VIP (Vasoactive Intestinal Peptide)
Also known as: Vasoactive intestinal peptide, Vasoactive intestinal polypeptide, Aviptadil, Zyesami, RLF-100, Invicorp (aviptadil/phentolamine combination)
Not FDA-approved for any use (EUA for aviptadil declined 2021 and 2022); aviptadil/phentolamine (Invicorp) licensed for erectile dysfunction in some European countries
5 notable studies · 9 references
TLDR
VIP is a natural 28-amino-acid neuropeptide that relaxes blood vessels and airways, drives gut secretion, helps run the circadian clock, and calms immune responses. Animal studies show strong anti-inflammatory effects, and small open-label human studies in pulmonary hypertension and sarcoidosis looked promising. However, the largest rigorous trial, IV aviptadil in critical COVID-19, was negative, and VIP is not FDA-approved for any use as of October 2026.
At a Glance
Classification: Endogenous 28-amino-acid neuropeptide of the secretin/glucagon family; VPAC1/VPAC2 receptor agonist; neurotransmitter, vasodilator and immunomodulatory peptide
VIP is a 28-amino-acid peptide the body makes in nerves throughout the gut, lungs, brain, blood vessels and immune tissues. It was first isolated in 1970 by Sami Said and Viktor Mutt from pig small intestine, where they found it powerfully widened blood vessels. That is where the name comes from. VIP is a multitasker: • relaxes smooth muscle in blood vessels, airways and the gut • stimulates intestinal water and electrolyte secretion • acts as a neurotransmitter, including in the brain's master clock (the suprachiasmatic nucleus) • calms immune responses, reducing inflammatory cytokines and favoring regulatory T cells. Its pharmaceutical form is called aviptadil (synthetic human VIP). Regulatory status (as of October 2026): • United States: not FDA-approved for any use. The FDA declined emergency use authorization for IV aviptadil (Zyesami) in COVID-19 respiratory failure in 2021 and 2022, and a large NIH-sponsored trial found no benefit. • Some European countries: aviptadil combined with phentolamine has been licensed as an injection into the penis for erectile dysfunction (Invicorp). That is a combination product for a narrow use. A medical curiosity: tumors that overproduce VIP (VIPomas) cause severe watery diarrhea, low potassium and low stomach acid ("WDHA syndrome"). This shows how potent its secretory effects are.
What Is VIP (Vasoactive Intestinal Peptide)?
VIP is an endogenous neuropeptide in the secretin/glucagon superfamily, related to PACAP, secretin, glucagon and GHRH. It acts on two main receptors: • VPAC1 (common in the lung, liver, gut and immune cells) • VPAC2 (smooth muscle, brain including the circadian clock, and immune cells). PACAP shares these receptors and also has its own (PAC1), where VIP is much weaker. VIP is broken down very quickly in the blood (a half-life of minutes), which is a major hurdle for using it as a drug. Researchers have tried inhaled, intranasal and continuous IV delivery, and stabilized analogs.
What Are Researchers Studying?
Pulmonary arterial hypertension
A 2003 study found VIP deficiency in the blood and lungs of people with primary pulmonary hypertension. Eight patients given inhaled VIP had lower pulmonary artery pressure and higher cardiac output. A 2008 single-dose study in 20 patients with pulmonary hypertension found only a small, short-lived pulmonary vasodilation. Inhaled VIP has not become an established treatment.
Sarcoidosis and lung inflammation
In an open phase II study in 20 people with active sarcoidosis, four weeks of inhaled VIP was well tolerated. It reduced TNF-α production by lung immune cells and increased regulatory T cells in lung fluid. There was no placebo group, and immune measures are not clinical outcomes.
COVID-19 respiratory failure
VIP drew wide attention during the pandemic as a possible protector of the lung's alveolar cells. The NIH-sponsored TESICO trial randomized 461 critically ill patients to IV aviptadil or placebo. There was no improvement at day 90, and death rates were similar (38% vs. 36%).
Autoimmune and inflammatory disease models
In mice with collagen-induced arthritis, VIP sharply reduced disease incidence and severity, completely preventing joint swelling and destruction, by dampening both inflammatory and autoimmune responses. Similar animal findings exist for colitis and sepsis models. These are animal results.
Erectile dysfunction
Aviptadil combined with phentolamine, injected into the penis, relaxes erectile tissue and is licensed in some European countries. This use relies on the combination and the route, and does not apply to other forms of VIP.
Chronic inflammatory response syndrome (CIRS)
Intranasal VIP is promoted in some clinical practices for CIRS, a mold- or biotoxin-related illness concept. We found no PubMed-indexed randomized controlled trial supporting this use.
How Does It Work?
VIP ↓ binds VPAC1/VPAC2 (G protein-coupled receptors) ↓ raises cyclic AMP in target cells ↓ in smooth muscle: relaxation → vasodilation, bronchodilation in gut epithelium: chloride and water secretion in immune cells: less TNF-α, IL-6 and IL-12; more IL-10; induction of regulatory T cells in neurons: neurotransmission and neuroprotective signaling, including circadian synchronization. Common effects when VIP is given systemically include flushing, low blood pressure, fast heart rate and diarrhea. These follow directly from its biology.
What Does the Research Show?
Human research
LOW–MODERATE Small open-label studies in pulmonary arterial hypertension and sarcoidosis reported encouraging results, but a large, rigorous randomized trial in COVID-19 respiratory failure was negative. Robust evidence of benefit from VIP in any condition beyond the erectile-dysfunction combination product is lacking.
Animal research
EXTENSIVE Strong anti-inflammatory and immunomodulatory effects in models of arthritis, colitis, sepsis, lung injury and neuroinflammation.
In-vitro research
EXTENSIVE Receptor pharmacology and immune-cell effects are well characterized.
Notable Studies
Polypeptide with broad biological activity: isolation from small intestine
animalJournal: Science. The discovery paper. A 28-amino-acid polypeptide isolated from hog small intestine produced systemic vasodilation, low blood pressure, increased cardiac output, respiratory stimulation and raised blood sugar. It was chemically distinct from kinins, substance P, glucagon and secretin.
Limitations: Historical isolation and bioactivity characterization only.
View publication →Vasoactive intestinal peptide prevents experimental arthritis by downregulating both autoimmune and inflammatory components of the disease
animalJournal: Nature Medicine. In mouse collagen-induced arthritis, VIP treatment significantly reduced the incidence and severity of arthritis, completely preventing joint swelling and cartilage and bone destruction. This was linked to reduced inflammatory and autoimmune responses.
Limitations: Mouse model. VIP's very short half-life and blood-pressure effects complicate translation to people with rheumatoid arthritis.
View publication →Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension
humanJournal: Journal of Clinical Investigation. People with primary pulmonary hypertension had lower VIP in blood and lung tissue, with upregulated VIP receptors. In eight patients, inhaled VIP lowered mean pulmonary artery pressure and increased cardiac output and mixed venous oxygen saturation, with no side effects reported.
Limitations: Eight patients, no control group. A later single-dose study found the vasodilating effect modest and short-lived, and inhaled VIP has not become an established therapy.
View publication →Inhaled vasoactive intestinal peptide exerts immunoregulatory effects in sarcoidosis
humanJournal: American Journal of Respiratory and Critical Care Medicine. Open-label phase II study in 20 people with active sarcoidosis. Four weeks of nebulized VIP was safe and well tolerated, significantly reduced TNF-α production by lung immune cells, and increased regulatory T cells in bronchoalveolar lavage fluid.
Limitations: No placebo group, small sample, short duration, and immunological rather than clinical endpoints.
View publication →Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial
humanJournal: Lancet Respiratory Medicine. 461 patients with COVID-19 acute hypoxemic respiratory failure, 94% in intensive care, were randomized to IV aviptadil or placebo. There was no improvement in day-90 recovery outcomes (odds ratio 1.11, p=0.54), and cumulative mortality was similar (38% vs. 36%). Early serious safety events were numerically more frequent with aviptadil (63% vs. 56%; not statistically significant).
Limitations: Critically ill COVID-19 population, so results do not address other conditions or routes. However, this is the most rigorous VIP trial to date, and it was negative.
View publication →What We Still Don't Know
• Whether any route of VIP delivery gives meaningful clinical benefit in a well-controlled trial (apart from the ED combination product) • How to overcome its very short half-life without unacceptable blood-pressure effects • Whether inhaled VIP helps pulmonary hypertension or sarcoidosis in placebo-controlled trials • Whether strong animal anti-inflammatory effects translate to human autoimmune disease • Efficacy and safety of intranasal VIP for CIRS or other uses promoted outside trials • Long-term safety of repeated dosing • Identity, purity and stability of non-pharmaceutical "research" VIP.
Related Compounds
Recent publications
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Sources & References
- Said SI, Mutt V. Polypeptide with broad biological activity: isolation from small intestine. Science. 1970;169(3951):1217–1218.
- Delgado M, Abad C, Martinez C, Leceta J, Gomariz RP. Vasoactive intestinal peptide prevents experimental arthritis by downregulating both autoimmune and inflammatory components of the disease. Nat Med. 2001;7(5):563–568.
- Petkov V, Mosgoeller W, Ziesche R, et al. Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J Clin Invest. 2003;111(9):1339–1346.
- Leuchte HH, Baezner C, Baumgartner RA, et al. Inhalation of vasoactive intestinal peptide in pulmonary hypertension. Eur Respir J. 2008.
- Prasse A, Zissel G, Lützen N, et al. Inhaled vasoactive intestinal peptide exerts immunoregulatory effects in sarcoidosis. Am J Respir Crit Care Med. 2010;182(4):540–548.
- Brown SM, Barkauskas CE, Grund B, et al. Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial. Lancet Respir Med. 2023;11(9):791–803.
- Delgado M, Abad C, Martinez C, et al. Vasoactive intestinal peptide in the immune system: potential therapeutic role in inflammatory and autoimmune diseases. J Mol Med (Berl). 2002.
- Dinsmore WW, Wyllie MG. Vasoactive intestinal polypeptide/phentolamine for intracavernosal injection in erectile dysfunction. BJU Int. 2008.
- NRx Pharmaceuticals. FDA declines Emergency Use Authorization for ZYESAMI (aviptadil). July 1, 2022.
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