VIP

vasoactive intestinal polypeptide, aviptadil (synthetic pharmaceutical form), Invicorp (aviptadil + phentolamine, intracavernosal), RLF-100 / Zyesami (investigational IV aviptadil)

Longevity & cellular

Awaiting medical reviewEN ES DE FR PT ZH+ Follow for updates

Note on this profile. Aviptadil (synthetic VIP) combined with phentolamine is an approved prescription medicine (Invicorp) for erectile dysfunction in the UK, Denmark, New Zealand and some other countries †, injected into the penis under medical instruction. Intravenous aviptadil for respiratory failure was given emergency authorisation in some settings during COVID-19 but has not received full approval †. All community use — intranasal sprays for "mould illness"/CIRS, subcutaneous injection, inhalation — is unapproved. This page explains the published science.

Summary

Class: Naturally occurring 28-amino-acid peptide hormone and neurotransmitter of the secretin/glucagon family; acts on VPAC1 and VPAC2 receptors (and weakly PAC1)
Mechanism: Relaxes smooth muscle (blood vessels, airways, gut), stimulates secretion, and is one of the body's main anti-inflammatory and immune-balancing neuropeptides; in the lung it protects the surfactant-producing cells
Routes studied: Intracavernosal injection (approved, with phentolamine); IV infusion (ARDS, pulmonary hypertension, sarcoidosis trials); inhaled/nebulised (pulmonary hypertension, sarcoidosis, COVID-19); intranasal spray (community; no human trial for CIRS); subcutaneous (community)
Dose range reported: Invicorp: 25 µg aviptadil + 1 or 2 mg phentolamine per intracavernosal dose, maximum one dose per 24 hours and three per week. IV (COVID-19 ARDS): 50, 100 then 150 pmol/kg/h for 12 hours on three successive days (RLF-100 protocol). Inhaled: 50–100 µg aviptadil 4 times daily (pulmonary hypertension, sarcoidosis studies). Intranasal community (CIRS protocol as published by Shoemaker): 50 µg per spray, 4 times daily, commonly 1 spray per nostril. No approved dose exists for nasal or subcutaneous use
Half-life: ~1–2 minutes in plasma (rapidly cleared by peptidases); tissue effects outlast the plasma level
Storage: Lyophilised: refrigerate or freeze, protect from light. Reconstituted: refrigerate; VIP is fragile and community practice is use within 2–3 weeks; compounded nasal sprays carry a pharmacy beyond-use date (often 30–60 days refrigerated)
Regulatory status: Approved only as Invicorp (intracavernosal, with phentolamine) in a limited set of countries; IV/inhaled aviptadil investigational; nasal VIP available only as a compounded prescription product in the US

Doses are as reported in studies or by the community — never recommendations.

1What it is

VIP is a 28-amino-acid hormone the body already makes, discovered in 1970 by Sami Said and Viktor Mutt in pig intestine, where it causes blood-vessel dilation (hence the name). It turned out to be made throughout the nervous system, gut, lung, heart and immune system, and is now understood less as a gut hormone than as a widely distributed neuropeptide that relaxes smooth muscle, regulates secretion, and calms inflammation. In the lung it is concentrated around the alveolar type II cells that make surfactant, which is why it became a candidate treatment for acute respiratory distress syndrome (ARDS). It also has a role in the circadian clock (VIP neurons in the suprachiasmatic nucleus) and in erectile tissue.

"Aviptadil" is the international non-proprietary name for synthetic VIP used as a drug. A VIP-secreting tumour (VIPoma) causes profuse watery diarrhoea and flushing — a useful real-world reminder of what high systemic VIP does. In the community VIP appears in two unrelated contexts: as a compounded nasal spray in the "chronic inflammatory response syndrome" (CIRS) protocol associated with Ritchie Shoemaker, and, more recently, as a research peptide injected for immune or anti-inflammatory purposes.

2How it's thought to work

Smooth muscle. VPAC receptor activation raises cyclic AMP, relaxing vascular, bronchial, gut and corpus cavernosum smooth muscle — the basis for the ED, pulmonary hypertension and asthma research.

Lung protection. VIP inhibits inflammatory cytokines (IL-6, TNF-α), blocks apoptosis of type II alveolar cells, and increases surfactant production; in COVID-19 the hypothesis was that it protects the very cells the virus targets (Youssef 2022, review).

Immune modulation. VIP shifts T-cell responses away from inflammatory Th1/Th17 patterns toward regulatory and Th2 patterns, induces regulatory T cells, and dampens macrophage activation — shown extensively in rodent models of arthritis, colitis, sepsis and multiple sclerosis (Delgado 2004, Pharmacol Rev; Gonzalez-Rey 2007).

Nervous system. supports neuronal survival in culture; synchronises circadian neurons; involved in nasal and gut secretion.

CIRS hypothesis. the Shoemaker protocol proposes that low VIP (measured in blood) in people exposed to water-damaged buildings underlies many symptoms, and that nasal VIP corrects downstream gene expression and symptoms. This rests on one uncontrolled study and case series from the protocol's originators; the CIRS construct itself is not accepted by mainstream medicine.

VIP at the VPAC1 and VPAC2 receptors. The vessel widens and exocrine glands release fluid — the two effects that give vasoactive intestinal peptide its name, and that make a VIP-secreting tumour cause watery diarrhoea.Schematic — not to scale

3What the research shows

Erectile dysfunction (intracavernosal aviptadil + phentolamine)

Randomised, double-blind, placebo-controlled trials in several hundred men with ED of mixed cause showed erections sufficient for intercourse in around 60–70% of attempts, with less penile pain and priapism than alprostadil (Dinsmore 1999, BJU Int; Sandhu 1999, Int J Impot Res; Dinsmore & Wyllie 2008, BJU Int — long-term safety). Marketed as Invicorp in the UK (2014), Denmark, New Zealand and others †. [4][5]

Graded A (mixed)

COVID-19 respiratory failure (IV aviptadil, RLF-100/Zyesami)

A Phase 2b/3 in 196 patients with critical COVID-19 (NeuroRx) reported no significant difference in the primary endpoint (alive and free of respiratory failure at day 60) overall, with post-hoc signals in high-flow oxygen subgroups; the NIH ACTIV-3b/TESICO trial (n≈460 aviptadil arm) found no benefit on recovery or survival (ACTIV-3b/TESICO Study Group 2023, JAMA). The FDA declined emergency authorisation. Published open-label and case data are more favourable but uncontrolled. [9]

Acute respiratory distress syndrome (pre-COVID)

Small Phase 1–2 studies of IV aviptadil in sepsis-related ARDS in the 2000s reported safety and some physiological signals but did not progress (Said 1990s–2000s work; Bisgaard/Mondino trials †).

Graded B/A (negative)

Pulmonary arterial hypertension (inhaled)

An open-label pilot in 8 patients showed reduced pulmonary pressures and improved exercise capacity (Petkov 2003, J Clin Invest), but a subsequent randomised Phase 2 trial of inhaled aviptadil found no sustained haemodynamic benefit (Leuchte 2008, Eur Respir J). [6][7]

Sarcoidosis (inhaled)

Twenty patients given nebulised VIP for 4 weeks showed reduced TNF-α from lung lavage cells and more regulatory T cells, without clinical endpoints (Prasse 2010, Am J Respir Crit Care Med). [8]

Graded B/C

Asthma, COPD

Inhaled VIP relaxed airways in early studies but was degraded too fast to be useful; long-acting analogues (e.g. Ro 25-1553) were tested and abandoned (Lindén 2003, Thorax).

Graded B (single uncontrolled study)

Chronic inflammatory response syndrome (intranasal)

One open-label study of 20 patients on the Shoemaker protocol reported symptom improvement, normalised inflammatory markers and gene-expression changes with nasal VIP (Shoemaker 2013, Health). No controlled trial; no independent replication. [11]

Autoimmune and neurodegenerative disease

Robust rodent data in rheumatoid arthritis, Crohn's disease, sepsis and multiple sclerosis models (Delgado 2001, Nat Med; Abad 2003, Gastroenterology). No human trials for these indications. [3]

4Reported side effects and interactions

Literature-reported

Literature (Invicorp). facial flushing (the most common, in roughly a third of patients — a VIP vasodilation effect), penile pain and bruising at the injection site, headache, transient fall in blood pressure, dizziness; priapism and penile fibrosis rare and less frequent than with alprostadil. Literature (IV aviptadil): hypotension, diarrhoea, flushing, tachycardia, and importantly at infusion rates used in COVID-19 some patients needed vasopressor support; occasional transient liver-enzyme rises. Literature (inhaled): cough and transient drops in systemic blood pressure at higher doses.

Community-reported

Community-reported (nasal spray). nasal irritation, flushing, headache, light-headedness, transient racing heart; some report increased symptoms initially; CIRS protocol users report improved cognition and energy, others nothing. users report flushing, warmth and occasional nausea or loose stools.

Theoretical. VIP stimulates secretion in the gut (VIPoma causes severe diarrhoea), so systemic exposure at meaningful doses would be expected to cause diarrhoea and hypotension. Chronic immune suppression toward Th2 patterns could in theory worsen allergy or reduce anti-tumour immunity; the Shoemaker protocol screens for mould exposure and MARCoNS before use for its own reasons. Pancreatic enzyme (lipase) rises were reported in the CIRS protocol literature and are listed as a reason to stop †.

Interactions. additive hypotension with PDE5 inhibitors, nitrates, alpha-blockers and antihypertensives; phentolamine in Invicorp adds alpha-blockade. No formal interaction studies for nasal VIP.

Markers researchers commonly monitor

Marker	Why it's watched
Blood pressure and heart rate	vasodilation and hypotension are the dominant acute effects by any systemic route.
Serum lipase (and amylase)	pancreatic enzyme rises are a stated stopping rule in the CIRS protocol literature †; VIP stimulates pancreatic secretion.
Inflammatory markers used in the CIRS protocol (C4a, TGF-β1, MMP-9, MSH, VIP itself)	these are the protocol's own tracking markers and their interpretation is specific to it; mainstream reference ranges for several are not established.
Liver enzymes	transient rises reported with IV infusion.
Stool frequency	diarrhoea signals excessive systemic VIP activity.
Oxygenation and respiratory measures in the ARDS research context
General baselines (CBC, CMP) otherwise; no compound-specific blood test is validated for nasal or subcutaneous use

Free for everyone. Safety information is never behind a paywall.

5Reconstitution and handling

Invicorp is a pre-filled dual-chamber syringe used after clinician training. Compounded nasal VIP is dispensed by the pharmacy as a metered spray (typically 50 µg/0.1 ml) and kept refrigerated. Research-grade VIP (commonly 2–5 mg vials) is with ; it is one of the less stable peptides, so small batches, cold storage and protection from light matter.

Open in calculator, pre-loaded →

6Commonly studied alongside

Phentolamine (in Invicorp); standard ARDS care, remdesivir and corticosteroids (COVID-19 trials); PACAP (its closest relative, sharing receptors); the Shoemaker CIRS sequence (cholestyramine, MARCoNS treatment, then VIP) in community protocols; in rodent immunology, VIP is compared with glucocorticoids and anti-TNF agents.

Informational cross-links. Not stack recommendations.

7Regulatory status by region

Region	Status (checked —)
United States	Not FDA-approved in any form. IV aviptadil denied emergency use authorisation (2021–2022); investigational. Intranasal VIP available only as a compounded prescription product †
European Union	Invicorp approved in Denmark and some other member states for ED †; aviptadil otherwise investigational (orphan designation for ARDS and sarcoidosis historically)
United Kingdom	Invicorp (aviptadil 25 µg + phentolamine 2 mg) MHRA-licensed since 2014 for ED; prescription-only. Other forms unlicensed
Australia	Not registered †
South Africa	Not registered †
Sport (WADA)	Not named on the Prohibited List; non-approved forms fall under S0 †

8Open questions

Does intranasal VIP achieve meaningful systemic or CNS exposure at 50 µg doses? No pharmacokinetic study has been published.
The CIRS construct and nasal VIP's role in it await any controlled trial.
Whether a subgroup of ARDS patients benefits from IV aviptadil, as post-hoc analyses hinted.
Long-acting VIP analogues or formulations that overcome the 2-minute .

9References

1Said SI, Mutt V (1970). Polypeptide with broad biological activity: isolation from small intestine. Science. PubMed · DOI
2Delgado M, Pozo D, Ganea D (2004). The significance of vasoactive intestinal peptide in immunomodulation. Pharmacol Rev. PubMed · DOI
3Delgado M et al. (2001). Vasoactive intestinal peptide prevents experimental arthritis by downregulating both autoimmune and inflammatory components of the disease. Nat Med. PubMed · DOI
4Dinsmore WW et al. (1999). Treating men with predominantly nonpsychogenic erectile dysfunction with intracavernosal vasoactive intestinal polypeptide and phentolamine mesylate in a novel auto-injector system: a multicentre double-blind placebo-controlled study. BJU Int. PubMed · DOI
5Dinsmore WW, Wyllie MG (2008). Vasoactive intestinal polypeptide/phentolamine for intracavernosal injection in erectile dysfunction. BJU Int. PubMed · DOI
6Petkov V et al. (2003). Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J Clin Invest. PubMed · DOI
7Leuchte HH et al. (2008). Inhalation of vasoactive intestinal peptide in pulmonary hypertension. Eur Respir J. PubMed · DOI
8Prasse A et al. (2010). Inhaled vasoactive intestinal peptide exerts immunoregulatory effects in sarcoidosis. Am J Respir Crit Care Med. PubMed · DOI
9ACTIV-3b/TESICO Study Group (2023). Aviptadil and remdesivir for critically ill COVID-19 patients: a randomised clinical trial. JAMA. PubMed
10Youssef JG et al. (2022). Vasoactive intestinal peptide for the treatment of severe COVID-19 respiratory failure. Expert Opin Investig Drugs [verify]. PubMed
11Shoemaker RC, House D, Ryan JC (2013). Vasoactive intestinal polypeptide (VIP) corrects chronic inflammatory response syndrome (CIRS) acquired following exposure to water-damaged buildings. Health. DOI
12Invicorp summary of product characteristics (UK, current). PubMed

References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.

† Being confirmed by our reviewers against current sources.

10Community

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Self-reported side effects Phase 2

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11Page history

25 Oct 2026Profile published — awaiting medical review

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