gabaa receptors, making them more susceptible to the sleep-inducing effect of gaba. for one person, daily administration of flumazenil by sublingual lozenge and topical cream has proven effective for several years. a 2014 case report also showed improvement in primary hypersomnia symptoms after treatment with a continuous subcutaneous flumazenil infusion. the supply of generic flumazenil was initially thought to be too low to meet the potential demand for treatment of primary hypersomnias. however, this scarcity has eased, and dozens of people are now being treated with flumazenil off-label. clarithromycin in a test tube model, clarithromycin (an antibiotic approved by the fda for the treatment of infections) was found to return the function of the gaba system to normal in people with primary hypersomnias. investigators therefore treated a few people with narcolepsy with off-label clarithromycin, and most felt their symptoms improved with this treatment. in order to help further determine whether clarithromycin is truly beneficial for the treatment of narcolepsy and idiopathic hypersomnia, a small, double-blind, randomized, controlled clinical trial was completed in 2012. "in this pilot study, clarithromycin improved subjective sleepiness in gaba-related hypersomnia. larger trials of longer duration are warranted." in 2013, a retrospective review evaluating longer-term clarithromycin use showed efficacy in a large percentage of people with gaba-related hypersomnia. "it is important to note that the positive effect of clarithromycin is secondary to a benzodiazepine antagonist-like effect, not its antibiotic effects, and treatment must be maintained." orexin receptor agonists orexin-a (a.k.a. hypocretin-1) has been shown to be strongly wake-promoting in animal models, but it does not cross the blood–brain barrier. the first line treatment for narcolepsy, modafinil, has been found to interact indirectly with the orexin system. it is also likely that an orexin receptor agonist will be found and developed for the treatment of hypersomnia. one such agent which is currently in clinical trials is danavorexton. l-carnitine abnormally low levels of acylcarnitine have been observed in people with narcolepsy. these same low levels have been associated with primary hypersomnia in general in mouse studies. “mice with systemic carnitine deficiency exhibit a higher frequency of fragmented wakefulness and rapid eye movement (rem) sleep, and reduced locomotor activity.” administration of acetyl-l-carnitine was shown to improve these symptoms in mice. a subsequent human trial found that people with narcolepsy given l-carnitine spent less total time in daytime sleep than people who were given a placebo. animal models animal studies try to mimic the disorder in humans by either modifying the hypocretin/orexin receptors or by eliminating this peptide. an orexin deficit caused by the degeneration of hypothalamic neurons is suggested to be one of the causes of narcolepsy. more recent clinical studies on both animals and humans have also revealed that hypocretin is involved in other functions beside regulation of wakefulness and sleep. these functions include autonomic regulation, emotional processing, reward learning behaviour or energy homeostasis. in studies where the concentration of the hypocretin was measured under different circumstances, it was observed that the hypocretin levels increased with the positive emotion, anger or social interaction but stayed low during sleep or during pain experience. the most reliable and valid animal models developed are the canine (narcoleptic dogs) and the rodent (orexin-deficient mice) ones which helped investigating the narcolepsy and set the focus on the role of orexin in this disorder. dog models dogs, as well as other species like cats or horses, can also exhibit spontaneous narcolepsy with similar symptoms as the ones reported in humans. the attacks of cataplexy in dogs can involve partial or full collapse. narcolepsy with cataplexy was identified in a few breeds like labrador retrievers or doberman pinschers where it was investigated the possibility to inherit this disorder in the autosomal recessive mode. according to a reliable canine model for narcolepsy would be the one in which the narcoleptic symptoms are the result of a mutation in the gene hcrt 2. the animals affected exhibited excessive daytime sleepiness with a reduced state of vigilance and severe cataplexy resulted after palatable food and interactions with the owners or with other animals. rodent models mice that are genetically engineered to lack orexin genes demonstrate many similarities to human narcolepsy. during nocturnal hours, when mice are normally present, those lacking orexin demonstrated murine cataplexy and displayed brain and muscle electrical activity similar to the activity present during rem and nrem sleep. this cataplexy is able to be triggered through social interaction, wheel running, and ultrasonic vocalizations. upon awakening, the mice also display behavior consistent with excessive daytime sleepiness. mice models have also been used to test whether the lack of orexin neurons is correlated with narcolepsy. mice whose orexin neurons have been ablated have shown sleep fragmentation, soremps, and obesity. rat models have been used to demonstrate the association between orexin deficiency and narcoleptic symptoms. rats who lost the majority of their orexinergic neurons exhibited multiple soremps as well as less wakefulness during nocturnal hours, shortened rem latency, and brief periods of cataplexy.