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PYY(3-36)

Also known as Peptide YY 3-36, PYY3-36, peptide tyrosine tyrosine

Gut satiety hormone whose anti-obesity development has been repeatedly defeated by nausea.

early-clinical Metabolic & weight endogenous peptide

At a glance

Category
Metabolic & weight
Status
endogenous peptide
Route
intravenous infusion or subcutaneous injection in studies; an intranasal formulation was trialled and abandoned
Half-life
roughly 8-30 minutes in humans depending on the assay and route
Onset
appetite suppression within roughly 30-90 minutes of dosing
Molecular weight
approximately 4050 g/mol
Sequence
IKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY (34 residues, C-terminal amide; PYY(1-36) minus the N-terminal Tyr-Pro dipeptide)

A naturally occurring human hormone released by intestinal L cells after eating. It has been investigated as an anti-obesity drug for over two decades, including an intranasal formulation that failed in clinical development, and no PYY-based product has ever been approved. Long-acting PYY analogues remain in early development, often paired with GLP-1 agonists.

Doping status: Prohibited (WADA S0 when used as a non-approved substance)

Checked against the WADA 2026 Prohibited List. For a specific product and country, Global DRO is the lookup athletes are expected to use — the List names substances, not brand names.

Mechanism of action

PYY is stored in intestinal L cells alongside GLP-1 and released into the circulation after a meal, in proportion to calories consumed and particularly in response to fat and protein. The secreted form, PYY(1-36), is cleaved at the N-terminus by dipeptidyl peptidase-4 to give PYY(3-36), and this cleavage changes the pharmacology fundamentally.

PYY(1-36) binds Y1, Y2 and Y5 receptors with broadly similar affinity. Removing the first two residues yields a peptide that is selective for the Y2 receptor. Y2 is an inhibitory presynaptic autoreceptor on the orexigenic NPY/AgRP neurons of the hypothalamic arcuate nucleus. Activating it silences those neurons, which disinhibits the neighbouring anorexigenic POMC neurons — the net effect is reduced appetite. PYY(3-36) also acts on vagal afferents and on brainstem circuits, and slows gastric emptying and intestinal transit, the so-called ileal brake.

The receptor selectivity is the whole story: PYY(1-36) is not anorectic and can even be orexigenic through Y1 and Y5, so any therapeutic use requires the 3-36 form specifically. The difference between the two forms was tested directly in obese men given subcutaneous PYY(1-36) or PYY(3-36): only the 3-36 form changed appetite ratings, although neither form changed measured food intake in that study 4.

The problem is that Y2 receptors are also present in the area postrema and in circuits mediating nausea and visceral malaise. In practice the doses that meaningfully suppress food intake in humans overlap almost completely with the doses that make people feel sick. This is not a formulation problem that better delivery has solved — it is the central pharmacological obstacle, and it has defeated every attempt so far to turn PYY(3-36) into a drug.

What the research shows

PYY(3-36) has been studied in humans repeatedly and the acute anorectic effect is real and reproducible. What has never been demonstrated is clinically useful, sustained weight loss at a tolerable dose. The field also has an unusual and instructive history: a 2004 Nature paper reported that multiple independent laboratories could not reproduce the original rodent food-intake finding 3, which triggered a long dispute about experimental conditions. The current position is that the effect is genuine but exquisitely sensitive to stress and handling in animals, and dose-limited by nausea in humans.

Research in humans

The 2002 Nature paper by Batterham and colleagues showed that infusing PYY(3-36) to postprandial concentrations reduced food intake at a subsequent buffet meal by roughly a third in lean volunteers 1. A 2003 New England Journal of Medicine study extended this to obese subjects, showing they were not resistant to the peptide and reduced intake by a comparable proportion — an important finding, since it distinguished PYY from leptin 2. A 2007 study compared subcutaneous PYY(1-36) and PYY(3-36) in obese males and found no effect on ad libitum energy intake for either form; only PYY(3-36) shifted the subjective ratings, raising satiety and lowering hunger, and the authors concluded that PYY(1-36) is unlikely to matter for energy intake while doubting that subcutaneous PYY(3-36) would reduce real-world intake in the long run 4. Injection, in other words, did not reproduce what infusion had shown. An intranasal PYY(3-36) formulation was taken into clinical development by Nastech and Merck in the mid-2000s and discontinued, with dose-limiting nausea and inadequate efficacy the reported reasons. More recent work focuses on long-acting Y2-selective analogues, frequently in combination with GLP-1 agonists, where the hope is that lower doses of each are additive on appetite without being additive on nausea.

Animal and lab research

The original rodent work showed reduced food intake and body weight with peripheral PYY(3-36) administration, and localised the effect to the arcuate nucleus. The 2004 Nature correspondence by Tschop and colleagues, representing several independent groups, reported failure to reproduce the food-intake effect in rodents under their conditions 3. Subsequent work indicated that the effect is critically dependent on acclimatising animals to handling and injection, because stress-induced anorexia masks or confounds the signal. The effect is now generally accepted, but the episode remains a well-known case study in preclinical reproducibility.

Caveats. Human trials are small and mostly acute — single infusions and buffet-meal endpoints rather than months of treatment. The nausea problem is severe and dose-defining: in several studies a meaningful fraction of participants at effective doses experienced nausea or vomiting, and infusions have had to be stopped. No adequately powered long-term weight-loss trial of native PYY(3-36) has been published. The peptide's short half-life makes chronic dosing impractical without engineering. The reproducibility dispute means older rodent literature should be read with care. Material sold outside research settings is of unverified identity and purity, and the 1-36 and 3-36 forms differ by only two residues while differing completely in effect.

What it is used for

  • Research tool for studying gut-brain appetite signalling and Y2 receptor pharmacology
  • Investigational anti-obesity target, mainly now as long-acting analogues and in combination with GLP-1 receptor agonists
  • Studied to explain part of the appetite suppression and weight loss seen after Roux-en-Y gastric bypass, where postprandial PYY rises sharply
  • Used occasionally on the grey market for appetite suppression, where the very short half-life and dose-limiting nausea make it a poor practical choice

Dosing

Dose
In published human trials: intravenous infusion to normal postprandial concentrations over 90 minutes, or, in the only published subcutaneous study, 25-100 pmol per kg lean body mass
Frequency
Single doses or short infusions before a meal in most studies; no validated chronic regimen exists
Route
Intravenous infusion or subcutaneous injection
Duration
Acute in most studies; no published trial of native PYY(3-36) has run long enough to establish sustained weight loss
  • Dose is limited by nausea, not by efficacy. Studies that pushed above roughly the postprandial physiological range consistently ran into vomiting and had to stop infusions. Any protocol that ignores this is ignoring the main finding of the human literature.
  • The doses above are study doses used under supervision with intravenous access, not a self-administration schedule.
  • The short half-life means a subcutaneous injection produces a brief window of effect, and route matters: infusion to postprandial concentrations cut 24-hour food intake by about a third 1, whereas subcutaneous injection at 25-100 pmol/kg lean body mass shifted satiety and hunger ratings but did not change measured ad libitum energy intake at all 4. The long-acting analogues in development are chemically distinct molecules and their dosing does not transfer.
  • Doses circulating in online user protocols are not clinically validated, and the difference between PYY(1-36) and PYY(3-36) in unlabelled material is not detectable without analysis.

These figures describe what the literature and published protocols report. They are not advice and not a dosing instruction.

Reconstitution

Vial sizes
5 mg, 10 mg
Solvent
Bacteriostatic water (0.9% benzyl alcohol) is used in practice; clinical studies used pharmacy-prepared sterile saline with albumin to reduce adsorption
Storage
No published stability study for reconstituted PYY(3-36). General peptide practice is 2-8 °C after reconstitution and freezer storage of powder, protected from light.

Worked example

A 5 mg vial reconstituted with 2.5 ml of bacteriostatic water gives 2 mg/ml. A 30 nmol dose is approximately 0.12 mg, or roughly 0.06 ml — about 6 units on a U100 insulin syringe, which is at the edge of what can be measured accurately.

There is no licensed injectable presentation; the 5 mg and 10 mg vial sizes are research material. PYY adsorbs appreciably to plastic and glass surfaces, which is why clinical infusion protocols added albumin to the carrier. Reconstitution without a carrier protein may lose a meaningful fraction of the peptide to the container walls, and no one has published how much. Run the diluent down the side of the vial and do not shake.

Work it out for PYY(3-36)

Safety

Side effects

  • Nausea — the defining, dose-limiting side effect, and the reason no PYY drug has reached market
  • Vomiting at or slightly above effective doses; infusions have been terminated for this reason in published studies
  • Malaise and general unwellness distinct from nausea
  • Reduced appetite and early satiety, the intended effect
  • Slowed gastric emptying and intestinal transit
  • Injection site reactions
  • Headache
  • Long-term effects are unknown; no chronic-dosing trial of the native peptide has been published

Do not use if

  • Gastroparesis or significant gastrointestinal motility disorder
  • Eating disorders, including anorexia nervosa and a history of restrictive eating
  • Pregnancy, breastfeeding and wish to conceive
  • Any condition in which repeated vomiting is hazardous, including significant electrolyte disturbance
  • Underweight or normal-weight individuals, in whom appetite suppression has no rationale
  • Use outside a research setting: no body verifies the identity, potency or sterility of grey-market material, and the inactive PYY(1-36) form is indistinguishable by inspection

Interactions

Not systematically studied. Slowed gastric emptying can delay the absorption of orally administered medication. The combination with GLP-1 receptor agonists is under active investigation and is expected to be additive on appetite suppression — but also plausibly additive on nausea, which is the practical constraint. Combining PYY(3-36) with a licensed GLP-1 drug outside a trial has not been evaluated for safety. Antiemetics have been used in study settings to permit higher doses, but this does not make the underlying dose tolerable in ordinary use.

Sources