Orexin A

What it is

Orexin A is an excitatory neuropeptide produced primarily by neurons in the lateral hypothalamus (PMID 39470537; PMID 52). It signals through two G-protein-coupled receptors, OX1R (orexin receptor type 1) and OX2R (orexin receptor type 2) (PMID 38892431; PMID 29680730). Key documented signaling pathways include: activation of the mTOR/p70S6K1 pathway to inhibit autophagy and promote cortisol secretion in adrenocortical cells; inhibition of the NF-κB and MAPK/ERK/p38 pathways to reduce astrocytic inflammation and apoptosis in cerebral ischemia-reperfusion injury (PMID 34358627; PMID 33212156); suppression of exosomal PD-L1 via the JAK2/STAT3 pathway in colon cancer cells; inhibition of the JNK and NF-κB pathways in hepatocytes; inhibition of the NEK7/NLRP3 inflammasome pathway to reduce neuroinflammation; induction of ferroptosis in glioblastoma via regulation of TFRC, FTH1, and GPX4 through NFE2L2; and modulation of VTA dopamine neuron firing via OX1R, interacting with the μ-opioid receptor system. Orexin A is expressed not only in the brain but also in human peripheral tissues including the gastrointestinal tract myenteric plexuses, pancreatic islet cells, sympathetic ganglia, and placenta. Its broad physiological roles include regulation of sleep-wake cycles, feeding behavior, sympathetic tone, energy homeostasis, pain modulation, stress responses, gut-brain signaling, reward/motivational activation, and immune modulation (PMID 52; PMID 31068086; PMID 28360013; PMID 39470537).

Class: Hypothalamic neuropeptide / excitatory peptide neurotransmitter

What it's studied for

• Narcolepsy — CSF biomarker and pathophysiology Human observational
  • CSF orexin-A levels were significantly lower in narcolepsy type 1 patients (median <35 pg/mL) vs. controls (98 pg/mL). LC-MS/MS values were ~5× lower than commercial RIA values. Orexin-A was stable in CSF for 12 months when frozen. PMID 33539807 Lindström et al., Clinical biochemistry (2021)
  • CSF hypocretin-1 (orexin-A) levels examined in childhood narcolepsy and neurologic disorders (no abstract text available beyond MeSH). PMID 15623725 Arii et al., Neurology (2004)
• Parkinson's disease — CSF and plasma biomarker Mixed
  • Meta-analysis of 18 studies (244 PD patients): CSF orexin-A was lower in PD than controls (mean difference −59.21, 95% CI −89.10 to −29.32), though within normal range. Mean OXA level in PD: 281.52 pg/mL (95% CI 226.65–336.40). PMID 38781804 Suresh et al., Clinical neurology and neurosurgery (2024)
  • Plasma orexin-A was significantly higher in PD patients (n=121) vs. healthy controls (n=117). Levels elevated in early/medium-stage PD but decreased in advanced-stage. Correlated with sleep disorders, anxiety, cognitive dysfunction, and REM-sleep behavior disorder. PMID 33161104 Huang et al., Neuroscience letters (2021)
• Alzheimer's disease — biomarker and potential role in pathology Mixed
  • Orexin-A expression upregulated in APP/PS1 transgenic mice; increased wakefulness and reduced NREM sleep observed alongside higher density/distribution of orexin-A-positive neurons. PMID 35066609 Zhao et al., Brain structure & function (2022)
  • In AD mice with acute sleep deprivation, orexin-A expression was reduced. Molecular dynamics simulations showed orexin-A binds Aβ with high affinity and inhibits aggregation. Orexin-A transgenic rat data suggested potential neuroprotective role. PMID 41335394 Singh et al., Molecular neurobiology (2025)
  • Intracerebroventricular injection of orexin-A in APP/PS1 mice aggravated cognitive deficits, promoted Aβ accumulation, and worsened mitochondrial impairment (conflicting/context-dependent role). PMID 31927055 Li et al., Neuroscience letters (2020)
  • In HEK293-APPSWE cells treated with orexin-A (50, 100 nmol/L), mitochondrial biogenesis decreased, mitophagy increased, and mitochondrial structure was damaged compared to non-treated AD model cells. PMID 33080054 Zhu et al., Clinical and experimental pharmacology & physiology (2021)
• Lewy body disease — CSF biomarker Human observational
  • Meta-analysis (179 LBD patients, 253 controls): orexin-A CSF levels in LBD were lower than in AD (SMD −0.35) and higher than in FTLD (SMD 0.61); approximately equal to healthy elderly. LBD with excessive daytime sleepiness had lower levels. PMID 34867809 Gan et al., Frontiers in endocrinology (2021)
• Frontotemporal dementia — CSF biomarker Human observational
  • CSF orexin-A significantly higher in bvFTD patients vs. controls (p<0.001). Correlated with MMSE scores, drug assumption, compulsive behavior, extrapyramidal signs, and CSF tau/Aβ1-42 markers. PMID 33904007 Roveta et al., Neurological sciences (2022)
  • In 214 participants, highest CSF orexin-A in iNPH (263.31±56.89 pg/mL), elevated in NFPA (210.86±61.99 pg/mL) and msAD (173.04±19.76 pg/mL) vs. controls (145.18±27.01 pg/mL). mAD lowest among patient groups. PMID 40198471 Lozano-Tovar et al., Neurological sciences (2025)
• Schizophrenia — biomarker of treatment response and metabolic effects Human observational
  • In 199 schizophrenia patients, clozapine-responsive patients had higher orexin-A levels than clozapine-resistant or antipsychotic-free patients. Orexin-A was the only factor significantly associated with treatment response after adjustment. PMID 38279671 Chen et al., Journal of psychopharmacology (2024)
  • Antipsychotic-treated patients had higher orexin-A than drug-free patients; aripiprazole group had higher levels than clozapine group. Effect persisted after adjustment for metabolic syndrome. PMID 35396156 Chen et al., Journal of the Formosan Medical Association (2022)
  • Higher orexin-A independently associated with lower risk of metabolic syndrome (OR=0.04) in antipsychotic-treated schizophrenia patients. PMID 30204875 Chen et al., International journal of neuropsychopharmacology (2019)
• Obesity and metabolic regulation Mixed
  • 12-month RCT (n=30, BMI≥30): TRF16:8 showed most consistent longitudinal increase in orexin-A levels. Increases in orexin-A were associated with markers of improved metabolic flexibility and reduced inflammation across all diet groups. PMID 41599851 Monda et al., Nutrients (2026)
  • Plasma orexin-A was lower in obese (85.34±42.85 ng/L) vs. overweight (97.38±36.72 ng/L) vs. normal-weight (106.56±52.09 ng/L) adults (P=0.03). Orexin-A correlated with total, moderate, and walking physical activity. PMID 27038345 Hao et al., Eating and weight disorders (2017)
• Sleep disorders and sleep-wake regulation Human observational
  • In 214 pregnant women, serum OXA was higher in poor sleep quality group vs. no poor sleep quality group (0.33 vs. 0.27, P<0.001). Higher OXA associated with greater risk of poor sleep quality (OR 1.385). PMID 36368074 Qin et al., Sleep medicine (2023)
  • Review: orexin signaling implicated in sleep disorder-heart failure comorbidity; orexin signaling pathway proposed as novel therapeutic target. PMID 28215031 Pan et al., Current heart failure reports (2017)
• Ischemic stroke — neuroprotection and biomarker Mixed
  • Serum orexin-A positively associated with short-term neurological improvement in mild-to-moderate AIS (31.78 vs. 16.24 pg/mL in improvers vs. non-improvers, p=0.038). PMID 36573700 Hu et al., Brain and behavior (2023)
  • In MCAO/R rat model and OGD/R cell model, orexin-A (OXA) treatment improved neurological deficit score, reduced infarct volume, decreased inflammatory mediators, and suppressed astrocytic apoptosis via OX1R-mediated NF-κB and MAPK inhibition. PMID 34358627 Xu et al., Biochimica et biophysica acta (2021)
  • OXA reduced neuronal apoptosis and inhibited over-activated autophagy in CIRI via OX1R-mediated MAPK/ERK/mTOR pathway in rat MCAO model and OGD/R cell model. PMID 33212156 Xu et al., Cellular signalling (2021)
• Inflammatory bowel disease / colitis — anti-inflammatory effects Animal studies only
  • In DSS-induced colitis C57BL/6 mice, intraperitoneal OxA (administered at day 7 for 4 days) promoted mucosal healing, decreased colonic myeloperoxidase, reduced circulating LBP, IL-6, and TNF-α, with better efficacy than infliximab for re-epithelization. PMID 37298505 Blais et al., International journal of molecular sciences (2023)
• Glioblastoma — anti-proliferative via ferroptosis Mixed
  • Orexin-A inhibited GBM proliferation by inducing ferroptosis through unstable iron pool increases and GPX4 depletion, regulated via NFE2L2 targeting of TFRC, FTH1, and GPX4 (in vitro and mouse model). PMID 38685674 Huan et al., Journal of cellular and molecular medicine (2024)
• Colon cancer — immune modulation via PD-L1 Mixed
  • Orexin A suppressed cellular and exosomal PD-L1 in colon cancer cells and promoted T cell activity by inhibiting JAK2/STAT3; orthotopic transplant model showed slower growth with orexin-A treatment. PMID 34097168 Wen et al., Digestive diseases and sciences (2022)
• Cognitive impairment — rescue of NMDA antagonist-induced deficits Animal studies only
  • Nasal administration of orexin A partially rescued MK-801 (0.15 mg/kg)-induced cognitive impairment in visual discrimination in female but not male C57BL/6J mice. PMID 37172740 Durairaja et al., Behavioural brain research (2023)
  • Orexin A transgenic rats showed improved memory retrieval under high-altitude hypoxia (5,000 m and 7,000 m) with upregulated BDNF/TrkB and PI3K/AKT/mTOR signaling, decreased IL-1β/IL-6, and attenuated microglial activation vs. wild-type. PMID 41072850 Zhu et al., Behavioural brain research (2026)
• Osteoarthritis — chondrocyte protection In vitro only
  • Orexin-A ameliorated IL-1β-induced chondrocyte senescence in TC-28a2 cells, rescued telomerase activity, prevented increases in Acetyl-p53 and p21, and mitigated reduction of SIRT3. Effects abolished by SIRT3 silencing. PMID 38829778 Shen et al., Aging (2024)
• Polycystic kidney disease — elevated expression Human observational
  • Serum orexin-A significantly higher in ADPKD patients (477.07±69.42 pg/mL) vs. healthy controls (321.49±78.01 pg/mL, p<0.001). Orexin-A inversely correlated with blood pressure and directly correlated with eGFR. PMID 38892431 Nigro et al., International journal of molecular sciences (2024)
• Rheumatoid arthritis — anti-inflammatory in synoviocytes In vitro only
  • Orexin A reduced IL-1β, IL-6, IL-8, ROS, MMP-3, and MMP-13 secretion in TNF-α-treated fibroblast-like synoviocytes by inhibiting NF-κB signaling. OX1R expression was decreased in RA-FLSs. PMID 30142537 Sun et al., Biomedicine & pharmacotherapy (2018)
• Sympathetic vascular tone modulation — intranasal administration in healthy humans Human RCT
  • In a double-blind crossover RCT (n=10 healthy males), intranasal orexin A (500 nmol) significantly increased resting MSNA burst rate (+5.8±0.8 vs. +2.1±0.6 bursts/min, p=0.007) and total MSNA activity (169% vs. 115%, p=0.002) compared to placebo. BP, HR, and HRV were unaltered. PMID 35044844 Meusel et al., Journal of neurophysiology (2022)
• Pain modulation Animal studies only
  • Review: antinociceptive effects of orexins demonstrated in thermal, mechanical, and chemical nociception models. Modulation at spinal and supraspinal levels (including PAG). Possible endocannabinoid involvement in supraspinal orexin-induced analgesia. Role in morphine analgesic tolerance discussed. PMID 28360013 Razavi & Hosseinzadeh, Biomedicine & pharmacotherapy (2017)
• Substance use disorders — biomarker of opioid/stimulant exposure Human observational
  • Serum orexin-A was significantly higher in 50 male heroin use disorder patients on methadone maintenance treatment vs. 25 healthy controls (BMI-adjusted ANCOVA). PMID 29680730 Tsai & Huang, Psychiatry research (2018)
  • Fasting serum orexin-A was significantly higher in 35 recently abstinent male methamphetamine abusers vs. 36 healthy controls. No association found with METH use variables. PMID 27137956 Chen et al., Psychiatry research (2016)
  • CSF orexin-A levels increased in postmortem brains of pure-opioid abusers and multi-drug abusers vs. matched controls (p<0.05). PMID 32741526 Sadat-Shirazi et al., Neuropeptides (2020)
• Epileptic seizure — differential diagnosis biomarker Human observational
  • Mean serum orexin-A: epileptic seizures 11.08 ng/mL vs. PNES 7.17 ng/mL vs. controls 5.16 ng/mL. ES group significantly different from both control and PNES groups (p<0.001). PMID 32485288 Çikriklar et al., Neuroscience letters (2020)
• Anxiety disorders in adolescents Human observational
  • Serum orexin-A significantly higher in 56 medication-free adolescents with anxiety disorders vs. 32 healthy controls (ANCOVA, controlling for age, sex, depression). Orexin-A positively correlated with depression and negatively with cortisol. PMID 31913740 Akça et al., International journal of psychiatry in clinical practice (2020)
• Major depressive disorder — biomarker Human observational
  • Serum orexin-A showed no clear group differences between 69 antidepressant-free MDD patients and 32 healthy controls. PMID 41376522 Erdem et al., Social neuroscience (2025)
  • Serum orexin-A levels in adolescents with MDD (n=40) were similar to healthy controls (n=38) after controlling for age, gender, BMI, and anxiety. No correlation between orexin-A and MDD symptom severity. PMID 34032542 Akça et al., International journal of psychiatry in clinical practice (2021)
• Multiple sclerosis — disease progression biomarker Human observational
  • Serum orexin-A significantly lower in MS patients vs. healthy controls; SPMS had lower levels than RRMS. Orexin-A negatively correlated with 9-hole peg, timed 25-ft walk, and progression index in RRMS. PMID 30645749 Gencer et al., Neurological sciences (2019)
• ADHD — biomarker Human observational
  • Serum orexin-A significantly lower in 56 drug-naive children with ADHD vs. 40 healthy controls (p=0.001). Lowest in inattentive subtype vs. hyperactive and combined subtypes (p=0.009). PMID 30617449 Baykal et al., Neurological sciences (2019)
• Traumatic brain injury — hypothalamic expression marker Human observational
  • Postmortem immunohistochemistry: orexin-A immunoreactivity absent in 10.2% of TBI cases, moderately reduced in 18.4%, and severely reduced in 14.3%. Inverse correlation between β-APP expression and orexin-A in the hypothalamus (p<0.005). PMID 34454377 Kousi et al., Forensic science international (2021)
• Diabetic retinopathy — serum biomarker Human observational
  • Serum orexin-A significantly lower in type 2 diabetes subgroups vs. healthy controls (p<0.001), but did not differ significantly across diabetic retinopathy severity stages within the diabetes subgroups. PMID 39009974 Alkan et al., Clinical & experimental optometry (2025)
• Gut-brain axis regulation Animal studies only
  • Review: orexin-A affects GI motility, gastric acid secretion, and nutritional cephalic-phase processes. Immunomodulatory role in colitis models (reducing TNF-α, IL-6, MCP-1). Proposed therapeutic value in IBD, IBS, and cancer-related hyperalgesia/fatigue. PMID 33068686 Mediavilla, Neurochemistry international (2020)
• Cushing syndrome / hypercortisolism — adrenocortical mechanism In vitro only
  • Orexin-A/OX1R activated mTOR/p70S6K1 pathway, inhibited autophagy, and increased cortisol secretion in H295R and Y-1 adrenocortical cells by upregulating 3β-HSD expression. PMID 37572990 Guo et al., Biochimica et biophysica acta (2024)
• Reward and motivational behavior / food seeking Animal studies only
  • Review: orexins produced in dorsolateral hypothalamus primarily mediate behavior under high motivational relevance conditions (physiological need states, threats, reward). Hypothesized to translate motivational activation into organized physiological and psychological processes. PMID 25254979 Mahler et al., Nature neuroscience (2014)
  • Microinjection of orexin-A into VTA promoted palatable food seeking in rats, blocked by OX1R antagonist SB-334867. Orexin-A and μ-opioid receptor signaling (NTX) both modulate VTA DA neuron firing. PMID 41762866 Luan et al., Biochemical and biophysical research communications (2026)
• Internet gaming disorder — peripheral biomarker Human observational
  • Orexin A was significantly elevated (p=0.016) in blood of 33 adolescents with IGD compared to 40 healthy controls. Melatonin tended to be higher (p=0.055) in IGD group. PMID 31957460 Choi et al., Journal of behavioral addictions (2020)
• Chronic cerebral hypoperfusion / vascular dementia — neuroprotection Animal studies only
  • 4 weeks of intranasal orexin A (250 μg/kg) in rats after 8-week CCH modeling ameliorated cognitive dysfunction, restored M1/M2 microglial balance via NEK7/NLRP3 inhibition, and reduced neuroinflammation and neuronal pyroptosis. PMID 40691984 Chen et al., Experimental neurology (2025)

Community-reported dosing

Tier key: Research = PMID-cited study · [C] = scraped community source · [S] = model-synthesized from aggregate community reports (softer evidence). How we source.