Neuropeptide S
The 20-amino-acid brain peptide that both wakes animals up and calms them, what measuring it in people shows, and why the nasal route has stayed in rodents
Neuropeptide S (NPS) is a 20-amino-acid peptide made by a few small clusters of brainstem neurons. It acts on one receptor, NPSR1. Given into the brains of mice and rats it increases wakefulness and activity yet reduces anxiety-like behaviour, an unusual combination for a drug target. It also aids fear extinction and memory in rodents and raises stress hormones. In people, plasma NPS has been measured in anxiety, depression and schizophrenia, and the cells that make it have been mapped in the human brainstem. Nasal NPS reached the brain and reduced anxiety in rats and mice, but no study read has given NPS to a person.
No established human dose Details ↓
Recommended Dosing
No established human dose
No dose exists for neuropeptide S. The human studies here measure it in blood or map the neurons that make it in donated brain tissue, or test it on human cells and intestinal muscle in the laboratory.
What is it?
Neuropeptide S was described in 2004 as the partner of an orphan receptor now called NPSR1. It is named for the serine at its start. In rodents only a few clusters of cells make it, mostly in the brainstem near the locus coeruleus, but its receptor is spread widely, including through the amygdala, thalamus and hippocampus. In the human pons the picture differs: about 22,000 NPS-making neurons were counted, most of them in the parabrachial area rather than beside the locus coeruleus.
The first experiments set the theme. Injected into the brain, NPS made mice more active and cut both deep and REM sleep in rats, yet it reduced anxiety-like behaviour in four different stress tests. Arousal drugs normally make animals more anxious, so this pairing drew interest as a possible treatment for anxiety and panic. Later rodent work found NPS also activates the stress-hormone axis, briefly raises or lowers food intake depending on where it is given, activates orexin neurons, and helps fear-memory extinction and object memory.
Getting NPS into the brain is the obstacle. Reviews note that it breaks down quickly and crosses the blood-brain barrier poorly. Rodent studies tried the nose: nasal NPS was taken up into receptor-bearing neurons in mice and kept its anti-anxiety effect, and in rats nasal NPS improved object memory and reduced anxiety while the same amount injected under the skin did nothing. These studies suggest a route for people, but none of them gave NPS to a human, and a search of PubMed and ClinicalTrials.gov found no human study that did.
Human work so far measures NPS. Plasma NPS was higher in generalised anxiety disorder, at a level that tracked anxiety scores, but no different in major depression. In men with schizophrenia, serum NPS fell as symptoms improved during rehabilitation therapy. Circulating NPS was about tenfold below the level needed to occupy its receptor, and was the same in inflammatory bowel disease and in healthy people. A common European variant of the NPS gene makes a weaker peptide, and a separate gene study found no link between that variant and sleep apnoea.
Much of the human genetics concerns the receptor gene, NPSR1, rather than NPS itself, and a 2021 review summarises links between receptor variants and anxiety, asthma and other traits. Those receptor studies are not counted as studies of the peptide here. NPS has no approved use and no dose.
Mechanism of Action
Neuropeptide S acts on a single receptor, NPSR1, found far more widely than the few brainstem clusters that make the peptide; in rodents that signalling raises arousal while lowering anxiety.
NPSR1 and calcium
NPS activates NPSR1, which mobilises calcium inside the cell; the receptor is spread through the amygdala, thalamus and hippocampus (PMIDs 15312648, 33922620).
Wakefulness
In rodents it cuts deep and REM sleep and raises activity; the parabrachial cluster of NPS neurons drives waking and faster breathing in mice (PMIDs 15312648, 38056461).
Fear and stress
It reduces anxiety-like behaviour and speeds fear extinction in rodents while raising ACTH and corticosterone, so arousal and anxiety come apart (PMIDs 15312648, 16574794, 40758097).
Outside the brain
It draws human monocytes toward it through its receptor and relaxes human intestinal muscle through nitric oxide (PMIDs 23142110, 26206857).
Published Research
These are studies of neuropeptide S and its own gene read from their PubMed abstracts: its discovery and rodent behaviour studies, the nasal-route experiments in rats and mice, measurements in human blood and brain tissue, laboratory work on human cells and the human NPS variant, and three reviews. Studies of the NPSR1 receptor gene and of synthetic receptor ligands are a different question and are not carded.
An arousal peptide that also lowers anxiety
NPS activated its receptor and raised calcium inside cells. Given into the brain it increased movement in mice and reduced deep and REM sleep in rats, and it produced anti-anxiety-like effects in mice in four different stress tests. NPS was made in a previously undefined cell cluster between the locus coeruleus and Barrington's nucleus.
Stress hormones and feeding
Given into the brain ventricles or the paraventricular nucleus of rats, NPS raised plasma ACTH and corticosterone and increased rearing and movement. In hypothalamic tissue it increased CRH and vasopressin release, and in the paraventricular nucleus it reduced food intake for the first hour.
Orexin neurons and feeding
Injected into rat brain ventricles, NPS switched on cells in the hypothalamus, midline thalamus and amygdala, including orexin-making neurons in the lateral hypothalamus. It increased food intake at 2 hours but not at 4 or 24 hours.
Breathing and arousal neurons
Mapping NPS neurons in mice, the authors found three clusters whose activity followed sleep and wake. Only the cluster in the lateral parabrachial area became active before waking, quietened in REM sleep, and when switched on increased wakefulness, reduced REM sleep and sped breathing.
Nasal NPS in rats
Given into rat brain ventricles, NPS improved object discrimination four hours later and reduced anxiety on the elevated plus-maze, but it did not change social memory or social preference. Applied to the nose, it improved object discrimination dose-dependently and reduced anxiety, while the same amounts injected under the skin did not.
Where nasal NPS goes in the mouse brain
Fluorescent NPS mapped target neurons throughout the mouse brain, and in the hippocampus it altered synaptic transmission and plasticity. The peptide entered neurons together with its receptor, and NPS applied to the nose reached the brain and kept its anti-anxiety effect, which the authors offer as a non-invasive route for rodent studies.
Higher plasma NPS in generalised anxiety disorder
In 40 patients with generalised anxiety disorder and 40 healthy controls, median plasma NPS was 28.8 against 19.1 pg/mL. It correlated weakly with anxiety rating scores, and a cutoff of 25.06 pg/mL identified the disorder with 68% sensitivity and 63% specificity.
No difference in major depression
In 79 patients with major depressive disorder and 78 controls, plasma NPS did not differ between the groups despite much higher anxiety and depression scores in the patients, and it did not correlate with age, body mass index or symptom scores.
Falls as schizophrenia symptoms improve
Thirty-three men with schizophrenia were assigned to three months of structured rehabilitation or standard support, with 15 healthy men for reference. Clinical improvement in the rehabilitation group went with a significant fall in serum NPS, most consistently on the excitement and hostility symptom factor, and not with metabolic measures.
NPS and cognition during rehabilitation
In the same trial of 33 men with schizophrenia, a falling serum NPS level accompanied better scores on sustained-attention and cognitive-insight tests and better clinical ratings, while auditory evoked potentials and quantitative EEG showed no relationship.
Mapped in the human pons
Using in situ hybridisation and stereology, the authors counted about 22,300 NPS-expressing neurons in the human pons, 84% of them in the parabrachial area, with only about 5% near the locus coeruleus, unlike rodents. Receptor-expressing neurons sat mainly in tegmental nuclei and the periaqueductal grey.
Gut motility and permeability, in rats and human tissue
In rats, NPS infusions slowed intestinal motility, lowered gut pressures and increased duodenal permeability through nitric oxide. In human intestine NPS sat in nerve cell bodies and fibres, and in human muscle strips it caused nitric-oxide-dependent relaxation; circulating NPS was about tenfold below its receptor's binding constant and no different in active inflammatory bowel disease than in health.
Human monocytes move toward NPS
NPS made human monocytes migrate across a wide concentration range, and three different NPS receptor blockers abolished the effect while leaving random movement untouched, so it works through the receptor. The pro-inflammatory peptide fMLP was used for comparison and was unaffected by those blockers.
A weaker European version of the peptide
A gene variant (rs4751440) swaps one amino acid in the mature peptide and is commoner in Europeans, probably arising there about 25,000 years ago. The variant peptide activated the receptor about 20-fold less potently than the usual form, and further work confirmed how much that position matters.
Gene variant and sleep apnoea
In 253 patients with obstructive sleep apnoea and 70 healthy people, the rs4751440 variant of the NPS gene was distributed the same way in both groups and was not linked to apnoea risk, daytime sleepiness, body mass index or insulin resistance, with a borderline exception for diastolic blood pressure.
The NPS system reviewed
This review of a transmitter system described less than twenty years earlier covers its pharmacology, where the peptide and receptor sit in the brain, and its roles in behaviour and immune function. It summarises hypotheses linking human receptor gene variants to disease and behaviour and looks at the therapeutic potential of drugs acting on the system.
Post-traumatic stress disorder and beyond
Surveying studies from 2000 to 2024, this review links a functional receptor variant to greater risk and severity of post-traumatic stress disorder, and describes how NPS given to rodents reduces anxiety and fear behaviour, speeds fear extinction, steadies the stress-hormone axis and reduces alcohol and opioid intake. It names rapid breakdown and poor blood-brain-barrier entry as the limits on translation, with nasal delivery and modified analogues as the proposed way round.
Learning and memory, systematically reviewed
This review of human and animal studies finds the NPS system acts at every stage of memory, including acquisition, consolidation, retrieval and extinction. It reports that NPS lessens learning impairments, strengthens spatial and object memory, supports fear extinction and can reinstate drug-seeking, and that it works alongside the orexin, dopamine and noradrenaline systems.
No Established Human Dose
No dose exists for neuropeptide S. The human studies here measure it in blood or map the neurons that make it in donated brain tissue, or test it on human cells and intestinal muscle in the laboratory. The nasal studies that are often cited as a route into the brain were done in rats and mice, and PubMed and ClinicalTrials.gov return no study that gave the peptide to a person. There is no approved product.
What this rests on: PMID 30911238, PMID 35741653, PMID 26441556.
Educational information, not medical advice. The doses on this page come from approved labels, published studies and, where no study exists, amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
What a Buyer Needs to Know
What is sold, how it is mixed, stored and taken, and what is known about its safety, quality and legal status. Each part names its source. Where we have none, it says unknown.
What is sold
Unknown: we hold no label and no published test that says what forms or vial sizes Neuropeptide S is sold in. A vial's own label is a seller's claim, not a source.
Mixing a vial: a worked example
Unknown: no human dose of Neuropeptide S has been established (see No Established Human Dose below), so there is no amount to work out. The reconstitution calculator does the arithmetic for any vial, water and dose.
Storage before and after mixing
Unknown: no label or published stability study on file says how to store Neuropeptide S, before or after mixing. The mixing guide sets out the general rules, with their sources: keep a mixed vial in the fridge, and use it promptly, as the bacteriostatic water label says of any drug dissolved in it. The 28 days often quoted is the limit for an opened multiple-dose vial from a manufacturer, an outer limit set for sterility, not a time a mixed solution has been shown to keep. Nobody has published how long Neuropeptide S stays intact once mixed.
How it is taken
Unknown: with no established human dose, there is no established way of taking Neuropeptide S. What the human studies gave and how is set out under No Established Human Dose.
What to expect, and when
Unknown: no cited half-life and no label or trial duration on this page says how long Neuropeptide S lasts or how long it was given. Results reported in the studies are under Published Research.
Side effects, and when to stop or get help
From the Side Effects section: More movement and less sleep in rodents, including less REM sleep (PMID 15312648); Higher stress hormones, ACTH and corticosterone, after injection into the rat brain (PMID 16574794); Slower gut motility and a leakier gut lining in rats given NPS infusions (PMID 26206857); No safety data in people. Full list and cautions ↓
When to stop or get help: unknown; no label or trial on file sets rules for stopping Neuropeptide S. Treat a severe or unexpected reaction as a reason to stop and see a doctor.
Source: the Side Effects section below.
Interactions
Unknown: a PubMed search for human interaction studies of Neuropeptide S (reviewed 2026-10-28) found none. Unknown is not the same as safe to combine.
Every peptide's record, with its source: the interaction matrix.
Checking what you bought
Unknown: no published independent test of Neuropeptide S products is in our lab-results database yet, so how products sold under this name measure up is not known.
To read a certificate of analysis, paste it into the COA decoder; it checks the measured mass against Neuropeptide S's expected mass, 2,187.5 Da, from this entry's molecular data. Trust & Verification explains what independent testing can and cannot show.
Legal status
US: Research Chemical (Not a medicine: an endogenous neuropeptide). Sport: Prohibited (S0 catch-all).
Country by country ↓ · Regulatory tracker
Source: this entry's approval status and the WADA Prohibited List, as in Legal Status below.
Side Effects & Contraindications
Reported Side Effects
Nobody has been given neuropeptide S, so the following are effects observed in animals.
Contraindications & Cautions
There is no product label. These cautions follow from the evidence.
Legal Status
Neuropeptide S is an endogenous research peptide; it is not approved as a medicine anywhere in the sources read.
Frequently Asked Questions
?What is neuropeptide S?
A 20-amino-acid peptide made by a few clusters of brainstem neurons, acting on one receptor called NPSR1. In rodents it raises arousal while lowering anxiety-like behaviour.
?Has anyone been given neuropeptide S?
Not in any study found. The nasal experiments often cited were done in rats and mice; human research measures the peptide in blood or maps its neurons in donated brain tissue.
?Is it a treatment for anxiety?
Only as a possibility. Rodent work shows anti-anxiety effects and faster fear extinction, and reviews call the system a promising target, but its rapid breakdown and poor entry into the brain have kept it out of human trials.
?What does measuring it in people show?
Plasma levels were higher in generalised anxiety disorder, unchanged in major depression, and fell as symptoms improved in men with schizophrenia. Circulating levels are far below those needed to occupy its receptor, so blood NPS is best read as a marker, not an active signal.
?Is the human system the same as the rodent one?
Not quite. In the human pons most NPS neurons sit in the parabrachial area, with very few near the locus coeruleus, the opposite of rodents, which matters when reading rodent results.
?What is its half-life?
No figure was found in the sources read; reviews describe it as rapidly degraded.
References
- [other] UniProt P0C0P6: neuropeptide S, Homo sapiens; peptide residues 70 to 89, SFRNGVGTGMKKTSFQRAKS. Read October 28, 2026. https://www.uniprot.org/uniprotkb/P0C0P6/entry
- [pubmed] Xu YL, et al. "Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects." Neuron, 2004;43(4):487-97. PMID: 15312648.
- [pubmed] Smith KL, et al. "Neuropeptide S stimulates the hypothalamo-pituitary-adrenal axis and inhibits food intake." Endocrinology, 2006;147(7):3510-8. PMID: 16574794.
- [pubmed] Niimi M. "Centrally administered neuropeptide S activates orexin-containing neurons in the hypothalamus and stimulates feeding in rats." Endocrine, 2006;30(1):75-9. PMID: 17185795.
- [pubmed] Angelakos CC, et al. "A cluster of neuropeptide S neurons regulates breathing and arousal." Curr Biol, 2023;33(24):5439-5455.e7. PMID: 38056461.
- [pubmed] Lukas M, et al. "Nasal application of neuropeptide S reduces anxiety and prolongs memory in rats: social versus non-social effects." Neuropharmacology, 2012;62(1):398-405. PMID: 21871467.
- [pubmed] Ionescu IA, et al. "Intranasally administered neuropeptide S (NPS) exerts anxiolytic effects following internalization into NPS receptor-expressing neurons." Neuropsychopharmacology, 2012;37(6):1323-37. PMID: 22278093.
- [clinical-trial] Baykan H, et al. "Plasma Neuropeptide-S Levels in Populations Diagnosed with Generalized Anxiety Disorder: A Controlled Study." Noro Psikiyatr Ars, 2019;56(1):52-56. PMID: 30911238.
- [clinical-trial] Baykan H, et al. "Investigating the relationship between plasma neuropeptide-S levels and clinical depression." Nord J Psychiatry, 2018;72(4):292-295. PMID: 29488437.
- [clinical-trial] Markiewicz-Gospodarek A, et al. "Relationship of Neuropeptide S with Clinical and Metabolic Parameters of Patients during Rehabilitation Therapy for Schizophrenia." Brain Sci, 2022;12(6). PMID: 35741653.
- [clinical-trial] Markiewicz-Gospodarek A, et al. "Relationship of Neuropeptide S (NPS) with Neurocognitive, Clinical, and Electrophysiological Parameters of Patients during Structured Rehabilitation Therapy for Schizophrenia." J Clin Med, 2022;11(18). PMID: 36142912.
- [clinical-trial] Adori C, et al. "Neuropeptide S- and Neuropeptide S receptor-expressing neuron populations in the human pons." Front Neuroanat, 2015;9:126. PMID: 26441556.
- [clinical-trial] Wan Saudi WS, et al. "Neuropeptide S inhibits gastrointestinal motility and increases mucosal permeability through nitric oxide." Am J Physiol Gastrointest Liver Physiol, 2015;309(8):G625-34. PMID: 26206857.
- [pubmed] Filaferro M, et al. "Neuropeptide S stimulates human monocyte chemotaxis via NPS receptor activation." Peptides, 2013;39:16-20. PMID: 23142110.
- [pubmed] Deng C, et al. "A single-nucleotide polymorphism of human neuropeptide s gene originated from Europe shows decreased bioactivity." PLoS One, 2013;8(12):e83009. PMID: 24386135.
- [clinical-trial] Sánchez-de-la-Torre M, et al. "Non-synonymous polymorphism in the neuropeptide S precursor gene and sleep apnea." Sleep Breath, 2011;15(3):403-8. PMID: 20405330.
- [review] Reinscheid RK, et al. "Pharmacology, Physiology and Genetics of the Neuropeptide S System." Pharmaceuticals (Basel), 2021;14(5). PMID: 33922620.
- [review] Zhu ZC, et al. "Neuropeptide S pathway in PTSD and neuropsychiatric disorders: A review." Biomol Biomed, 2025;26(2):227-239. PMID: 40758097.
- [review] Caragea VM, et al. "Neuropeptide S modulation of learning and memory: a systematic review." Behav Brain Funct, 2026;22(1). PMID: 42069596.
Sources & Citations
Every study on this page was read from its PubMed record on October 29, 2026. Status comes from Drugs@FDA (openFDA), the EMA medicines list and ClinicalTrials.gov, searched October 28 and 29, 2026. Grey Peptides sells nothing and links to no vendor.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.