VIP (Vasoactive Intestinal Peptide) is a naturally occurring neuropeptide that dilates blood vessels, dampens inflammation, and regulates gut and lung function — used experimentally for pulmonary hypertension, ARDS, and chronic inflammatory conditions.
What it does
VIP is a 28-amino acid neuropeptide — a small signaling protein used by both the nervous system and immune system. It works by binding two receptors, VPAC1 and VPAC2, which are found throughout the lungs, gut, brain, and immune tissues. Binding these receptors triggers a chain reaction inside cells (via adenylyl cyclase → cAMP, a common intracellular signaling molecule) that leads to muscle relaxation and immune modulation.
In the lungs and blood vessels, VIP is one of the body's most potent endogenous vasodilators — meaning it causes smooth muscle to relax, widening airways and blood vessels. This is the basis for aviptadil, a synthetic form of VIP, being studied in pulmonary arterial hypertension and acute respiratory distress syndrome (ARDS) A 2025. In the gut, VIP stimulates fluid secretion and relaxes intestinal smooth muscle to support motility Jing-Yan 2025. Tumors that secrete excess VIP (VIPomas) cause profuse, watery diarrhea — which illustrates just how active this peptide is in that tissue.
On the immune side, VIP suppresses pro-inflammatory signaling: it reduces TNF-α, IL-6, and IL-12 production by macrophages and dendritic cells, and shifts immune activity away from Th1-driven inflammation toward a more regulatory Th2/Treg profile Xueyue 2025. In the brain, VIP supports neuronal survival and synaptic function Wenhui 2025, and in the suprachiasmatic nucleus (the brain's internal clock), it helps regulate circadian rhythm.
What the evidence shows
Acute Respiratory Distress Syndrome (ARDS) and Pulmonary Hypertension Moderate — multiple small human trials and a 2025 meta-analysis, but no large phase III RCTs yet
A 2025 systematic review and meta-analysis of aviptadil (IV and inhaled) in ARDS patients found improvements in oxygenation and a trend toward reduced mortality, though study sizes were small and heterogeneous A 2025. VIP's mechanism here is direct: it relaxes pulmonary vascular smooth muscle, reducing the elevated pressures that define these conditions. The signal is real enough to drive ongoing clinical trials, but the evidence base is not yet sufficient to call this an established treatment.
Chronic Inflammatory Response Syndrome (CIRS) / Mold Illness Mostly clinical protocol-level evidence; limited controlled trial data in humans
The Shoemaker CIRS protocol uses intranasal VIP (typically 25–50 mcg four times daily) as a late-stage intervention after biotoxin load is reduced, based on observations that VIP levels are depressed in CIRS patients and that replacement correlates with symptom improvement. The biological rationale is solid — VIP's anti-inflammatory and regulatory immune effects are well-characterized Xueyue 2025 — but controlled trials in CIRS specifically are lacking. This remains a clinician-driven protocol rather than an evidence-based standard of care.
Neuroprotection and Neurological Conditions Strong rodent and mechanistic data; limited human evidence
VIP promotes neuronal survival, and its levels appear altered in neurodegenerative settings. A 2025 review identified VIP as playing a significant role in Parkinson's disease pathophysiology, with animal models showing neuroprotective effects Wenhui 2025. Separately, overexpression of colonic VIP in aged rats reduced cognitive decline and barrier dysfunction following anesthesia Huihui 2025. These are compelling mechanistic findings, but human clinical data in neurological conditions are essentially absent so far.
Headache and Cranial Hemodynamics Small controlled human study
A registered clinical trial infused VIP in healthy volunteers and measured its effects on headache induction, cranial blood flow, and autonomic symptoms NCT03989817. VIP infusion can provoke headache, likely through its vasodilatory effects on cranial vessels — a finding that's relevant for understanding cluster headache and migraine biology, but also a practical safety consideration for anyone using VIP at higher doses.
Gut Motility and GI Function Good mechanistic and animal data; human evidence mostly indirect
VIP's role in the enteric nervous system is well-established: it relaxes GI smooth muscle and coordinates intestinal motility Jing-Yan 2025. Studies on TENS (transcutaneous electrical nerve stimulation) in pediatric constipation found that effective treatment correlated with changes in VIP levels, suggesting VIP as a mediating signal Piao 2025. Direct therapeutic use via exogenous VIP for GI disorders is not currently a standard protocol.
How it's used
In studies and self-reported protocols, intranasal VIP is most commonly used at 25 mcg per nostril four times daily (the Shoemaker CIRS starting dose), with some protocols titrating to 50 mcg four times daily. In clinical trials for ARDS and pulmonary hypertension, aviptadil has been administered IV or via inhalation at doses ranging from 25–100 mcg, often as continuous infusion A 2025. Subcutaneous use is reported anecdotally but less common. VIP's plasma half-life is approximately 2 minutes, meaning receptor-level effects persist longer than circulating levels suggest, but dosing must still be distributed throughout the day to maintain effect. Intranasal formulations require pharmaceutical-grade compounding for proper mucosal absorption.
Side effects and safety
The most clinically significant risk is hypotension (a drop in blood pressure), which follows directly from VIP's vasodilatory mechanism — this is both dose-dependent and rapid in onset, particularly with IV administration NCT03989817. Flushing, tachycardia (elevated heart rate), and headache are reported at moderate doses, again reflecting systemic vasodilation. GI effects — loose stool or mild diarrhea — are expected given VIP's role in intestinal secretion. Nasal congestion is reported with intranasal use. VIP is contraindicated in patients with existing hypotension, active diarrheal illness, or known hypersensitivity. People with cardiovascular instability should use caution. Long-term safety data from controlled human trials are essentially absent — most human exposure data come from short-duration clinical studies or uncontrolled clinical use.
Bottom line
VIP has a well-understood mechanism and credible biology behind several of its proposed uses, particularly in pulmonary conditions and immune regulation. The ARDS evidence is the strongest clinically, supported by a 2025 meta-analysis, while CIRS use rests more on protocol experience than controlled trials. Anyone considering VIP should treat the hypotension risk as real and not theoretical — this is a potent vasodilator with a narrow margin at higher doses.