Sleep Disruption

Orexin (DORAs)

The discovery that orexin loss causes narcolepsy led to three FDA-approved dual orexin receptor antagonists (2014–2022). These drugs block wake-promoting signals rather than sedating the brain—a fundamentally different mechanism than benzodiazepines or Z-drugs. The most successful translation of peptide neuroscience into sleep medicine.

Desmopressin

FDA-approved synthetic vasopressin analog that reduces nighttime urine production. Cochrane review of 47 RCTs confirms efficacy for nocturia—the most common cause of sleep disruption in adults over 50. Not a sleep drug per se, but eliminates the single most frequent reason people wake up at night.

Cosyntropin

FDA-approved ACTH fragment used diagnostically to test adrenal function. Relevant to sleep through the HPA axis—the stress-response system whose dysregulation drives insomnia in anxiety, PTSD, and chronic stress. Not prescribed for sleep, but understanding cortisol's role in sleep architecture starts here.

MK-677 (Ibutamoren)

A non-peptide ghrelin mimetic with the most direct human sleep evidence in this condition. Copinschi et al. (1997) polysomnography study showed 50% increase in Stage IV (slow-wave) sleep duration and 20% increase in REM over 7 days in healthy young men. The best objective sleep data of any GH secretagogue.

Sermorelin

FDA-approved GHRH analog with indirect sleep relevance. The GHRH–slow-wave sleep coupling is well-established: GHRH injected into the brain reliably deepens slow-wave sleep in both animal and human studies. Sermorelin's clinical sleep data show improved subjective sleep as a secondary outcome, but no dedicated polysomnography trial.

DSIP

Delta sleep-inducing peptide—discovered in 1977 when fluid from sleeping rabbits induced delta waves in awake rabbits. Double-blind human RCT data exist. The paradox: despite 45+ years of research, the gene encoding DSIP and its receptor have never been identified. A real biological phenomenon without a known mechanism.

Galanin

The VLPO sleep-switch peptide. Galanin-expressing neurons in the ventrolateral preoptic area are the brain's primary sleep-promoting cells—they inhibit wake-promoting regions to initiate and maintain sleep. One human IV study exists. The biology is foundational; the therapeutic application is nascent.

Cortistatin

A somatostatin-related peptide that promotes deep slow-wave sleep when injected centrally. Discovered by Luis de Lecea in 1996. The name literally means 'cortical statin'—it quiets cortical activity. Zero human data for sleep. Elegant neuroscience that has not left the animal lab.

Melanin-Concentrating Hormone

A neuropeptide that selectively promotes REM sleep—the phase associated with dreaming, emotional processing, and memory consolidation. MCH neuron activation increases REM duration in animals. MCHR1 antagonists are being explored for narcolepsy (too much REM). Zero human sleep data for the peptide itself.

PACAP

Pituitary adenylate cyclase-activating polypeptide. A critical modulator of the suprachiasmatic nucleus—the brain's master circadian clock—and the retinohypothalamic pathway that entrains sleep-wake cycles to light. Extensive animal data on circadian regulation. No direct human sleep trials.

Corticotropin-Releasing Hormone

CRH is the master peptide of the stress response—the hypothalamic signal that triggers the HPA cascade leading to cortisol release. Elevated nocturnal CRH is consistently observed in insomnia, PTSD, and chronic anxiety populations. Human infusion studies confirm CRH fragments sleep architecture. Not a therapy—a target for antagonists still in early development.