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Orexin-A

Updated · 27 sources · Editorial policy

Orexin-A, also called hypocretin-1, is a neuropeptide made by a small cluster of neurons in the hypothalamus. It is one of the brain’s main signals for staying awake. Two research groups described it independently in 1998, one naming the peptides “orexins” and the other “hypocretins” (Sakurai et al., Cell 1998; de Lecea et al., PNAS 1998).

The single most important fact about orexin-A is what happens when it is missing. People with narcolepsy type 1 (narcolepsy with cataplexy) have lost most of their orexin-producing neurons, and orexin-A is very low or undetectable in their spinal fluid. The orexin system is now the target of approved drugs: orexin receptor blockers for insomnia and, since August 2026, an oral orexin receptor agonist for narcolepsy type 1. Orexin-A itself is not an approved medicine. In people it has only been tested as single intranasal doses in a few small pilot studies.

This page summarizes what the discovery papers, the clinical studies and the FDA labels report. It is for education only and is not medical advice.

Property Detail
Type Endogenous neuropeptide (brain signaling molecule) from the hypothalamus
Other names Hypocretin-1, Hcrt-1, OXA
Structure 33 amino acids, two internal disulfide bridges, blocked at both ends; same sequence in humans, rats and mice
Receptors Binds both orexin receptors (OX1R and OX2R) with high affinity
Role in disease Lost in narcolepsy type 1; spinal fluid hypocretin-1 below 110 pg/mL is diagnostic
Approval status Not an approved drug; human data limited to single intranasal research doses (435–500 nmol)
Half-life ≈27 min in rat plasma after IV infusion; no human pharmacokinetic data
Approved drugs acting on the system Suvorexant, lemborexant, daridorexant (receptor antagonists, insomnia, US Schedule IV); oveporexton (OX2R agonist, narcolepsy type 1, approved August 2026)
WADA status Not named on the 2026 Prohibited List; class S0 covers substances with no approval for human therapeutic use

What it is

Orexin-A and orexin-B are cut from the same precursor protein, prepro-orexin (Scammell and Winrow, Annu Rev Pharmacol Toxicol 2011). The two peptides differ in shape:

Feature Orexin-A Orexin-B
Length 33 amino acids 28 amino acids
Shape Held in a folded shape by two disulfide bridges Linear, likely forms two helices
Ends Front end capped as a ring (pyroglutamyl); tail end amidated Tail end amidated
Species differences Identical in humans and mice Two amino acids differ between humans and mice
Receptor preference Both OX1R and OX2R Mainly OX2R

The capped ends and disulfide bridges probably protect orexin-A from breakdown, which may be why it has longer-lasting effects than orexin-B in animal studies (Scammell and Winrow 2011). PubChem lists the molecule (CID 56842143) with the formula C₁₅₂H₂₄₃N₄₇O₄₄S₄ and a molecular weight of 3561.1 g/mol (PubChem).

Receptors

The orexins act on two G protein-coupled receptors (receptors that signal into the cell through G proteins), OX1R and OX2R. In the original binding experiments, OX1R bound orexin-A much more tightly than orexin-B (IC50 20 nM vs 420 nM; lower means tighter binding). OX2R bound both peptides about equally (38 nM and 36 nM) (Scammell and Winrow 2011, summarizing Sakurai et al. 1998). Activating these receptors generally excites the target neuron.

Where it comes from and what it does

The human brain has about 50,000–80,000 orexin neurons, all in the lateral and nearby hypothalamus. They send fibers to the main arousal centers: the noradrenaline cells of the locus coeruleus, the histamine cells of the tuberomammillary nucleus, the serotonin cells of the raphe and the dopamine cells of the ventral tegmental area (Scammell and Winrow 2011).

The peptides were first named “orexins” (from the Greek for appetite) because injecting them into rat brains increased food intake (Sakurai et al. 1998). Their role in wakefulness became clear a year later. Mice lacking the orexin gene showed a pattern of sleep and sudden collapses closely resembling human narcolepsy (Chemelli et al., Cell 1999).

Orexin loss in narcolepsy type 1

Within two years of the mouse findings, several human studies showed that narcolepsy with cataplexy (sudden muscle weakness triggered by emotions such as laughter) is an orexin-deficiency disease:

  • Spinal fluid. Hypocretin-1 was undetectable in 7 of 9 people with narcolepsy (Nishino et al., Lancet 2000).
  • Brain tissue. Autopsy brains of people with narcolepsy showed an 85–95% reduction in the number of hypocretin neurons. Neighboring neurons that make a different peptide (MCH) were not reduced, so the loss was specific (Thannickal et al., Neuron 2000). A second study found a global loss of hypocretin peptides in all brains examined (Peyron et al., Nat Med 2000).
  • Genes. Mutations in the hypocretin gene were very rare. Only one was found in 74 patients screened, in a child with unusually early onset (Peyron et al. 2000). In most people the neurons are lost rather than never formed.

A study of 274 patients and 296 controls set the diagnostic cut-offs still used today. Spinal fluid hypocretin-1 below 110 pg/mL was diagnostic for narcolepsy, and values above 200 pg/mL were considered normal. The immune-system gene variant HLA-DQB1*0602 was found in 93% of people with narcolepsy and typical cataplexy vs 17% of controls. This is one reason the neuron loss is thought to be immune-driven (Mignot et al., Arch Neurol 2002).

In narcolepsy type 2 (without cataplexy), the orexin neurons are generally thought to keep working (Thomaz et al., Cureus 2024). That is why the orexin-replacement approaches below are tested in type 1.

Pharmacokinetics

There are no human pharmacokinetic studies of orexin-A given as a drug. The available data are from animals:

Finding Species Source
Plasma half-life ≈27 min (27.1 ± 9.5 min) after IV infusion, with first-order kinetics Rats Ehrström et al., Regul Pept 2004
Orexin-A crossed from blood into brain by simple diffusion, mostly intact; orexin-B was rapidly degraded in blood Mice Kastin and Akerstrom, JPET 1999
After intranasal dosing, brain exposure measured by PET imaging was poor; overall brain uptake was similar to IV dosing, with possibly more in the olfactory bulbs Rodents and nonhuman primates Van de Bittner et al., ACS Chem Neurosci 2018

The PET study matters for the human research below. The rationale for intranasal orexin-A is a direct “nose-to-brain” route. In this imaging work, that route did not deliver much peptide to the brain beyond what reached it from the blood.

Regulatory status and approved drugs acting on the orexin system

Orexin-A itself is not approved as a medicine by the FDA. Four approved US drugs act on its receptors. None of them contains orexin-A.

Orexin receptor antagonists (insomnia)

Dual orexin receptor antagonists (“DORAs”) block both OX1R and OX2R. Their labels state that blocking orexin-A and orexin-B “is thought to suppress wake drive.”

Drug (brand) First US approval Labeled dose Half-life (label) US schedule
Suvorexant (Belsomra) 2014 10 mg at bedtime; maximum 20 mg ≈12 h IV
Lemborexant (Dayvigo) 2019 5 mg at bedtime; maximum 10 mg 17–19 h (effective) IV
Daridorexant (Quviviq) 2022 25–50 mg at bedtime ≈8 h IV

Sources: Belsomra label, Dayvigo label, Quviviq label.

All three are approved for insomnia with trouble falling or staying asleep. All three labels:

  • Contraindicate use in narcolepsy. Blocking orexin in someone who already lacks it is expected to worsen the disease.
  • Warn of narcolepsy-like effects. These include sleep paralysis, hallucinations at sleep onset or waking, and cataplexy-like weakness.
  • Warn of next-day impairment and complex sleep behaviors. Examples are impaired driving and sleep-walking.

Orexin receptor 2 agonist (narcolepsy type 1)

On August 5, 2026, the FDA approved oveporexton (Orzeyful, Takeda), an oral small-molecule drug that stimulates OX2R. It is indicated for narcolepsy type 1 in adults (Takeda, 2026). It is the first approved drug designed to replace the missing orexin signal. It is a synthetic small molecule (molecular weight 520.51), not orexin-A, and it acts on OX2R.

From the prescribing information (Orzeyful PI, August 2026):

Item Label detail
Strengths 0.5 mg, 1 mg, 2 mg tablets
Dose 1 mg or 2 mg after waking, then the same dose 3–5 hours later; maximum 4 mg/day
Half-life ≈23.2 h; metabolized mainly by CYP3A4
Contraindication Strong CYP3A inhibitors
Controlled-substance status Schedule pending DEA review at approval; a human abuse-potential study found “drug liking” above placebo and similar to or below phentermine

What the research shows

Intranasal orexin-A in people

All human studies of orexin-A as a treatment used a single intranasal dose in small crossover trials. In a crossover trial, each person receives both the active spray and placebo on different days.

Study Participants Dose Main findings
Baier et al., Brain 2008 7 people with narcolepsy with cataplexy (double-blind, randomized, placebo-controlled crossover) Not stated in abstract Smell detection threshold score improved: median 11.5 after orexin-A vs 7.75 after placebo (P under 0.05)
Baier et al., Sleep Med 2011 8 people with narcolepsy with cataplexy, dosed before night sleep 435 nmol No significant change in nighttime wakefulness; less REM sleep, especially in the second half of the night; fewer direct wake-to-REM transitions
Weinhold et al., Behav Brain Res 2014 14 people with narcolepsy with cataplexy, dosed in the morning 435 nmol vs sterile water Fewer wake-to-REM transitions and shorter REM sleep; more N2 sleep the next night; fewer errors on a divided-attention test
Meusel et al., J Neurophysiol 2022 10 healthy lean young men 500 nmol Sympathetic nerve activity to muscle blood vessels rose (+5.8 vs +2.1 bursts/min, P = 0.007). Blood pressure, heart rate and heart-rate variability did not change

In the 2008 study, patients also had a mildly reduced sense of smell compared with 10 matched controls. The authors proposed that orexin loss contributes to this (Baier et al. 2008).

A 2024 systematic review found only three randomized human studies of orexin-A for narcolepsy type 1. It concluded that orexin-A reduced REM sleep and wake-to-REM transitions but did not increase wake time or relieve daytime sleepiness (Thomaz et al., Cureus 2024). This is the core symptom patients need treated. Possible explanations include poor brain delivery by the nasal route (see Pharmacokinetics) and the single-dose design.

Animal studies

In sleep-deprived rhesus monkeys, orexin-A given intravenously or as a nasal spray improved performance on a short-term memory task (Deadwyler et al., J Neurosci 2007). This result has not been tested in people, and monkey cognitive data do not show an effect in humans.

Orexin agonist drugs: what replacing orexin signaling can do

The clearest evidence that restoring orexin signaling treats narcolepsy type 1 comes from oral OX2R agonists, not from orexin-A itself.

TAK-994 (phase 2, 73 patients, 8 weeks). Sleepiness and cataplexy improved strongly vs placebo. Mean sleep latency on the Maintenance of Wakefulness Test (MWT, minutes a person can stay awake in a dark, quiet room) improved by 26.4–35.0 minutes more than placebo. However, the trial and its extension were stopped early because of liver toxicity. Three patients met Hy’s law criteria for drug-induced liver injury (Dauvilliers et al., NEJM 2023).

Oveporexton (two phase 3 trials, 273 patients, 12 weeks). The FirstLight trial enrolled 168 participants and RadiantLight 105 (Dauvilliers et al., NEJM 2026). Label results:

Outcome at week 12 Study 1: 1 mg twice daily Study 1: 2 mg twice daily Study 2: 2 mg twice daily
MWT sleep latency, difference vs placebo (95% CI) +13.8 min (10.2–17.4) +17.2 min (13.7–20.7) +20.1 min (16.6–23.6)
Epworth Sleepiness Scale, difference vs placebo (95% CI) −8.0 (−9.9 to −6.1) −9.8 (−11.6 to −7.9) −9.5 (−11.1 to −8.0)
Weekly cataplexy rate, ratio vs placebo (95% CI) 0.34 (0.20–0.57) 0.38 (0.23–0.61) 0.25 (0.15–0.42)

Source: Orzeyful PI. Baseline MWT latency was about 4–6 minutes, and the label defines 20 minutes or more as normal.

Side effects and risks

Orexin-A itself

No systematic safety data exist. The human studies gave a single dose to a few dozen participants in total, and their abstracts do not report adverse-event rates. The one study in healthy men showed that a single 500 nmol nasal dose raised sympathetic (“fight or flight”) nerve activity to blood vessels, although blood pressure did not change (Meusel et al. 2022). Long-term effects of repeated dosing are unknown.

Orexin-A is not an approved product. Any product sold outside a clinical study has no label, no verified dose and no quality standard.

Effects seen when orexin receptors are stimulated by an approved drug

The oveporexton label shows what strong OX2R stimulation can do in people. These effects come from a different, longer-acting molecule and cannot be assumed to apply to orexin-A. In the pooled phase 3 trials (Orzeyful PI):

Adverse reaction Placebo (n = 76) 1 mg twice daily (n = 60) 2 mg twice daily (n = 136)
Insomnia 1% 55% 60%
Urinary frequency 5% 53% 58%
Urinary urgency 1% 15% 16%
Excess saliva 0% 8% 7%
  • Insomnia usually began in the first 2 days. About 63% of cases resolved within a week, and none led to stopping treatment.
  • Muscle enzyme (CPK) rises over 5 times the upper limit occurred in 11% on oveporexton vs 5% on placebo. Two patients with marked CPK and liver-enzyme rises stopped treatment.
  • Blood pressure and heart rate. In-clinic systolic rises of over 20 mm Hg occurred in 22% vs 13% on placebo, and heart-rate rises of over 15 bpm in 30% vs 22%. These were seen mostly on day 1. By week 12, the placebo-adjusted mean changes were under 5 mm Hg and under 2 bpm.
  • LDL cholesterol rose by a mean 17.6 mg/dL vs 4.4 mg/dL on placebo.

Effects of blocking orexin

The antagonist labels show the reverse picture: sleepiness the next day, sleep paralysis, hallucinations and cataplexy-like weakness. This is why all three are contraindicated in narcolepsy (Belsomra label).

  • United States. Orexin-A is not an FDA-approved drug and is not named in the controlled-substance schedules (21 CFR part 1308). Suvorexant, lemborexant and daridorexant are listed in Schedule IV (21 CFR 1308.14). Oveporexton’s schedule was pending DEA review when it was approved, and it was not yet listed in the October 2026 eCFR text.
  • Sport. Orexin-A and orexin agonists are not named on the WADA 2026 Prohibited List. Its class S0 bans, at all times, any pharmacological substance that is not covered elsewhere on the list and has no government approval for human therapeutic use.

Key takeaways

  • A natural wake-promoting brain peptide. Orexin-A is a 33-amino-acid hypothalamic peptide that activates both orexin receptors and drives arousal.
  • Its loss causes narcolepsy type 1. People with this condition have lost 85–95% of orexin neurons, and spinal fluid hypocretin-1 below 110 pg/mL is diagnostic.
  • Intranasal orexin-A is still experimental. Four small single-dose studies showed effects on REM sleep, smell and sympathetic nerve activity, but not on daytime sleepiness.
  • Nose-to-brain delivery is uncertain. PET imaging in animals found poor brain exposure after nasal dosing.
  • Approved drugs target the receptors, not the peptide. Suvorexant, lemborexant and daridorexant block orexin for insomnia. Oveporexton, approved in August 2026, stimulates OX2R and markedly improved wakefulness and cataplexy in narcolepsy type 1.
  • Receptor stimulation has real side effects. With oveporexton these included insomnia and urinary frequency in over half of patients, plus CPK, blood pressure and LDL rises.

Sources

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