Also known as: Vasoactive Intestinal Peptide · Vasoactive Intestinal Polypeptide · PHM-27
VIP (Vasoactive Intestinal Peptide) is an endogenous 28-amino acid neuropeptide produced throughout the gut, brain, and immune tissues. It activates VPAC1 and VPAC2 receptors to produce potent vasodilation, broad-spectrum anti-inflammatory effects, neuroprotection, and immune regulation. It is the primary pharmacological intervention in the Shoemaker CIRS (Chronic Inflammatory Response Syndrome) protocol and has significant emerging research across autoimmunity, pulmonary hypertension, and neurodegeneration.
VIP was first isolated from porcine small intestine in 1970 by Said and Mutt and initially characterised as a vasodilatory peptide. Subsequent decades of research revealed it to be one of the most pleiotropic neuropeptides known — with roles spanning gastrointestinal motility, vasodilation, immune modulation, circadian rhythm regulation, neuroprotection, and reproductive function.
VIP is produced by neurons throughout the enteric, central, and peripheral nervous systems, as well as by immune cells (T-cells, mast cells, macrophages). It signals through two G-protein coupled receptors: VPAC1 (widely expressed, high affinity) and VPAC2 (brain, pancreas, peripheral tissues). Both couple to Gs proteins, activating adenylyl cyclase and raising intracellular cAMP — the primary signal mediating most of VIP's downstream effects.
In clinical research, VIP has gained significant attention through the work of Ritchie Shoemaker MD, who identified VIP deficiency as a hallmark of Chronic Inflammatory Response Syndrome (CIRS) — a multi-system illness associated with biotoxin exposure (mould, cyanobacteria, Lyme disease). Intranasal VIP supplementation is now a cornerstone of the Shoemaker CIRS treatment protocol. Beyond CIRS, VIP is under investigation for pulmonary arterial hypertension, inflammatory bowel disease, multiple sclerosis, and COVID-19-related inflammation.
VIP binds VPAC1 and VPAC2 receptors with high affinity (Kd ~1 nM), activating Gs-coupled adenylyl cyclase and elevating intracellular cAMP. This triggers PKA (protein kinase A) activation, which phosphorylates transcription factors (CREB) and ion channels responsible for smooth muscle relaxation (vasodilation), immune cell modulation, and neurotrophic gene expression. The breadth of VIP's effects reflects the wide tissue distribution of its receptors.
VIP is one of the most potent endogenous anti-inflammatory agents. In activated macrophages and dendritic cells, it suppresses NF-κB signalling, reducing production of pro-inflammatory cytokines (TNF-α, IL-6, IL-12, IL-1β) while promoting IL-10 (anti-inflammatory). It shifts macrophages from M1 (inflammatory) toward M2 (regulatory) phenotype. In T-cells, VIP suppresses Th1 responses and promotes Treg (regulatory T-cell) differentiation — making it broadly immunosuppressive in inflammatory contexts.
VIP is a potent dilator of pulmonary and systemic vasculature, acting directly on vascular smooth muscle via cAMP-mediated Ca²⁺ channel inhibition. Patients with pulmonary arterial hypertension (PAH) have been shown to have reduced pulmonary VIP expression, and inhaled VIP has been trialled in PAH with significant haemodynamic improvements. VIP also reduces pulmonary vascular resistance and bronchodilates airway smooth muscle — contributing to its interest in CIRS and post-COVID respiratory dysfunction.
VIP acts as a neurotrophic factor in the CNS, promoting neuronal survival, axonal growth, and synaptic plasticity through VPAC receptor-mediated CREB activation and BDNF upregulation. It is produced by interneurons in the cortex and hippocampus and modulates circadian rhythms through the suprachiasmatic nucleus (SCN). VIP deficiency has been linked to neuroinflammatory conditions and disrupted sleep-wake cycles — consistent with the cognitive and sleep symptoms observed in CIRS patients.
VIP is an endogenous peptide with a strong physiological safety profile. The primary acute adverse effects at therapeutic doses are vasodilatory: facial flushing, transient drop in blood pressure, and mild tachycardia — dose-dependent and short-lived given the 1–2 minute half-life. Intranasal administration (Shoemaker protocol) is generally well-tolerated with minimal systemic vasodilation at 50 µg doses. VIP requires compounding pharmacy preparation and specialised storage. It degrades rapidly at room temperature — always store cold and use freshly reconstituted preparations. In the CIRS context, VIP should only be used after prior detoxification steps are completed; premature use can worsen inflammatory symptoms.
In the Shoemaker CIRS protocol, VIP is used for extended periods (months) with periodic assessment of inflammatory biomarkers (TGF-β1, MMP-9, VEGF) to guide dosing. Unlike peptides with receptor desensitisation, VIP does not typically cause tachyphylaxis — VPAC1/VPAC2 receptor expression is maintained with continued use. Patients with CIRS often require extended courses as the underlying biotoxin-driven inflammation is a chronic process.
VIP causes vasodilation and blood pressure reduction — use with caution in patients with pre-existing hypotension, cardiac arrhythmias, or on antihypertensive medications. In the Shoemaker protocol, VIP must be the final step after prior treatment phases are complete; skipping protocol steps significantly increases the risk of adverse inflammatory reactions.
CIRS (Shoemaker Protocol): Ritchie Shoemaker's research identified low VIP levels in patients with CIRS — a complex multi-system illness following biotoxin exposure. Intranasal VIP (50 µg 4×/day) has been shown to normalise inflammatory markers (TGF-β1, MMP-9), improve VO2 max, restore pulmonary function, and reduce symptom burden in CIRS patients. This remains the most clinically detailed human application of VIP to date, though it lacks large double-blind RCT validation.
Pulmonary arterial hypertension: A Phase 2 trial (Said et al.) of inhaled VIP in PAH showed significant reductions in pulmonary vascular resistance and improvements in exercise capacity. VIP deficiency in pulmonary vasculature is well-documented in PAH pathophysiology.
COVID-19 / post-COVID: VIP's anti-inflammatory profile generated strong interest during the COVID-19 pandemic. Observational data showed VIP levels inversely correlated with COVID severity. Multiple trials of inhaled/IV VIP in severe COVID-19 were conducted; some showed cytokine reduction and clinical improvement. Post-COVID syndrome research continues to explore VIP deficiency as a contributing mechanism to long COVID symptoms.
Autoimmune applications: Preclinical studies demonstrate therapeutic effects of VIP in rheumatoid arthritis, Crohn's disease, multiple sclerosis, and lupus models. Human trials are limited but the anti-inflammatory mechanism is well-validated.
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