VIP, or vasoactive intestinal peptide, is a natural signalling molecule built from 28 amino acids. It was discovered in the gut, but it turned out to act throughout the body: it widens blood vessels, relaxes smooth muscle and calms the immune system. Its synthetic, identical version is called aviptadil. Unlike most “research peptides”, VIP has an unusually large body of human data: from a clinically used medicine for erectile dysfunction (in combination with phentolamine), through small studies in lung diseases, to two large clinical trials in COVID-19 respiratory failure — in which the primary result was negative. In this review we explain in plain terms what VIP is, how it works and what those studies really showed.
What VIP is
VIP was first isolated in 1970 from the intestine — hence “intestinal” and “vasoactive” (because it widened blood vessels). It soon became clear that it is not an ordinary gut hormone but a neuropeptide: a substance released by nerve cells in the brain and in peripheral nerves, and also by immune cells. It belongs to a large family of related peptides that also includes secretin, glucagon, GLP-1 and GHRH (review by Delgado and Ganea, 2013). Aviptadil is the international name of the synthetic VIP used in clinical trials and in medicines.
How it works — the VPAC receptors
VIP acts through three “switches” on the cell surface: the receptors VPAC1, VPAC2 and PAC1 (the last of which prefers the related peptide PACAP). When they are activated, the level of cAMP rises inside the cell — a universal messenger that causes relaxation in the smooth muscle of vessels and airways, and suppresses the production of inflammatory signals in immune cells. The most interesting part is the immune system itself. Delgado and colleagues (2005) showed in mice that giving VIP together with an antigen increases the number of regulatory T cells (so-called Tregs) — cells that “brake” other lymphocytes and protect against an excessive immune reaction. The Tregs generated under the influence of VIP were more effective brakes per cell, transferred tolerance to other animals and prevented graft-versus-host disease in mice after bone-marrow transplantation. Hence the description of VIP as a “tolerogenic neuropeptide”.
Structure, origin and a very short life
VIP is a linear peptide of 28 amino acids. Its biggest obstacle as a medicine is its instability in the blood. Domschke and colleagues (1978) infused VIP intravenously into four healthy volunteers at three increasing doses. After the infusion stopped, the plasma concentration fell with a half-life of about one minute; the clearance was about 9 ml/kg/min. Even at the lowest dose the VIP concentration far exceeded physiological values, and at the highest dose the typical consequences of vasodilation appeared: a faster pulse, a wider blood-pressure amplitude and skin flushing, as well as small rises in glucose, free fatty acids and calcium. Such a short action explains why in clinical trials VIP is given as a continuous infusion, by inhalation (nebulisation) or as a local injection — not as a single shot.
What was studied — cells and animals
The review by Delgado and Ganea (2013) collects data from animal models: VIP inhibited the production of pro-inflammatory cytokines, turned dendritic cells (the cells that “present” antigens) into tolerogenic cells and eased the course of experimental arthritis, experimental multiple sclerosis and other autoimmune diseases in rodents. The key paper by Delgado and colleagues (2005) showed that the effect on Tregs occurs in living animals, not only in the test tube. It must be remembered, though, that translating these results to humans is limited by pharmacokinetics: in rodent experiments VIP is given by injection, whereas in humans the one-minute half-life forces other routes of administration.
Human data — three different areas
Erectile dysfunction. The best-established use is intracavernosal injection of VIP combined with phentolamine (a vasodilating drug). Dinsmore and colleagues (1999), in a multicentre placebo-controlled study of 236 men with erectile dysfunction of organic origin, obtained a response in 82% in the dose-finding phase; in the placebo-controlled phase (171 patients) 75% responded to the combination with 1 mg phentolamine versus 12% to placebo, and 66% versus 18% for the combination with 2 mg. The most frequent adverse event was transient facial flushing after 40% of 1,711 injections; one case of priapism was recorded. According to the 2013 review, this combination (trade name Invicorp) is used clinically. Note: these are data for a combination of two substances, not for VIP alone.
Sarcoidosis (an inflammatory lung disease). Prasse and colleagues (2010), in an open-label phase II study, gave 20 patients with active sarcoidosis nebulised VIP for 4 weeks. The treatment was well tolerated; cells from bronchoalveolar lavage produced significantly less TNF-α, and the number of regulatory T cells in the lungs rose. The authors called this the first evidence of an immunoregulatory effect of VIP in humans. Limitation: there was no placebo group and no assessment of disease course — laboratory markers were measured. The 2013 review also mentions inhaled VIP in pulmonary hypertension, where transient pulmonary vasodilation was observed.
Respiratory failure in COVID-19. This is the most important and most contested chapter. Youssef and colleagues (2022), in a placebo-controlled study at 10 US hospitals, gave 196 patients with respiratory failure three days of intravenous aviptadil or placebo (2:1 randomisation). The primary endpoint — being alive and free of respiratory failure at day 60 — did not reach statistical significance (odds ratio 1.6; 95% CI 0.86–3.11). As secondary findings the authors reported a twofold higher odds of survival to day 60 (OR 2.0; 95% CI 1.1–3.9; p = 0.035), lower interleukin-6 by day 3 and favourable subgroups. When reading these results it helps to know that the trial was funded by the drug’s manufacturer (NRx Pharmaceuticals), one author was its employee, and the sponsor extended the protocol during the trial (follow-up from 28 to 60 days, enrolment from 144 to 198) — that does not invalidate the result, but it calls for caution with conclusions drawn from secondary endpoints. The answer came from the much larger TESICO trial (Brown and colleagues, 2023), funded by the US NIH, at 28 sites: 461 patients received aviptadil (231) or placebo (230) by infusion for three days. The independent safety board stopped the trial for futility in May 2022. The odds of a better clinical outcome at day 90 were 1.11 (95% CI 0.80–1.55; p = 0.54), and 38% of patients died in the aviptadil group versus 36% in the placebo group (HR 1.04). The composite safety endpoint up to day 5 occurred in 63% versus 56% (OR 1.40; 95% CI 0.94–2.08; p = 0.10) — a non-significant difference, but in the unfavourable direction. The meta-analysis by Udupa and colleagues (2025), covering both RCTs and seven case series (665 patients), gave a survival odds ratio of 1.01 (95% CI 0.72–1.42; p = 0.93): no effect on survival. These results are contradictory only on the surface: the smaller trial produced a signal in a secondary endpoint, and the larger, better-powered one did not confirm it in the primary endpoint.
Safety and the limits of the evidence
The adverse effects of VIP follow directly from its biology: vasodilation produces skin flushing, a faster pulse and blood-pressure changes (Domschke 1978; facial flushing after 40% of injections in Dinsmore's trial). Domschke noted that the concentrations reached during infusion matched those of the Verner–Morrison syndrome — a rare VIP-secreting tumour that causes watery diarrhoea — and that some of the observed effects resembled that syndrome. In TESICO the composite safety endpoint (death, serious adverse events, organ failure, serious infection) occurred numerically more often in the aviptadil group. The main limits of the evidence: the erectile-dysfunction data concern a combination with phentolamine; the sarcoidosis study was open-label and small; in COVID-19 the largest trial was negative. On the basis of these results aviptadil has no confirmed efficacy in respiratory failure. We deliberately give no methods of use and no doses.
The wider context — the secretin and glucagon family
VIP belongs to the same peptide family as glucagon and GLP-1 — hormones described in our piece on the metabolic peptides GLP-1, GIP and glucagon — and as GHRH, the growth-hormone-releasing hormone whose analogue is CJC-1295. All of them act through similar cAMP-coupled receptors, but their jobs in the body are entirely different. Against this background VIP stands out as a peptide with an immunological role — and as one of the few that have been through large clinical trials with a negative result.
Summary
VIP is a natural neuropeptide of 28 amino acids that widens blood vessels and calms the immune system, among other things by generating regulatory T cells — in mouse studies and, in one open-label study, in sarcoidosis patients. Its half-life in the blood is about a minute. In humans the strongest evidence concerns the combination with phentolamine in erectile dysfunction. In COVID-19 respiratory failure a smaller trial produced a signal in a secondary endpoint, but the large TESICO trial (461 patients) was stopped for futility, and a meta-analysis showed no effect on survival. The state of the evidence is therefore mixed: a strong mechanism, confirmed vascular action, no confirmed efficacy in severe lung disease.
Sources
- Brown SM, Barkauskas CE, Grund B, et al.; ACTIV-3b/TESICO Study Group. Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial. The Lancet Respiratory Medicine. 2023;11(9):791–803. PMID: 37348524. DOI: 10.1016/S2213-2600(23)00147-9. pubmed.ncbi.nlm.nih.gov/37348524
- Youssef JG, Lavin P, Schoenfeld DA, et al. The Use of IV Vasoactive Intestinal Peptide (Aviptadil) in Patients With Critical COVID-19 Respiratory Failure: Results of a 60-Day Randomized Controlled Trial. Critical Care Medicine. 2022;50(11):1545–1554. PMID: 36044317. DOI: 10.1097/CCM.0000000000005660. pubmed.ncbi.nlm.nih.gov/36044317
- Udupa AA, Todur P, Chaudhuri S, et al. Aviptadil Therapy in Acute Respiratory Distress Syndrome Patients: A Systematic Review and Meta-analysis. Indian Journal of Critical Care Medicine. 2025;29(11):942–953. PMID: 41368449. DOI: 10.5005/jp-journals-10071-25084. pubmed.ncbi.nlm.nih.gov/41368449
- Dinsmore WW, Gingell C, Hackett G, et al. 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 International. 1999;83(3):274–279. PMID: 10233493. DOI: 10.1046/j.1464-410x.1999.00935.x. pubmed.ncbi.nlm.nih.gov/10233493
- Prasse A, Zissel G, Lützen N, et al. Inhaled vasoactive intestinal peptide exerts immunoregulatory effects in sarcoidosis. American Journal of Respiratory and Critical Care Medicine. 2010;182(4):540–548. PMID: 20442436. DOI: 10.1164/rccm.200909-1451OC. pubmed.ncbi.nlm.nih.gov/20442436
- Domschke S, Domschke W, Bloom SR, et al. Vasoactive intestinal peptide in man: pharmacokinetics, metabolic and circulatory effects. Gut. 1978;19(11):1049–1053. PMID: 730072. DOI: 10.1136/gut.19.11.1049. pubmed.ncbi.nlm.nih.gov/730072
- Delgado M, Chorny A, Gonzalez-Rey E, Ganea D. Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo. Journal of Leukocyte Biology. 2005;78(6):1327–1338. PMID: 16204628. DOI: 10.1189/jlb.0605299. pubmed.ncbi.nlm.nih.gov/16204628
- Delgado M, Ganea D. Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions. Amino Acids. 2013;45(1):25–39. PMID: 22139413. DOI: 10.1007/s00726-011-1184-8. pubmed.ncbi.nlm.nih.gov/22139413
For in-vitro laboratory research only. It is not a human medicine and is not for treatment.