Intranasal Orexin Therapeutics for Sleep and Cognition: A Review of Pharmacological and Chronobiological Perspectives in Space Medicine

Astronauts on prolonged space missions experience profound sleep–wake disturbances due to
microgravity, circadian desynchronization, and radiation exposure, leading to impaired cognition
and reduced operational performance. Similar pathophysiological features are observed in
terrestrial disorders such as narcolepsy, Alzheimer’s disease, and age-related cognitive decline,
where current pharmacotherapies provide only partial benefit. This review highlights
multidisciplinary approaches for mitigating circadian and cognitive dysfunction, including light
based entrainment, pharmacological modulation, gut–brain axis interventions, and complementary
traditional practices. Particular emphasis is placed on the hypothalamic orexin (hypocretin)
system, a central regulator of arousal, motivation, and memory. Intranasal administration of
orexin-A peptides has emerged as a promising non-invasive strategy to bypass the blood–brain
barrier and restore neural signaling. Preclinical evidence demonstrates enhanced cognitive
resilience and reversal of sleep-related deficits with this approach. By integrating chronobiology,
neuropharmacology, and innovative drug delivery, orexin-targeted therapeutics hold strong
potential not only for space medicine but also for aging populations and neurodegenerative
disease management on Earth.