VIP (Vasoactive Intestinal Peptide): Research Guide
Most peptides earn their names from where they were first found. Vasoactive intestinal peptide is no exception -- it was pulled from porcine gut tissue in 1970 and named for its ability to relax blood vessels. But the name is misleading.
Most peptides earn their names from where they were first found. Vasoactive intestinal peptide is no exception -- it was pulled from porcine gut tissue in 1970 and named for its ability to relax blood vessels. But the name is misleading. VIP does far more than dilate intestinal blood vessels, and it operates far beyond the gut.
Over the past five decades, researchers have identified VIP in the brain, lungs, immune cells, and nearly every major organ system. It regulates inflammation, synchronizes your circadian clock, modulates immune responses, and protects neurons from damage. Among clinicians who treat chronic inflammatory response syndrome (CIRS), VIP has become one of the most discussed -- and most debated -- therapeutic peptides in practice.
This guide covers what the research actually shows: the established science, the promising findings, and the gaps that remain.
Table of Contents
- Quick Facts
- What Is VIP?
- Discovery and History
- How VIP Works: Mechanisms of Action
- Research Evidence
- Administration and Dosing
- Safety Profile and Side Effects
- Legal and Regulatory Status
- Limitations of Current Research
- Frequently Asked Questions
- The Bottom Line
Quick Facts
| Property | Detail |
|---|---|
| Full Name | Vasoactive Intestinal Peptide (VIP) |
| Also Known As | Aviptadil (synthetic form), VIP-28 |
| Structure | 28-amino-acid neuropeptide |
| Peptide Family | Glucagon/secretin superfamily |
| Discovered | 1970, by Sami I. Said and Viktor Mutt |
| Primary Receptors | VPAC1 and VPAC2 (G protein-coupled receptors) |
| Natural Half-Life | Approximately 2 minutes in blood |
| Found In | Gut, brain (suprachiasmatic nucleus), lungs, pancreas, immune cells |
| Primary Research Areas | CIRS/mold illness, pulmonary hypertension, neuroprotection, autoimmune disease, circadian regulation |
| Administration Routes | Nasal spray, intravenous, inhaled, subcutaneous |
| FDA Status | Not FDA-approved as a standalone drug; aviptadil has Orphan Drug designation for ARDS and pulmonary hypertension |
What Is VIP?
Vasoactive intestinal peptide is a 28-amino-acid neuropeptide that belongs to the glucagon/secretin superfamily. Your body produces it naturally -- in nerve fibers throughout the gut, in specific regions of the brain (particularly the suprachiasmatic nucleus, which controls your internal clock), in the lungs, pancreas, and in immune cells themselves.
VIP acts as both a neurotransmitter and a hormone, depending on where it's released. It binds to two specific receptors -- VPAC1 and VPAC2 -- which are distributed across nearly every tissue type in the body. This broad receptor distribution explains why VIP influences such a wide range of biological processes: blood flow, immune responses, digestion, sleep-wake cycles, and nerve cell survival.
In clinical medicine, VIP gained attention through two main paths. Researchers studying pulmonary hypertension noticed that patients often had low VIP levels. Separately, Dr. Ritchie Shoemaker's work on CIRS identified VIP deficiency in roughly 91% of patients with biotoxin illness. The synthetic form, aviptadil, has been studied in clinical trials for pulmonary hypertension and COVID-19-related respiratory failure. Compounded VIP nasal spray has been used off-label for CIRS, though its regulatory status remains complicated.
Discovery and History
The story of VIP begins with a scientist looking in the wrong organ -- or rather, the right organ for the wrong reason.
In the late 1960s, Dr. Sami I. Said, working at the Medical College of Virginia, found that injecting lung tissue extracts into animals produced strong vasodilation and drops in blood pressure. He suspected the lungs contained an unidentified vasodilatory peptide. But lung tissue was difficult to obtain in the quantities needed for isolation.
Said teamed up with Viktor Mutt at the Karolinska Institute in Stockholm, and they pivoted to duodenal extracts -- gut tissue was more readily available, and they hypothesized the same peptide might exist there. In 1970, they isolated a 28-amino-acid peptide from porcine duodenum with the same vasodilatory effects, naming it vasoactive intestinal peptide.
The irony, as Said later noted in a paper titled "The discovery of VIP: initially looked for in the lung, isolated from intestine, and identified as a neuropeptide," is that VIP turned out to be none of these things exclusively. Researchers found VIP throughout the central and peripheral nervous systems, reclassifying it as a neuropeptide with far broader significance than its name implied.
By the 1980s, VIP had been identified in the suprachiasmatic nucleus -- the brain's master circadian clock. By the 1990s, its immunomodulatory properties were becoming clear. In 2001, the synthetic form (aviptadil) received FDA Orphan Drug Designation for acute respiratory distress syndrome (ARDS), and in 2005 for pulmonary arterial hypertension. Dr. Shoemaker's work with CIRS patients beginning around 2008 brought VIP nasal spray into clinical practice for biotoxin illness.
How VIP Works: Mechanisms of Action
VIP's biology is unusually broad for a single peptide. Here's how it operates across its major pathways.
Receptor Binding: VPAC1 and VPAC2
VIP binds to two G protein-coupled receptors: VPAC1 and VPAC2. Most immune cells express VPAC1 constantly, while VPAC2 expression increases when cells are activated -- meaning VIP's influence on immune cells shifts depending on the state of immune activation.
When VIP binds to either receptor, it activates adenylyl cyclase, increasing cyclic AMP (cAMP) levels inside the cell. Rising cAMP activates protein kinase A (PKA), which phosphorylates transcription factors like CREB -- changing gene expression patterns that affect inflammation, cell survival, and immune cell behavior. VIP also activates secondary pathways, including the phospholipase C (PLC) cascade and the MAPK/ERK pathway.
Immune Modulation
VIP's most therapeutically relevant action may be its effect on the immune system. It works on multiple levels:
- Cytokine regulation: VIP inhibits the production of pro-inflammatory cytokines (TNF-alpha, IL-6, IL-12) while promoting anti-inflammatory mediators (IL-10, TGF-beta, IL-1Ra).
- T-cell polarization: VIP shifts the balance from pro-inflammatory Th1 and Th17 responses toward Th2 and regulatory T-cell (Treg) profiles. In rheumatoid arthritis research, this shift has been shown to reduce both autoimmune and inflammatory components of disease.
- Macrophage and microglia suppression: VIP inhibits the release of inflammatory mediators from macrophages (in the body) and microglia (in the brain).
This combination gives VIP a broad anti-inflammatory footprint. For comparison, Thymosin Alpha-1 also modulates immune function, but through different receptor pathways and with a stronger emphasis on boosting immune surveillance rather than dampening inflammation.
Vasodilation
True to its name, VIP relaxes smooth muscle in blood vessel walls. It does this through VPAC1 receptors on endothelial cells (triggering nitric oxide release) and VPAC2 receptors on vascular smooth muscle cells (directly promoting relaxation). This dual mechanism produces vasodilation in pulmonary, cerebral, coronary, and splanchnic vascular beds.
Neuroprotection
VIP protects neurons through several mechanisms. It stimulates astrocytes to produce activity-dependent neuroprotective protein (ADNP), a glial-cell mediator that itself contains a potent neuroprotective fragment called NAP. VIP also reduces oxidative stress in neuronal tissue and suppresses microglial activation -- the brain's version of inflammatory macrophage activity.
Circadian Regulation
In the suprachiasmatic nucleus (SCN), VIP acts as the primary synchronizing signal between individual clock neurons. Without VIP, SCN neurons still oscillate, but they lose coordination with each other. VIP-deficient mice show severely disrupted circadian rhythms, loss of coherent sleep-wake cycles, and abnormal corticosterone and heart rate rhythms. VIP also mediates the connection between retinal light signals and the circadian clock, a process called photic entrainment.
Research Evidence
CIRS and Mold Illness
The most extensive clinical use of VIP has been in chronic inflammatory response syndrome (CIRS), a condition linked to exposure to water-damaged buildings. Dr. Ritchie Shoemaker's research identified VIP deficiency as a near-universal finding in CIRS patients and developed a treatment protocol using VIP nasal spray as the final step in a multi-stage intervention.
Shoemaker and colleagues published a 2013 study in Health showing that intranasal VIP corrected multiple inflammatory markers in 20 patients with refractory CIRS. After at least 18 months of VIP nasal spray (50 mcg per spray, 4-8 sprays daily), the study reported reductions in C4a, TGF-beta-1, MMP9, and MASP2, along with improvements in pulmonary artery pressure and regulatory T-cell function. A 2017 follow-up in Internal Medicine Review found that intranasal VIP restored grey matter volume in multiple brain nuclei, as measured by NeuroQuant MRI.
The protocol requires strict prerequisites before VIP administration: a safe living environment (ERMI score below 2), passing visual contrast sensitivity test, MARCoNS eradication, and completion of the prior 10 protocol steps. VIP does not work -- and can worsen outcomes -- if these prerequisites are not met.
These studies are open-label, conducted by researchers with a stake in the protocol, and have not been independently replicated. Still, the accumulated clinical experience -- over 10,000 patients treated by more than 1,000 physicians -- represents a meaningful body of observational data.
For related anti-inflammatory peptide research, see our profiles on KPV and LL-37, both of which have overlapping applications in chronic inflammatory conditions.
Pulmonary and Respiratory Research
VIP's vasodilatory and anti-inflammatory properties make it a natural candidate for pulmonary hypertension (PH) research. Patients with idiopathic pulmonary arterial hypertension (PAH) show lower serum VIP levels and overexpression of VIP receptors in pulmonary tissue, suggesting a compensatory response to VIP deficiency.
Petkov and colleagues published a 2003 proof-of-concept study showing that inhaled VIP improved hemodynamics in PAH patients. A later study of 20 PH patients found that a single 100-microgram inhaled dose of aviptadil produced modest but significant pulmonary vasodilation and improved stroke volume without systemic side effects.
However, subsequent placebo-controlled data were less encouraging. One trial found no significant reduction in pulmonary vascular resistance, and the full data were never published in a peer-reviewed journal, leaving the field in an ambiguous state.
The next-generation approach involves PB1046 (pemziviptadil), a long-acting VIP analogue that allows once-weekly subcutaneous dosing. PB1046 received FDA Orphan Drug designation for PAH in 2015 and has been studied in Phase 1/2 trials with over 70 patients and no drug-related serious adverse events.
A 2025 study in the American Journal of Respiratory and Critical Care Medicine used VIP-knockout mice to show that VIP deficiency amplified inflammatory and fibrotic changes in lung tissue exposed to World Trade Center dust.
Neuroprotection
Preclinical research on VIP's neuroprotective properties spans both Alzheimer's and Parkinson's disease models.
In Alzheimer's research, a 2012 PLOS ONE study found that VIP promoted microglial clearance of amyloid-beta aggregates while suppressing the neurotoxic inflammatory response in APP/PS1 transgenic mice. VIP expression is reduced in AD brains, and overexpression improved outcomes in AD mouse models.
In Parkinson's research, VIP prevented MPTP-induced dopaminergic neuron death by blocking microglial activation. A superactive analogue (stearyl-Nle17-VIP), 100-fold more potent than native VIP, showed neuroprotection against dopamine toxicity at very low doses. VPAC2-selective agonists like LBT-3627 have also demonstrated neuroprotection in rat PD models by boosting regulatory T-cell function.
No human clinical trials for VIP in neurodegenerative diseases have been completed. The neuroprotection data remains preclinical. For another peptide with neuroprotective research, see Selank.
GI Function
Although VIP was discovered in the gut, research on its GI applications has taken a backseat to its immunological and neurological roles. VIP regulates ion secretion, nutrient absorption, gut motility, and glycemic control in the GI tract. It stimulates water and electrolyte secretion into the intestinal lumen and relaxes gut smooth muscle.
A 2024 study published in Stem Cell Research & Therapy explored VIP's direct effects on intestinal epithelial cells, finding that VIP promoted secretory cell differentiation and protected against radiation-induced intestinal injury in organoid models. The effect was mediated through the p38 MAPK and MEK1 pathways.
VIPomas -- rare pancreatic tumors that overproduce VIP -- demonstrate what excess VIP looks like: profuse watery diarrhea, hypokalemia, and achlorhydria (Verner-Morrison syndrome). This pathology confirms VIP's potent secretory effects in the gut and highlights that balance, rather than simple supplementation, is the goal.
For peptides more directly studied for gut healing, see BPC-157 and our guide on best peptides for gut health.
Autoimmune and Inflammatory Disease
VIP has been studied extensively in animal models of autoimmune disease, particularly rheumatoid arthritis (RA).
A landmark 2001 study by Delgado and colleagues, published in Nature Medicine, showed that VIP completely prevented the development of collagen-induced arthritis in mice, eliminating joint swelling and cartilage/bone destruction. The therapeutic effect came from simultaneous suppression of both the autoimmune component (shifting T-cells from Th1 to Th2) and the inflammatory component (reducing pro-inflammatory cytokines).
A 2018 study in the Journal of Immunology Research confirmed similar mechanisms in human cells from RA patients, showing that VIP modulated Th subset differentiation and boosted the Treg/Th17 ratio. Beyond RA, VIP has shown efficacy in animal models of multiple sclerosis, inflammatory bowel disease, and type 1 diabetes. Human clinical data in autoimmune diseases, however, remain limited. For other immune-modulating peptides, see Thymosin Alpha-1 and our guide to best peptides for immune support.
Administration and Dosing
VIP has been administered through several routes, each suited to different clinical contexts.
Nasal Spray
The most widely used form in clinical practice, particularly for CIRS. The Shoemaker protocol uses compounded VIP nasal spray at 50 mcg per spray. Typical dosing starts at one spray four times daily (alternating nostrils), advancing to two sprays four times daily in the second month. Total daily doses range from 200-400 mcg.
Nasal administration bypasses first-pass liver metabolism and provides access to cranial nerve pathways.
Inhalation
Used in pulmonary hypertension research at 100 mcg aerosolized over approximately 8 minutes. Targets pulmonary vasculature directly, minimizing systemic side effects.
Intravenous
Used in clinical trials and acute care settings. IV VIP produces the most pronounced systemic effects, including significant drops in blood pressure, making it less practical for outpatient use. Aviptadil IV was studied in COVID-19 respiratory failure trials.
Subcutaneous
The long-acting VIP analogue pemziviptadil (PB1046) is administered subcutaneously once weekly, overcoming the native peptide's two-minute half-life through fusion with an elastin-like polypeptide.
Note: VIP is a prescription medication. Dosing decisions should be made by a qualified healthcare provider based on individual patient factors, relevant lab work, and clinical context.
Safety Profile and Side Effects
VIP's safety record has been generally favorable, though data comes from small studies and clinical observations rather than large-scale randomized trials.
Common Side Effects
- Nasal irritation (with nasal spray)
- Flushing (due to vasodilation)
- Mild diarrhea (consistent with VIP's known secretory effects in the gut)
- Headache
- Mild dizziness
- Transient drops in blood pressure
Less Common Effects
- Stomach upset
- Tachycardia (increased heart rate, usually mild)
- Mood changes (rare)
IV-Specific Concerns
Intravenous administration carries a higher risk of systemic hypotension, tachycardia, and cutaneous flushing. The inhaled route showed minimal systemic side effects in pulmonary hypertension trials.
VIPomas as a Caution
VIPomas -- tumors that produce massive amounts of VIP -- cause severe watery diarrhea and dangerous electrolyte imbalances. Therapeutic doses are far lower, but this pathology illustrates the importance of appropriate dosing. Fasting lipase monitoring is recommended in the Shoemaker protocol as a precaution.
Clinical Track Record
Shoemaker and colleagues report VIP nasal spray use in over 10,000 patients with no serious adverse events, though this comes from practice records rather than controlled trials. In Phase 1/2 trials of PB1046, more than 70 patients have been treated with no drug-related serious adverse events.
Legal and Regulatory Status
VIP occupies a complicated regulatory space.
FDA approval: VIP is not available in any FDA-approved product in the United States. The synthetic form, aviptadil, has received FDA Orphan Drug designation for ARDS (2001) and pulmonary arterial hypertension (2005), and Fast Track designation for COVID-19-related ARDS. But none of these designations resulted in full marketing approval.
Compounding: VIP has been available through compounding pharmacies, primarily as a nasal spray for CIRS. However, the FDA has moved to remove VIP from the list of substances that may be legally compounded, beginning with a 2016 advisory committee review and 2019 proposals for exclusion. The CIRS treatment community, led by ISEAI and the survivingmold.com advocacy effort, has pushed back, citing VIP's safety record and the absence of FDA-approved alternatives.
2025 regulatory shifts: The FDA's January 2025 interim guidance tightened rules on compounding without USP monographs. Under this framework, 503A pharmacies cannot compound substances lacking monographs, FDA approval, or Category 1 classification until review is conducted. VIP's compounding future remains uncertain.
International: Regulatory status varies by country. VIP is not widely approved outside of research and compounding contexts. Patients considering VIP therapy should discuss the regulatory situation with their prescribing physician.
Limitations of Current Research
Despite decades of study, VIP research has several notable gaps:
Small, uncontrolled CIRS studies. The Shoemaker data comes from open-label studies by researchers who developed the protocol. No independent, randomized, placebo-controlled trial of VIP for CIRS has been published.
Inconsistent pulmonary hypertension results. Early PAH trials showed promise, but placebo-controlled data was never fully published and reportedly negative. The field awaits longer-acting VIP analogues to clarify whether the problem was efficacy or pharmacokinetics.
No human neurodegenerative disease trials. All neuroprotection data comes from cell cultures and animal models.
Half-life challenges. VIP's two-minute half-life makes dosing difficult. The field lacks robust pharmacokinetic data for the nasal spray formulation most commonly used in practice.
Publication bias. Much CIRS literature comes from a small group of affiliated researchers. Independent replication would strengthen the evidence base.
Limited autoimmune translation. Animal model results in RA, MS, and IBD are compelling, but human clinical trials in these conditions are absent.
Frequently Asked Questions
What conditions is VIP most commonly used for?
In clinical practice, VIP nasal spray is most commonly used as part of the Shoemaker protocol for chronic inflammatory response syndrome (CIRS), typically caused by exposure to water-damaged buildings. It has also been studied in pulmonary hypertension, COVID-19-related respiratory failure, and various autoimmune conditions, though these applications remain experimental.
How does VIP compare to other anti-inflammatory peptides?
VIP operates through different mechanisms than most anti-inflammatory peptides. While KPV works primarily through NF-kB inhibition and BPC-157 promotes tissue repair, VIP shifts immune cell behavior from inflammatory to regulatory profiles through VPAC signaling. It also has vasodilatory and neuroprotective effects that other anti-inflammatory peptides lack. See our guide on best peptides for inflammation reduction.
Is VIP safe for long-term use?
Available data suggests a favorable safety profile. The Shoemaker group reports safe use in over 10,000 patients. Phase 1/2 clinical trials of VIP analogues have reported no serious drug-related adverse events. However, long-term data from controlled trials is lacking. Periodic monitoring of lipase levels and blood pressure is standard practice.
Why can't I just buy VIP over the counter?
VIP is a prescription compounded medication, not a dietary supplement. It requires a physician's prescription and must be prepared by a compounding pharmacy. Its regulatory status in the United States is currently uncertain, with the FDA proposing to remove it from the list of substances approved for compounding.
Does VIP help with sleep?
VIP synchronizes the neurons in your brain's master clock (the suprachiasmatic nucleus), and VIP-deficient mice show severely disrupted sleep-wake cycles. However, research on using supplemental VIP to treat sleep disorders in humans has not been conducted. Sleep improvements in CIRS patients using VIP may reflect correction of underlying inflammation rather than a direct sleep effect.
What's the difference between VIP and aviptadil?
Aviptadil is the synthetic (man-made) form of vasoactive intestinal peptide. It has the same 28-amino-acid sequence as naturally occurring VIP. Aviptadil is the name used in pharmaceutical development and clinical trials. When people refer to "VIP nasal spray" from a compounding pharmacy, the active ingredient is the same molecule.
Can VIP be combined with other peptides?
In CIRS treatment, VIP is used after other interventions (cholestyramine, hormonal correction, MARCoNS eradication). Some practitioners combine it with Thymosin Alpha-1, though published data on combinations is limited. Any combination therapy should be supervised by a qualified clinician. For tissue repair alongside immune modulation, Thymosin Beta-4 is sometimes discussed.
The Bottom Line
VIP is one of the most biologically versatile peptides in the human body. Its involvement in immune regulation, vasodilation, neuroprotection, gut function, and circadian timing gives it a physiological footprint that few other single molecules can match.
The clinical evidence is strongest -- though still imperfect -- for CIRS treatment, where VIP nasal spray has accumulated the most patient data. Pulmonary hypertension research is ongoing, with long-acting analogues potentially solving earlier half-life limitations. The neuroprotection and autoimmune data, while preclinical, points toward future clinical applications.
The honest assessment: VIP is supported by strong basic science, meaningful clinical observations, and biological plausibility across multiple disease areas. What it lacks is gold-standard randomized controlled trial data. The regulatory uncertainty around compounding adds another layer of complexity.
For those exploring VIP as part of a treatment plan, working with an experienced physician -- particularly one trained in the Shoemaker protocol for CIRS applications -- is not just recommended but necessary.
This article is for educational purposes only and does not constitute medical advice. Consult a qualified healthcare provider before starting any peptide therapy. PeptideJournal.org does not sell peptides or have financial relationships with peptide vendors.