VIP (vasoactive intestinal peptide)

01 · What it is

VIP is a 28-amino-acid neuropeptide and a member of the structurally related superfamily that includes glucagon, the glucagon-like peptides, secretin and pituitary adenylate cyclase-activating polypeptide (PACAP) ². It is endogenous, widely distributed in enteric, autonomic and central neurons, and its pharmacology is defined at the receptor level: VIP acts at VPAC1 and VPAC2, class B G-protein-coupled receptors that also bind PACAP with comparable affinity and signal principally through Gs and adenylyl cyclase to raise intracellular cyclic AMP ².

Nothing else in Family A is characterised to that standard. VIP has named receptors, an international pharmacology committee review of its receptor biology ², a synthetic analogue (aviptadil), a marketing authorisation on record for a fixed combination ¹², and — uniquely in this family — a large, independently funded, placebo-controlled trial.

That trial failed. TESICO, run at 28 US sites with National Institutes of Health funding, randomised patients with COVID-19 acute hypoxaemic respiratory failure to intravenous aviptadil or placebo. In the 461-patient modified intention-to-treat population, the odds ratio for a better category of the 90-day ordinal primary outcome was 1.11 (95% CI 0.80–1.55, p = 0.54). Death by day 90 occurred in 38% on aviptadil and 36% on placebo (hazard ratio 1.04, 95% CI 0.77–1.41, p = 0.78). The data and safety monitoring board stopped the aviptadil arm for futility ⁹. A 2025 meta-analysis of nine studies and 665 patients put the pooled survival odds ratio against placebo at 1.01 (95% CI 0.72–1.42, p = 0.93) ¹¹.

There is also a pharmacological fact that rarely accompanies discussion of this peptide: infused VIP reliably produces headache and extracranial vasodilation in healthy volunteers, and provokes migraine in people who get migraines ^4,6.

02 · Evidence at a glance

Evidence grade

Approved Pharma

Basis of grade

A fixed combination of aviptadil with phentolamine holds a marketing authorisation on the UK regulator’s product information database ¹²

Molecular identity

Endogenous 28-residue neuropeptide ²

Molecular targets

VPAC1 and VPAC2, class B GPCRs signalling through Gs/cAMP ²

Largest randomised trial

461 in the modified intention-to-treat analysis ⁹

Result of that trial

Null; stopped for futility ⁹

Pooled survival odds ratio, ARDS meta-analysis

1.01 (95% CI 0.72–1.42, p = 0.93) ¹¹

Patients in the ARDS evidence base

665 across nine studies, 361 receiving aviptadil ¹¹

Documented dose-limiting effect in humans

Headache and vasodilation on infusion ^4,6

Approval for the indications VIP is discussed for

None

Sponsor independence

High — the largest trial was publicly funded ⁹

03 · Mechanism of action

VPAC1 and VPAC2

VIP binds two class B G-protein-coupled receptors, VPAC1 and VPAC2, both of which also bind PACAP with similar affinity; a third receptor, PAC1, is selective for PACAP. Activation is coupled principally to Gs and adenylyl cyclase, raising intracellular cyclic AMP ². This is textbook receptor pharmacology with an official nomenclature review behind it, and it is the single largest difference between VIP and every other compound in this family: the target is not inferred, it is classified.

Smooth muscle relaxation and vasodilation

Elevated cAMP in vascular and non-vascular smooth muscle produces relaxation. That is the basis of VIP’s best-established clinical effect — intracavernous VIP induced erection in a double-blind placebo-controlled trial ¹ — and of the combination product that reached authorisation, in which aviptadil is paired with the alpha-adrenergic antagonist phentolamine ¹². It is also the basis of the compound’s principal adverse effect. A two-hour VIP infusion induced delayed headache and extracranial vasodilation in healthy volunteers ⁴, and in a randomised, double-blind, placebo-controlled crossover study VIP infusion induced migraine attacks in people with migraine ⁶.

Vasodilation is not a side effect of VIP; it is the mechanism, expressed where it is not wanted.

Anti-inflammatory and surfactant effects in lung

The rationale for the respiratory programme was that VIP upregulates surfactant production, inhibits cytokine synthesis, and protects alveolar type II cells, which are the cells SARS-CoV-2 infects ⁷. Supporting work exists in other inflamed tissues: a recombinant VIP analogue ameliorated trinitrobenzene sulfonic acid-induced colitis in rats, with modulation of inflammatory signalling ³.

The mechanistic case for the lung was coherent, was taken seriously enough to fund a multicentre trial, and did not translate.

Neuroendocrine and affective signalling

VIP is a neuropeptide before it is anything else. Plasma VIP concentrations have been associated with affective symptoms and with brain structure and function in healthy women ⁵, and the migraine work situates VIP alongside PACAP in headache mechanisms ^4,6.

These lines of work describe what the peptide does physiologically rather than what administering it achieves therapeutically, and they are the part of the VIP literature least connected to how the compound is used outside clinical research.

04 · Key research findings

COVID-19 respiratory failure — the definitive trial. TESICO randomised patients within four days of onset of acute hypoxaemic respiratory failure to intravenous aviptadil or matched placebo, at 28 US sites, in a design that also included a remdesivir comparison. Aviptadil was given as a daily 12-hour infusion for three days, escalating from 600 to 1,800 pmol/kg. The modified intention-to-treat population comprised 461 participants; 94% were in intensive care at baseline and 40% were on invasive mechanical ventilation. The odds ratio for a better category of the six-category 90-day ordinal outcome was 1.11 (95% CI 0.80–1.55, p = 0.54). Cumulative mortality to day 90 was 38% versus 36% (HR 1.04, 95% CI 0.77–1.41, p = 0.78). The primary safety composite occurred in 63% of the aviptadil group and 56% of placebo (OR 1.40, 95% CI 0.94–2.08, p = 0.10). The data and safety monitoring board recommended stopping the aviptadil trial for futility in May 2022 ⁹.

This is the largest, best-funded and most independent trial of any compound covered on this site, and its result was unambiguous.

Other respiratory trials, and the meta-analysis. A separate 60-day randomised controlled trial evaluated intravenous aviptadil in critical COVID-19 respiratory failure ⁷, and a randomised trial of inhaled aviptadil was conducted in patients at high risk of ARDS ¹⁰, with a further multicentre inhaled protocol published ⁸. Pooling the evidence, a 2025 systematic review and meta-analysis identified nine studies with 665 patients, 361 of whom received aviptadil. Across the two randomised trials, pooled survival prevalence was 0.71 (95% CI 0.53–0.87), and the survival odds ratio versus placebo was 1.01 (95% CI 0.72–1.42, p = 0.93) — no significant benefit. Across seven case series, 48 of 54 patients survived, with consistent improvements in oxygenation and inflammatory markers ¹¹.

The case series look encouraging and the randomised evidence does not, which is the standard shape of a treatment that does not work and the reason uncontrolled data are weighted as they are.

Erectile dysfunction — where the pharmacology delivered. A double-blind, placebo-controlled trial of intracavernous VIP in 24 men with erectile dysfunction of diabetic, neurogenic and psychogenic origin was published in 1990 ¹. The clinical descendant is a fixed combination of aviptadil with phentolamine, for which a marketing authorisation appears on the UK regulator’s product information database ¹².

The one indication in which VIP reached authorisation is the one that exploits its most direct pharmacological action — local smooth muscle relaxation — rather than an anti-inflammatory hypothesis.

Headache and migraine — a reproducible human effect. A two-hour intravenous VIP infusion induced delayed headache and extracranial vasodilation in healthy volunteers ⁴. A randomised, double-blind, placebo-controlled crossover clinical trial then examined the development of migraine headaches after VIP administration in people with migraine ⁶.

These are among the cleanest human experiments in the whole of Family A: a defined intervention, a placebo control, a crossover design, and a reproducible effect — and the effect is an adverse one.

Gastrointestinal inflammation. A recombinant VIP analogue reduced disease severity in trinitrobenzene sulfonic acid-induced colitis in rats across six treatment groups ³.

Consistent with the anti-inflammatory mechanism and never taken into human inflammatory bowel disease trials.

Physiology and biomarkers. Plasma VIP concentrations were associated with affective symptoms and with brain structure and function in healthy women ⁵.

Observational, and a reminder that VIP is an endogenous signalling molecule with functions that have nothing to do with tissue repair.

05 · Evidence overview

06 · Safety profile

Animal data. The rodent literature in colitis and related inflammatory models reports tolerability at the doses used, without dedicated toxicology programmes in the papers cited here ³.

Human data. This is the best-characterised safety profile in Family A, because it was generated in controlled trials rather than inferred. In TESICO, the primary safety outcome — death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events by day 5 — occurred in 146 of 231 patients on aviptadil (63%) versus 129 of 230 on placebo (56%), odds ratio 1.40 (95% CI 0.94–2.08, p = 0.10) ⁹. That difference did not reach significance, and it did not favour the drug.

The dose-limiting pharmacological effect is unambiguous and reproducible: systemic VIP infusion causes vasodilation and headache in healthy people ⁴, and provokes migraine in migraineurs ⁶. Any systemic use has to contend with that, and it is a mechanistic consequence rather than an idiosyncratic reaction.

What is genuinely unknown. Long-term repeated systemic administration has not been studied — the respiratory trials dosed for three days ⁹. No chronic exposure data exist for any route. Effects on blood pressure under sustained dosing, given that vasodilation is the core action, have not been characterised outside acute settings. Reproductive, developmental and carcinogenicity data are not described in the literature cited here. And for the intranasal use that circulates outside clinical research, no controlled trial, pharmacokinetic study or safety dataset was identified for this guide in any indication.

07 · US regulatory status

Current as of 6 September 2026. VIP itself is not approved as a drug in the United States, and is not a controlled substance. A fixed combination of aviptadil with phentolamine mesilate for intracavernosal injection appears in the UK regulator’s summary of product characteristics and patient information database, indicating a granted marketing authorisation for erectile dysfunction ¹². This guide grades the compound Approved Pharma on that basis. Two qualifications belong with the grade: the authorisation is for a fixed combination rather than VIP alone, and it is for an indication unrelated to the tissue-repair and anti-inflammatory uses the compound is discussed for elsewhere.

No aviptadil product holds US approval. The intravenous COVID-19 programme did not result in authorisation, and the definitive publicly funded trial was stopped for futility ⁹.

VIP does not appear in FDA’s category 2 bulk drug substances tables and was not among the substances reviewed by FDA’s Pharmacy Compounding Advisory Committee in July 2026.

Under the World Anti-Doping Code, substances not approved by any governmental regulatory health authority for human therapeutic use fall within category S0. Because an aviptadil-containing product holds an authorisation in at least one jurisdiction, the S0 analysis for this compound is not straightforward, and competitors should consult the current Prohibited List directly rather than rely on secondary summaries, including this one.

08 · Limitations of the evidence

1. The largest and best-designed trial was null, and it was stopped for futility. TESICO found an odds ratio of 1.11 (95% CI 0.80–1.55) on its primary 90-day outcome and 38% versus 36% mortality ⁹. This is not a trial that missed narrowly or was underpowered; it was halted because continuing could not have produced a positive result.

1. The meta-analysis agrees with it. Pooled survival odds ratio 1.01 (95% CI 0.72–1.42, p = 0.93) across the randomised evidence ¹¹. When a large trial and an independent pooled analysis point the same way, the question in that indication is settled to the standard clinical research normally accepts.

1. The case series diverge from the randomised data, and that divergence is informative. Forty- eight of 54 patients survived across seven uncontrolled series ¹¹, against no survival benefit in randomised comparison. This is the clearest demonstration available anywhere in Family A of why uncontrolled data cannot substitute for controlled data.

1. Approval does not extend to the uses discussed here. The authorisation on record is for a fixed combination with phentolamine, delivered by intracavernosal injection, for erectile dysfunction ¹². It says nothing about systemic anti-inflammatory or tissue-repair applications, and the grade should not be read as though it did.

1. A reproducible adverse pharmacological effect limits systemic use. Infused VIP causes vasodilation and headache in healthy volunteers and provokes migraine in migraineurs ^4,6. Any dosing regimen has to be built around that, and none of the informal use of this peptide appears to acknowledge it.

1. Nothing supports intranasal administration. No controlled trial, pharmacokinetic study or safety dataset for intranasal VIP was identified during preparation of this guide, in any indication. The route most discussed outside clinical research is the route with no published evidence at all.

1. Chronic exposure is untested. The respiratory trials dosed for three days ⁹; the erectile dysfunction application is episodic and local ^1,12. No study has examined sustained systemic administration, which is what any tissue-repair rationale would require.

09 · References

1. Roy JB, Petrone RL, Said SI. A clinical trial of intracavernous vasoactive intestinal peptide to induce penile erection. J Urol. 1990;143(2):302–304.

   PMID 2405186 ↗

2. Harmar AJ, Fahrenkrug J, Gozes I, et al. Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1. Br J Pharmacol. 2012;166(1):4–17.

   PMID 22289055 ↗

3. Xu CL, Guo Y, Qiao L, Ma L, Cheng YY. Recombinant expressed vasoactive intestinal peptide analogue ameliorates TNBS-induced colitis in rats. World J Gastroenterol. 2018;24(6):706–715.

   PMID 29456409 ↗

4. Pellesi L, Al-Karagholi MA, Chaudhry BA, et al. Two-hour infusion of vasoactive intestinal polypeptide induces delayed headache and extracranial vasodilation in healthy volunteers. Cephalalgia. 2020;40(11):1212–1223.

   PMID 32594760 ↗

5. Simon RA, Barazanji N, Jones MP, et al. Vasoactive intestinal polypeptide plasma levels associated with affective symptoms and brain structure and function in healthy females. Sci Rep. 2021;11(1):1406.

   PMID 33446759 ↗

6. Pellesi L, Al-Karagholi MA, De Icco R, et al. Effect of vasoactive intestinal polypeptide on development of migraine headaches: a randomized clinical trial. JAMA Netw Open. 2021;4(8):e2118543.

   PMID 34357396 ↗

7. 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. Crit Care Med. 2022;50(11):1545–1554.

   PMID 36044317 ↗

8. Boesing M, Abig K, Brändle M, et al. Inhaled aviptadil for the possible treatment of COVID-19 in patients at high risk for ARDS: study protocol for a randomized, placebo-controlled, and multicenter trial. Trials. 2022;23(1):790.

   PMID 36127739 ↗

9. 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.

   PMID 37348524 ↗

10. Esendagli D, Sarı N, Akhan S, et al. Inhaled aviptadil is a new hope for recovery of lung damage due to COVID-19. Med Princ Pract. 2025;34(2):191–200.

    PMID 39870064 ↗

11. Udupa AA, Todur P, Chaudhuri S, et al. Aviptadil therapy in acute respiratory distress syndrome patients: a systematic review and meta-analysis. Indian J Crit Care Med. 2025;29(11):942–953.

    PMID 41368449 ↗

12. Medicines and Healthcare products Regulatory Agency. SPC-PIL database entry: INVICORP 25 micrograms/2 mg solution for injection. Regulatory document; no PMID.

    Source ↗