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Neuropeptide Y (NPY)36 residuesYPSKPDNPGEDAPAEDMARYYSALRHYINLITRQRYEach bubble = one amino acid. Size = residue mass. Color = chemical class.Also known as: NPY, Pro-neuropeptide Y
Two completed human clinical trials, both intranasal, both targeting psychiatric endpoints nobody expected from a hunger peptide. Neuropeptide Y (NPY) is a 36-amino-acid signaling molecule and the most abundant neuropeptide in the mammalian brain. It operates through five receptor subtypes (Y1 through Y5), each triggering distinct effects. The appetite stimulation data comes entirely from rodent intracerebroventricular infusion; no human has shown orexigenic effects from peripheral dosing. What did translate to humans: dose-dependent anxiolytic activity at 4.6 to 9.6 mg intranasal in a PTSD dose-ranging trial (NCT01533519, PMC5795352). The barrier is access. Lab-grade NPY runs $337 to $537 per milligram, and no gray-market vendor carries it.
Two psychiatric trials. Zero appetite trials in humans. That gap tells you everything about where NPY research actually stands. Neuropeptide Y (CAS 82785-45-3) is a 36-amino-acid, C-terminally amidated peptide first isolated from porcine brain by Tatemoto in 1982. It belongs to the pancreatic polypeptide family alongside peptide YY and pancreatic polypeptide. The "most potent orexigenic peptide in the brain" label comes from decades of rodent studies using intracerebroventricular (ICV) infusion, a route that delivers NPY directly into brain ventricles. Inject it centrally in a rat, and feeding behavior starts within minutes. But NPY does not cross the blood-brain barrier after subcutaneous injection. That single pharmacokinetic fact eliminates peripheral dosing as a path to appetite or anxiety endpoints. What does work in humans is intranasal delivery. The PTSD dose-ranging trial (NCT01533519) tested five escalating doses from 1.4 to 9.6 mg through an olfactory-targeted device. Anxiolytic signal appeared above 4.6 mg, with BAI scores dropping roughly 2 points per milligram increase (PMC5795352). A separate MDD trial showed MADRS score improvement at 5 hours (Cohen's d = 0.61) and 24 hours (d = 0.67) after a single 6.8 mg dose. The effect faded by 48 hours. NPY signals through Y1, Y2, Y4, Y5, and Y6 G-protein-coupled receptors. The anxiolytic arm runs through Y1 receptors in the amygdala. The appetite arm runs through Y1 and Y5 receptors in the hypothalamus. Military studies correlated high plasma NPY with stress resilience in Special Forces trainees [1]. The molecule is real. The access problem is also real: $337 to $537 per milligram from lab suppliers, no consumer vendor, no compounding pathway.
NPY signals through five G-protein-coupled receptors (Y1, Y2, Y4, Y5, Y6) that couple to inhibitory Gi/Go proteins. Receptor activation suppresses adenylyl cyclase, drops intracellular cyclic AMP, and modulates calcium and potassium channel conductance to shift neuronal excitability. The appetite pathway starts in the arcuate nucleus. Low leptin and high ghrelin activate NPY neurons during energy deficit. Released NPY binds Y1 and Y5 receptors on downstream neurons in the paraventricular nucleus. This drives orexigenic signaling while simultaneously shutting down anorexigenic POMC/CART neurons through Y1-mediated GABA release. The Y2 receptor sits presynaptically on NPY terminals, providing negative feedback to cap further release. The anxiety arm is anatomically separate. In the amygdala, Y1 receptor activation dampens CRF (corticotropin-releasing factor) signaling. This reduces amygdalar excitability, producing the anxiolytic effects confirmed in the NCT01533519 intranasal trial. Military stress resilience data aligns with this pathway; soldiers with higher endogenous NPY showed better performance under extreme conditions [1]. Peripherally, NPY is co-stored and co-released with norepinephrine from sympathetic nerve terminals. Postjunctional Y1 receptors on vascular smooth muscle potentiate norepinephrine-mediated vasoconstriction. This is the main peripheral effect of subcutaneous administration and the reason blood pressure monitoring is non-negotiable. In bone, hypothalamic Y2 receptor signaling modulates sympathetic output to osteoblasts. Local Y1 activation on osteoblasts directly promotes bone formation.
Intranasal NPY shows dose-dependent anxiolytic and antidepressant effects in two completed human trials. Appetite stimulation is well-documented in rodent ICV models only, not in humans via peripheral routes. No subcutaneous human dosing data exists.
NCT01533519: PTSD dose-ranging trial; 5 escalating intranasal doses (1.4–9.6 mg); dose-dependent anxiolytic effect with signal above 4.6 mg; BAI score reduced ~2 points per 1 mg increase (IJNP 2018, PMC5795352)
All human data is intranasal only. NPY does not cross the BBB after peripheral SC injection. No approved indication. Not on FDA 503A/B bulks lists: no US compounding pathway. MDD trial (IJNP 2020) effect lasted only 24h, suggesting need for repeated dosing not yet characterized.
No established community self-administration protocol. NPY is not sold by gray-market research peptide vendors. Theoretical interest in appetite stimulation and stress resilience derived from literature: no documented personal protocols.
Two completed human clinical trials exist (intranasal, mg-range doses) but community self-administration is essentially nonexistent. No gray-market vendor carries NPY. The compound exists at the intersection of research laboratory and clinic only.
| Level | Dose / Injection | Frequency |
|---|---|---|
| Beginner | 50mcg | Daily |
| Moderate | 100mcg | Daily |
| Aggressive | 200mcg | 2x Daily |
Start with the most important practical point: subcutaneous NPY will not produce appetite or anxiety effects. Those endpoints require intranasal delivery through an olfactory-targeted device, not a standard nasal spray bottle. The clinical trials used a custom OptiNose-type device. Reconstitution math for SC research use: a 2 mg vial reconstituted with 2 mL bacteriostatic water gives 1 mg/mL (1000 mcg/mL). At the beginner dose of 50 mcg, that's 5 units on a 100-unit insulin syringe. Moderate dose (100 mcg) is 10 units. Aggressive (200 mcg) is 20 units. With a 1 mg vial in 2 mL, concentrations halve; double your unit counts. NPY degrades fast. Plasma half-life is 20 to 25 minutes because DPP-IV clips the N-terminal Tyr-Pro dipeptide almost immediately. Reconstitute fresh, store at 2 to 8 degrees Celsius, use within 14 days, and minimize needle punctures through the stopper. Every freeze-thaw cycle accelerates degradation. The sourcing situation is unusual. No gray-market peptide vendor stocks NPY. Lab-grade material from Hello Bio, Thermo Fisher, or Tocris runs $337 to $537 per milligram. Verify CoA with HPLC purity at or above 95% and mass spec confirming MW 4272.7 Da.
Cycling is recommended due to potential receptor desensitization with chronic Y1/Y5 activation. Rodent studies show tachyphylaxis to orexigenic effects after sustained central infusion. Off-periods allow receptor resensitization. Protocols are extrapolated from animal data; no established human cycling guidelines exist.
Rodent studies demonstrate tachyphylaxis to NPY orexigenic effects after sustained central infusion, consistent with Y1/Y5 receptor downregulation and uncoupling from Gi/Go signaling. The 4-week on / 4-week off cycle in peptides.ts is extrapolated from animal data; no human cycling guidelines exist. Off-periods allow Y1/Y5 receptor resensitization.
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Expected: Dose-dependent reduction in anxiety symptoms (BAI); MADRS score improvement in MDD at 24h. Efficacy at 48h+ not established: repeated dosing likely required.
Monitor: Monitor blood pressure and heart rate after each dose. Transient bradycardia observed in one participant at 2.8 mg in NCT01533519. Monitor body weight with repeated dosing.
Reconstitute the lyophilized NPY powder with bacteriostatic water using sterile technique. For a 2 mg vial, add 2 mL of bacteriostatic water to get 1000 mcg/mL. Gently swirl the vial. Do not shake.
NPY is sensitive to proteolytic degradation, so minimize time at higher temperatures.
At 1000 mcg/mL concentration: 50 mcg = 5 units, 100 mcg = 10 units, 200 mcg = 20 units on a standard 100-unit insulin syringe.
Inject subcutaneously into the abdominal area or upper thigh. Rotate injection sites each time to avoid lipodystrophy.
Administer on an empty stomach or 30 minutes before a meal if appetite-related peripheral effects are being tracked.
Monitor heart rate during and 60 minutes after the first administration.
Use within 14 days. Minimize needle punctures through the vial stopper to reduce peptide degradation.
Document dose, timing, injection site, and any blood pressure or heart rate readings for each administration.
4.6–9.6 mg per dose (vs. 50–200 mcg SC listed in peptides.ts: see FLAG P0)
Requires specialized olfactory-targeted delivery device (not a standard pump nasal spray). Bypasses BBB via olfactory nerve pathway to deliver NPY directly to hypothalamus and limbic system. Custom OptiNose-type device used in clinical trials. No consumer equivalent available.
No validated human dose; 50–200 mcg listed in peptides.ts extrapolated from animal data (see FLAG P0)
NPY does not cross the BBB after SC injection in clinically relevant quantities. SC cannot replicate appetite stimulation or anxiolytic effects from intranasal trials. Only peripheral Y1-mediated vasoconstriction effects are observable via this route.
Animal models: 1–20 nmol direct brain infusion (basis of most orexigenic feeding data)
ICV infusion is the primary route behind essentially all appetite stimulation and weight gain data in rodent models. These effects are NOT translatable to any peripheral administration route in humans. Critical context for interpreting orexigenic benefit claims.
Ghrelin stimulates NPY release from arcuate nucleus neurons: both operate on the same orexigenic pathway (ARC → PVN). Mechanistic synergy for appetite stimulation. No human combination data exists; theoretical only.
Both exert anxiolytic effects via distinct mechanisms: NPY via Y1 receptor CRF suppression, Selank via GABA-A/serotonin modulation. Theoretical complementary anxiolytic stack. No human combination data.
Direct pharmacological opposition: GLP-1 agonists suppress NPY/AgRP neurons in the arcuate nucleus, counteracting any orexigenic intent of NPY administration
Do not combineNPY potentiates norepinephrine-mediated vasoconstriction via postjunctional Y1 receptors on vascular smooth muscle; additive hypertensive and cardiovascular risk
Do not combineNPY-mediated vasoconstriction may oppose therapeutic antihypertensive effects; reduced drug efficacy and unpredictable blood pressure response
Leptin suppresses NPY/AgRP neurons: exogenous leptin directly antagonizes NPY orexigenic signaling; opposing effects on appetite and energy balance
The most serious safety concern is cardiovascular. NPY is co-released with norepinephrine from sympathetic nerve terminals and potentiates vasoconstriction through Y1 receptors on vascular smooth muscle. Peripheral administration can raise blood pressure. Anyone with uncontrolled hypertension or cardiovascular disease should not use this compound. Blood pressure checks before and 30 minutes after every dose are a baseline safety requirement. The NCT01533519 trial flagged transient bradycardia in one participant at 2.8 mg intranasal, adding cardiac rhythm to the monitoring list. Hyperphagia is the second concern, though context matters. The appetite-stimulating effects documented in rodent models used intracerebroventricular infusion, not peripheral routes. Subcutaneous NPY does not cross the blood-brain barrier in clinically relevant quantities, so orexigenic effects from SC injection are unlikely. If using intranasal delivery (the only route with human CNS data), unintended appetite stimulation and weight gain become plausible risks. Weekly body weight tracking is appropriate with repeated intranasal dosing. Chronic central NPY infusion in rodents produced sustained hyperphagia, increased adiposity, and metabolic shifts favoring fat storage. These effects are route-specific and have not been confirmed through any peripheral administration method in humans. Still, the animal data warrants caution around repeated high-dose intranasal protocols. Sedation and reduced locomotor activity appeared in some rodent studies following central administration. Hypothermia was reported after intracerebroventricular injection in certain models. These observations may or may not translate to intranasal delivery in humans at milligram-range doses. NPY modulates multiple neurotransmitter systems, including GABA, glutamate, and norepinephrine. Off-target neurological effects are possible at supratherapeutic concentrations. Gastrointestinal effects, specifically delayed gastric emptying and altered intestinal motility, are documented in animal models. Drug interactions deserve specific attention. Sympathomimetics (ephedrine, phenylephrine) create additive vasoconstriction risk. Beta-blockers and antihypertensives may lose efficacy because NPY opposes their mechanism. Benzodiazepines could produce additive sedation with central NPY effects. GLP-1 receptor agonists and leptin directly antagonize NPY's orexigenic pathways. Contraindications: uncontrolled hypertension or cardiovascular disease, obesity or metabolic syndrome (where appetite stimulation is counterproductive), active eating disorders, pregnancy or breastfeeding (no safety data), and known hypersensitivity to NPY or formulation excipients. When to stop: systemic blood pressure elevation above 140 mmHg, sustained bradycardia below 50 bpm, any new arrhythmia on ECG, or unintended weight gain outside research parameters. These are hard stop criteria, not suggestions.
Verify Neuropeptide Y (NPY) dosing and safety with a second opinion
NPY is not sold by gray-market research peptide vendors. Available only from laboratory biochemical suppliers (Hello Bio, Thermo Fisher, Tocris Bioscience) at $337–537/mg with lab-grade CoA. No third-party purity testing benchmarks exist for consumer-grade sourcing, and no 503B compounding pathway allows legal US pharmacy sourcing.
| Test | When | Target |
|---|---|---|
| Blood pressure (systolic/diastolic) | Before and 30 min post-dose each administration | Systolic <140 mmHg; discontinue if persistently elevated above baseline |
| Heart rate / ECG | During and 60 min after first administration | HR >50 bpm; no new arrhythmia on ECG |
| Body weight and caloric intake log | Weekly with repeated dosing | Within intended research parameters |
Y1 receptor-mediated vasoconstriction on vascular smooth muscle is a primary peripheral NPY effect
Bradycardia observed in one NCT01533519 participant at 2.8 mg intranasal; cardiac co-modulation via sympathetic NPY/norepinephrine co-release
Unintended hyperphagia and adiposity gain documented with repeated central dosing in animal models; relevant tracking for any orexigenic research protocol
Rapid onset of orexigenic signaling following central administration in animal models; peripheral vasoconstrictor effects observed within minutes
Sustained hyperphagia and increased caloric intake with repeated central dosing; measurable changes in anxiety-related behavior in rodent models
Chronic central infusion produces significant weight gain, increased adiposity, and metabolic shifts toward lipogenesis in animal studies
Potential tachyphylaxis to orexigenic effects; receptor desensitization may attenuate feeding response; bone density changes detectable in long-term Y2 receptor studies
Acute (0 to 30 minutes): Peripheral vasoconstriction and potential heart rate changes appear within minutes of subcutaneous injection. Plasma NPY clears in roughly 20 to 25 minutes via DPP-IV degradation. Intranasal delivery through an olfactory-targeted device reaches brain tissue within about 15 minutes (ACS Pharm Transl Sci 2025)[2]. Transient blood pressure elevation and injection site reactions are the main acute side effects. One case of bradycardia was flagged at 2.8 mg intranasal in the PTSD trial. Day 1 to 7: Intranasal-only data here. The MDD trial showed MADRS depression score improvement at 5 hours (Cohen's d = 0.61) and 24 hours (d = 0.67) after a single 6.8 mg dose. By 48 hours, the effect was gone. That rapid falloff suggests repeated dosing would be needed for sustained benefit, but no multi-dose human schedule has been validated. Subcutaneous dosing during this window would only produce peripheral vasoconstrictor effects; no CNS anxiolytic or orexigenic response is expected. 2 to 4 weeks: Everything in this window comes from rodent ICV models, not humans. Sustained central infusion in rodents produces hyperphagia, body weight gain, increased adiposity, and metabolic shifts toward lipogenesis. Tachyphylaxis to the orexigenic effect begins during this period. None of this data translates to peripheral human dosing. 4 to 8 weeks: Y1/Y5 receptor desensitization is documented in rodent models with continued central dosing. The appetite-stimulating response attenuates. Bone density changes become detectable in long-term Y2 receptor studies in animals. Off-cycling (4 weeks on, 4 weeks off) is recommended to allow receptor resensitization, though this schedule is extrapolated from animal data with no human validation.
Vasoconstriction and potential heart rate changes within minutes of administration; plasma NPY cleared within ~20–25 min by DPP-IV. Intranasal: brain uptake begins within ~15 min (ACS Pharm Transl Sci 2025, PMID 40242586).
No documented community reports
Intranasal: significant anxiolytic effect within hours; MDD trial showed MADRS improvement at 5h (d=0.61) and 24h (d=0.67) but not 48h: repeated dosing likely needed. SC route: no CNS effects expected.
No documented community reports
Sustained hyperphagia and body weight gain with repeated central infusion in rodents; significant adiposity increase favoring lipogenesis. No equivalent human data for this duration.
No documented community reports
Documented Y1/Y5 receptor desensitization in rodent models; attenuated feeding response. Long-term Y2 receptor signaling influences bone homeostasis: osteoblast changes detectable in long-term animal studies.
No documented community reports
Source: Plasma elimination studies; NPY has a half-life of approximately 20-25 minutes in circulation due to rapid enzymatic degradation by dipeptidyl peptidase IV (DPP-IV) and other peptidases
Loading the interactive decay curve.
NPY carries a "research-only" regulatory status. It has no FDA approval for any therapeutic indication. It is not listed on the FDA 503A or 503B bulks lists, which means US compounding pharmacies have no legal pathway to produce NPY preparations for patient use. No gray-market consumer peptide vendor currently sells NPY. Sourcing is limited to laboratory biochemical suppliers (Hello Bio, Thermo Fisher, Tocris Bioscience) at research-grade pricing. WADA status should be verified by any athlete, though NPY's impracticality as a performance compound makes competitive testing unlikely. Two Investigational New Drug (IND) applications have supported clinical trials in the US (NCT01533519 for PTSD, a separate MDD trial), but these were conducted under strict FDA IND protocols with specialized delivery devices. No consumer-accessible intranasal delivery system replicates the olfactory-targeted devices used in those studies. All information on this page is for educational and research reference purposes only. Nothing here constitutes medical advice, a treatment recommendation, or encouragement to use any compound outside of approved clinical or research settings.
Peptide Schedule Research TeamReviewed Apr 20268 Citations
