Almost precisely a decade ago, a young Atlanta lawyer named Anna was returning to work, after being treated for an extraordinary sleep disorder. Her story has been told here at Emory and by national media outlets.

Fast forward a decade to Idiopathic Hypersomnia Awareness Week 2018 (September 3-9), organized by Hypersomnolence Australia. What this post deals with is essentially the correction of a date at the tail end of Anna’s story, but one with long-term implications for many people with difficult-to-treat sleep disorders.

In the summer of 2008, Anna Sumner (now Pieschel) was planning on getting back to her life and career. A few years before, she had been diagnosed with a condition with a frustrating name: idiopathic hypersomnia. It means “she sleeps a lot and we don’t know why.”

Neurologist David Rye and nurse practitioner Kathy Parker had treated Anna first with conventional stimulants, which were spectacularly unsatisfactory. See this 2013 Emory Medicine story for details. Parker and Rye eventually landed on something less conventional: flumazenil, an antidote for sedatives that was scarce and difficult to administer. After wrangling with the FDA and with flumazenil’s manufacturer, a longer-term solution came into view. At that time, Anna was unique: the only person taking flumazenil chronically for a sleep disorder.

Then she developed bronchitis. She lost her voice, which was a problem for someone whose professional role sometimes takes her to court. To treat her bronchitis, Anna’s internist had prescribed the antibiotic clarithromycin, known commercially as Biaxin. After taking it, she developed insomnia and couldn’t sleep for three days. She left frantic messages for neurologist Lynn Marie Trotti, who had become her main sleep specialist.

“This had never happened to me before,” she recalled recently. “I was concerned that it was some bizarre individual reaction to the medication.”

In our original Emory Medicine story, this event was described as taking place in 2010. That date was incorrect. By examining a paper that Trotti and others later published on the wake-promoting effects of clarithromycin, it is possible to see a clue to when it actually occurred:

From the group of hypersomnia patients demonstrating levels of enhancement greater than controls on this assay, we selected all those who had taken oral clarithromycin from September 2008 through November 2012.

The timing can be confirmed in other ways. Anna recalls that around that time, she was defending the manager of a foster home for abused dogs. The foster home was facing noise complaints in Gwinnett County court. Most of Anna’s legal work is conducted behind the scenes, but this late August 2008 proceeding was covered by the Atlanta Journal Constitution. She co-founded a group called Atlanta Lawyers for Animal Welfare and is a board member for Paws Atlanta.

In addition, Rye offhandedly mentioned that he was attending a sleep research meeting in Glasgow (September 9-13) when Anna’s insomnia came to Trotti’s attention. In hindsight, it was impossible for this episode to have happened in 2010. Inspired by the report of Anna’s experience, neuroscientists Andy Jenkins and Paul Garcia investigated clarithromycin’s cellular effects and presented their results at a 2009 conference.

Garcia and Jenkins found that clarithromycin is different from flumazenil, which was originally developed as an antidote to benzodiazepines, the class of drugs that includes Valium and Xanax. For Anna, flumazenil seems to fend off a sleep-promoting benzodiazepine-like substance whose identity is still unclear. If that substance is not present, flumazenil is not supposed to do much. However, clarithromycin will still inhibit GABA-A receptors – the molecular gates where benzodiazepines act – even if the “sleepy stuff” is absent. What tipped the balance in Anna’s case was the combination of the two drugs together.

The discovery of clarithromycin’s effects was a door-opener for Rye and Trotti, who then had a practical option for treating patients with refractory hypersomnia. Clarithromycin was relatively inexpensive and, in contrast to flumazenil, was available outside of regulatory constraints. It led to a randomized controlled clinical trial of clarithromycin, published in 2015.

To be sure, clarithromycin has its own set of drawbacks: occasional reports of “agitation, euphoria, and insomnia” as well as a common side effect of leaving a lingering metallic taste. A look at the FDA’s Adverse Event Reporting System shows that hundreds of adverse events, mainly gastrointestinal and skin problems, were associated with clarithromycin’s use as an antibiotic last year. In 2018, the FDA issued a warning about the risks of clarithromycin in people with heart disease.

Paul Garcia and colleagues went on to probe clarithromycin’s effects on neurons and GABA signaling, but how much it gets into the central nervous system and how it works in the body are still unclear. It may be acting in an anti-inflammatory mode or even disrupting the intestinal microbiome. However, the example of clarithromycin led to other clinical trials of agents that may act through a similar anti-GABA mechanism. The results of those studies are yet to come.