Research Only Cognitive & Nootropic

Orexin-A

also known as: Hypocretin-1, OX-A, HCRT-1

The hypothalamic wakefulness peptide — loss of orexin neurons causes narcolepsy, and blocking its receptors produced the blockbuster insomnia drugs suvorexant and lemborexant.

A 33-amino-acid peptide produced exclusively by ~70,000 neurons in the lateral hypothalamus that maintains wakefulness, stabilizes sleep-wake transitions, and regulates appetite — its deficiency is the definitive cause of narcolepsy type 1.

Mechanism of action

Binds OX1R (selective) and OX2R (non-selective) — both Gq-coupled GPCRs that depolarize target neurons. Orexin neurons project widely to the locus coeruleus, dorsal raphe, tuberomammillary nucleus, and basal forebrain, stabilizing the 'wake' state of the sleep-wake flip-flop switch. Loss of orexin neurons (autoimmune destruction) causes narcolepsy type 1 with cataplexy.

Primary uses

Endogenous wakefulness stabilization
CSF orexin-A measurement as diagnostic biomarker for narcolepsy type 1 (<110 pg/mL)
Drug target: DORAs for insomnia; orexin agonists in development for narcolepsy

Typical dosing

N/A N/A N/A (endogenous)

Not used as a drug. Normal CSF orexin-A levels are >200 pg/mL; narcolepsy type 1 is diagnosed when CSF levels fall below 110 pg/mL.

Regulatory status

Orexin-A itself is not an approved drug, but dual orexin receptor antagonists (DORAs) targeting its receptors are FDA-approved blockbusters: suvorexant (Belsomra, 2014), lemborexant (Dayvigo, 2019), and daridorexant (Quviviq, 2022). Orexin agonists are in clinical trials for narcolepsy.

References

[pubmed] de Lecea L, et al. "The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity." Proc Natl Acad Sci USA. 1998;95(1):322-327.
[pubmed] Sakurai T, et al. "Orexins and orexin receptors." Cell. 1998;92(4):573-585.
[review] Mahoney CE, et al. "The neurobiological basis of narcolepsy." Nat Rev Neurosci. 2019;20(2):83-93.

Related peptides

Orexin-B

The second orexin isoform — a 28-amino-acid peptide that preferentially activates the OX2 receptor most critical for maintaining wakefulness.

Neuropeptide Y

The brain's most abundant neuropeptide — a 36-amino-acid master regulator of appetite, stress resilience, and anxiety that connects metabolic and cognitive peptide networks.

Ghrelin

The 'hunger hormone' — the only known circulating appetite stimulant, and the endogenous ligand that GHRP-2, GHRP-6, and MK-677 were designed to mimic.

DSIP

An endogenous 9-amino-acid peptide named for its ability to induce delta-wave sleep in early rabbit experiments, with broader effects on stress response, pain modulation, and circadian regulation.

Disclaimer

This entry is for educational purposes only and does not constitute medical advice. Dosing information reflects published regulatory or research data and is not a recommendation. Many compounds described here are not approved for human use in the United States. Consult a licensed medical professional before considering any peptide therapy.