VIP (Vasoactive Intestinal Peptide) research and evidence overview

VIP is an endogenous 28-amino-acid neuropeptide whose physiology is thoroughly characterised — receptors identified, signalling mapped, roles in gut motility, vasodilation, bronchodilation, circadian timing, and immune regulation described in detail. Turning that into a medicine has been much harder. The synthetic form, aviptadil, has been studied in respiratory failure, sarcoidosis and pulmonary hypertension, and has not been approved for any of them; the published trials are small and their endpoints are mostly short-term. Intranasal VIP as sold for "chronic inflammatory response syndrome" has no controlled trial evidence behind it in the indexed literature.

VIP acts at two class B G-protein-coupled receptors, VPAC1 and VPAC2, which it shares with PACAP. A 2020 review in Frontiers in Cellular Neuroscience illustrates how finely those two receptors divide the work in a single tissue: in the hippocampus, VPAC1 activation promotes disinhibition of pyramidal cells while VPAC2 activation enhances their excitability, and both shape long-term potentiation and long-term depression (Cunha-Reis & Caulino-Rocha). The review frames VIP receptors as potential targets in cognitive decline and mesial temporal lobe epilepsy — target identification, not therapy.

This receptor split is the practical obstacle to VIP as a drug: an unselective agonist hits both receptors in every tissue that expresses them, which is most of them, and the peptide's native half-life in circulation is very short.

A substantial body of work, much of it from Mario Delgado's group, describes VIP as an endogenous mechanism for inducing immune tolerance: downregulating inflammatory and Th1 responses, and inducing antigen-specific regulatory T cells and tolerogenic dendritic cells. A 2012 review in Endocrine, Metabolic and Immune Disorders Drug Targets summarises its therapeutic effectiveness across experimental models of autoimmune disease, notes an application in human sarcoidosis, and proposes transplant tolerance as the next target (Souza-Moreira, Delgado-Maroto & Delgado).

Note the balance of that sentence: experimental models plural, human applications singular and preliminary. This literature is the source of most claims about VIP for autoimmune and inflammatory conditions, and it is overwhelmingly animal work.

The most concrete recent human data come from a multicentre, randomized, double-blind, placebo-controlled trial of inhaled aviptadil in hospitalised adults with COVID-19 across nine Turkish centres, published in Medical Principles and Practice in 2025 (Esendagli et al.). 80 patients (mean age 55.8 ± 18.5 years) were randomized 1:1 alongside standard care. Mean time to discharge was 7.8 ± 4.0 days with aviptadil versus 10 ± 5.0 days with placebo (P=0.049). Modified Borg dyspnoea scores did not differ at day 3 but were lower with aviptadil at day 7 (P=0.033), and CT lung-damage score improvement at day 28 favoured aviptadil. No participants withdrew for side effects.

This is a small trial with a marginal primary result (P=0.049 at n=80), and it concerns an inhaled formulation in acute viral pneumonia. Intravenous aviptadil for COVID-19 respiratory failure received considerable attention during the pandemic without producing an approval.

• VIP is not FDA-approved for any indication; aviptadil is investigational in the US.
• Route determines everything here. Inhaled, intravenous, and intranasal VIP are effectively different exposures, and evidence does not transfer between them.
• The trials were conducted in acutely ill hospitalised patients under monitoring — a population and setting unrelated to self-administered wellness use.
• Because VIP is a potent vasodilator, hypotension and flushing are predictable dose-limiting effects, which is part of why systemic formulations have been difficult to develop.