Vasoactive intestinal peptide (VIP) is a 28-amino-acid neuropeptide that nerves throughout the body release. It relaxes smooth muscle, widens blood vessels and drives fluid secretion in the gut. Aviptadil is the drug name for synthetic VIP.
VIP has one established medical use. In several European countries, aviptadil is approved only as a fixed combination with phentolamine (Invicorp), injected into the penis for erectile dysfunction. No VIP product is approved by the FDA. During the COVID-19 pandemic, the FDA declined two requests for emergency use authorization of intravenous aviptadil (Zyesami). An NIH-run trial of the same drug was stopped for futility.
This page summarizes what the European product information, clinical trials and US regulators report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Class | Endogenous neuropeptide of the glucagon/secretin family; acts on VPAC1 and VPAC2 receptors |
| Drug name | Aviptadil (synthetic VIP) |
| Approved product | Invicorp: aviptadil 25 µg + phentolamine mesilate 2 mg, intracavernosal injection, for erectile dysfunction (European national authorizations) |
| Labeled dose (Invicorp) | One 25 µg/2 mg dose; no more than once a day or 3 times a week |
| Investigational routes | Intravenous infusion (COVID-19 respiratory failure); inhalation (pulmonary hypertension, sarcoidosis) |
| Half-life | About 1 min after IV infusion in volunteers; 1.7 min IV and 5.3 min intracavernosal in the Invicorp studies |
| US status | Not FDA-approved; COVID-19 EUA requests declined in November 2021 and July 2022 |
| US compounding | FDA 503A Category 1 (“under evaluation”) as of May 14, 2026 |
| WADA | Not named on the 2026 Prohibited List |
What it is
Sami Said and Viktor Mutt isolated VIP from pig small intestine in 1970. They described a 28-residue peptide that caused widespread vasodilation, low blood pressure, higher cardiac output and raised blood sugar (Said and Mutt, Science 1970).
Structurally, VIP is a straight chain of 28 amino acids with an amide group capping its C-terminal end. It is cut from a larger precursor protein that also yields related peptides, including PHM (peptide histidine methionine). Its sequence is the same in most mammals (Harmar et al., Br J Pharmacol 2012). PubChem lists aviptadil, human VIP and porcine VIP under one entry, with formula C₁₄₇H₂₃₇N₄₃O₄₃S and molecular weight 3,326.8 g/mol (PubChem). Aviptadil is therefore not an analog: it is the natural peptide made synthetically.
VIP belongs to a family of structurally related peptides that includes glucagon, the glucagon-like peptides, secretin, GIP and growth hormone-releasing hormone (GHRH). It works through two receptors, VPAC1 and VPAC2. Both are class B G-protein-coupled receptors that also respond to the related peptide PACAP (Harmar et al., Br J Pharmacol 2012).
How it works in the body
VIP acts mainly as a local nerve signal (a co-transmitter), not as a circulating hormone. The IUPHAR receptor review lists these roles (Harmar et al., Br J Pharmacol 2012):
- Gut: stimulates electrolyte and fluid secretion. VIP-knockout mice have slower gut motility.
- Smooth muscle: mediates “nonadrenergic, noncholinergic” relaxation of blood vessels and other smooth muscle.
- Immune system: dampens T-cell proliferation and regulates T-cell traffic.
- Brain: neurons in the suprachiasmatic nucleus, the body’s master clock, make VIP. Mice lacking VIP have badly disrupted circadian rhythms.
- Other tissues: affects insulin release from the pancreas and catecholamine release from the adrenal glands.
Pharmacokinetics
VIP is broken down within minutes. In the classic human study, 4 healthy volunteers received 30-minute IV infusions of 0.6, 1.3 and 3.3 pmol/kg/min (Domschke et al., Gut 1978):
| Measure | Result |
|---|---|
| Disappearance half-time after infusion | About 1 min |
| Apparent metabolic clearance | About 9 mL/kg/min |
| Apparent volume of distribution | About 14 mL/kg |
| Effects at the highest dose | Small rises in glucose, free fatty acids and calcium; faster pulse; skin flushing |
Even the lowest dose pushed plasma VIP well above normal. The highest doses produced levels similar to those in patients with VIP-secreting tumors. Because normal levels are so low, the authors concluded the data did not support VIP acting as a circulating hormone under normal conditions.
The Invicorp product information reports these values for the VIP component of a single 25 µg/2 mg dose (study VP001, healthy men) (Invicorp SmPC):
| Parameter | IV injection | Intracavernosal injection |
|---|---|---|
| Peak level (Cmax) | 396.6 pmol/L | 37.2 pmol/L |
| Time to peak | 1.4 min | 4.3 min |
| Half-life | 1.7 min | 5.3 min |
The SmPC states that VIP’s action ends when enzymes break the peptide down after it binds its receptor.
VIPomas: what too much VIP does
A VIPoma is a rare neuroendocrine tumor that secretes VIP, usually arising in the pancreas. Its features show what sustained high VIP levels do in people.
- 1958. Verner and Morrison described an islet-cell tumor with “refractory watery diarrhea and hypokalemia” (Verner and Morrison, Am J Med 1958). The condition is still called Verner-Morrison syndrome, or WDHA (watery diarrhea, hypokalemia, achlorhydria).
- 1973. Bloom, Polak and Pearse linked the watery-diarrhea syndrome to VIP (Bloom et al., Lancet 1973).
A 2022 review summarizes the condition (Una Cidon, World J Gastrointest Oncol 2022):
| Feature | What the review reports |
|---|---|
| Estimated incidence | About 1 in 10 million people per year |
| Link to MEN1 syndrome | About 5% of cases |
| Spread at diagnosis | About 60% have already metastasized |
| Stool volume | Usually over 3 L/day; under 700 mL/day virtually rules it out |
| Plasma VIP | Over 75 pg/mL is consistent with a VIPoma |
| Other findings | Hypokalemia (low potassium), metabolic acidosis, low stomach acid, high blood sugar, high calcium, flushing |
Surgery to remove the tumor is the only potential cure. The somatostatin analog octreotide (Sandostatin) is FDA-approved “for the treatment of profuse watery diarrhea associated with VIP-secreting tumors.” The label’s starting range is 200–300 µg/day in 2–4 divided doses for the first 2 weeks. The same label notes that its trials did not show a reduction in tumor size or growth (Sandostatin label).
Approved medical use: erectile dysfunction (Europe)
Regulatory history
Invicorp combines two drugs with complementary actions. Phentolamine, an alpha-blocker, increases arterial inflow into the penis. VIP mainly helps close off venous outflow (Dinsmore and Wyllie, BJU Int 2008).
- 1997. The developer, Senetek, filed for approval with the Danish Medicines Authority and in other countries.
- 1999. Trials were put on hold after the FDA raised safety concerns about a competitor’s phentolamine product.
- October 2000. The UK Medicines Control Agency granted marketing approval. Filings in other European countries under the EU mutual-recognition procedure were then underway (Keijzers, Curr Opin Investig Drugs 2001).
- Today. Evolan Pharma AB holds the authorization. In Sweden it was first authorized on May 7, 2015, for “symptomatic treatment of erectile dysfunction” of neurogenic, vascular, psychogenic or mixed cause in adult men (Invicorp SmPC). France authorized it through mutual recognition on October 5, 2018 (HAS opinion 2019).
These are national authorizations, not a centralized EMA approval.
Labeled use
From the Swedish SmPC (Invicorp SmPC):
- Product: one 0.35 mL ampoule contains 25 µg aviptadil and 2 mg phentolamine mesilate.
- Frequency: no more than once a day or 3 times a week.
- Duration of erection: should not exceed one hour.
- Supervision: the first injections must be given by healthcare staff. Home use follows training, with regular check-ups.
What the trials show
Two placebo-controlled UK trials (VP004 and VP005) supported approval. Both used an autoinjector and tested 25 µg VIP with either 1 mg or 2 mg phentolamine in men with mainly non-psychogenic erectile dysfunction:
| Trial | Men in dose-finding phase | Response to active vs placebo |
|---|---|---|
| Sandhu et al. 1999 (VP004) | 304 | 1 mg: 75.1% vs 12%; 2 mg: 66.5% vs 10.3% |
| Dinsmore et al. 1999 (VP005) | 236 | 1 mg: 75% vs 12%; 2 mg: 66% vs 18% |
Response meant an erection suitable for intercourse; all comparisons had p under 0.001 (Sandhu et al., Int J Impot Res 1999; Dinsmore et al., BJU Int 1999). Median erection lasted 54–56 minutes. Transient facial flushing followed about 34–40% of injections.
France’s Transparency Committee reviewed the data for the marketed 2 mg dose in 2019 (HAS opinion 2019):
- Efficacy by injection: about 69% of Invicorp injections vs 14–15% of placebo injections produced a grade 3 erection.
- Caveat: these results came from subgroup analyses, and placebo was not considered a clinically relevant comparator.
- Comparison with alprostadil: an open-label crossover trial (VP007, 239 men) found pain at the injection in 3 per 100 Invicorp injections vs 28 per 100 alprostadil injections. Facial flushing was more common with Invicorp (17 vs 3 per 100).
- Verdict: the committee rated the clinical benefit “insufficient” to justify reimbursement in France.
What the research shows
COVID-19 respiratory failure
NRx Pharmaceuticals developed IV aviptadil as Zyesami. Its 196-patient trial at 10 US hospitals randomized patients 2:1 to 3 days of IV aviptadil or placebo (Youssef et al., Crit Care Med 2022). The primary endpoint, alive and free of respiratory failure at day 60, did not reach significance (OR 1.6, 95% CI 0.86–3.11). The authors highlighted a secondary survival result (OR 2.0, 95% CI 1.1–3.9).
The larger, independent NIH-funded trial, ACTIV-3b/TESICO, randomized 461 patients at 28 US sites. Patients received aviptadil or placebo as 12-hour IV infusions on 3 days, targeting 600, 1,200 and 1,800 pmol/kg (Brown et al., Lancet Respir Med 2023). On May 25, 2022, the independent monitoring board recommended stopping the aviptadil comparison for futility.
| Outcome at day 90 | Aviptadil (n = 231) | Placebo (n = 230) | Effect |
|---|---|---|---|
| Better recovery category (primary) | — | — | OR 1.11 (95% CI 0.80–1.55); p = 0.54 |
| Cumulative mortality | 38% | 36% | HR 1.04 (95% CI 0.77–1.41) |
| Composite safety outcome by day 5 | 63% | 56% | OR 1.40 (95% CI 0.94–2.08) |
The US emergency use requests
From NRx’s own SEC filings and announcements:
- May 31, 2021. NRx applied for Emergency Use Authorization (EUA), based on the first trial.
- November 2021. FDA said it was “unable to issue the EUA at that time.” It cited insufficient data on the benefits and risks of Zyesami in critical COVID-19 with respiratory failure, and noted it had reviewed safety in only 131 randomized patients treated with the drug. FDA also denied a Breakthrough Therapy designation (NRx 2021 annual report).
- February 2022. NRx filed a second, narrower request for patients at immediate risk of death despite remdesivir and other approved treatments.
- July 1, 2022. NRx announced that FDA had declined that request. The application rested on a post-hoc subgroup analysis. NRx said it had already shifted focus to another drug after the TESICO futility result (NRx, July 1, 2022).
Pulmonary hypertension and sarcoidosis
Both uses of inhaled VIP rest on small, uncontrolled studies:
- Pulmonary hypertension. In an open study of 8 patients with primary pulmonary hypertension, inhaled VIP lowered mean pulmonary artery pressure and raised cardiac output (Petkov et al., J Clin Invest 2003).
- Sarcoidosis. In an open phase II study, 20 patients inhaled nebulized VIP for 4 weeks. Their lung-wash cells produced less TNF-α, and regulatory T cells increased. The study measured immune markers, not clinical outcomes (Prasse et al., Am J Respir Crit Care Med 2010).
Neither use has been approved anywhere. We found no randomized controlled trial supporting VIP by nasal spray or under-the-skin injection for any condition.
Side effects and risks
Intracavernosal use (Invicorp)
The SmPC reports side effects in about 10% of patients (Invicorp SmPC):
| Frequency | Effects |
|---|---|
| Common (1–10%) | Flushing; bruising at the injection site |
| Uncommon (0.1–1%) | Headache, dizziness, fast heartbeat, palpitations, hematoma |
| Rare (0.01–0.1%) | Priapism or prolonged erection; penile nodules or fibrosis after repeated injections; pain after injection |
| Very rare (under 0.01%) | Heart attack, angina |
The SmPC also states:
- Prolonged erection. Any erection lasting 4 hours or more needs immediate medical care. Priapism should be treated within 6 hours.
- Penile fibrosis. Fibrosis, curvature and Peyronie’s disease can occur, so regular penile examination is advised.
- Contraindications. Conditions predisposing to priapism (sickle cell disease or trait, multiple myeloma, leukemia), penile deformity or fibrosis, and penile implants.
- Interactions. Use caution with anticoagulants such as warfarin, heparin, dabigatran, rivaroxaban and apixaban. Do not combine with other erectile dysfunction drugs, such as sildenafil or papaverine.
Intravenous use
In TESICO, aviptadil caused more infusion reactions than placebo, especially on the higher-dose days (Brown et al., Lancet Respir Med 2023):
| Infusion reaction (days 0–2) | Aviptadil | Placebo |
|---|---|---|
| Hypotension (low blood pressure) | 58.4% | 41.3% |
| Diarrhea | 39.8% | 11.3% |
| Facial flushing | 14.7% | 6.1% |
| Tachycardia | 9.5% | 4.8% |
| Infusion paused for an adverse event | 30.7% | 15.2% |
Mean arterial pressure ran 5–7 mmHg lower during aviptadil infusions on days 2 and 3, returning to placebo levels within 2 hours. These effects match VIP’s known actions: it widens blood vessels and drives intestinal fluid secretion, as seen in VIPomas.
Regulatory status and compounding in the US
- Approval. No VIP or aviptadil product is FDA-approved. The FDA declined both COVID-19 EUA requests.
- Compounding. A drug substance can be used by a 503A compounding pharmacy only in limited cases: it has a USP/NF monograph, it is a component of an FDA-approved drug, or it appears on FDA’s 503A bulks list (FDA, 503A bulk drug substances).
- Where VIP stands. VIP has been nominated for the bulks list. FDA’s list dated May 14, 2026 places “Vasoactive Intestinal Peptide” in Category 1, bulk drug substances under evaluation (FDA 503A categories, May 2026).
- What Category 1 means. Under its interim policy, FDA “does not intend to take action against a compounder” using Category 1 substances, provided the policy’s other conditions are met. This is enforcement discretion while the review continues. It is not an approval, and it is not a finding that the substance is safe or effective.
The same FDA list puts some other peptides, such as Kisspeptin-10, in Category 2 for significant safety risks. BPC-157 does not appear in Category 1.
VIP and aviptadil are not named on the WADA 2026 Prohibited List.
Key takeaways
- A natural neuropeptide, not an analog. Aviptadil is synthetic VIP, a 28-amino-acid amidated peptide. It acts through VPAC1 and VPAC2 receptors to relax smooth muscle, widen blood vessels and drive gut secretion.
- Extremely short-lived. Its half-life is about 1–2 minutes in the blood, and about 5 minutes after injection into the penis.
- VIPomas show the effects of excess VIP. Tumors that secrete it cause large-volume watery diarrhea, low potassium and flushing. Octreotide is FDA-approved to control the diarrhea.
- One approved use, in Europe only. Invicorp (aviptadil 25 µg + phentolamine 2 mg) is authorized in several European countries for erectile dysfunction. France judged its benefit insufficient for reimbursement.
- COVID-19 claims did not hold up. The NIH TESICO trial found no benefit on recovery or 90-day survival. FDA declined both EUA requests for IV aviptadil, and the drug caused more hypotension and diarrhea than placebo.
- Compounding is under review, not approved. FDA lists VIP in 503A Category 1 (under evaluation) as of May 2026. No randomized trials support VIP by nasal spray or under-the-skin injection.
Sources
- Said SI, Mutt V. Polypeptide with broad biological activity: isolation from small intestine. Science. 1970;169(3951):1217–1218. PubMed.
- 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. PubMed.
- National Center for Biotechnology Information. Aviptadil, PubChem CID 16132300. PubChem.
- Domschke S, Domschke W, Bloom SR, et al. Vasoactive intestinal peptide in man: pharmacokinetics, metabolic and circulatory effects. Gut. 1978;19(11):1049–1053. PubMed.
- Verner JV, Morrison AB. Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia. Am J Med. 1958;25(3):374–380. PubMed.
- Bloom SR, Polak JM, Pearse AG. Vasoactive intestinal peptide and watery-diarrhoea syndrome. Lancet. 1973;2(7819):14–16. PubMed.
- Una Cidon E. Vasoactive intestinal peptide secreting tumour: an overview. World J Gastrointest Oncol. 2022;14(4):808–819. PubMed.
- Novartis Pharmaceuticals. Sandostatin (octreotide acetate) injection prescribing information. DailyMed.
- Evolan Pharma AB. Invicorp 25 mikrogram/2 mg injektionsvätska, lösning: produktresumé (summary of product characteristics). Läkemedelsverket; revised July 9, 2026. Läkemedelsverket.
- Haute Autorité de Santé, Commission de la Transparence. Invicorp (aviptadil/phentolamine mésilate): avis, 2019 (CT-17544). HAS.
- Keijzers GB. Aviptadil (Senatek). Curr Opin Investig Drugs. 2001;2(4):545–549. PubMed.
- Dinsmore WW, Wyllie MG. Vasoactive intestinal polypeptide/phentolamine for intracavernosal injection in erectile dysfunction. BJU Int. 2008;102(8):933–937. PubMed.
- Sandhu D, Curless E, Dean J, et al. A double blind, placebo controlled study of intracavernosal vasoactive intestinal polypeptide and phenotolamine mesylate in a novel auto-injector for the treatment of non-psychogenic erectile dysfunction. Int J Impot Res. 1999;11(2):91–97. PubMed.
- 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 Int. 1999;83(3):274–279. PubMed.
- 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. PubMed.
- 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. PubMed.
- NRx Pharmaceuticals. Annual report on Form 10-K for the fiscal year ended December 31, 2021. US Securities and Exchange Commission; filed March 31, 2022. SEC.
- NRx Pharmaceuticals. FDA declines Emergency Use Authorization for ZYESAMI (aviptadil) for subgroup of patients with critical COVID-19. Press release; July 1, 2022. NRx.
- 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. PubMed.
- 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. PubMed.
- US Food and Drug Administration. Bulk drug substances nominated for use in compounding under section 503A of the FD&C Act (categories 1–3). Updated May 14, 2026. FDA.
- US Food and Drug Administration. Bulk drug substances used in compounding under section 503A of the FD&C Act. FDA.
- World Anti-Doping Agency. World Anti-Doping Code International Standard: Prohibited List 2026. WADA.