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VIP (vasoactive intestinal peptide)

Also known as Vasoactive intestinal polypeptide, Aviptadil, VIP, Zyesami (aviptadil)

Endogenous 28-amino-acid neuropeptide; intranasally known mainly from Shoemaker's CIRS protocol.

early-clinical Immune & longevity research chemical

At a glance

Category
Immune & longevity
Status
research chemical
Route
intranasal (CIRS protocol), subcutaneous, intravenous and nebulised (research setting)
Half-life
very short — on the order of 1-2 minutes in plasma after intravenous administration
Onset
haemodynamic effects within minutes; the effects targeted in CIRS protocols are only assessed after weeks to months
Molecular weight
approximately 3325 g/mol
Sequence
HSDAVFTDNYTRLRKQMAVKKYLNSILN-NH2 (28 amino acids, C-terminally amidated)

VIP is not registered for the applications for which it is used in the peptide world. The synthetic form aviptadil has been studied as an injectable preparation in pulmonary arterial hypertension and in severe COVID-19 (Zyesami/RLF-100) without leading to registration; in Europe there is a local registration of aviptadil in combination with phentolamine for intracavernosal injection in erectile dysfunction. The intranasal spray used within the CIRS protocol is a compounding pharmacy preparation on prescription, not an approved medicine.

Doping status: Not listed by WADA

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

VIP is a neuropeptide of the secretin/glucagon family produced by neurons in the enteric nervous system, the lungs and the central nervous system. It acts via the G protein-coupled receptors VPAC1 and VPAC2, raising cyclic AMP in the target cell.

Physiologically VIP causes vasodilation — particularly in the pulmonary vascular bed — relaxation of smooth muscle in the airways and gut, and stimulation of secretion. In the lungs it is regarded as an endogenous counterpart to vasoconstrictive and pro-fibrotic signals.

Immunologically VIP is strongly anti-inflammatory: it inhibits production of TNF-alpha, IL-6 and IL-12 by macrophages, promotes regulatory T cells and shifts the balance from Th1 to Th2. These properties form the rational basis for its use in chronic inflammatory conditions.

Within Shoemaker's CIRS model, VIP is seen as a regulatory neuropeptide that becomes depleted on exposure to biotoxins from water-damaged buildings; supplementation is supposed to restore hypothalamic regulation. That is a hypothesis within a disease model that is itself not generally recognised — see below.

What the research shows

For VIP as a molecule the physiology is solidly established; for the clinical applications it is not. Controlled studies of aviptadil in pulmonary hypertension and in COVID-19 produced no convincing benefit 4. Intranasal use within the CIRS protocol rests entirely on open-label research by the originator of the protocol himself, without a placebo group and without independent replication 1. The CIRS model moreover sits outside mainstream medicine: 'chronic inflammatory response syndrome' following exposure to water-damaged buildings is not a recognised diagnosis in mainstream guidelines, and the associated diagnostics (visual contrast sensitivity, HLA-DR haplotypes, cytokine panels) are not regarded as valid by mainstream immunology.

Research in humans

In pulmonary arterial hypertension, a randomised phase 2 trial of nebulised aviptadil showed no clinical benefit after three months 4; an acute haemodynamic test showed only a small, short-lived selective pulmonary vasodilation 3. In severe COVID-19, aviptadil (Zyesami) was studied intravenously and nebulised; the results were unconvincing and registration did not follow. For CIRS use, the published data are open-label series by Shoemaker and colleagues: a series with 20 people and a series with 35 treated people against 4 controls, plus imaging research reporting an increase in grey matter volume in a few brain nuclei 1. A review article on the clinical substantiation of the Shoemaker protocol (Annals of Medicine and Surgery, 2024) establishes that the VIP research is exclusively open-label, without placebo control, and that peer-reviewed publications from groups other than Shoemaker himself are minimal 1.

Animal and lab research

In animal models of asthma, colitis, arthritis, sepsis and neuroinflammation, VIP reliably suppresses the inflammatory response and protects tissue. Those effects are reproducible, but are achieved with doses and routes of administration that do not translate to intranasal practice, and in models of acute inflammation rather than the chronic conditions for which the agent is used.

Caveats. A half-life of one to two minutes makes it pharmacokinetically unclear how intranasal administration four times a day would produce a sustained systemic effect; the presumed route is direct uptake into the central nervous system, which has not been demonstrated in humans. The CIRS studies are small, unblinded, carried out by the developer of the protocol and not independently replicated 1. Without a placebo group, in a symptom complex with many subjective complaints, no reliable distinction can be made between treatment effect and expectation or natural course.

What it is used for

  • Intranasally within Shoemaker's CIRS/biotoxin protocol, as the final step after remediation, binders and treatment of MARCoNS — a protocol outside mainstream medicine, whose VIP evidence is entirely open-label and almost entirely from its originator 1
  • Pulmonary arterial hypertension (studied as nebulised aviptadil, no clinical benefit demonstrated) 34
  • Severe COVID-19 with acute respiratory failure (studied as aviptadil, not registered)
  • Erectile dysfunction: aviptadil in combination with phentolamine as an intracavernosal injection (locally registered, an entirely different application)
  • Sarcoidosis and chronic pneumonitis: small, exploratory research

Dosing

Dose
CIRS protocol, intranasal: 50 mcg per spray actuation, one spray per dose. Doses in the research setting are a separate matter and are set out in the notes below.
Frequency
4x daily, alternating nostrils
Route
intranasal (compounded preparation); in research also nebulised, subcutaneous and intravenous
Duration
Within the CIRS protocol, months to more than a year; according to the protocol, improvement in markers is only assessed after 4-12 weeks
  • The intranasal CIRS schedule is 50 mcg per spray actuation, one spray four times daily, alternating nostrils. Shoemaker's own material describes 50 mcg per spray and 4-8 sprays per day; it describes no 100 mcg actuation. Where protocols escalate, they do so by giving two 50 mcg sprays per dose — that is 100 mcg per dose from the same 50 mcg spray, not a stronger spray. The figures come from Shoemaker's protocol and compounding pharmacy documentation, not from randomised research.
  • The doses used in aviptadil research are a different product, route and indication, and none of them is the intranasal CIRS schedule. In pulmonary hypertension, Leuchte and colleagues (European Respiratory Journal, 2008) gave a single 100 mcg inhaled dose to 20 patients during right-heart catheterisation — an acute haemodynamic test, not a repeated daily regimen 3. The separate three-month randomised phase 2 trial of inhaled aviptadil in PAH was negative 4; its per-dose regimen is not stated here because no source for it could be confirmed.
  • The protocol prescribes starting VIP only after exposure to the water-damaged building has been ended and earlier steps have been completed; this sequence is a protocol rule, not a finding tested in research.
  • Before use, the protocol advises a VCS test and measurement of VIP and other markers; the diagnostic value of those tests has not been validated outside the CIRS community.
  • Because of the very short half-life, the pharmacokinetic rationale for any intranasal schedule is weak.
  • Doses are set out here descriptively and do not constitute advice.

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

Protocols

Intranasal VIP in the CIRS protocol

user protocol — not validated

Source: Shoemaker CIRS protocol and compounding pharmacy documentation

This is not a validated schedule. It is a pattern that circulates among users and sellers, reproduced because it is what people actually follow — not because it has been tested. No trial established these doses, this interval or this duration, and nobody is checking what is in the vial. Treat every number below as an assertion, not a finding.

First month50 mcg per spray actuation, four times daily, alternating nostrils
After the first monthoptionally two sprays per dose — 100 mcg per dose from the same 50 mcg spray — four times daily
Durationmonths to more than a year; markers are re-assessed after 4-12 weeks

This is an intranasal spray compounded on prescription, not an approved medicine, and not the injected or nebulised aviptadil used in pulmonary hypertension and COVID-19 research — those are different products at different strengths for different indications, and no dose transfers between them. Escalation is by number of sprays, not by spray strength: the actuation stays at 50 mcg. The protocol places VIP only after exposure to the water-damaged building has ended and earlier steps are complete, which is a protocol rule rather than a tested finding. VIP's half-life is very short, so the pharmacokinetic rationale for any intranasal schedule is weak.

Schedules are reproduced as their source states them. Units, IU and milligrams explains why the figures are not interchangeable between products.

Reconstitution

Vial sizes
Intranasal spray, usually compounded at 50 mcg per actuation, Powder for research: 5 mg, 10 mg
Solvent
The nasal spray is supplied by a compounding pharmacy, ready to use and buffered. For non-pharmaceutical powder, bacteriostatic water is used in practice.
Storage
The nasal spray is kept refrigerated (2-8 °C) and usually has a limited shelf life of a few weeks to months. Powder in the freezer, protected from light.

Worked example

To match the compounded strength of 50 mcg per actuation: 5 mg powder + 10 ml bacteriostatic water = 0.5 mg/ml; with a spray bottle delivering 0.1 ml per actuation that gives 50 mcg per actuation. Diluting the same 5 mg into 5 ml instead gives 1 mg/ml and therefore 100 mcg per actuation — double the strength the protocol is written around, which is a mistake worth avoiding rather than a shortcut to the escalated dose.

VIP is chemically not very stable in aqueous solution; compounding pharmacies therefore use specific buffers and preservatives. Preparing it yourself gives an unknown and probably rapidly declining concentration.

Safety

Side effects

  • Flushing, a sensation of warmth and headache from vasodilation — the most predictable effect, given the physiology
  • Drop in blood pressure, palpitations, dizziness; pronounced with intravenous administration
  • Diarrhoea and abdominal cramps (VIP stimulates intestinal secretion; VIPoma syndrome consists precisely of severe watery diarrhoea)
  • Local irritation of the nasal mucosa with intranasal use; a rat toxicity evaluation of a VIP nasal spray found minor irritation that resolved spontaneously within a week of stopping 2
  • With nebulised use: coughing, breathlessness
  • The long-term safety of daily intranasal use has not been studied

Do not use if

  • Low blood pressure or a tendency to orthostatic hypotension
  • Continuing exposure to a water-damaged building is regarded within the protocol itself as a reason not to start 1
  • Presence of a pancreatic tumour or suspicion of a VIPoma
  • Pregnancy and breastfeeding: no data
  • Severe cardiac or vascular disease in which a fall in blood pressure is undesirable

Interactions

May amplify the blood pressure-lowering effect of antihypertensives, nitrates, alpha blockers and PDE5 inhibitors (sildenafil, tadalafil). Further interactions have not been systematically studied.

Sources