VIP: One Minute in Plasma, and Two Trials That Disagreed

Infuse this peptide into a healthy volunteer, stop the pump, and half of it is gone from plasma in about sixty seconds [2].

That single measurement, made in 1978, explains most of what follows. Every therapeutic attempt with VIP amounts to an argument about how to keep it somewhere long enough to matter.

Two of those attempts ran head to head during the pandemic. A 196-patient industry trial missed its primary endpoint and reported a survival benefit [10]. A 461-patient federally funded trial was stopped for futility [11].

Nobody doubts the peptide itself. Said and Mutt isolated it in 1970, both receptors are cloned, and a mouse lacking one of them loses its circadian rhythm [1][4]. What remains unsettled is whether anything useful follows.

Chemical identity

A 28-residue peptide of the secretin and glucagon superfamily, C-terminally amidated, sold synthetically as aviptadil.

Reading the sequence

This peptide carries a single methionine and no cysteine, so it has no disulfide. Nothing holds it in a fixed shape. It takes a helical conformation only on binding.

Its family matters for reading the literature. Secretin, glucagon, GLP-1, PACAP and growth hormone releasing hormone share the same fold. Analogues in one branch therefore inform the others.

The amidated C-terminus is a functional requirement rather than a decoration. Losing the amide reduces receptor activation, so a certificate of analysis should confirm it.

The receptors

Two class B G-protein-coupled receptors respond to it, VPAC1 and VPAC2, both signalling through cyclic AMP [7]. A third receptor, PAC1, prefers PACAP.

Neither VPAC receptor sits in one tissue. Lung, gut, immune cells, vascular smooth muscle and the hypothalamus all express them [7]. Hence the long list of reported actions and the short list of selective ones.

What Said and Mutt found in 1970

The discovery paper is a single page in Science and it names the problem in its title: a polypeptide with broad biological activity [1].

Said and Mutt isolated 28 residues from hog small intestine. They reported systemic vasodilation, hypotension, increased cardiac output, respiratory stimulation and hyperglycaemia [1]. The same paper separated the peptide chemically from the kinins, substance P, glucagon and secretin.

Breadth was the finding. A molecule that lowers blood pressure, raises cardiac output, stimulates respiration and raises glucose is not a drug candidate with one indication. Fifty-five years later that has not changed.

One minute in plasma

The pharmacokinetics were settled early, in a small study that deserves more attention than it gets.

Domschke’s infusion study

Four healthy volunteers received graded intravenous infusions at 0.6, 1.3 and 3.3 pmol/kg/min, with plasma measured by radioimmunoassay (PMID 730072) [2].

Even the smallest dose pushed plasma concentrations well above normal. After each infusion stopped, concentrations fell by first-order kinetics with an average disappearance half-time of one minute [2]. Metabolic clearance ran near 9 mL/kg/min, with an apparent volume of distribution near 14 mL/kg.

The authors drew a conclusion rarely quoted by anyone selling the peptide. Their data, they wrote, do not support a role for VIP as a circulating hormone under physiological conditions [2].

A later infusion study in six volunteers puts numbers on the haemodynamics. Intravenous VIP raised heart rate and lowered diastolic but not systolic blood pressure [12]. Given into the brachial artery it increased forearm blood flow, and it raised circulating cardiodilatin without moving adrenaline or noradrenaline.

That study also compared two sibling peptides from the same precursor. Peptide histidine valine shares the vasodilator action at lower potency, and it has a notably longer half-life than VIP [12]. One prepro-peptide yields several products with different durations, which is worth knowing before attributing any measured effect to VIP alone.

What that forces on any dose

A one-minute half-life removes most delivery options. Bolus injection produces a spike and nothing else. Oral administration is not a serious proposal for an unprotected 28-residue peptide.

Every clinical programme has therefore used either continuous infusion or local delivery. The COVID trials ran 12-hour infusions for three consecutive days [11]. Erectile dysfunction products inject into the target tissue [13]. Pulmonary hypertension work inhaled it [5].

That constraint is the useful frame for reading any claim here. Ask where the peptide went and for how long. A systemic effect from a subcutaneous injection is hard to reconcile with a sixty-second half-life.

The fix its own family already found

One comparison makes the missed opportunity concrete. GLP-1 sits in the same superfamily and had the same problem: a native half-life of a minute or two, useless as a drug.

Medicinal chemists solved it twice over. An unnatural residue near the N-terminus blocks dipeptidyl peptidase-4, and a fatty diacid on a mid-chain lysine binds albumin. Together those turn a two-minute peptide into a once-weekly injection, and semaglutide, tirzepatide, survodutide and mazdutide all use some version of the recipe.

Both halves of that recipe are generic. Neither depends on anything specific to the incretin receptors, and both have been applied to unrelated peptide classes since.

Nothing equivalent has reached the clinic for VIP. The 2019 review describes exactly this work as the current priority, listing stability, selectivity and route of administration as the open problems [7], which is where the GLP-1 field stood in the 1990s.

Two things make it harder here. The GLP-1 programmes had a single clear endpoint to optimise against, while this peptide acts at two receptors expressed almost everywhere. And a longer-acting version would hold plasma concentrations up rather than letting them fall, which the VIPoma phenotype suggests is exactly what nobody wants [3].

So the delivery problem is not simple neglect. Sustained systemic exposure to this particular peptide has a known and unpleasant description.

The excess phenotype has a name

Most peptides in this catalogue have no human chronic-excess data. This one has a named disease.

What a VIPoma does

VIP-secreting tumours are rare and produce a stereotyped picture: profuse watery diarrhoea and hypokalaemia, diagnosed by plasma VIP concentration [3].

The mechanism is direct. VIP acts on intestinal epithelial cell receptors to drive fluid and electrolyte loss, and colonic potassium secretion produces the hypokalaemia [3]. Somatostatin analogues control the diarrhoea partly by suppressing release from the tumour.

Why the infusion study connects to it

Domschke’s higher doses produced plateau plasma concentrations in the range found in the Verner-Morrison syndrome, which is the older name for the VIPoma picture [2].

At those concentrations the volunteers showed raised glucose, free fatty acids and calcium. Pulse rate and blood pressure amplitude rose, and cutaneous flushing appeared. The authors noted the spectrum accorded well with abnormalities of the syndrome [2].

That is an unusually clean piece of translational reasoning. Raising plasma concentration to tumour levels reproduces part of the tumour phenotype. The syndrome amounts to a dose-response experiment nobody had to run deliberately.

The pulmonary hypertension programme

One line of work argued the peptide goes missing in a specific disease. That is a stronger rationale than breadth of activity.

The deficiency finding

Petkov and colleagues found the peptide deficient in serum and lung tissue of patients with primary pulmonary hypertension (PMID 12727925) [5]. Receptor sites were upregulated in the same tissue.

They then gave it to eight patients. Mean pulmonary artery pressure fell, cardiac output rose, and mixed venous oxygen saturation improved, with no reported side effects [5].

Eight patients, unblinded, from the group that reported the deficiency. The paper calls it grounds for further investigation, which is the right description.

What followed

The same group sequenced the VIP gene in ten patients with idiopathic pulmonary arterial hypertension [6]. Alterations turned up in eight. The single coding-region change also appeared in 46% of controls.

The authors concluded that the coding alteration does not correlate with the disease [6]. Whatever causes the deficiency, a simple sequence variant does not explain it, and the therapy never reached a large controlled trial.

The COVID-19 trials

Aviptadil became briefly famous in 2020 and 2021. Two randomised trials produced different answers, and the difference is instructive rather than mysterious.

The industry trial

The 196-patient trial randomised 2:1 to three days of intravenous aviptadil or placebo [10]. Its primary endpoint did not reach significance.

The paper then reports twofold odds of improved survival at 60 days, reduced interleukin-6, and subgroup findings in patients on high-flow nasal oxygen and on mechanical ventilation [10]. Its conclusion states that the primary endpoint showed no difference. It then states that the authors believe the benefit-risk balance favours treatment.

Both statements are in the same abstract. The sponsor’s chief medical officer is a listed author.

TESICO

The larger trial enrolled at 28 US sites, with a factorial design against remdesivir [11]. Aviptadil ran as a 12-hour infusion for three days, escalating from 600 to 1,800 pmol/kg.

The odds ratio for a better outcome category at day 90 came to 1.11, with a confidence interval spanning one [11]. Cumulative mortality reached 38% on drug and 36% on placebo. The primary safety composite occurred in 63% of the aviptadil group against 56% on placebo.

An independent data and safety monitoring board recommended stopping for futility in May 2022 [11].

How to read the pair

Neither trial met its primary endpoint. They differ in what happened next: one reported secondary and subgroup findings as grounds for continued use, the other stopped.

Sample size explains part of it and prior probability explains the rest. A secondary survival signal in 196 patients is exactly what a 461-patient trial exists to test. The larger trial did not reproduce it.

One published case report describes recovery in a pregnant patient under an expanded access protocol [9]. Recovery from a disease most patients survive carries very little evidential weight. The report itself states that the role in pregnancy is unknown.

Where the peptide is doing something in a normal animal

Set the therapy aside and the biology is solid. Two lines are worth knowing.

The clock

Mice carrying a null mutation of the VPAC2 receptor cannot sustain normal circadian rest and activity rhythms [4]. They lose rhythmic expression of the core clock genes in the suprachiasmatic nuclei. They also fail to induce those genes after nocturnal light.

Later work separated the neurons from the receptor. Ablating VIP neurons in adult mice shortened circadian period and dampened the corticosterone rhythm severely [8]. Deleting the same neurons neonatally reproduced the global knockout phenotype.

So the peptide is a genuine intercellular synchronising signal, and its role differs between the developing and adult clock.

The immune system

VIP is produced by neurons and by endocrine and immune cells, and it modulates both innate and adaptive responses through VPAC1 and VPAC2 [7].

Giving it exogenously protects animals in models of autoimmune and inflammatory disease [7]. The same review is candid about why this has not translated. Current effort goes into improving stability, selectivity and routes of administration, which restates the one-minute problem.

The one approved use

There is a marketed product, and it works by putting the peptide where it is needed.

Aviptadil combined with phentolamine is injected intracavernosally for erectile dysfunction. A 2025 single-centre series of 308 men reported 59% overall effectiveness in patients who had failed or could not tolerate alprostadil [13].

The split within that series is the informative part. Effectiveness reached 76% in men who had stopped alprostadil because of pain, against 36% in men whose maximal-dose alprostadil had failed [13]. Facial flushing occurred in 22.5%, consistent with a vasodilator reaching the circulation. Ischaemic priapism occurred in one patient.

Local injection, immediate effect, no reliance on sustained plasma concentration. That is the delivery problem solved by avoiding it.

Four questions to ask of any VIP result

The literature is broad and the failure modes are consistent.

Where was it delivered, and for how long?

A one-minute half-life makes route and duration decisive [2]. Infusion, inhalation and intracavernosal injection are different experiments. None of them supports a claim about another route.

Primary endpoint or secondary?

Both COVID trials missed their primary endpoints [10][11]. Every positive number quoted from that programme is a secondary or subgroup finding.

Who funded it, and who wrote it?

The trial reporting a favourable balance carries sponsor authorship; the trial stopped for futility was federally funded [10][11]. Note it and weigh accordingly.

Is the effect specific?

The 1970 discovery paper lists vasodilation, hypotension, raised cardiac output, respiratory stimulation and hyperglycaemia for one molecule [1]. Anything acting on two widely expressed receptors shows effects in most assays.

Verifying research material

A 3,327 Da unmodified peptide with a single methionine has a specific analytical profile.

Identity

Intact mass is the primary check, at 3,326.8 Da average and 3,324.74 monoisotopic. That separates it cleanly from its relatives. Secretin runs near 3,040, glucagon at 3,483 and PACAP-27 near 3,148.

The C-terminal amide is the modification to confirm. A free acid weighs one unit more, a difference that is trivial to measure and easy to ignore. Peptide mapping gives full sequence coverage at this length without difficulty.

Purity and related substances

Methionine oxidation is the characteristic degradation product, adding 16 Da. Air and light drive it, and it is the first thing to look for in older material.

Deletion sequences are the expected synthesis impurity. Reversed-phase chromatography with mass detection finds both classes, while ultraviolet detection alone finds neither reliably. Peptide content also differs from chromatographic purity, so counterion and water content belong on the certificate.

Handling

Store lyophilised, cold, dry and dark, and reconstitute close to the point of use. The peptide is basic, surface-active and prone to adsorption, so dilute solutions lose material to plastic.

Aliquot on reconstitution rather than sampling one vial repeatedly. Serum peptidases degrade it within minutes. That is a pharmacokinetic fact and also a warning about any assay leaving it in a biological matrix at room temperature.

Kimera publishes third-party certificates of analysis for every lot in its COA database. Laboratories source VIP as a VPAC1 and VPAC2 receptor agonist reference. It pairs with gonadorelin, another peptide whose delivery pattern matters more than its dose, with ARA-290 as a receptor-selective tissue-protective comparator, and with LL-37 among immunomodulatory peptides. Related work appears in the peptides category.

Common questions about VIP

What is VIP? A 28-residue peptide isolated from hog intestine in 1970, acting at the VPAC1 and VPAC2 receptors [1][7].

How long does it last in plasma? About one minute, by first-order kinetics, with clearance near 9 mL/kg/min [2].

What is aviptadil? The synthetic form of the same 28 residues, used in the COVID trials and, with phentolamine, for erectile dysfunction [11][13].

Did it work for COVID-19? No trial met its primary endpoint, and the larger federally funded trial was stopped for futility [10][11].

What does too much of it do in humans? VIP-secreting tumours cause profuse watery diarrhoea and hypokalaemia, and infusion to similar plasma levels reproduces part of that picture [2][3].

What is it doing normally? Among other things, synchronising the circadian clock; VPAC2 null mice lose rhythmic behaviour and clock gene expression [4][8].

Summary of the evidence

Identity: 28 residues, C₁₄₇H₂₃₇N₄₃O₄₃S, 3,326.8 Da, amidated C-terminus, no disulfide, CAS 37221-79-7.

Discovery: isolated from hog small intestine in 1970, with vasodilation, hypotension, raised cardiac output, respiratory stimulation and hyperglycaemia all reported in the first paper [1].

Pharmacokinetics: plasma disappearance half-time of about one minute, clearance near 9 mL/kg/min, volume of distribution near 14 mL/kg [2]. The authors of that study doubted its role as a circulating hormone. Intravenous infusion raises heart rate and lowers diastolic pressure [12].

Excess phenotype: VIP-secreting tumours produce watery diarrhoea and hypokalaemia. Infusion to comparable plasma levels reproduces flushing and metabolic changes [2][3].

Pulmonary hypertension: a reported tissue deficiency with upregulated receptors, and haemodynamic improvement in eight unblinded patients [5]. Gene sequencing found no supporting coding variant [6].

COVID-19: neither randomised trial met its primary endpoint. The 196-patient industry trial reported a secondary survival benefit [10]. The 461-patient federally funded trial stopped for futility, with mortality of 38% against 36% [11].

Normal physiology: VPAC2 null mice lose circadian rhythmicity [4]. Ablating VIP neurons in adults shortens period and dampens corticosterone rhythms [8]. The peptide also modulates innate and adaptive immunity [7].

Approved use: intracavernosal aviptadil with phentolamine, 59% effective in 308 men refractory to other options [13].

Status: supplied for laboratory research use only.

References

1. Said SI, Mutt V. Polypeptide with broad biological activity: isolation from small intestine. Science. 1970;169(3951):1217-1218. PMID 5450698. DOI
2. Domschke S, Domschke W, Bloom SR, Mitznegg P, Mitchell SJ, Lux G, Strunz U. Vasoactive intestinal peptide in man: pharmacokinetics, metabolic and circulatory effects. Gut. 1978;19(11):1049-1053. PMID 730072. DOI
3. O’Dorisio TM, Mekhjian HS, Gaginella TS. Medical therapy of VIPomas. Endocrinol Metab Clin North Am. 1989;18(2):545-556. PMID 2545444.
4. Harmar AJ, Marston HM, Shen S, Spratt C, West KM, Sheward WJ, et al. The VPAC2 receptor is essential for circadian function in the mouse suprachiasmatic nuclei. Cell. 2002;109(4):497-508. PMID 12086606. DOI
5. Petkov V, Mosgoeller W, Ziesche R, Raderer M, Stiebellehner L, Vonbank K, et al. Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J Clin Invest. 2003;111(9):1339-1346. PMID 12727925. DOI
6. Haberl I, Frei K, Ramsebner R, Doberer D, Petkov V, Albinni S, et al. Vasoactive intestinal peptide gene alterations in patients with idiopathic pulmonary arterial hypertension. Eur J Hum Genet. 2007;15(1):18-22. PMID 17003842. DOI
7. Martínez C, Juarranz Y, Gutiérrez-Cañas I, Carrión M, Pérez-García S, Villanueva-Romero R, et al. A clinical approach for the use of VIP axis in inflammatory and autoimmune diseases. Int J Mol Sci. 2019;21(1):65. PMID 31861827. DOI
8. Mazuski C, Chen SP, Herzog ED. Different roles for VIP neurons in the neonatal and adult suprachiasmatic nucleus. J Biol Rhythms. 2020;35(5):465-475. PMID 32536240. DOI
9. Youssef JG, Bitar MZ, Zahiruddin F, Al-Saadi M, Elshawwaf M, Yau S, et al. Rapid clinical recovery from critical coronavirus disease 2019 with respiratory failure in a pregnant patient treated with IV vasoactive intestinal peptide. Crit Care Explor. 2022;4(1):e0607. PMID 35018346. DOI
10. Youssef JG, Lavin P, Schoenfeld DA, Lee RA, Lenhardt R, Park DJ, 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. Crit Care Med. 2022;50(11):1545-1554. PMID 36044317. DOI
11. Brown SM, Barkauskas CE, Grund B, Sharma S, Phillips AN, Leither L, 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. PMID 37348524. DOI
12. Gill JS, Yiangou Y, Webb DJ, Meleagros L, Benjamin N, Chrysanthou BJ, et al. Peptide histidine valine: its haemodynamic actions and pharmacokinetics in man differ from those of vasoactive intestinal peptide and peptide histidine methionine. Clin Sci (Lond). 1990;78(5):487-492. PMID 2162275. DOI
13. Al-Mitwalli A, Holden F, Di Giovanni A, Gobbo A, Shah M, Chiriaco G, et al. Intracavernosal injection of aviptadil and phentolamine for refractory erectile dysfunction. J Sex Med. 2025;22(5):726-730. PMID 40192471. DOI

VIP is sold for laboratory research use only. Not for human consumption, nor medical, veterinary, or household uses.

Literature retrieved from PubMed.