Orexin-A (Hypocretin-1)

The native 33-amino-acid hypothalamic neuropeptide whose loss causes narcolepsy type 1, tested intranasally in small narcolepsy studies and in sleep-deprived monkeys, with no approved product anywhere and no registered development program.

Also referenced as: Orexin A, Hypocretin-1, Hcrt1, Hcrt-1

Also appears in: Hormone · Metabolic

COA Public product evidence No certificate records are bound to a tracked Orexin-A (Hypocretin-1) product page A record counts here only when a vendor publishes a certificate against one of its own tracked Orexin-A (Hypocretin-1) product pages. Other certificates naming this compound may still exist — search the wider certificate database. →

---

What is Orexin-A (Hypocretin-1)?

Orexin-A is a native human neuropeptide of 33 amino acids, cut from a 131-residue precursor encoded by the HCRT gene. Its mature sequence occupies residues 34 to 66 of that precursor and runs pyroGlu-Pro-Leu-Pro-Asp-Cys-Cys-Arg-Gln-Lys-Thr-Cys-Ser-Cys-Arg-Leu-Tyr-Glu-Leu-Leu-His-Gly-Ala-Gly-Asn-His-Ala-Ala-Gly-Ile-Leu-Thr-Leu, with a pyroglutamate at the N-terminus, an amidated C-terminal leucine, and two internal disulfide bridges linking the first cysteine to the third and the second to the fourth. The same precursor also yields orexin-B, a separate 28-residue peptide.

The molecule carries two names because two laboratories found it within weeks of each other in 1998. One group purified it from hypothalamic extracts while screening orphan G protein-coupled receptors and named the pair orexin-A and orexin-B for their effect on feeding (Sakurai et al., Cell, 1998;92(4):573-585). The other identified the precursor mRNA as a hypothalamus-specific transcript with partial similarity to secretin and called the products hypocretin-1 and hypocretin-2 (de Lecea et al., Proceedings of the National Academy of Sciences, 1998;95(1):322-327). Orexin-A and hypocretin-1 are the same peptide, and both names remain in routine use, the hypocretin form mainly in sleep medicine and the orexin form in pharmacology.

The peptide is made by a small population of neurons in the lateral and posterior hypothalamus whose axons reach the brainstem, thalamus, basal forebrain, and cortex. Destruction of those neurons produces narcolepsy type 1, which made orexin-A one of the most-studied neuropeptides in sleep research. No orexin-A product has been approved in any country, Drugs@FDA lists no application for it, and ClinicalTrials.gov lists no interventional study with the peptide as the intervention. Synthetic orexin-A circulates as a laboratory reagent, and the attention it attracts outside laboratories comes mainly from a single primate experiment on nasal delivery and sleep deprivation.

How it works

• Agonist at both orexin receptors, with the activating signal in its C-terminal half. Orexin-A binds the orexin-1 and orexin-2 receptors, two closely related Gq-coupled receptors, while orexin-B is selective for the orexin-2 receptor (Sakurai et al., Cell, 1998;92(4):573-585). Solution structures show a disulfide-constrained, hydrophilic N-terminal region unique to orexin-A followed by a helical C-terminal region shared with orexin-B, and the N-terminal region is what allows orexin-1 receptor recognition (Kim et al., Journal of Biochemistry and Molecular Biology, 2004;37(5):565-573; Takai et al., Journal of Peptide Science, 2006;12(7):443-454). Cryo-electron microscopy of the active-state orexin-2 receptor bound to an endogenous orexin peptide shows the extended C-terminal segment reaching into the receptor core to stabilize the active conformation, the same pocket a small-molecule agonist occupies (Hong et al., Nature Communications, 2021;12(1):815).
• Excitatory drive onto the arousal nuclei. Orexin-containing neurons project to multiple neuronal systems, including monoaminergic and cholinergic wake-promoting centers (Peyron et al., Journal of Neuroscience, 1998;18(23):9996-10015). The densest orexinergic innervation lands on the locus coeruleus, where applying orexin-A increases the firing of noradrenergic neurons and, in behaving rats, increases arousal and locomotor activity (Hagan et al., Proceedings of the National Academy of Sciences, 1999;96(19):10911-10916).
• Feeding and energy signaling. Centrally administered orexin-A and orexin-B stimulate food consumption in rats, and prepro-orexin mRNA rises with fasting, which is the observation that gave the peptides their name and placed them in the hypothalamic circuitry that links energy state to behavior (Sakurai et al., Cell, 1998;92(4):573-585).
• Unusual passage into the brain, which shapes how it has been given. In mice, radiolabeled orexin-A crossed the blood-brain barrier rapidly, by non-saturable simple diffusion, reached the parenchyma as intact peptide, and showed an octanol-buffer partition coefficient of 0.232, while orexin-B was degraded in blood and far less lipophilic (Kastin and Akerstrom, Journal of Pharmacology and Experimental Therapeutics, 1999;289(1):219-223). That finding, with evidence that nasally applied neuropeptides reach the human central nervous system (Born et al., Nature Neuroscience, 2002;5(6):514-516), is the stated rationale for the nasal and intravenous routes used in the human and primate work.

Research status

Deficiency in narcolepsy is the best-established finding. Hypocretin-1 was undetectable in the cerebrospinal fluid of seven of nine people with narcolepsy in the first clinical report (Nishino et al., Lancet, 2000;355(9197):39-40). Postmortem work found an 85 to 95% reduction in hypocretin neuron counts in narcoleptic brains, with neighboring melanin-concentrating hormone neurons spared and gliosis in the hypocretin cell field, pointing to a degenerative loss rather than a developmental absence (Thannickal et al., Neuron, 2000;27(3):469-474). A parallel study reported generalized absence of hypocretin peptides in narcoleptic brains and, in one unusually early-onset case, a Leu16Arg variant in the precursor that impaired trafficking and processing, the only HCRT coding variant linked to the disease (Peyron et al., Nature Medicine, 2000;6(9):991-997). A case series of 274 patients and 296 controls then set the diagnostic thresholds still in use: cerebrospinal fluid hypocretin-1 below 110 pg/mL was diagnostic for narcolepsy, values above 200 pg/mL were normal, and HLA-DQB1*0602 was present in 93% of patients with typical cataplexy against 17% of controls (Mignot et al., Archives of Neurology, 2002;59(10):1553-1562). Animal genetics reached the same circuit independently, with orexin knockout mice showing a narcolepsy phenotype (Chemelli et al., Cell, 1999;98(4):437-451) and canine narcolepsy traced to an orexin-2 receptor gene mutation (Lin et al., Cell, 1999;98(3):365-376).

The primate sleep-deprivation study. Rhesus monkeys kept awake for 30 to 36 hours were tested on a multi-image delayed match-to-sample memory task immediately after receiving orexin-A intravenously or as an atomizer spray mist to the nostrils. Both routes significantly improved performance in sleep-deprived animals, the nasal route outperformed the highest intravenous dose tested, and the gain was confined to trials classified as high cognitive load. Neither route changed performance in alert animals except at the top intravenous dose, and positron emission tomography showed the nasal route producing a more pronounced reversal of sleep-deprivation-related changes in regional cerebral glucose metabolism (Deadwyler et al., Journal of Neuroscience, 2007;27(52):14239-14247). It has not been followed by a human equivalent.

The three human studies, all from one center. A group in Kiel, Germany ran the only published human trials, each a double-blind, placebo-controlled crossover in patients with narcolepsy with cataplexy. In the first, ten patients had significantly worse olfactory threshold, discrimination, identification, and combined scores than matched controls, and in the seven patients given intranasal orexin-A the phenyl-ethyl alcohol detection threshold score rose from a median of 7.75 on placebo to 11.5 on active treatment (Baier et al., Brain, 2008;131(Pt 10):2734-2741). In the second, eight patients received human recombinant hypocretin-1 intranasally before night sleep with standard polysomnography: nocturnal wakefulness did not change significantly, rapid-eye-movement sleep quantity fell, particularly in the second half of the night, and direct wake-to-REM transitions were significantly reduced (Baier et al., Sleep Medicine, 2011;12(10):941-946). In the third, fourteen patients received intranasal orexin-A in the morning followed by a modified maintenance of wakefulness test, attention testing, and a further polysomnographic night; they again had fewer wake-to-REM transitions and shorter REM sleep, more stage N2 sleep the following night, and fewer false reactions on a divided-attention task (Weinhold et al., Behavioural Brain Research, 2014;262:8-13). A systematic review that screened 70 records and found only these three eligible human studies concluded that administered orexin reduces wake-REM transitions and total REM sleep without increasing wake time, and that the failure to relieve daytime sleepiness argues orexin deficiency is not the only mechanism in narcolepsy type 1 (Thomaz et al., Cureus, 2024;16(12):e76692).

Development moved to small molecules. No sponsor registered a clinical program for the peptide, and the therapeutic question it raised was answered instead by orally available orexin-2 receptor agonists. Two 12-week phase 3 trials of one such agonist in narcolepsy type 1, enrolling 168 and 105 participants, reported mean sleep latency gains of 14.3 to 19.8 minutes on the maintenance of wakefulness test against losses of 0.4 to 0.8 minutes on placebo, Epworth Sleepiness Scale changes of -9.7 to -11.8 against -1.5 to -1.7, and median weekly cataplexy reductions of 79.0 to 88.8% against 27.7 to 39.1%, with adverse events in 86 to 89% of treated participants and increased urinary frequency and transient insomnia in a majority (Dauvilliers et al., New England Journal of Medicine, 2026;395(12):1166-1179). Drugs@FDA records the approval of that agonist under NDA 220860 on August 5, 2026. Orexin-A itself remains a laboratory tool, and as of November 2026 the recent literature using it is preclinical.

Common dosage forms

• No approved presentation. No marketed orexin-A product exists in any jurisdiction, so there is no licensed vial, ampoule, pen, spray, or tablet presentation.
• Investigational intranasal solution. The human studies used human recombinant orexin-A in an aqueous vehicle delivered by a metered nasal applicator, prepared and administered by study staff at an academic sleep center.
• Investigational parenteral and nasal forms in animals. The primate work used an intravenous injectable solution and an atomizer that delivered a spray mist to the nostrils, both prepared for laboratory use only.
• Research-market powder. Synthetic orexin-A is supplied as a milligram-scale lyophilized powder in sealed vials as a laboratory reagent, which is not a sterile or labeled presentation for human administration.

Key considerations

• Regulatory status. The Research Market status reflects the absence of any orexin-A application in Drugs@FDA, of any approved orexin-A product in any country, and of any registered interventional trial listing the peptide as an intervention. The only US-approved drug acting on this system is an oral small-molecule orexin-2 receptor agonist approved on August 5, 2026 under NDA 220860, which is a different molecule.
• Measuring the peptide is clinical practice, replacing it is not. Cerebrospinal fluid hypocretin-1 below 110 pg/mL is an established diagnostic marker for narcolepsy type 1, and that assay is the peptide’s real foothold in medicine. Giving the peptide back has never been shown to restore wakefulness in a human trial.
• The human evidence is three small crossover studies from one center. Fewer than 30 patients in total received intranasal orexin-A, each in a single-administration design, and the consistent signals were on REM sleep architecture and one attention measure rather than on daytime sleepiness. No repeat-dose, multicenter, or dose-ranging human study has been published.
• Safety is uncharacterized. No toxicology program, pharmacokinetic study, or repeat-dose safety dataset for administered orexin-A in humans has been published, so the adverse-effect profile is unknown rather than reassuring. The phase 3 experience with a small-molecule orexin-2 receptor agonist indicates that sustained agonism at this target commonly produces insomnia and increased urinary frequency, which are on-target effects at this receptor.
• Naming and look-alikes. Orexin-A, hypocretin-1, and Hcrt1 denote the same 33-residue peptide; orexin-B and hypocretin-2 are a different peptide from the same precursor and are not interchangeable with it. The orexin-2 receptor agonist oveporexton and the orexin receptor antagonists used for insomnia, such as suvorexant, lemborexant, and daridorexant, are small molecules rather than forms of this peptide, and listings that use the bare word “orexin” do not establish which molecule is meant.