VIP for CIRS/Mold Illness: Clinical Evidence

Vasoactive intestinal peptide (VIP) sits at the end of one of the most controversial treatment protocols in modern medicine. As the final step in the Shoemaker Protocol for Chronic Inflammatory Response Syndrome (CIRS), this 28-amino-acid neuropeptide has been prescribed to over 10,000 patients by more than 1,000 physicians — yet it has never received FDA approval for mold illness, and the clinical trials supporting it come almost entirely from a single research group.

That tension between promising patient outcomes and limited independent replication defines the VIP-CIRS story. This article breaks down what the published research actually shows, where the evidence is strong, where it falls short, and what patients and clinicians need to know in 2026.

Table of Contents

What Is VIP and Why Does It Matter in CIRS?
VIP Deficiency in Mold Illness Patients
The 2013 Open-Label Trial: Shoemaker, House, and Ryan
The 2016 RNA-Seq Study: Transcriptomic Evidence
The 2017 Brain Volumetrics Study
How VIP Works at the Immune Level
VIP's Role in the Shoemaker Protocol
Clinical Biomarker Summary Table
Safety Profile and Side Effects
Limitations of the Current Evidence
Regulatory Status: FDA and Compounding Access
The Bottom Line
References

What Is VIP and Why Does It Matter in CIRS?

VIP (vasoactive intestinal peptide) is a 28-amino-acid neuropeptide produced in the gut, pancreas, lungs, and a region of the hypothalamus called the suprachiasmatic nuclei. It functions as a neuroendocrine hormone, a neurotransmitter, and an immune modulator. In healthy individuals, VIP helps regulate inflammation, maintain circadian rhythm, control pulmonary artery pressure, and balance immune responses between pro-inflammatory and anti-inflammatory states.

In CIRS patients — people whose immune systems have been destabilized by exposure to water-damaged buildings containing mold, bacteria, and actinomycetes — VIP levels consistently measure far below normal. This deficiency appears to be both a marker of disease and a driver of ongoing symptoms.

CIRS itself is a multi-system illness. It can produce fatigue, cognitive impairment ("brain fog"), joint pain, shortness of breath, chronic sinus problems, headaches, temperature dysregulation, and hormonal disruption. The condition affects an estimated 25% of the population who carry certain HLA-DR genotypes that impair biotoxin clearance, though not all exposed individuals develop full-blown CIRS.

VIP Deficiency in Mold Illness Patients

Across three case series totaling 1,829 patients with CIRS from water-damaged buildings, Dr. Ritchie Shoemaker's research group found that 98% had deficient VIP levels. Normal VIP ranges above 25 pg/mL; the vast majority of CIRS patients fell below that threshold. In a subset of over 500 patients with multiple chemical sensitivity, every single one had low VIP.

Less than 10% of healthy controls showed the same deficiency. This near-universal finding in CIRS patients — coupled with VIP's known role in regulating innate immune responses — provided the rationale for treating CIRS patients with replacement VIP delivered as a nasal spray.

The logic was straightforward: if the body is not producing enough of a regulatory peptide that keeps inflammation in check, replacing that peptide might restore balance. But the question was whether it would actually work in practice.

The 2013 Open-Label Trial: Shoemaker, House, and Ryan

The first formal study of VIP in CIRS patients was published in 2013 by Shoemaker, House, and Ryan in the journal Health. It was an open-label trial — meaning there was no placebo group and both patients and researchers knew the treatment being administered.

Study Design

Twenty patients with refractory CIRS — meaning their illness had not responded to the other steps of the Shoemaker Protocol — received VIP nasal spray (50 mcg per spray, 4-8 sprays daily) for a minimum of 18 months. These patients were similar in symptom severity and lab findings to the previously published cohorts of 1,829 patients and 169 controls.

Results

The findings were striking:

Symptom scores dropped from 12.9 to 3.3 — a 74% reduction in reported symptoms
100% of patients reported quality-of-life improvement
Multiple inflammatory biomarkers normalized, including C4a, TGF beta-1, MMP-9, and VEGF
Hormonal markers improved: estradiol, testosterone, and vitamin D3 returned toward normal ranges
Pulmonary artery systolic pressure (PASP) decreased
CD4+CD25+ T regulatory cells increased from 8.9 to 22.5 units, indicating restored immune regulation

The biomarker corrections were notable because many of these markers had proven refractory to all other treatment steps. VIP appeared to address abnormalities that cholestyramine, correcting MARCoNS, and other earlier protocol steps could not reach.

Key Biomarker Changes from the 2013 Trial

Biomarker	Direction After VIP	Clinical Significance
C4a	Decreased	Reduced complement activation
TGF beta-1	Decreased	Reduced fibrotic/inflammatory signaling
MMP-9	Decreased	Reduced tissue-destructive enzyme
VEGF	Increased	Improved vascular growth factor
Estradiol	Normalized	Corrected aromatase overactivity
Testosterone	Normalized	Restored androgen balance
Vitamin D3	Increased	Improved metabolic and immune function
CD4+CD25+ Tregs	Increased (8.9 to 22.5)	Restored immune regulation
PASP	Decreased	Reduced pulmonary hypertension

The 2016 RNA-Seq Study: Transcriptomic Evidence

In 2016, Ryan and Shoemaker published a follow-up study in Medical Research Archives that moved beyond blood markers to examine what VIP was doing at the gene expression level. Using RNA sequencing (RNA-Seq), they analyzed the full transcriptome — every gene being actively read and translated — in 15 CIRS patients before and after VIP treatment.

What They Found

Out of approximately 20,000 protein-coding genes and 30,000 non-protein-coding genes examined, 1,900 were differentially expressed in CIRS patients compared to controls. After VIP treatment, the researchers documented significant changes in over 700 genes related to metabolism, inflammation, and immune function.

Several categories stood out:

Immune regulators shifted toward normal expression — including CD244, CD3D, CD48, CD52, granzymes, defensins, and Ikaros family transcription factors
Metabolic genes showed a pattern consistent with reversal of molecular hypometabolism — a state where cellular energy production is suppressed
Ribosomal gene activation improved, suggesting restored protein synthesis capacity
Mitochondrial gene expression normalized, pointing to improved cellular energy output

The transcriptomic data suggested that VIP was not simply masking symptoms or temporarily lowering inflammatory markers. It appeared to be reprogramming gene expression toward a healthier baseline — what the researchers described as "a shift in metabolic state and innate immune functions that coincide with healing."

This work also laid the foundation for the GENIE (Gene Expression: Inflammation Explained) test, a clinical transcriptomics panel of 188 genes distilled from the original 1,900 differentially expressed genes, now used to monitor CIRS disease activity and treatment response.

The 2017 Brain Volumetrics Study

Perhaps the most dramatic finding came in 2017 when Shoemaker, Katz, McMahon, and Ryan published data showing that intranasal VIP could reverse brain atrophy in CIRS patients. The study appeared in Internal Medicine Review.

Background

Earlier research using NeuroQuant, an automated brain MRI volumetric analysis tool, had established that CIRS patients showed specific abnormalities in brain structure volumes. Compared to controls, patients had atrophy (shrinkage) of the caudate nucleus and enlargement of the pallidum — patterns consistent with chronic neuroinflammation driven by inflammatory markers (C4a, TGF beta-1, MMP-9) crossing the blood-brain barrier.

Results

Patients receiving intranasal VIP at 600 mcg/day saw their excessive grey matter nuclear atrophy reverse to match control values. The treatment window required more than 12 weeks and at least 6 doses per day for optimal effect.

No significant adverse effects were reported. The safety and durability of the brain volume restoration was confirmed across the study population. In unpublished practice experience since 2017, additional benefits have been observed, including correction of enlarged superior lateral ventricles.

The finding that a nasal spray could measurably restore shrunken brain structures was remarkable — and remains one of the most compelling pieces of evidence in the VIP-CIRS literature.

How VIP Works at the Immune Level

The biological plausibility of VIP for CIRS rests on well-established immunology research conducted far beyond the CIRS field. VIP's immune effects have been studied in autoimmune encephalomyelitis, collagen-induced arthritis, transplant rejection, and cancer immunology.

The core mechanisms include:

T Regulatory Cell Generation. VIP generates CD4+CD25+FoxP3+ T regulatory cells (Tregs) both in vitro and in vivo. These Tregs suppress overactive immune responses — exactly what CIRS patients need. In animal models of autoimmune encephalomyelitis, VIP expanded Tregs in both the periphery and the central nervous system, producing more efficient suppressors on a per-cell basis than naturally occurring Tregs.

Tolerogenic Dendritic Cell Programming. When VIP is present during early dendritic cell differentiation, it produces DCs that cannot fully mature in response to inflammatory signals. These tolerogenic DCs express low costimulatory molecules, produce more IL-10, and drive naive T cells toward a regulatory phenotype rather than an inflammatory one.

Cytokine Rebalancing. VIP suppresses pro-inflammatory cytokines (TNF-alpha, IL-6, IL-12) and promotes anti-inflammatory cytokines (IL-10, TGF-beta), shifting the immune environment from the Th1/Th17-dominant state characteristic of CIRS toward a more balanced profile.

VPAC Receptor Signaling. VIP acts through two G protein-coupled receptors, VPAC1 and VPAC2, on immune cells. Receptor engagement triggers intracellular cAMP elevation, suppressing inflammatory gene transcription, reducing IL-2 production, and dampening T cell proliferation.

These mechanisms provide a clear scientific rationale for why replacing VIP in deficient CIRS patients could restore immune balance.

VIP's Role in the Shoemaker Protocol

VIP nasal spray is the final step — step 12 — of the Shoemaker Protocol, a sequential treatment framework for CIRS. It is not a first-line treatment. Patients must complete all prior steps before starting VIP, and several prerequisites must be met:

Passing Visual Contrast Sensitivity (VCS) test — indicating baseline neurological improvement
Clean living environment — ERMI mold score below 2, or HERTSMI-2 score of 10 or less
MARCoNS eradicated — multiple antibiotic-resistant coagulase-negative staphylococci must be cleared from nasal passages
Other biomarkers addressed — earlier protocol steps should have corrected what they can

The reasoning is practical: if a patient still has active mold exposure or persistent MARCoNS colonization, VIP may trigger a paradoxical rise in TGF beta-1 rather than the expected decrease. A rise of TGF beta-1 above 5,000 pg/mL after starting VIP typically signals ongoing environmental exposure or unresolved Th17/Treg imbalance.

Pre-VIP Lab Panel

Before the first VIP dose, clinicians order baseline labs for MSH, VIP, ACTH, ADH/osmolality, C4a, MMP-9, TGF beta-1, VEGF, testosterone, estradiol, vitamin D3, and lipase. After the first office dose, labs for TGF beta-1, C4a, MMP-9, and lipase are redrawn to check for acute response.

Standard dosing is 50 mcg per spray, 4-8 sprays daily, though the 2017 brain volumetrics study used 600 mcg/day (approximately 12 sprays) for optimal neurological benefit.

Clinical Biomarker Summary Table

Study	Year	N	Design	Key Findings
Shoemaker, House, Ryan (Health)	2013	20	Open-label, 18+ months	74% symptom reduction; biomarker normalization; 100% QoL improvement
Ryan, Shoemaker (Med Res Archives)	2016	15	RNA-Seq transcriptomics	700+ gene expression changes; metabolic and immune shift toward healing
Shoemaker, Katz, McMahon, Ryan (Intern Med Rev)	2017	Reported	NeuroQuant volumetrics	Grey matter nuclear atrophy reversed to match controls
Shoemaker et al. (Ann Med Surg)	2024	Review	Systematic literature review	Shoemaker Protocol only CIRS treatment with documented clinical efficacy

Safety Profile and Side Effects

VIP's safety record is one of its strongest data points. Since its first use in CIRS patients in November 2008, over 10,000 patients have received VIP nasal spray from more than 1,000 prescribing physicians. As of the 2013 publication, over 7,000 prescriptions had been filled with no reported toxicity.

Reported side effects are generally mild and transient:

Headache
Dizziness
Heart palpitations
Irritability
Nasal irritation

The primary safety concern is pancreatitis, which is why lipase monitoring is mandatory. Any lipase elevation warrants immediate discontinuation. However, clinically significant pancreatitis has been exceedingly rare in the published literature and physician-reported data.

A rise in TGF beta-1 after starting VIP is not a side effect of the peptide itself — it is a signal that the patient has unresolved mold exposure or immune dysregulation that should have been addressed in earlier protocol steps.

Limitations of the Current Evidence

Despite the promising results, the VIP-CIRS evidence base has real gaps that deserve honest acknowledgment:

No randomized controlled trials. The 2013 study was open-label with no placebo group. Symptom improvement could be influenced by placebo effect, regression to the mean, or the cumulative benefit of the 11 prior protocol steps.

Small sample sizes. Twenty patients in the primary trial and 15 in the transcriptomics study are small numbers. While physician-reported data covers thousands of patients, formal publication data remains limited.

Single research group. Nearly all published VIP-CIRS data comes from Dr. Shoemaker and his collaborators. A 2024 systematic review in Annals of Medicine & Surgery found that 11 of 13 published articles on CIRS treatment described the Shoemaker Protocol, with minimal independent replication.

CIRS itself lacks universal recognition. Major agencies (CDC, WHO, FDA) have not formally adopted CIRS as a standardized diagnosis, and the Shoemaker Protocol is not yet standard of care in mainstream medicine. This does not invalidate the research, but it limits the institutional support for larger trials.

Confounding variables. Because VIP is the last step in a 12-step protocol, it is difficult to isolate its specific contribution from the cumulative effects of earlier interventions.

Publication venue. The primary studies were published in journals like Health (SCIRP) and Internal Medicine Review rather than high-impact, peer-reviewed medical journals. This affects the weight of the evidence in the broader medical community.

None of these limitations are disqualifying. They simply mean the evidence is preliminary — promising enough to justify clinical use in the eyes of many practitioners, but not yet strong enough to be considered definitive.

Regulatory Status: FDA and Compounding Access

VIP is not commercially available as an FDA-approved drug in the United States. It has only been accessible through compounding pharmacies, where it is prepared as a nasal spray on a prescription basis.

In 2016, the FDA's Pharmacy Compounding Advisory Committee (PCAC) reviewed VIP and determined there was insufficient evidence to move it from the Category 1 list (allowed for compounding pending further review) to the positive Bulk Substances List. The FDA subsequently signaled its intent to remove VIP from the compounding list entirely.

As of January 2025, the FDA released revised guidance tightening controls on bulk drug substance compounding. Under these rules, 503A compounding pharmacies can compound substances that are FDA-approved, have a USP monograph, or are on the Category 1 list. Most peptides — including VIP — face an uncertain path.

The International Society for Environmentally Acquired Illness (ISEAI) has been organizing efforts to support VIP's continued availability, including collating clinical and manufacturing data for potential FDA review.

Some political figures have signaled support for loosening FDA restrictions on peptides, but as of early 2026, no formal regulatory changes have materialized for VIP. Some compounding pharmacies continue to dispense VIP nasal spray, but the legal situation remains in flux — creating real uncertainty for patients who rely on VIP as part of their recovery from mold-related illness.

The Bottom Line

The clinical evidence for VIP in CIRS treatment tells a coherent story: a neuropeptide that is nearly universally deficient in mold illness patients, with established immunological mechanisms for restoring immune regulation, and open-label clinical data showing substantial symptom improvement, biomarker normalization, gene expression correction, and even reversal of brain atrophy.

At the same time, this evidence comes with meaningful caveats. No randomized controlled trial has been published. Sample sizes are small. Independent replication is sparse. And the regulatory future of compounded VIP remains uncertain.

For patients and clinicians navigating CIRS, VIP represents what researchers would call "strong biological rationale with preliminary clinical support." The mechanisms are real, the biomarker changes are measurable, and thousands of patients have used it safely. But the data still lacks the rigorous, multi-center, placebo-controlled trials that evidence-based medicine demands.

The path forward requires independent replication, larger controlled studies, and continued advocacy for regulatory access. Until then, patients considering VIP should work with physicians experienced in the Shoemaker Protocol and understand it is designed as a final restoration step — not a standalone treatment. For more on peptides supporting respiratory health and immune modulation, explore our related guides.

References

Shoemaker RC, House D, Ryan JC. Vasoactive intestinal polypeptide (VIP) corrects chronic inflammatory response syndrome (CIRS) acquired following exposure to water-damaged buildings. Health. 2013;5(3):396-401. Full text (PDF)
Ryan JC, Shoemaker RC. RNA-Seq on patients with chronic inflammatory response syndrome (CIRS) treated with vasoactive intestinal polypeptide (VIP) shows a shift in metabolic state and innate immune functions that coincide with healing. Medical Research Archives. 2016;4(7):1-11. Abstract
Shoemaker RC, Katz D, McMahon S, Ryan JC. Intranasal VIP safely restores volume to multiple grey matter nuclei in patients with CIRS. Internal Medicine Review. 2017;3(4):1-14. Full text (PDF)
Shoemaker RC, Johnson K, Jim L, et al. Chronic inflammatory response syndrome: a review of the evidence of clinical efficacy of treatment. Annals of Medicine & Surgery. 2024;86(12):7248-7254. PubMed
Shoemaker RC, House D, Ryan JC. Structural brain abnormalities in patients with inflammatory illness acquired following exposure to water-damaged buildings: a volumetric MRI study using NeuroQuant. Neurotoxicology and Teratology. 2014;45:18-26. PubMed
Chorny A, Gonzalez-Rey E, Fernandez-Martin A, et al. Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo. Annals of the New York Academy of Sciences. 2006;1070:507-509. PubMed
Fernandez-Martin A, Gonzalez-Rey E, Chorny A, et al. Vasoactive intestinal peptide induces regulatory T cells during experimental autoimmune encephalomyelitis. European Journal of Immunology. 2006;36(2):318-326. PubMed
Gonzalez-Rey E, Chorny A, Delgado M. Regulation of dendritic cell differentiation by vasoactive intestinal peptide: therapeutic applications on autoimmunity and transplantation. Annals of the New York Academy of Sciences. 2007;1088:187-194. PubMed
Gonzalez-Rey E, Anderson P, Delgado M. Emerging roles of vasoactive intestinal peptide: a new approach for autoimmune therapy. Annals of the Rheumatic Diseases. 2007;66(Suppl 3):iii70-iii76. PMC
Dorninger E. The CIRS Protocol: a sequential, evidence-based treatment for biotoxin-associated chronic inflammatory response syndrome. Medical Research Archives. 2025. Abstract