VIP

VIP belongs to the secretin/glucagon superfamily and signals through VPAC1 and VPAC2 receptors on immune cells, vascular smooth muscle, lung alveolar type II cells and neurons. cAMP elevation downstream suppresses TNF-alpha, IL-6 and IL-12 while promoting IL-10 and regulatory T cells, which is the basis for its use as an immune-rebalancing agent. In the lung it protects alveolar type II cells and inhibits surfactant loss, which is why aviptadil was trialled intravenously in COVID-19 respiratory failure. In the intranasal CIRS protocols popularised by Ritchie Shoemaker, it is positioned as the final step used to restore hypothalamic-pituitary regulation after exposure and colonisation issues have been dealt with. VIP is also the principal neurotransmitter of the suprachiasmatic nucleus, which is why circadian effects are attributed to it.

Targets: VPAC1 receptor, VPAC2 receptor, cAMP / PKA signalling, TNF-alpha, IL-6 and IL-12 suppression, Alveolar type II cells

• · The Shoemaker standard is 50 mcg per spray four times daily for the first month, sometimes increased to 100 mcg per spray four times daily thereafter. The lyophilised vial is reconstituted and transferred into a metered nasal spray bottle by a compounding pharmacy.
• · Less common than intranasal and more likely to produce flushing and blood pressure drops, because you are delivering a potent vasodilator systemically.

Work out your exact syringe units →

• commonFlushing and warmth— Direct consequence of vasodilation.
• commonLight-headedness or drop in blood pressure— More likely with subcutaneous or intravenous routes than intranasal.
• commonNasal irritation or burning
• uncommonDiarrhoea— VIP is the hormone responsible for the watery diarrhoea in VIPoma; large systemic doses can reproduce a mild version of it.
• uncommonHeadache

• Low baseline blood pressure or orthostatic hypotension - VIP is a potent vasodilator and will make this worse.
• Active mould or biotoxin exposure in the CIRS framework - practitioners consider starting VIP before exposure is removed to be both wasted and potentially symptom-provoking.
• Pancreatitis history - VIP has significant exocrine pancreatic effects.

• cautionAntihypertensives and nitrates — Additive vasodilation and hypotension.
• cautionPDE5 inhibitors — Both raise cyclic nucleotide signalling in vascular smooth muscle; the blood pressure effects stack.

• · Blood pressure, particularly in the first week and after any dose increase.
• · In CIRS protocols, practitioners track VCS testing, TGF-beta1, C4a and MSH, though the validity of that panel is contested outside that community.

Not approved in the US for any indication, and not approved anywhere for the inflammatory, CIRS or repair uses described here. Aviptadil is, however, an approved medicine in Europe in combination with phentolamine as Invicorp (25 mcg aviptadil per intracavernosal dose) for erectile dysfunction, licensed in Denmark and the UK. Aviptadil's intravenous COVID-19 programme (Zyesami/RLF-100) did not result in approval. Intranasal VIP is available through compounding pharmacies on prescription in the US.

• Shoemaker et al., intranasal VIP corrects chronic inflammatory response syndrome following water-damaged building exposure (open-label) (trial)
• ACTIV-3b / TESICO randomised trial of aviptadil in COVID-19 respiratory failure (trial)
• Delgado & Ganea, vasoactive intestinal peptide as an immunoregulatory neuropeptide (review) (review)

VIP signals through two class B GPCRs, VPAC1 and VPAC2, both coupled to Gs. Receptor engagement raises intracellular cAMP and activates PKA, and essentially every downstream effect follows from that single second messenger step - which is why the effects look so scattered across organ systems. cAMP in vascular smooth muscle is relaxation, so you get vasodilation and the flushing and blood pressure drop that come with it. cAMP in immune cells suppresses NF-kB-driven transcription of TNF-alpha, IL-6 and IL-12 while promoting IL-10 and pushing T cells toward a regulatory phenotype. cAMP in intestinal epithelium drives chloride and water secretion, which is precisely the mechanism of the watery diarrhoea seen in VIPoma and the reason large systemic doses reproduce a mild version of it. The receptor distribution explains the route choices. VPAC1 dominates on lung and immune tissue; VPAC2 dominates on vascular smooth muscle and in the suprachiasmatic nucleus. Aviptadil was given intravenously for COVID-19 because alveolar type II cells are VPAC1-rich, and the hypothesis was protection of surfactant-producing cells. That hypothesis was tested properly in TESICO and it failed - no significant improvement at day 90, and mortality of 38 percent versus 36 percent on placebo. VIP is also the principal neurotransmitter of the suprachiasmatic nucleus, where VPAC2 signalling synchronises the circadian clock cells with each other. That is the mechanistic basis for the sleep and circadian effects people report on the nasal protocol, and it is real biology - it is just biology observed in the SCN, not a demonstration that intranasal dosing reaches it. That is the crux of the compound. The receptor pharmacology is excellent and well characterised. The intranasal CIRS protocol that most people are actually running rests on case series and open-label work from a single group, and the existence of large randomised intravenous trials in a completely different indication should not be allowed to lend it credibility.

The first thing that goes wrong is the spray bottle. VIP is genuinely fragile in solution, and a metered nasal bottle sitting on a bathroom shelf at room temperature between doses is losing peptide continuously. It belongs in the fridge, including the one in use, and gets replaced monthly. People who report VIP 'stopping working' after a few weeks are frequently describing a degraded bottle. The second is improvising the delivery device. A metered pump calibrated to deliver 50 mcg per actuation is a compounding pharmacy job. Reconstituting a vial and squirting it up your nose delivers an unknown dose of an expensive, fragile peptide. The third is the blood pressure. A potent vasodilator with a two-minute half-life produces a sharp, short effect rather than a gentle one. Anyone already running low, orthostatic or on antihypertensives should be sitting down for the first dose. The fourth is diarrhoea at systemic doses. This is not an idiosyncratic reaction - VIP is the hormone responsible for the watery diarrhoea of VIPoma syndrome, and cAMP-driven intestinal chloride secretion is the mechanism. Systemic dosing reproduces a mild version of a recognised paraneoplastic syndrome, by design. The fifth, and the most consequential, is evidence laundering. VIP has been in large randomised trials. Those trials were intravenous, in critically ill COVID-19 patients, and they were negative. None of that supports an intranasal protocol for a contested illness. Anyone citing 'clinical trials of VIP' at you in a CIRS context is citing a trial that failed in a different indication by a different route.

1. 50 mcgDay 1 — A single 50 mcg spray, then wait an hour before doing anything else. You are looking for flushing, warmth or light-headedness. That is a vasodilatory response and it tells you where your ceiling is.
2. 50 mcgWeeks 1-4 — 50 mcg per spray four times daily, alternating nostrils, spread through the waking day. This is the standard first-month protocol.
3. 100 mcgMonth 2 onward — Some protocols increase to 100 mcg per spray four times daily after the first month. Recheck standing blood pressure after the first dose at the new strength - the vasodilatory effect scales.
4. 50 mcgSystemic route — 50-100 mcg subcutaneously once or twice daily is used but is considerably more likely to produce flushing and a blood pressure drop, because you are putting a potent vasodilator straight into the circulation rather than onto a mucosa. Start at 50 mcg once daily and only in the evening.

• VPAC1 receptor (VIPR1) — VIP binds VPAC1 with high, sub-nanomolar to low-nanomolar affinity; PACAP binds comparably, so the two are not distinguishable at this receptor

  Gs-coupled cAMP elevation. Dominant on immune cells and lung epithelium - the anti-inflammatory and alveolar protective arm.

• VPAC2 receptor (VIPR2) — High affinity, comparable to VPAC1

  Vasodilation in vascular smooth muscle and circadian synchronisation in the suprachiasmatic nucleus. The source of both the blood pressure effects and the sleep claims.

• cAMP / PKA signalling — Downstream second messenger, not a binding target

  The single common pathway behind every VIP effect - vasodilation, cytokine suppression, IL-10 and regulatory T cell promotion, and intestinal chloride secretion.

• Alveolar type II cells — VPAC1-mediated

  Inhibition of surfactant loss and protection from apoptosis - the rationale for the aviptadil COVID-19 programme, which did not translate into a survival benefit.

• ACTIV-3b / TESICO: intravenous aviptadil and remdesivir for COVID-19-associated hypoxaemic respiratory failure Phase 3 · n=461 · 13 weeks · 2023

  471 participants randomised to aviptadil or matched placebo across 28 US sites, 461 in the modified intention-to-treat population. Aviptadil was given as a daily 12-hour infusion for three days, escalating from 600 to 1200 to 1800 pmol/kg. The odds ratio for improvement in the six-category ordinal outcome at day 90 was 1.11 (95% CI 0.80-1.55, p=0.54). Mortality to day 90 was 38 percent with aviptadil versus 36 percent with placebo. A clean, well-powered negative result.

• Open-label intranasal VIP in chronic inflammatory response syndrome following water-damaged building exposure Open-label

  The foundational work for the intranasal CIRS protocol, reporting improvement in symptom scores, pulmonary artery pressure on exercise and a panel of inflammatory markers. No indexed publication could be resolved for it in the preparation of this entry, and it was open-label rather than randomised or placebo-controlled.

Minutes: flushing, warmth or light-headedness if you are going to get them. This is the vasodilatory response and it is your dose-finding signal. Weeks 1-2: nasal users commonly report a shift in energy or in inflammatory symptoms. This is the earliest point anything is described. Months 1-3: the window over which the CIRS protocol is judged, typically alongside repeat VCS testing and the marker panel. Months 3-6 and beyond: intranasal courses routinely run this long under supervision. There is no controlled data at any of these timepoints. Systemic: effects are immediate and short. There is no accumulating effect to wait for, because there is no accumulation.

The most important stacking consideration is pharmacological rather than protocol-driven: VIP raises cAMP in vascular smooth muscle, and so do PDE5 inhibitors, by blocking the breakdown of cGMP in the same tissue. Nitrates do the same job through a different door. Stacking any of these with VIP compounds the hypotension, and the two-minute half-life means it arrives fast. Same logic for antihypertensives generally. If you are on an ACE inhibitor, an ARB, a calcium channel blocker or an alpha blocker, the standing blood pressure check after the first dose is not optional. Within the CIRS framework, VIP is positioned deliberately as the last step - after exposure removal, binder therapy and treatment of MARCoNS colonisation. Practitioners consider starting it early to be both wasted and symptom-provoking. Whether or not you accept the framework, the sequencing logic is at least internally consistent: you are trying to reset a regulatory signal, and doing that while the driver is still present is pointless. With other peptides in this class there is no particular synergy and no interaction data. VIP is not a soft-tissue repair compound and does not belong in a tendon stack.

Against the rest of this class: VIP is not a repair peptide in the soft-tissue sense at all. It sits here because of the immune-rebalancing framing, but its pharmacology is vasodilation and cytokine modulation through cAMP, not angiogenesis or matrix remodelling. If you have a tendon problem, this is the wrong shelf. Against PACAP: nearly the same receptor pharmacology, since PACAP binds VPAC1 and VPAC2 with comparable affinity and additionally hits PAC1. If VPAC signalling is what you want, the two are close substitutes. Against approved anti-inflammatory therapy for a defined inflammatory disease: not comparable. VIP has no approval for any inflammatory indication anywhere. The one approved product containing aviptadil is Invicorp, a combination with phentolamine for erectile dysfunction, licensed in parts of Europe at 25 mcg per intracavernosal dose - which is a completely different use of the same vasodilatory pharmacology. Against doing nothing while still exposed: within the CIRS framework itself, practitioners agree that VIP before exposure removal is wasted. That is the one point on which the protocol's own advocates and its outside critics would agree.

$150–$500/month. Compounded intranasal VIP from a US pharmacy is the usual channel and is priced accordingly; the nasal bottle is typically replaced monthly, which is a recurring rather than an occasional cost. Order-of-magnitude estimate, not price-checked in the preparation of this entry.

• ?No human intranasal pharmacokinetics - no nasal bioavailability figure, no tmax, no measure of how much reaches any target tissue.
• ?Whether intranasally delivered VIP reaches the suprachiasmatic nucleus or any central target in meaningful quantity is unestablished. The blood-brain barrier rating of 'partial' reflects reported limited transport of native VIP, not a demonstration of central delivery from a nasal spray.
• ?The Shoemaker open-label intranasal work could not be resolved to an indexed publication in this session, so its participant numbers and outcomes are unverified.
• ?The 50 mcg four-times-daily protocol has no dose-ranging study behind it in this indication.
• ?The CIRS marker panel (TGF-beta1, C4a, MSH, VCS) is contested outside the community that uses it and has no validated relationship to VIP response in independent literature.
• ?There is no data on the long-term safety of multi-month intranasal VIP, which is how it is routinely used.
• ?Cost figures are estimates and were not price-verified in this session.

• Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial Brown SM et al. (ACTIV-3b/TESICO Study Group), Lancet Respiratory Medicine, 2023 · PMID 37348524

  The largest and best-conducted trial of VIP in any indication, and it was negative. Essential context for anyone who has been told VIP has 'clinical trial evidence'.