Anesthesiologist Paul Garcia and his colleagues are presenting two posters at the Society of Neuroscience meeting this week, whose findings may raise concerns about two non-stimulant drugs Emory sleep specialists have studied for the treatment of hypersomnia: flumazenil and clarithromycin.

For both, the data is in vitro only, so caution is in order and more investigation may be needed.

With flumazenil, Garcia and colleagues found that when neurons are exposed to a low dose for 24 hours, the cells increase expression of some GABA receptor forms.

This could be part of a mechanism for tolerance. I heard some anecdotes describing how flumazenil’s wake-promoting effects wear off over time at the Hypersomnia Foundation conference in July, but it’s not clear how common the phenomenon is.

Flumazenil’s utility in hypersomnia became known after the pioneering experience of Anna Sumner, who has reported being able to use the medicine for years. See this 2013 story in Emory Medicine.

Please recall that GABA is the major inhibitory neurotransmitter in the brain, and GABA receptors are the site of action for sedative/anti-anxiety medicines called benzodiazepines and the mysterious “sleepy juice” found in the spinal fluid of hypersomnia patients.

Despite flumazenil’s use as a benzodiazepine antidote, Garcia says: “Flumazenil is not really an antidote for benzodiazepines, it’s just a really poor benzodiazepine agonist.”

That means that at high concentrations, it could actually induce sleepiness. But at lower concentrations, it interferes with either exogenous benzodiazepines or the endogenous “sleepy juice.”

The other GABA-counteracting drug studied for the treatment of hypersomnia is clarithromycin, which has an independent life as an antibiotic. In this case, researchers found that exposing cells to clarithromycin increases their excitability, which suggests that it may elevate susceptibility to seizure in certain patients, Garcia says. The abstract concludes:

The stimulatory properties of clarithromycin may have a positive impact on clinical applications such as emerging from anesthesia and promoting vigilance in hypersomnic patients. However, the administration of clarithromycin should be carefully considered in patients with seizure disorders.

Seizures were also a concern when flumazenil first was studied in hypersomnia, but that’s because it has been used in cases of benzodiazepine dependency. Block the benzos, and the nervous system is suddenly more excitable.