FANDOM AND SELF-EXPERIMENTATION

  The earliest posts on the Living with Hypersomnia site do not mention the Emory research; they were mostly personal stories and humor. But soon posts included explicit instructions (“What you say to your doctor if you want to trial clarithromycin”) and petitions to make flumazenil more widely available.

  A couple years before, members of the IH Facebook group had noticed listings for the flumazenil and clarithromycin studies on clinicaltrials.gov, but they didn’t get much attention. This time, Lloyd was head cheerleader. He urged his followers to nominate Rye for a Lifetime Achievement Award from the National Sleep Foundation.

  Throughout 2013, Emory patients shared information about the Living with Hypersomnia site and the Facebook groups with their doctors. Lloyd contributed to the surge in hypersomnia-related online activity both as a social media cheerleader and by experimenting on himself. He made a series of Facebook posts and YouTube videos about his experiences.

  Although he displayed bursts of energy while setting up his site, Lloyd was getting bogged down. According to Hughes’s story, at one point he stopped eating and drinking for three days, leaving his bed only to stumble to the bathroom. He applied for disability, but hypersomnia was not recognized as an illness by the Australian disability office. He had trouble explaining his illness to family and friends. At the beginning of 2013, according to the case report from his doctors, he was taking lithium because he had reported suicidal thoughts.

  He first tried clarithromycin, available with a prescription in Australia for its standard use as an antibiotic. He did get a temporary benefit for several days but experienced gastrointestinal side effects and a nasty taste in his mouth. After persisting more than a month, he gave up on clarithromycin.

  Lloyd then discovered that a doctor based in Perth, George O’Neil, had been treating benzodiazepine withdrawal with flumazenil implants.15 He was surprised that something that seemed so distant was only minutes away. In April 2013, he was able to walk out of O’Neil’s clinic with a syringe infusing flumazenil into his abdomen.

  In Australia, O’Neil was known for a history of public controversy over his enthusiasm for unlicensed naltrexone implants to treat opiate addiction.16 Naltrexone is analogous to flumazenil in that it is the pharmacological opposite of a class of drugs that many people become dependent on; it is an opioid receptor antagonist, one lasting longer than flumazenil.

  When Anna Sumner was first trying flumazenil, her doctors were concerned the drug might precipitate seizures. Paradoxically, addiction specialists in Australia and Italy have found that a low continuous dose of flumazenil can stave off anxiety and withdrawal symptoms in people who have developed benzodiazepine dependency. The mechanism is not well understood but is consistent with flumazenil acting as a very weak benzodiazepine. The risk of seizures is low, investigators in Italy have reported.17

  Erin Kelty, a researcher at University of Western Australia working with O’Neil, speculated that in this context, flumazenil might work like naltrexone.18 Low doses of flumazenil might reset the sensitivity of GABA receptors in brain circuits related to anxiety or withdrawal symptoms, she told me.

  With an initial infusion, Lloyd felt great, and he was able to reduce his sleep from more than thirteen hours per day (including naps) to less than eight hours. Four days later, he returned for a longer-lasting implant, costing about $3,000, which was similarly effective—for a while. Kelty, O’Neil, and colleagues calculated that most of the flumazenil in an implant would run out after two weeks.

  Lloyd tried additional implants and infusions, but even when he refilled the syringe every few days, the effects wore off. He was becoming tolerant to flumazenil. He found several weeks of abstinence were necessary to have its effect return. In 2014, Lloyd made Facebook posts about shortening the time needed to regain sensitivity to flumazenil by taking a sedative. In early 2015, he wrote: “When I take the flumazenil I take it by itself with no stimulants. It clears the brain fog, allows me to focus properly and my mood is back to happy/normal Lloyd.”

  Lloyd’s online activity tailed off after this point. Because of his poor health, Lloyd stopped maintaining the Living with Hypersomnia site, according to his mother. The last several posts on Living with Hypersomnia came from a friend in the United States. In the hypersomnia community, patient advocacy has—overall—shifted away from personal websites and blogs.

  BODY ON THE LINE

  Several years later, opinions still differed about Lloyd Johnson’s influence in the IH community in the United States. He was accused on social media of being manipulative, of hijacking the nascent IH community for his own goals, and of selling drugs such as modafinil online.19 Some distaste for the term “sleepyhead” may linger from his enthusiasm for it.

  For a time, Lloyd was close to the Ryes, staying at their house when he visited Atlanta and appearing on a “Doctors’ Roundtable” podcast with them. Yet they also parted ways with him after the Living with Hypersomnia conference. In an interview, Page-Rye declined to comment on Lloyd’s past activities.

  Michelle Chadwick has contended that he was more motivated by personal advancement than by building the IH community. Yet Lloyd also retained some supporters. “I am one of the most pro-Lloyd people out there,” said Oregon IHer David Kellogg, who credited Lloyd with saving his life with encouragement and emotional support. David recognized that Lloyd was willing to undergo a risky experiment with flumazenil implants. “He was putting his body on the line,” he said.

  A FREE COUNTRY

  Even though flumazenil’s mode of delivery was awkward and the benefits were not sustained, Lloyd’s personal example was critical in pushing Rye to make the drug more widely available in the United States. Rye did not want his patients to be left behind. He said later: “I was tired of seeing people who had run out of options, whose lives seemed stuck.” Several members of the hypersomnia community have said they considered traveling to Australia to try flumazenil implants themselves. Rye told Hughes: “I’m like, ‘This is bullshit.’ If this guy can do this in Australia and get access to this drug, there’s got to be something we can do. We live in a free frickin’ country.”

  In the United States, the first person after Anna to receive flumazenil for a chronic sleep disorder was Danielle Hulshizer, a former schoolteacher and administrator in Georgia who had been diagnosed with IH several years before. Hulshizer described herself as sleepy since childhood and recalled falling asleep in class in high school, but her family and teachers had attributed her sleepiness to her demanding schedule as a competitive figure skater.20

  Before being referred to Rye by one of his colleagues, Hulshizer was taking large amounts of Adderall—more than 100 mg per day—to compensate for her sleepiness. That level of dosing gave her debilitating headaches and tremors. “I couldn’t hold a pen steady,” she said. “Putting a spoon to my mouth was difficult. I had heart palpitations.”

  When she went on medical leave and abstained from stimulants, Hulshizer could only stay awake for a few hours per day. She had trouble driving to the grocery store. Her husband Scot repeatedly pushed Rye for alternatives. With flumazenil, Hulshizer found she could think clearly—an effect stimulants did not have. “Everyone focuses on the sleepiness, but that’s not the worst part of IH for me,” she said. “It’s the cognitive impairment while awake. Not being able to find the right words. I have always described it as being behind a semi-transparent wall.” Before she met Rye, she had felt alone. She didn’t know other people like her existed. “It was a huge revelation,” she said. “When I left his office, I felt like a weight had been lifted from my shoulders.”

  Rye’s records show he first started prescribing flumazenil for “hypersomnolence refractory to psychostimulants” around March/April 2013. He found a compounding pharmacy in Atlanta willing to process flumazenil into under-the-tongue lozenges and a skin cream. When he began contacting potential suppliers of flumazenil, one threatened to report him to the FDA. He consulted a friend at the FDA, who was reassuring but could give no official ruling.

  More cautious than Rye, Trotti disagreed with his haste, and they argued about it at the sleep clinic early in 2013. Rye and Trotti had been haggling with the FDA over potential sources of flumazenil for a more extensive clinical study. She then contacted the FDA to ask for permission to prescribe flumazenil for sleep disorders in modes other than intravenous administration. She did not receive a response until November 2013, just after the Narcolepsy Network meeting. The agency indicated it would not interfere with their ability to prescribe drugs but did not provide explicit clearance.

  By the end of 2013, Rye and Trotti had prescribed flumazenil to more than fifty patients with hypersomnolence and various diagnoses. Most of those who responded well had refilled the prescription, costing about $250 per month. One person had successfully negotiated with their insurance company to cover the cost. Many more were waiting for an appointment.

  Patients’ sources of access for flumazenil, compound pharmacies, represent a gray area within the health care system. They are regulated by states, not by the FDA. Their traditional role is to offer drugs in customized formulations that would not be available at a regular commercial pharmacy. This could mean smaller or liquid doses for pediatric use or removing certain additives for patients with allergies or sensitivities. With flumazenil, compounding pharmacies make it possible to offer the drug in a substantially different form. The FDA website states: “Compounded drugs can serve an important medical need for patients, but they do not have the same safety, quality and effectiveness assurances as approved drugs.”

  THE FIRST AND ONLY LIVING WITH HYPERSOMNIA CONFERENCE

  When organizers first posted notices online about the 2014 Living with Hypersomnia conference online, they thought they would just attract thirty or forty people, but the number kept growing. The managers at the airport hotel had to keep assigning them a larger room. The final count was more than 150 people.

  The majority was from Georgia, but a few people came from France, Canada, and Australia. Prabhjyot Saini, Rye’s “right hand” in the sleep clinic, served as cameraman. A few others besides patients and supporters were there, including Hughes and a medical science liaison from Jazz Pharmaceuticals. (Jazz will play a larger role in the IH story later, but its product Xyrem was not discussed extensively at the 2014 conference.)

  The proceedings started earlier than many would have liked. Not many people dozed off in their chairs, countering organizers’ expectations. The organizers sold T-shirts with the apples/oranges “seized by sleep/consumed by sleep” logo. Other shirts proclaimed “Living with Hypersomnia” or “Powered with Flumazenil.”

  The conference was Lloyd’s day in the sun—he served as jovial moderator, while Diana was on a patient panel. He kept the group chuckling with a series of jokes. Rye reprised his “What’s in a Name” talk on patient evaluation and diagnosis. Trotti methodically went through data available on both conventional treatments for hypersomnia: modafinil and stimulants such as methylphenidate and amphetamines. In a second presentation on newer treatments, she posed the question: “Should you be lobbying your doctor to give you flumazenil?” Not yet, without robust efficacy or safety data. “It may turn out to be safer than amphetamines, but we just don’t know right now.”

  Trotti laid out a four-part checklist she and Rye would use for prescribing flumazenil for hypersomnia. These were: at least two other drugs didn’t work, hypersomnia interfered substantially with job or family life, hypersomnia wasn’t caused by something else, and a spinal tap revealed the presence of GABA-enhancing “sleepy stuff” in the patient’s cerebrospinal fluid. At that point, Trotti said she was willing to prescribe clarithromycin without seeing results from a lumbar puncture, unlike flumazenil.

  She also disclosed the results of a small clinical trial of clarithromycin.21 The study was performed from July 2010 to September 2012 with a crossover design: two weeks of either clarithromycin or control, with a week in between. Taste and gastrointestinal side effects may have made some participants aware of what they received, she said. All had “GABA-related hypersomnia,” as verified by lumbar puncture. Participants could not be taking flumazenil, but they could be taking medications such as modafinil.

  With clarithromycin, participants reported an average improvement of almost four points on the Epworth Sleepiness Scale (from 14 to 10, on a scale from 0 to 24), but they did not experience an improvement in reaction time, as measured by the Psychomotor Vigilance Test. Despite the hiccups, Trotti later concluded: “The benefit observed is large enough to be clinically meaningful, and is of the same magnitude or higher than that reported with modafinil in narcolepsy and shiftwork trials.”

  When patients asked her about current studies, Trotti answered, “We don’t have a study,” since small-scale trials with flumazenil and clarithromycin were finished. However, the supply of compounded flumazenil she and Rye had established for the 2010 study was kept open. On paper, it was an improvised “expanded access” program without a corporate sponsor.

  During an energetic talk on “GABA 101,” Jenkins was asked why people with hypersomnia have more GABA-enhancing activity in their spinal fluid, after a day when several people had been speculating about the role of anesthesia. Lloyd stepped in and asked how many in the audience believed that their hypersomnia was a result of anesthesia. More than a dozen hands went up, surprising Jenkins. It was an example of how organizing could aggregate patient anecdotes. An Emory paper later documented the phenomenon of sleepiness exacerbation after anesthesia, sometimes lasting weeks or months.22

  In a symbolic move at the end of his talk, Jenkins donned an orange “Powered by Flumazenil” T-shirt. Addressing the group, he said: “Your brains are so tough—you’re fighting off the anesthesiologist in your head.”

  BEYOND EMORY

  At the end of the afternoon, Page-Rye introduced the newly formed Hypersomnia Foundation. A foundation could act as a research charity and advocate for people with IH, going beyond Emory University, she said.

  The Ryes had hosted prospective donors at their house the evening before, and earlier that day he had admitted that his lab’s research funds were running low, explaining delays in testing patient samples. Rye’s voice choked up while he described his patients’ experiences and the skepticism of other sleep specialists. “Do I think I know everything about this? No,” he said. “But one thing I do know is that these medications work.”

  Rye had set up a simple website for the Hypersomnia Foundation at the end of 2012.23 At its inception, the foundation appeared to be a vehicle for Rye and his colleagues at Emory. Early versions of the foundation’s website featured a prominent photo of him. Initially, the three medical and scientific advisors listed were Rye, Trotti, and Jenkins.

  When the foundation was formally established in 2014, all three founding officers—Jennifer Beard, Cate Murray, and Catherine Page-Rye—had some connection to Rye.24 Jennifer Beard’s link was through Diana. Murray had worked with Rye as executive director of the Restless Legs Syndrome Foundation.25 Murray had a personal stake, since her daughter recently had been diagnosed with IH, along with other conditions. Page-Rye was named as the first CEO.26 While Rye’s links to the Hypersomnia Foundation raised eyebrows at Emory because of past conflict-of-interest controversies at the medical school, there has been no self-dealing. The foundation has provided small-scale research awards to junior researchers at Emory but not to Rye, Jenkins, or Trotti.

  Patient advocacy organizations come in a wide range of sizes, depending on their specific foci.27 In the sleep disorders world, others such as Narcolepsy Network, the Restless Legs Syndrome Foundation, and the American Sleep Apnea Association were organized earlier, at the time of rapid growth in the sleep medicine field. Such groups also vary in terms of how much funding they accept from pharmaceutical industry sources; the Hypersomnia Foundation initially did not seek industry funding but later did for specific programs.

  Speakers at a 2015 conference, the first organized by the foundation, included the neurologist Isabelle Arnulf from Paris and the psychiatrist David Plante from the University of Wisconsin. Since that time, the foundation has recruited a broader stable of medical advisors, and they don’t necessarily agree with all of Rye’s ideas about hypersomnia. What he launched grew into something larger.

  Later conferences allowed the foundation to attract several parents of young people with IH, as well as people with IH themselves, as board members. One example was Diane Powell, a licensed clinical social worker and psychotherapist who attended the 2015 Hypersomnia Foundation conference. “Until I went to one of the conferences, I didn’t really get it,” Powell said. Her daughter had experienced excessive sleepiness throughout her teen years, and a physician at her college campus finally sent her daughter for a sleep study. After her daughter was diagnosed with IH, she had been hungry to find out what was known about the disorder. Her first reaction upon hearing her daughter’s diagnosis was relief—“Great, she’ll get treatment, she’ll be fine”—followed by puzzlement and frustration. Powell joined the organization’s board later that year and eventually became chair and CEO in 2017.

  In additional to updates on medical research, the foundation’s conferences have included motivational speakers, advice on educational accommodations, and presentations from an attorney and board member who specializes in Social Security Disability Insurance. Following Twery’s suggestion, the foundation established a relationship with South Dakota–based CORDS (Coordination of Rare Diseases at Sanford) and formed a registry for idiopathic hypersomnia patients, which both academic researchers and pharmaceutical companies have tapped.

  At a foundation conference in Baltimore, I attended a session for supporters of people with IH. Several spoke with regret about how they had previously viewed their loved ones’ sleepy behavior as a pattern of laziness or complaining. A few supporters seemed like they were on the verge of tears. They said they could see how difficult it was to have IH, and they were proud of their partners for facing up to it.