VIP

Also known as: Vasoactive Intestinal Polypeptide, Aviptadil (synthetic form used in trials), VIP-28

Evidence: Clinical

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Overview

Vasoactive intestinal peptide, a 28-amino-acid neuropeptide acting at VPAC1 and VPAC2 receptors; studied for vasodilation, immune modulation and neuroprotection.

VIP is a 28-residue neuropeptide first isolated from small intestine for its vasodilator activity (Said and Mutt, 1970). Its synthetic form, aviptadil, is what human studies have used. Intravenous infusion in volunteers produced flushing, a faster pulse and a wider blood pressure amplitude, with a plasma half-time of about a minute (Domschke et al., 1978). Inhaled aviptadil gave small, brief pulmonary vasodilation in 20 patients with pulmonary hypertension (Leuchte et al., 2008). Two randomised trials in COVID-19 respiratory failure missed their primary endpoints, the larger one stopped for futility (Youssef et al., 2022; Brown et al., 2023). Aviptadil with phentolamine is used intracavernosally for erectile dysfunction (Al-Mitwalli et al., 2025). The intranasal CIRS protocol it is sold for has no published trial.

Benefits

Vasodilation (human, IV and inhaled); anti-inflammatory and neuroprotective effects in animal and cell models; two randomised trials in COVID-19 respiratory failure missed their endpoints

Dosing reference

Research dose: 50 to 200 mcg intranasal (community range, no published human dose for this route; trials used 100 mcg inhaled or 600 to 1800 pmol/kg/day intravenously)
Range: 50 to 200 mcg, 1-2x daily
Reconstitution: 2 mL bacteriostatic water
Common vial sizes: 6 mg

Published human dosing is inhaled or intravenous, never intranasal or subcutaneous: 100 mcg as a single inhaled dose during right-heart catheterisation (Leuchte et al., 2008), a 3-day intravenous course targeting 600, 1200 and 1800 pmol/kg on successive days (Brown et al., 2023), and graded infusions of 0.6 to 3.3 pmol/kg/min in volunteers (Domschke et al., 1978). The intranasal CIRS protocol the compound is sold for has no published trial. Measured effects of systemic dosing in volunteers were flushing, a faster pulse and a wider blood pressure amplitude. Plasma half-time is about one minute, so effects are brief.

Mechanism

VIP is a 28-residue neuropeptide isolated from small intestine in 1970 as a potent vasodilator (Said and Mutt, 1970). It acts at the VPAC1 and VPAC2 G-protein-coupled receptors and raises cyclic AMP. In healthy volunteers, intravenous infusion reproduced features of the Verner-Morrison syndrome: cutaneous flushing, higher pulse rate, wider blood pressure amplitude and small rises in glucose, free fatty acids and calcium (Domschke et al., 1978). Inhaled aviptadil caused selective pulmonary vasodilation with improved stroke volume and mixed venous oxygen saturation (Leuchte et al., 2008). The rationale tested in COVID-19 was surfactant production and cytokine suppression in alveolar cells (Youssef et al., 2022). Anti-inflammatory and neuroprotective actions are reported in animal and cell models.

Evidence

Clinical: at least one published human trial or an approved drug

Isolated from small intestine as a potent vasodilator peptide (Said and Mutt, 1970)
Graded intravenous infusion in healthy volunteers (0.6 to 3.3 pmol/kg/min) produced flushing, higher pulse rate and wider blood pressure amplitude, with a plasma disappearance half-time of about one minute (Domschke et al., 1978)
A single inhaled 100 mcg dose of aviptadil in 20 patients with pulmonary hypertension gave small, short-lived selective pulmonary vasodilation with no systemic blood pressure effect (Leuchte et al., 2008)
A 196-patient placebo-controlled trial of intravenous aviptadil in critical COVID-19 respiratory failure missed its primary endpoint, with a secondary 60-day survival difference reported (Youssef et al., 2022)
TESICO, 461 patients in the modified intention-to-treat analysis, was stopped for futility: intravenous aviptadil at 600 to 1800 pmol/kg/day over 3 days did not improve the ordinal recovery outcome (Brown et al., 2023)
Human-trial status: aviptadil with phentolamine is used by intracavernosal injection for erectile dysfunction, effective in 59% of 308 referred men in one centre's series, with facial flushing in 22.5% (Al-Mitwalli et al., 2025). openFDA returns no Drugs@FDA application for aviptadil or vasoactive intestinal peptide

References

Side effects

In healthy volunteers, intravenous infusion caused cutaneous flushing, a faster pulse and a wider blood pressure amplitude, with small rises in glucose, free fatty acids and calcium (Domschke et al., 1978). Facial flushing occurred in 22.5% of 308 men given aviptadil with phentolamine intracavernosally, and ischaemic priapism in 0.3% (Al-Mitwalli et al., 2025). Inhaled aviptadil caused no side effects in 20 patients and did not lower systemic blood pressure (Leuchte et al., 2008). The COVID-19 trials reported no drug-related serious adverse events (Youssef et al., 2022). There is no safety data for intranasal or subcutaneous use.

Storage

Storage: Refrigerate 2-8°C (36-46°F)
Lyophilized: 2+ years at room temp, 3+ years refrigerated
Reconstituted: 28-30 days refrigerated

Pharmacology

Half-life: ~1 min plasma disappearance half-time (human, IV infusion, first-order kinetics; clearance about 9 mL/kg/min; Domschke et al., 1978)
Bioavailability: Not quantified for any route. Human studies used intravenous infusion, inhalation or intracavernosal injection; the apparent volume of distribution on intravenous infusion was about 14 mL/kg with clearance near 9 mL/kg/min (Domschke et al., 1978). No intranasal or subcutaneous data exist.
Molecular weight: 3326.82 Da
Sequence: His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH2

VIP