Orexin-A (wake use)

Orexin-A is made by a few tens of thousands of neurons in the lateral hypothalamus and binds both orexin receptors — OX1R with high affinity and OX2R with comparable affinity, unlike orexin-B which prefers OX2R. Its job is not to generate wakefulness but to stabilise it: it excites the tuberomammillary histamine neurons, locus coeruleus noradrenergic neurons and dopaminergic and cholinergic arousal systems, preventing the abrupt state transitions that define narcolepsy. Narcolepsy type 1 is precisely the loss of these neurons, which is why replacing the ligand is such an obvious therapeutic idea. Intranasal delivery is used because orexin-A crosses the blood-brain barrier poorly and the nose-to-brain route bypasses that problem, at least partially. Orexin signalling also feeds into feeding behaviour, autonomic arousal, reward and panic circuitry, which is where the side-effect profile comes from.

Targets: Orexin receptor 1 (OX1R / HCRTR1), Orexin receptor 2 (OX2R / HCRTR2), Tuberomammillary histaminergic neurons, Locus coeruleus noradrenergic neurons

• · The narcolepsy-with-cataplexy crossover study used 435 nmol intranasally, which is about 1.55 mg. Doses of roughly 1 to 10 mg have appeared across human and primate intranasal work.
• · Far below the research dose, which is reasonable given the cost per milligram and the complete absence of a safety database. There is no established effective community dose - this range reflects what people use, not what has been shown to work.

Work out your exact syringe units →

• commonInsomnia if dosed too late in the day— Entirely predictable from the mechanism and the main practical problem.
• commonIncreased heart rate and blood pressure— Orexin drives sympathetic outflow; this is a real cardiovascular signal, not a theoretical one.
• commonIncreased appetite— Orexin was named for this effect before its wake role was understood.
• commonNasal irritation— Route-related.
• uncommonAnxiety, jitteriness or panic-like sensations— Orexin is heavily implicated in panic circuitry; people prone to panic attacks should avoid it.
• uncommonHeadache— Reported in intranasal studies.

• Panic disorder or severe anxiety - orexin signalling is directly implicated in panic attacks and can provoke them.
• Uncontrolled hypertension, arrhythmia or significant coronary disease - the sympathetic activation is real and measurable.
• Any evening or night-time dosing - the compound will keep you awake.
• Pregnancy and breastfeeding - no data.
• Stacking with high-dose stimulants such as amphetamine or modafinil, where the cardiovascular effects add up.

• conflictdsip — Direct functional opposition. Using both is only coherent if they are separated by a full 12-hour clock.
• cautionselank-anxiolytic — Selank is used to reduce anxious arousal; orexin raises it. The combination may simply cancel out.
• cautionsemax — Both are used intranasally for alertness and drive; combining them stacks stimulation without any data on the pair.

• · Check resting heart rate and blood pressure before and about an hour after a dose - this is the one genuinely worthwhile measurement for this compound.
• · Track that night's sleep after any daytime dose.
• · If narcolepsy is the actual problem, get a proper diagnosis including CSF hypocretin-1 measurement rather than self-treating.

Not approved anywhere as a therapeutic. Sold as a research reagent; expensive and frequently misrepresented in purity by grey-market suppliers.

• Baier et al. 2011, intranasal orexin-A on sleep, wakefulness and attention in narcolepsy with cataplexy (trial)
• Deadwyler et al. 2007, intranasal orexin-A restores cognitive performance in sleep-deprived rhesus monkeys (preclinical)
• Sakurai 2007, the neural circuit of orexin/hypocretin in sleep-wake regulation (review)
• Mignot et al., CSF hypocretin-1 deficiency in narcolepsy type 1 (trial)

Orexin-A does not generate wakefulness. It stabilises it, and that distinction is the whole story of this molecule. A few tens of thousands of neurons in the lateral hypothalamus make prepro-orexin, which is cleaved into orexin-A and orexin-B. Sakurai and colleagues identified both the peptides and their receptors in a single 1998 Cell paper, originally on the basis of feeding behaviour - hence the name, from the Greek for appetite. The wake role came later and turned out to be the important one. Orexin-A binds both OX1R and OX2R; orexin-B is OX2R-selective. Both receptors are class A GPCRs. OX1R couples predominantly to Gq, driving phospholipase C, IP3 and intracellular calcium; OX2R couples to Gq and also to Gi/Go, with the functional consequence depending heavily on the cell type. In arousal nuclei the net effect is depolarisation and increased firing. The circuit is the point. Orexin neurons project densely onto the tuberomammillary nucleus (histamine), the locus coeruleus (noradrenaline), the dorsal raphe (serotonin), the ventral tegmental area (dopamine) and the basal forebrain and laterodorsal tegmentum (acetylcholine). Every one of those is a wake-promoting node. Orexin sits above all of them and holds the whole assembly in a stable configuration. Take the orexin neurons away and the arousal nuclei still work - a person with narcolepsy type 1 is not permanently asleep - but the state becomes unstable. You get sudden intrusions of sleep into wake, sudden intrusions of REM phenomena into wake (that is cataplexy, sleep paralysis and hypnagogic hallucination), and fragmented night-time sleep. Narcolepsy type 1 is a flip-flop switch with the stabiliser removed. That also explains what the Baier trials found and why the results are less impressive than they should have been. In the 2011 Sleep Medicine crossover, 435 nmol of intranasal hypocretin-1 given to eight patients with narcolepsy and cataplexy before night-time sleep produced a clear REM-stabilising effect and significantly reduced direct wake-to-REM transitions, but did not significantly change night-time wakefulness. That is precisely what a stabiliser would do. It is not what someone hoping for a stimulant would want. The 2008 Brain paper from the same group found intranasal orexin-A restored the olfactory threshold deficit in narcolepsy patients, which is a striking demonstration that the peptide reached functionally relevant tissue, and also a demonstration of how far the measurable effects are from what a healthy person buying this would be after. The OX2R receptor is the one that matters for wake. This is not a subtle preference - OX2R knockout produces a much more narcoleptic phenotype than OX1R knockout, and OX2R is the receptor densely expressed on the histaminergic tuberomammillary neurons. The entire modern pharmaceutical effort has followed that fact. TAK-861 (oveporexton), an orally available OX2R-selective small-molecule agonist, produced wakefulness in monkeys and corrected narcolepsy phenotypes in mice, and Dauvilliers, Plazzi, Mignot and colleagues published its results in narcolepsy type 1 in the New England Journal of Medicine in 2025. That is the state of the art, and it makes the peptide look like what it is: a proof of concept that the field has already moved past. The side effect profile falls straight out of the mechanism. Orexin drives sympathetic outflow, so heart rate and blood pressure go up. Orexin was discovered through feeding, so appetite goes up. Orexin signalling in the amygdala and the panic circuitry of the periaqueductal grey is implicated in panic attacks, so anxiety goes up. None of these are idiosyncratic reactions. They are the drug working.

The commonest outcome is that nothing happens and you have spent a great deal of money. Community doses of 300 to 1000 mcg are well below the 1.55 mg used in the only controlled human study, the intranasal delivery fraction is unknown, and the peptide is fragile. A vial that has been shaken, freeze-thawed twice or sat in a fridge for a month in solution may contain very little intact orexin-A. Combine an unknown delivery fraction with a possibly degraded product and a sub-research dose and the modal result is nothing. The second is that something does happen and it is not what you wanted. The measured effect in humans was REM stabilisation and restored olfactory threshold, not a subjective alertness surge. People expecting a clean, drug-free wakefulness get, in the reports that exist, jitteriness, a raised heart rate and hunger. The third is panic. Orexin is deeply embedded in the panic circuitry of the amygdala and periaqueductal grey, and the anxiogenic effect is not a side effect in the incidental sense - it is the same signalling that produces the arousal. If you have panic disorder, this compound has a plausible mechanism for provoking an attack, and there is no antidote beyond waiting it out. The fourth is dosing after midday and destroying that night's sleep, which then generates the sleepiness that makes you dose again. This is an easy loop to fall into and it leaves you worse off than when you started. The fifth is product quality, and it is a bigger problem here than anywhere else in this class. Orexin-A carries two disulfide bonds. Disulfide-containing peptides scramble - the same four cysteines can pair the wrong way and produce an inactive isomer that is indistinguishable from the correct one by mass. Most vendor certificates of analysis are mass spectrometry and HPLC purity, neither of which reliably detects disulfide scrambling. Orexin-A is also expensive, which creates exactly the incentive to substitute or underfill. This is one of the peptides most frequently misrepresented on the grey market. And underneath all of it: if the reason you are considering this is that you are exhaustingly, disablingly sleepy in the daytime, the correct move is a sleep study and a CSF hypocretin measurement. Narcolepsy type 1 is a real disease with approved treatments and an active drug pipeline that has just produced a New England Journal of Medicine result. Self-medicating it with a research reagent means missing a diagnosis that gets you access to drugs that actually work.

1. 300 mcgFirst exposure — Well below any published dose. Morning only, on a day with nothing scheduled. Measure blood pressure and heart rate before and 45 to 90 minutes after. The purpose of this step is to find out whether you get a cardiovascular or panic response, not to feel anything.
2. 600 mcgSecond exposure, at least 72 hours later — Same conditions, same measurements. Track that night's sleep - a daytime orexin dose that wrecks the following night has cost you more than it gave you.
3. 1 mgThird exposure — The top of the community range. Still well under the published research dose.
4. 1.55 mgThe published research dose, for context only — The Baier 2011 narcolepsy crossover used 435 nmol intranasally, which works out to roughly 1.55 mg. This was given in a sleep laboratory to diagnosed narcolepsy patients under monitoring. It is listed as the number the data actually comes from, not as a home target - and note that even at this dose the measured effect was REM stabilisation, not a subjective alertness surge.

• Orexin receptor 2 (OX2R / HCRTR2) — Orexin-A and orexin-B are approximately equipotent at OX2R. Frequently quoted IC50 values in the region of 30 to 40 nM originate from Sakurai's 1998 Cell paper; the IUPHAR Guide to Pharmacology cautions that potency at orexin receptors depends heavily on the expression system and the response being measured, so treat any single number with suspicion.

  The wake receptor. Gq and Gi/Go coupled. Densely expressed on tuberomammillary histaminergic neurons. OX2R activation is what stabilises the wake state, and OX2R loss produces the narcoleptic phenotype far more than OX1R loss does. This is why every modern drug programme in this space is OX2R-selective.

• Orexin receptor 1 (OX1R / HCRTR1) — Orexin-A is roughly an order of magnitude more potent than orexin-B at OX1R. Quoted IC50 values around 20 to 30 nM for orexin-A trace to Sakurai 1998; same caveat about assay dependence applies.

  Predominantly Gq-coupled, driving PLC, IP3 and intracellular calcium. Expressed on locus coeruleus noradrenergic neurons among others. Contributes to arousal, and is also the receptor most associated with the anxiogenic, panic and sympathetic effects. OX1R is the receptor you would rather not be hitting if wakefulness is all you want, and orexin-A hits it.

• Tuberomammillary histaminergic neurons — Downstream circuit, not a binding site

  Excitation drives histamine release across the cortex. This is the principal wake-promoting output of orexin signalling and the reason antihistamines make you sleepy.

• Locus coeruleus noradrenergic neurons — Downstream circuit

  Excitation raises noradrenergic tone, contributing to arousal and to the suppression of REM. Also a route to the cardiovascular and anxiety effects.

• Ventral tegmental dopaminergic and basal forebrain cholinergic systems — Downstream circuit

  Contribute to the motivational and attentional components of the wake state. The VTA projection is also why orexin has a reward and addiction literature.

• Baier, Hallschmid, Seeck-Hirschner et al. - effects of intranasal hypocretin-1 (orexin A) on sleep in narcolepsy with cataplexy (Sleep Medicine 2011) Investigator-initiated double-blind, placebo-controlled crossover pilot · n=8 · 2011

  Polysomnographic sleep architecture after 435 nmol intranasal hypocretin-1 given before night-time sleep. Produced a clear REM sleep stabilising effect and significantly reduced direct wake-to-REM transitions; reduced REM sleep quantity particularly in the second half of the night; did not significantly affect night-time wakefulness.

• Baier, Weinhold, Huth, Gottwald, Ferstl and Hinze-Selch - olfactory dysfunction in narcolepsy with cataplexy is restored by intranasal orexin A (Brain 2008) Randomised, double-blind, placebo-controlled crossover · n=20 · 2008

  Olfactory threshold, discrimination and identification in 10 narcolepsy patients with cataplexy versus 10 matched controls, with intranasal orexin-A given to seven patients. Patients had significantly impaired olfaction; intranasal orexin-A raised the phenylethyl alcohol olfactory threshold score versus placebo. Important as proof that intranasally delivered orexin-A reaches functionally relevant tissue in humans.

• Deadwyler, Porrino, Siegel and Hampson - systemic and nasal delivery of orexin-A reduces the effects of sleep deprivation on cognitive performance in nonhuman primates (Journal of Neuroscience 2007) Preclinical, non-human primate · 2007

  Delayed match-to-sample performance in sleep-deprived rhesus monkeys after intravenous versus intranasal orexin-A, with PET imaging. Both routes improved performance; nasal was substantially more effective at the highest dose and produced more pronounced reversal of sleep-deprivation metabolic changes in task-relevant regions. This is the study the entire 'orexin as a sleep-deprivation rescue' idea rests on, and it is in monkeys.

• Dauvilliers, Plazzi, Mignot et al. - oveporexton, an oral orexin receptor 2-selective agonist, in narcolepsy type 1 (New England Journal of Medicine 2025) Phase 2b · 2025

  Wakefulness and narcolepsy symptom outcomes with an orally available OX2R-selective small-molecule agonist in narcolepsy type 1. Included here not because it is a peptide trial but because it is the reason peptide orexin-A is now of historical interest: the target was validated and the field moved to molecules with usable pharmacokinetics.

20 to 60 minutes after an intranasal dose: the window in which the published studies observed effects. In practice, what people describe is a mild lift in alertness and an increase in appetite, plus a measurable rise in heart rate if you bother to check. 1 to 3 hours: the plausible duration of any effect, based on the timescale over which the primate cognitive improvements were measured. There is no human pharmacodynamic curve. 3 to 6 hours: effect gone. Orexin-A has no depot behaviour and does not accumulate. That night: this is the part people forget. A morning dose is probably fine. An afternoon dose has a good chance of costing you sleep, and a late dose will. Track your sleep on any day you dose. Repeated use: unknown. There is no chronic human data of any kind. Whether receptor desensitisation occurs, whether the cardiovascular effect attenuates or compounds, and whether anything happens to the endogenous system are all open questions with no answers. Narcolepsy-specific note: in the Baier crossover the effect was on sleep architecture measured overnight, not on subjective daytime alertness. If you are expecting the compound to make you feel awake, the published human evidence does not support that expectation.

The honest answer is that orexin-A should not be in a stack, because there is no human safety data to stack on top of. What follows is harm reduction for people who are going to do it anyway. With caffeine: additive cardiovascular effect and additive anxiety. If you are going to use orexin-A, drop caffeine that morning rather than adding to it. This is the most common and most avoidable mistake. With modafinil or amphetamine: do not. Both raise sympathetic tone through different mechanisms, both raise blood pressure and heart rate, and orexin-A adds to both. The pharmacology stacks and there is nobody who has measured what the combination does. If you are already taking a prescribed stimulant for a diagnosed condition, adding an uncharacterised sympathomimetic peptide to it is the wrong move for a reason that does not require a study. With Semax: also intranasal, also used for drive and alertness, and competing for the same nasal mucosa on the same morning. Stimulation stacks and neither has been studied with the other. With DSIP: only coherent if separated by a full twelve hours - orexin in the morning, DSIP at night. And be clear about what you are doing, which is creating an artificial sleep-wake swing with two compounds that have no interaction data and no combined safety record. Most people who end up here would be better served by fixing their sleep schedule. With Selank or any anxiolytic: mechanically self-defeating. Orexin drives the panic circuitry that Selank is being used to quiet. You will spend money to cancel out. With anything that raises blood pressure - decongestants, yohimbine, high-dose thyroid, pre-workout formulas: this is the combination most likely to produce an actual adverse event. The cardiovascular signal from orexin is real and measurable and there is no reason to find out where the ceiling is. What pairs with it sensibly: bright light on waking, a fixed wake time, and food. All free, all better evidenced, all doing part of the same job.

Against oveporexton and the OX2R small molecules: this is the comparison that settles the question. Oveporexton is orally available, OX2R-selective, has real pharmacokinetics, and has published narcolepsy type 1 results in the New England Journal of Medicine. Peptide orexin-A is intranasal, non-selective (so you get the OX1R-mediated anxiety and sympathetic effects for free), has no measurable bioavailability, and has been given to a total of about fifteen people in two small studies from one group. If you have narcolepsy type 1, the correct action is to get diagnosed and get into that pipeline, not to buy a peptide. Against modafinil: modafinil is prescription, oral, has extensive trial data in narcolepsy and shift work disorder, costs very little generically, and works. It is not as mechanistically elegant - it does not replace what is missing - but for the practical goal of being awake it is not close. Against caffeine: caffeine is free, has the best-characterised dose-response of any psychoactive substance on earth, and produces a larger subjective alertness effect than anything reported for intranasal orexin-A in humans. If the goal is alertness after a bad night, caffeine plus twenty minutes of bright light is the intervention with the evidence. Against pitolisant or sodium oxybate: both approved for narcolepsy, both with real trial data. Both are the answer if the problem is a diagnosed disease. Against Neuropeptide S: NPS is the other wake-promoting peptide in this class and is even less developed - no human data at all, and no validated route to the receptor. Orexin-A at least has two controlled human studies and a clear delivery rationale. That comparison flatters orexin-A more than it should. As a piece of neuroscience rather than a product: orexin is one of the most important discoveries in sleep medicine of the last thirty years. Identifying the peptide, then identifying its loss as the cause of narcolepsy type 1, then building a drug that replaces the signal, is one of the cleanest translational arcs in the field. The peptide itself was a step along that path, not the destination.

$300–$2000/month. Orexin-A is among the most expensive peptides in ordinary circulation - 33 residues, two disulfide bonds, a pyroglutamate and a C-terminal amide all make it hard and costly to synthesise correctly. Research-supplier pricing typically runs into the hundreds of dollars per milligram. At community doses of 300 to 1000 mcg used a handful of times a month the cost lands in the low hundreds; anything approaching the 1.55 mg research dose used regularly runs into four figures monthly. These are indicative observations of research-reagent pricing, not sourced or surveyed data, and this is the compound where price varies most wildly between suppliers - which is itself a reason for suspicion.

• ?No human pharmacokinetic characterisation exists for intranasal orexin-A. No tmax, no bioavailability, no plasma or CSF concentration curve.
• ?The exact receptor binding affinities quoted for orexin-A at OX1R and OX2R could not be verified from a primary source in this session. The commonly cited IC50 values (roughly 20-30 nM at OX1R and 30-40 nM at OX2R) trace to Sakurai 1998, and the IUPHAR Guide to Pharmacology explicitly warns that orexin receptor potency is expression-system and readout dependent. Treat the numbers as indicative.
• ?Total human exposure across the two controlled studies is fewer than twenty subjects, all from one group in Kiel, all with narcolepsy. There is no controlled data in healthy people.
• ?The community dose range of 300 to 1000 mcg has no empirical basis. It reflects what people can afford, not what has been shown to do anything.
• ?There is no chronic safety data of any kind. Nobody has dosed a human repeatedly and looked.
• ?The magnitude of the blood pressure and heart rate effect at intranasal doses in humans has not been quantified. The cardiovascular concern is mechanistic inference plus animal data.
• ?Whether repeated administration causes receptor desensitisation or suppresses endogenous orexin production is entirely unknown.
• ?The participant count of 20 given for the Baier 2008 Brain study is the total study population (10 patients plus 10 controls); only seven patients actually received intranasal orexin-A.
• ?Participant numbers and duration for the Dauvilliers 2025 oveporexton trial were not extracted in this session.
• ?Disulfide bond integrity in commercially supplied orexin-A is not verifiable from a standard mass spectrometry or HPLC certificate of analysis. The purity figures vendors provide do not address the failure mode most likely to render the product inactive.
• ?The 3562 Da molecular weight in the Core record was not independently verified against an analytical source in this session, though the sequence and modifications were confirmed via UniProt O43612.
• ?Cost figures are indicative observations of research-reagent pricing, not sourced or surveyed data, and vary more for this compound than for any other in this class.

• Effects of intranasal hypocretin-1 (orexin A) on sleep in narcolepsy with cataplexy Baier PC, Hallschmid M, Seeck-Hirschner M, Weinhold SL, Burkert S, Diessner N, Goder R, Aldenhoff JB, Hinze-Selch D, Sleep Medicine, 2011 · PMID 22036605

  Sleep Med 12(10):941-6. The only placebo-controlled human trial of intranasal orexin-A on sleep. Eight subjects, 435 nmol, crossover. Everything anyone claims about intranasal orexin-A in humans traces back here or to the 2008 Brain paper.

• Olfactory dysfunction in patients with narcolepsy with cataplexy is restored by intranasal Orexin A (Hypocretin-1) Baier PC, Weinhold SL, Huth V, Gottwald B, Ferstl R, Hinze-Selch D, Brain, 2008 · PMID 18718966

  Brain 131(Pt 10):2734-41. Proof that intranasal orexin-A produces a measurable functional effect in humans, in a domain nobody was looking for.

• Systemic and nasal delivery of orexin-A (Hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates Deadwyler SA, Porrino L, Siegel JM, Hampson RE, Journal of Neuroscience, 2007 · PMID 18160631

  J Neurosci 27(52):14239-47. The primate sleep-deprivation study, and the direct comparison that established intranasal as the better route.

• Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al., Cell, 1998 · PMID 9491897

  Cell 92(4):573-85. The founding paper. Identified both peptides and both receptors, and named them for appetite because the wake role had not been recognised yet.

• Oveporexton, an Oral Orexin Receptor 2-Selective Agonist, in Narcolepsy Type 1 Dauvilliers Y, Plazzi G, Mignot E, et al., New England Journal of Medicine, 2025 · PMID 40367374

  N Engl J Med 392(19):1905-1916. The state of the art, and the reason to treat peptide orexin-A as a historical curiosity rather than a live option.

• TAK-861, a potent, orally available orexin receptor 2-selective agonist, produces wakefulness in monkeys and improves narcolepsy-like phenotypes in mouse models Mitsukawa K, Terada M, Yamada R, Monjo T, Hiyoshi T, Nakakariya M, Kajita Y, Ando T, Koike T, Kimura H, Scientific Reports, 2024 · PMID 39242684

  Sci Rep 14(1):20838. The preclinical package behind oveporexton, and a clear demonstration of why OX2R selectivity is the right design choice.

• Benefits of oveporexton in narcolepsy type 1 Wood H, Nature Reviews Neurology, 2025 · PMID 40490459

  Nat Rev Neurol 21(7):348. Short research-highlight summary of the NEJM result, useful as a plain-language entry point.

• Hypocretin: a promising target for the regulation of homeostasis Wang Y, Fu S, Mao J, Cui K, Jiang H, Frontiers in Neuroscience, 2025 · PMID 40927422

  Front Neurosci 19:1638270. Current review of orexin biology beyond sleep - feeding, autonomic, reward and metabolic roles.

• Orexin/hypocretin precursor (prepro-orexin), UniProtKB entry O43612 UniProt Consortium, UniProtKB

  Source for the orexin-A sequence, the pyroglutamate and C-terminal amide annotations, and the two disulfide bond positions given in this record. Resolved directly in this session.