doctors say the condition affects about as many Americans as multiple sclerosis, around 400,000.
Patients are often treated with drugs in the triptan family, which can be injected under the skin or inhaled. Inhaling pure oxygen helps shorten some people's attacks. Each of these helps about 70 percent of patients, said Jason Rosenberg, a headache specialist with Kaiser Permanente of the Mid-Atlantic States. Doctors often put patients in the midst of an attack on a course of high-dose steroids.
"Even the most proven treatments are suboptimal in terms of cost and convenience," Rosenberg said.
Hannah, who founded the Cluster Headache Support Group in 2012, said he has up to eight headaches a day. Of the medicines available, he said, "I've tried them all, with varying levels of success."
For the last 21/2 years, he's been receiving infusions of the anesthetic drug ketamine at Jefferson. By far, he said, that has worked best, though he still has constant, "light" head pain. His doctor, Young, said he is collecting information about patients such as Hannah.
Bob Wold, a Chicago-area man who has had cluster headaches for 38 years, started another support group, Clusterbusters, in 2002. He said he has tried 70 medications in myriad combinations with little relief. For the last 15 years, he has used something else that largely keeps the headaches at bay: magic mushrooms, or, presumably their active ingredient, psilocybin. He said four to six doses of mushrooms a year have let him stop all other medications for the last decade. He still uses oxygen occasionally.
Wold became intrigued when a Scottish patient on a message board mentioned in 1998 that his headaches had gone away after he took LSD recreationally. LSD was hard to get in this country, but other patients began reporting that mushrooms, which are similar chemically, helped them, too. Most, he said, consume amounts well below a recreational dose.
Both LSD and psilocybin are considered illegal, schedule I drugs in the United States, meaning they have no accepted medical use and a "high potential for abuse." State laws vary, but it is generally illegal to possess psilocybin mushrooms. However, Wold said, spores are readily available on the internet, and patients can grow their own. He was not aware of arrests.
Wold's group has been pushing for high-quality science on mushrooms. Wold, who owns his own construction business and doesn't have a college degree, was intimidated when he went to Harvard University to beg for research on psychedelics.
The result was a report in the scientific journal Neurology in 2006, based on a survey of 53 cluster-headache patients who had tried mushrooms or LSD on their own. Eighty-five percent of respondents who tried the drugs during attacks said the pain stopped. Fifty-two percent said psilocybin stopped a cluster of headaches. The authors point out that the online survey may have disproportionately attracted people who had gotten good results.
Because the placebo response is notoriously high in pain research, the results should be taken with a grain of salt, but they were a foot in the door.
An intriguing alternative
John Halpern, a Harvard psychiatrist who has studied hallucinogenic drugs and was involved in the Neurology survey, was intrigued enough to pursue further research. Before attempting to get approval to study an illegal substance, he looked at other compounds similar to LSD. He found one, 2-bromo-LSD, that was very much like LSD but did not cause hallucinations. He worked with some German doctors to test that drug, which has few side effects, on patients in Europe.
That very small study - just five patients - was also intriguing. Three doses were able to break a cycle or improve the frequency and intensity of attacks.
Halpern was so convinced that the drug could be useful - and better than psilocybin - that he started a company and began trying to attract pharmaceutical company funding to test it. He got nowhere.
"This can be potentially life-changing," he said. "It just breaks my heart."
He recently left Harvard to be medical director of a new addictions-treatment hospital.
Meanwhile, Wold said, a team at Yale University has decided to pick up the work on psilocybin. Yale declined to comment.
Several headache specialists said they couldn't endorse the use of mushrooms but expressed sympathy with their patients and interest in their results.
"There's starting to be more of a recognition that some of the naturally occurring substances that haven't been considered up till now may have a risk/benefit ratio that's as good or better than things we can prescribe," Penn's Detre said.
Several experts said the cluster-headache patients mostly do not seem interested in the recreational effects of the drugs. "I've met loads of these people, and they're not people who have done drugs before," said Joanna Kempner, a sociologist at Rutgers University who has studied migraine and cluster patients. "They take these drugs very much as medicine."
Caution on psilocybin
Hannah said he tried mushrooms and the treatment made his headaches worse. He worries that psilocybin might harm patients with psychological problems and wants bigger, scientific studies before urging patients to try it.
Doctors at Jefferson and Penn Medicine said new treatments are in the works. Both systems are testing whether a monoclonal antibody known as LY2951742 (galcanezumab) can prevent both episodic and chronic cluster headaches. It targets the CGRP peptide, which is elevated in migraines and cluster headaches.
Jefferson's headache center also tested the electroCore vagus nerve stimulator, an electrical device that patients held against the side of their necks during headaches. The vagus nerve runs from the brain stem into the chest and abdomen.
The trial found positive results for episodic, but not chronic, headache. The stimulator is already approved in Europe and Canada.
A current trial is testing the sphenopalatine ganglion (SPG) stimulator, also already in use in Europe, for people with chronic cluster headaches. A study from earlier this year found that 45 percent of the 33 chronic cluster-headache patients in the trial had a positive response to the ATI Neurostimulation System.
Hannah is hopeful that more pharmaceutical companies and device-makers will take an interest in cluster headaches. "There's money to be made," he said.