Abstract Excessive daytime sleepiness is a common feature of many neurologic disorders, including Parkinson’s disease, myotonic dystrophy, and multiple sclerosis. In the neurologic disorders of hypersomnolence, excessive daytime sleepiness occurs as the primary disease symptom, often accompanied by other sleep- related phenomena such as long sleep durations, pronounced sleep inertia, sleep-related hallucination, and sleep-related motor dysfunction. For two of these disorders, idiopathic hypersomnia and narcolepsy type 2, clinical features are indistinguishable and underlying pathophysiology is unknown. However, prior work has demonstrated that the macrolide antibiotic clarithromycin is more effective at reducing sleepiness than placebo in these two conditions, although the mechanism or mechanisms by which clarithromycin exerts this effect are unknown. Reduction in GABA-ergic neurotransmission, changes in resting state brain connectivity, suppression of soporific, pro-inflammatory cytokines, and alterations in gastrointestinal microbiome composition are all biologically plausible mechanisms for this effect, but have not been directly tested. In this work, a randomized, placebo-controlled trial of clarithromycin will be performed in patients with idiopathic hypersomnia and narcolepsy type 2 to evaluate for mediators of the beneficial effects of clarithromycin on pathologic sleepiness. The first aim is to identify central nervous system mediators of reduction in sleepiness by clarithromycin, including modulation of GABA-A receptor activity by cerebrospinal fluid in vitro and changes in default mode network connectivity via resting state fMRI. The second aim is to probe extra-neuronal mechanisms by which clarithromycin may reduce sleepiness, including changes in systemic inflammation and changes in gastrointestinal microbiota composition. For all aims, sleepiness will be characterized in a multi- modal fashion, with both self-reported measures of sleepiness, primarily the Epworth Sleepiness Scale, and objective measures of sleepiness, primarily the mean sleep latency measured on the Maintenance of Wakefulness Test. Each of the proposed mechanisms will be evaluated in relation to change in measures of sleepiness via mediation analysis to determine which mechanisms mediate clarithromycin’s reduction in sleepiness. This work leverages the PI and co-investigators’ clinical research expertise in the hypersomnolence disorders, the unique and highly motivated patient population at the Emory Sleep Center, and the complimentary expertise of a team of experienced collaborators. This work will impact the understanding of the central disorders of hypersomnolence and provide a foundation for future drug development for these and other neurologic disorders manifesting with pathologic daytime sleepiness.