Also known as: Hypocretin-1, OX-A
Half-life: ~30-60 minutes (CSF)
Last reviewed: · Published:
Orexin-A (also called Hypocretin-1) is a 33-amino-acid neuropeptide produced by a small population of neurons in the lateral hypothalamus. Together with its sister peptide Orexin-B (Hypocretin-2), it is one of the principal wake-promoting and arousal-regulating signals in the mammalian brain. Orexin neurons project broadly to monoaminergic and cholinergic arousal centers (locus coeruleus, dorsal raphe, tuberomammillary nucleus, laterodorsal/pedunculopontine tegmentum), and Orexin-A binds with high affinity to both orexin receptor subtypes (OX1R and OX2R).
The medical significance of the orexin system was established when narcolepsy type 1 (narcolepsy with cataplexy) was identified as an autoimmune destruction of the orexin neuron population. Patients with type 1 narcolepsy have essentially undetectable orexin-A in cerebrospinal fluid. This discovery has motivated extensive drug-development efforts: dual orexin receptor antagonists (DORAs — suvorexant/Belsomra, lemborexant/Dayvigo, daridorexant/Quviviq) are now FDA-approved for insomnia, and orexin receptor agonists are in clinical development for narcolepsy itself.
Research-grade synthetic Orexin-A is sold by peptide vendors and is used in animal research on arousal, sleep-wake regulation, and feeding (orexin neurons also play a role in feeding behavior and reward). Intranasal Orexin-A has been investigated in small clinical studies as a potential treatment for cognitive impairment and sleep disturbance, with some interesting but very early findings. Human therapeutic use is investigational only.
Orexin-A and Orexin-B were independently discovered in 1998 by two groups (Masashi Yanagisawa's lab at UT Southwestern, who named them "orexins" for their initial association with feeding; and Luis de Lecea's lab at the Scripps Research Institute, who named them "hypocretins" for their hypothalamic origin and structural similarity to secretin). Both names persist in the literature. The link to narcolepsy was established in 1999-2000 through work by Emmanuel Mignot at Stanford (canine narcolepsy genetics) and Yanagisawa's group (orexin knockout mice).
Single-dose intranasal Orexin-A in small clinical studies has been generally well-tolerated, with the main effect being the intended increase in wakefulness and arousal. Chronic safety in humans is not characterized. Because orexin signaling is involved in reward processing and the orexin system is implicated in addiction biology, sustained exogenous orexin administration has theoretical concerns about altering reward sensitivity that have not been studied.
Dose Range
20-80 mcg
Frequency
As needed for wakefulness
Duration
Acute use
Dose Range
Variable per protocol
Frequency
ICV or IV
Duration
Per protocol
Dosing information is for educational purposes only. Consult a healthcare professional before using any peptide.
Typical Vial Size
5 mg
Water Type
Bacteriostatic water (BAC water) or sterile saline for intranasal
Mixing Volume
2 mL
Half-Life
~30-60 minutes (CSF)
Molecular Weight
3,562 Da
Store reconstituted vial refrigerated at 2-8°C. Use within 14 days. Intranasal administration is the most studied non-research-lab route, taking advantage of direct CNS delivery via the olfactory pathway.
FDA Status
Not FDA approved as a therapeutic. Orexin receptor antagonists (suvorexant, lemborexant, daridorexant) are FDA-approved for insomnia.
Legal Status
Unregulated research chemical. Prohibited by WADA.
USA
Not approvedResearch-only; antagonists approved separately for insomnia
EU
Not approvedNot authorized as medicinal product
UK
Not approvedClassified as research chemical
Australia
Not approvedTGA has not authorized
Canada
Not approvedNot authorized for human use
Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M
Cell (1998)
Original discovery and characterization of orexin-A and orexin-B by Yanagisawa's group, establishing them as hypothalamic neuropeptides with feeding and arousal effects.
View Study →Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, Nevsimalova S, Aldrich M, Reynolds D, Albin R, Li R, Hungs M, Pedrazzoli M, Padigaru M, Kucherlapati M, Fan J, Maki R, Lammers GJ, Bouras C, Kucherlapati R, Nishino S, Mignot E
Nature Medicine (2000)
Landmark study establishing the absence of orexin-A from CSF and orexin neurons from brains of patients with narcolepsy type 1, validating the orexin system as the master regulator of wakefulness.
View Study →Baier PC, Hallschmid M, Seeck-Hirschner M, Weinhold SL, Burkert S, Diessner N, Göder R, Aldenhoff JB, Hinze-Selch D
Sleep (2011)
Early clinical study of intranasal orexin-A in narcolepsy patients showing measurable effects on REM sleep regulation and providing the proof-of-concept for direct orexin replacement therapy.
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