Orexin A

What orexin A is

Orexin A and orexin B are formed from the same precursor, prepro-orexin, in nerve cells of the lateral hypothalamus. Orexin A is the larger of the two peptides, activates both orexin receptors and, after the second group that discovered it, is also called hypocretin-1. We describe the 1998 discovery and the receptors in more detail on the page on orexin B.

The system keeps the waking state stable. When the orexin cells die off, narcolepsy type 1 develops, with daytime sleepiness, cataplexy, sleep paralysis and disrupted night sleep; in the cerebrospinal fluid of patients with narcolepsy with cataplexy, orexin A is greatly reduced or not detectable at all. From this deficiency comes the obvious idea of replacing the missing peptide from outside.

On the market, orexin A appears as a laboratory peptide labeled “for research purposes only”, sometimes as a nasal spray, advertised against fatigue and sleep loss. Sleep medications that block exactly these receptors take the opposite route: the orexin receptor antagonists.

How it is supposed to work

If the signal is missing, you give it back – with peptides, this usually fails because of the route into the brain. Here orexin A has a real advantage: Kastin and Akerstrom showed in mice in 1999 that labeled orexin A, after intravenous administration, passes quickly and by simple diffusion into brain tissue and arrives there largely intact. With an octanol partition coefficient of 0.232, it is considerably more fat-soluble than orexin B at 0.030, which in addition breaks down rapidly in the blood.

The human experiments rely on intranasal administration. The Kiel research group, from which three of the four human studies come, based this on earlier findings according to which neuropeptides reach the brain directly by this route. Other peptides are also used via the nose, for example Semax. How well this route works for orexin A, however, was called into question by a PET study in 2018 (see below).

What the studies show

Sleep-deprived monkeys (2007)

Deadwyler and colleagues kept rhesus monkeys awake for 30 to 36 hours and gave them orexin A before a short-term memory task, either intravenously or as a fine spray mist into the nose. Both routes improved the performance of the sleep-deprived animals, the nasal route even more than the highest intravenous dose tested. The effect appeared mainly in difficult tasks, and the glucose metabolism in the brain regions involved, altered by sleep deprivation, moved back toward normal. In rested animals the peptide did not change performance, except at the highest intravenous dose. On the question of sleep loss, it is the central study – there is no study on this in humans.

Smell in narcolepsy (2008)

Baier and colleagues found a weaker sense of smell in ten patients with narcolepsy with cataplexy than in matched healthy people. Seven of them then received orexin A or placebo intranasally in a double-blind fashion. After orexin A, the olfactory threshold rose in all patients, to a median of 11.5 versus 7.75 points under placebo. The authors see this as an indication that the orexin deficiency in the brain explains the smell disorder.

Night sleep in narcolepsy (2011)

In a pilot study, the same Kiel group gave eight patients orexin A or placebo intranasally before sleep and recorded the night in the sleep laboratory. Nocturnal wake time did not change significantly. REM sleep, however, decreased, especially in the second half of the night, and direct transitions from wakefulness into REM sleep, a typical feature of narcolepsy, became less frequent.

Wakefulness and attention during the day (2014)

Weinhold and colleagues repeated the approach with 14 patients and gave the peptide in the morning. This was followed by a modified maintenance of wakefulness test, attention tests and another night in the sleep laboratory. Again, transitions from wakefulness into REM sleep and REM duration decreased, in the following night the light sleep stage N2 lengthened, and in the divided attention test the patients made fewer errors. An improvement in the maintenance of wakefulness test is not among the reported results.

Healthy men: sympathetic activity instead of wakefulness (2022)

The only study in healthy people so far comes from Lübeck. Ten lean young men received orexin A or placebo intranasally in a double-blind fashion; what was measured was the nerve activity that constricts the blood vessels in the muscles. It rose considerably more after orexin A, by 5.8 versus 2.1 bursts per minute. Blood pressure, heart rate and heart rate variability stayed the same. The authors interpret this as an effect on higher-level centers in the hypothalamus. Wakefulness or mental performance were not measured.

What arrives in the brain via the nose (2018)

Researchers from Sanofi and the Martinos Center in Boston labeled orexin A radioactively and tracked it by PET in rodents and monkeys. After intranasal administration, only a little of it reached the brain, in most brain regions about as much as after intravenous administration. Only in the olfactory bulb was uptake possibly higher. This dampens the expectation that the nose opens a direct route into the whole brain.

Where the data stop

The claim under which orexin A is sold – a wake-promoting agent for sleep loss – has never been tested in humans. There is no study with sleep-deprived healthy people, and the 2007 monkey experiment has not been repeated in humans. And in narcolepsy patients, who actually lack the peptide, wakefulness did not measurably improve with intranasal orexin A.

All four human studies gave a single dose to 7 to 14 participants, and three of them come from the same Kiel research group. Nothing is known about repeated use, tolerance, duration of effect or long-term consequences. ClinicalTrials.gov contains no study with the peptide as investigational substance.

The route itself is also open: the PET data argue against much arriving in the brain via the nose. And since August 2026 there has been a tested active substance at the orexin system, oveporexton, that works as a tablet. Whether an intranasal peptide would have any advantage over it has not been studied.

Status, approval and legal

Orexin A is not an approved medicine in Germany or the EU. As a food supplement, it would require authorization under the Novel Food Regulation (EU) 2015/2283, which does not exist. It is sold as a laboratory chemical for research purposes, sometimes as a nasal spray.

What is approved at the orexin system is a different substance: on August 5, 2026, the US Food and Drug Administration (FDA) granted approval for oveporexton under the name Orzeyful, for adults with narcolepsy type 1. The agency also names restrictions: not tested in minors, not together with strong CYP3A inhibitors, and classification under US controlled substances law had been recommended and was still pending at the time of approval.

In sport, the peptide falls under group S0 of the World Anti-Doping Agency: pharmacologically active substances without approval for therapeutic use in humans are prohibited at all times, even if they are not named on the list.

Safety

There are no systematic tolerability data. The four human studies each gave a single dose; nothing is known about repeated doses, longer use or interactions.

One finding deserves attention: in healthy men, orexin A increased the sympathetic activity that constricts blood vessels. Blood pressure and pulse remained unchanged in the measurement, but the authors consider a role of the orexin system in neurogenic high blood pressure worth investigating. The consequences of repeated doses are unknown.

What activation of the orexin system over weeks triggers has so far been shown only by the approved tablet drug: the most common effects were insomnia, more frequent urination, urinary urgency and increased salivation.

More important than any list of side effects is how the symptom is handled: persistent daytime sleepiness, sleep attacks or sudden muscle weakness with emotions call for evaluation by a sleep medicine specialist. Narcolepsy type 1 is treatable, and self-experimentation with laboratory material delays the diagnosis. With research-grade material, content, purity and sterility are also unverified.

Sources

• Kastin and Akerstrom, J Pharmacol Exp Ther 1999 – orexin A passes from blood into the brain by simple diffusion
• Deadwyler et al., J Neurosci 2007 – intravenous and intranasal orexin A in sleep-deprived rhesus monkeys
• Baier et al., Brain 2008 – sense of smell in narcolepsy with cataplexy and intranasal orexin A
• Baier et al., Sleep Med 2011 – intranasal orexin A and night sleep in narcolepsy, 8 patients
• Weinhold et al., Behav Brain Res 2014 – intranasal orexin A: sleep, wakefulness and attention in narcolepsy, 14 patients
• Meusel et al., J Neurophysiol 2022 – intranasal orexin A and sympathetic activity in 10 healthy men
• Van de Bittner et al., ACS Chem Neurosci 2018 – PET measurement of brain uptake of intranasal orexin A
• FDA, press release of August 5, 2026 – approval of Orzeyful (oveporexton)
• ClinicalTrials.gov – search for orexin A as investigational substance, without a study on the peptide
• NADA – Prohibited List 2026, informational German translation (group S0)