Vasoactive intestinal peptide (VIP)
VIP, Aviptadil, vasoactive intestinal polypeptide, VIP(1-28), vasoactive intestinal octacosapeptide
VIP is a 28-residue neuropeptide of the secretin/glucagon family, produced by nerves and immune cells, signalling through the VPAC1 and VPAC2 receptors. It is a genuine anti-inflammatory and tolerogenic mediator that expands regulatory T cells. Aviptadil is synthetic VIP: licensed in the UK with phentolamine for erectile dysfunction, but its two randomised COVID-19 trials conflicted and the larger one was clearly negative.
Mechanism
VIP is a 28-residue, C-terminally amidated neuropeptide of the secretin/glucagon superfamily, produced by neurons of the enteric, central and peripheral nervous systems and also by immune cells including T lymphocytes and mast cells. Aviptadil is chemically identical synthetic VIP. It signals through two class B1 G protein-coupled receptors, VPAC1 and VPAC2, which bind VIP and the related peptide PACAP with comparable high affinity; the third family member, PAC1, is PACAP-selective. Receptor engagement is predominantly Gs-coupled, raising intracellular cAMP and activating protein kinase A, with additional phospholipase C and calcium signalling at VPAC2.
The consequences are tissue-specific. In airway and vascular smooth muscle, cAMP elevation produces relaxation: bronchodilation and vasodilation, which is where the peptide's name comes from and which also generates its dose-limiting side effects. In the lung, VPAC1 is densely expressed on alveolar type II cells, where VIP has been reported to support surfactant production and inhibit caspase-3-mediated apoptosis; this was the explicit rationale for testing it in COVID-19 respiratory failure. In the gut it drives secretion, which is why VIP-secreting tumours (VIPomas) cause profuse watery diarrhoea.
Immunologically, VIP is anti-inflammatory and tolerogenic in direction. It suppresses TNF-alpha, IL-6, IL-12 and nitric oxide production by macrophages, generates tolerogenic dendritic cells, and promotes the differentiation and expansion of regulatory T cells while damping Th1 and Th17 polarisation; VIP-knockout mice show regulatory T cell deficiency that is corrected by VIP treatment. It is worth stating this direction plainly, because it is the opposite of an immune stimulant: sustained pharmacological VIP signalling pushes the immune system towards tolerance. Its pharmacological weak point is stability (a plasma disappearance half-time of roughly one minute under attack from DPP-4 and neutral endopeptidase), which constrains every attempt to use the native peptide systemically.
What the research shows
Two randomised placebo-controlled trials tested intravenous aviptadil in critical COVID-19, and they disagreed, with the larger and more rigorous one negative.
Youssef and colleagues (Critical Care Medicine, 2022) randomised 196 patients with COVID-19 respiratory failure 2:1 to three days of IV aviptadil or placebo across ten US hospitals. The primary endpoint, alive and free from respiratory failure at day 60, was not met (odds ratio 1.6, 95% CI 0.86-3.11). A secondary analysis of 60-day survival favoured aviptadil (OR 2.0, p=0.035), and that secondary result formed the basis of most of the promotional claim-making that followed. It is worth being precise about the logic here: a trial that misses its primary endpoint and reports a positive secondary endpoint has generated a hypothesis, not a demonstration. The FDA declined emergency use authorisation on more than one occasion, citing insufficient data on the balance of known and potential benefits and risks.
TESICO, run within the NIH-sponsored ACTIV-3b platform and published in Lancet Respiratory Medicine in 2023, was the confirmatory test: a randomised, placebo-controlled factorial platform trial across 28 US sites enrolling 473 adults with COVID-19-associated acute hypoxaemic respiratory failure between April 2021 and May 2022, with a six-category ordinal outcome at day 90. Aviptadil did not significantly improve clinical outcomes to day 90 compared with placebo; mortality was 38% with aviptadil versus 36% with placebo, and serious adverse events occurred more frequently in the aviptadil group. The remdesivir comparison within the same trial was underpowered because of early termination for slow enrolment. Platform trials of this design, with independent oversight and pre-specified analysis, are the appropriate arbiter, and the answer was no.
Outside COVID-19, the picture is narrower but more solid where it exists. Aviptadil in fixed combination with phentolamine mesilate as an intracavernosal injection holds a UK marketing authorisation for erectile dysfunction, an indication where the relevant pharmacology is vasodilation, not immune modulation. Inhaled VIP has been studied in pulmonary arterial hypertension and sarcoidosis in small, mostly open-label or early-phase studies that have not progressed to approval anywhere.
Separately, intranasal VIP is widely promoted for 'chronic inflammatory response syndrome' (CIRS) attributed to mould or biotoxin exposure. There is no controlled trial evidence of any kind for this use, and CIRS is not a diagnostic entity recognised by mainstream medical bodies. The underlying immunology claims should be treated as unsupported.
Evidence assessment
Mixed evidence
Aviptadil with phentolamine holds a UK marketing authorisation for erectile dysfunction, where the mechanism is straightforwardly vasodilatory; but for the immune and respiratory indications the two randomised placebo-controlled COVID-19 trials conflicted, with the larger and more rigorous platform trial finding no benefit and more frequent serious adverse events on treatment, and the FDA twice declined emergency use authorisation.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial High-quality evidence
Aviptadil did not significantly improve clinical outcomes to day 90 compared with placebo; mortality 38% versus 36%, and serious adverse events were more frequent in the aviptadil group. The remdesivir comparison was underpowered following early termination for slow enrolment.
The Use of IV Vasoactive Intestinal Peptide (Aviptadil) in Patients With Critical COVID-19 Respiratory Failure: Results of a 60-Day Randomized Controlled Trial Mixed evidence
Primary endpoint (alive and free from respiratory failure at day 60) not met (OR 1.6, 95% CI 0.86-3.11); a secondary 60-day survival analysis favoured aviptadil (OR 2.0, p=0.035), with reported improvement in respiratory distress ratio and reduced IL-6 by day 3.
Vasoactive intestinal peptide in man: pharmacokinetics, metabolic and circulatory effects Limited evidence
After infusion stopped, plasma VIP fell by first-order kinetics with an average disappearance half-time of about one minute; higher doses raised blood glucose and free fatty acids, increased heart rate and caused flushing. The authors concluded VIP acts principally as a local rather than a circulating hormone.
VIP Regulates the Development & Proliferation of Treg in vivo in spleen Preclinical only
VIP gene deletion caused CD25+CD4- cell accumulation in the thymus, corrected by VIP treatment, and regulatory T cell deficiency in the spleen that VIP treatment normalised, supporting VIP's characterisation as a tolerogenic, immune-tolerance-promoting mediator rather than an immune stimulant.
Safety
VIP's adverse effects are directly predictable from its pharmacology, which is a point in favour of understanding them. Vasodilation produces hypotension, flushing, tachycardia and headache; Domschke's 1978 human infusion study documented increased heart rate and flushing alongside metabolic effects at higher doses. These effects are dose-limiting, and intravenous aviptadil in the COVID-19 trials required haemodynamic monitoring in an intensive care setting. It should be stated plainly that in TESICO serious adverse events were more frequent in the aviptadil group than on placebo. The largest trial found no benefit and a worse safety signal. Gastrointestinal secretion produces diarrhoea. VIP is the mediator responsible for the profuse watery diarrhoea of VIPoma syndrome, so this is a core rather than incidental effect. Intracavernosal use in erectile dysfunction carries the injection-site and priapism risks common to that route.
The less-discussed issue is the direction of the immune effect. VIP expands regulatory T cells, generates tolerogenic dendritic cells and suppresses Th1 and Th17 responses. In an acute hyperinflammatory illness that may be desirable; as a sustained self-administered regimen it amounts to chronic pharmacological immune suppression, with the plausible consequence of impaired antimicrobial and antitumour surveillance. No study has examined this, because no one has run a controlled trial of chronic VIP administration in healthy people. Intranasal VIP as sold in the wellness market has essentially no controlled safety data at all, and material obtained outside a pharmacy supply chain has no verified identity, sterility or endotoxin testing.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Aviptadil in fixed combination with phentolamine mesilate holds a UK marketing authorisation as an intracavernosal injection for erectile dysfunction and is available on the NHS within prescribing restrictions. (The precise year of authorisation stated in the draft could not be verified in this audit and is not asserted.) There is no UK authorisation for aviptadil or VIP for any immune, inflammatory or respiratory indication, and no authorisation for intranasal VIP. |
| United States | Not approved by the FDA for any indication. The FDA declined emergency use authorisation for intravenous aviptadil in critical COVID-19 on more than one occasion, citing insufficient data on the balance of benefits and risks. Aviptadil is not an approved erectile dysfunction product in the US. |
| WADA (sport) | Not named on the WADA Prohibited List. Athletes should be aware that a licensed vasodilator with systemic haemodynamic effects may still raise questions under other sections and in relation to the therapeutic use exemption process, and should verify against the current year's List. |
Questions
Yes. Aviptadil is the international non-proprietary name for synthetic vasoactive intestinal peptide, chemically identical to the natural 28-residue human peptide. The two names refer to the same molecule; aviptadil is used when it is being discussed as a pharmaceutical product.
No, on the best evidence. A 196-patient trial published in 2022 missed its primary endpoint but reported a positive secondary survival result, which was heavily promoted. The confirmatory test was TESICO, a randomised placebo-controlled platform trial run within the NIH ACTIV-3b programme across 28 US sites in 473 patients and published in Lancet Respiratory Medicine in 2023. It found no improvement in clinical outcomes, mortality of 38% versus 36% on placebo, and more frequent serious adverse events on aviptadil. The FDA declined emergency use authorisation.
Yes, but not for immune indications. Aviptadil in fixed combination with phentolamine mesilate holds a UK marketing authorisation as an intracavernosal injection for erectile dysfunction, where the relevant action is vasodilation. There is no approval anywhere for VIP or aviptadil as an immune, anti-inflammatory or respiratory treatment, and no approval for intranasal VIP.
There is no controlled trial evidence for this use, none. CIRS attributed to mould or biotoxin exposure is not a diagnosis recognised by mainstream medical bodies, and the protocols promoting intranasal VIP for it rest on clinical assertion rather than trial data. It is also worth noting the direction of VIP's immune effect: it expands regulatory T cells and suppresses Th1 and Th17 responses, meaning sustained use is immunosuppressive in character rather than restorative.