VIP (Vasoactive Intestinal Peptide)
VIP (Vasoactive Intestinal Peptide) — the circadian-clock hormone and its CIRS/mold-illness niche: honest evidence

Class: peptide
Synonyms: VIP
Vasoactive Intestinal Polypeptide
Function tags: anti-inflammatory / immunoregulation
circadian (SCN)
vasodilation / bronchodilation
neuroprotection
(gray-market: CIRS / mold-illness "capstone" therapy)
Overall evidence grade: A
WADA prohibited: no
Last updated: 2026-07-13

In brief: VIP is a 28-amino-acid endogenous neuropeptide with broad, well-established physiology — it's a potent vasodilator and bronchodilator, a strong anti-inflammatory/immune regulator, and, strikingly, a master neurotransmitter of the brain's circadian clock (the SCN uses VIP to keep the body on solar time; mice without VIP lose their rhythms). Given all that, its gray-market life is surprisingly narrow: it's used mainly as a compounded nasal spray in the "CIRS / mold-illness" protocol of one physician, Ryan Shoemaker, as the final "capstone" step after upstream treatments — on the theory that biotoxin illness depletes regulatory neuropeptides. The catch: almost all the human evidence (an open-label trial of 20 patients, a 15-patient RNA-Seq study, a brain-volume study) comes from Shoemaker's own group, is small and open-label, isn't independently replicated, and addresses a diagnosis (CIRS) that mainstream medicine doesn't broadly recognise. Meanwhile the FDA has moved to pull VIP from the compounding list, and the serious drug-development action is elsewhere (the analog aviptadil in ARDS/COVID). Honest read: a genuinely important hormone whose headline gray-market use is thinly evidenced and single-sourced — big biology, small and shaky proof for the thing it's sold for.

## Identity a **28-amino-acid endogenous neuropeptide** of the **secretin/glucagon family**, first isolated (Said & Mutt, ~1970) from intestine — hence the name — but in fact **distributed body-wide**: brain, gut, lungs, pancreas, immune system, vasculature. It signals through **VPAC1/VPAC2 receptors** (GPCRs, cAMP). Unlike most register entries (synthetic or gray-market-only), VIP is a **genuine human hormone with broad, textbook physiology** — which is exactly what makes its narrow gray-market positioning notable. ## Mechanism (as proposed) VIP signals through **VPAC1 and VPAC2 receptors** (G-protein-coupled, raising cAMP). Its natural actions are wide: **relaxing vascular and airway smooth muscle** (vasodilation/bronchodilation), **down-regulating innate immune/inflammatory responses** (shifting cytokine balance, calming over-active innate immunity), providing **neuroprotection**, and — in the **suprachiasmatic nucleus** — **synchronising the cellular circadian oscillators** (the CLOCK/BMAL1–PER/CRY feedback loop) to environmental light via ERK1/2 signalling. In the CIRS framework, the proposed therapeutic logic is **replacement**: if regulatory neuropeptides are depleted by biotoxin illness, restoring VIP provides the "capstone" regulatory signal that lets the inflammatory cascade resolve — but note this framework's clinical validation is exactly what's limited. The **biology is robust; the niche-therapeutic claim is not (yet) independently substantiated.**

Evidence grades by outcome:
outcome: Endogenous physiology (circadian/SCN, vasodilation, anti-inflammatory)
grade: A
base: Extensive, well-replicated basic science (VIP is a real, central hormone)
caveat: This grades the molecule's natural role, NOT any benefit of taking exogenous VIP. "VIP is important in the body" ≠ "VIP spray treats your condition"
outcome: CIRS / mold-illness ("capstone" nasal-spray therapy — the marketed use)
grade: D
base: Open-label 20-pt trial (18+ mo), 15-pt RNA-Seq, grey-matter-volume study
caveat: Almost entirely single-investigator (Shoemaker), open-label, small, unreplicated; CIRS is a contested diagnosis. Reported safety over long use is the strongest point
outcome: Inflammatory / pulmonary disease (inhaled VIP; aviptadil in ARDS/COVID)
grade: C
base: Legitimate research interest; aviptadil trials
caveat: Real drug-development interest — but not established/approved; results mixed/inconclusive
outcome: Circadian / sleep, anxiety/depression, "anti-aging," nootropic (speculative gray-market)
grade: F
base: Association studies + strong basic biology, but no interventional human proof
caveat: No controlled human trials for these self-use claims; extrapolating from VIP's natural roles is unjustified
outcome: Safety
base: Long CIRS-protocol use reported
caveat: Reported well-tolerated in the CIRS setting; but it's a potent vasoactive/immune hormone, off-protocol self-dosing is unstudied, and product quality is unverified

Legal status:
region: US
status: Compounded (Rx) where lawful
note: not an approved drug for CIRS or general use; historically available as a compounded nasal spray (503A) — but the FDA has moved to remove VIP from the compoundable list, clouding that route. The analog aviptadil has been investigational (ARDS/COVID), not generally approved.
region: EU
status: not an approved consumer product
note: not an approved consumer product; investigational. Not a cosmetic.

Cosmetic claims:

Note: A profoundly important natural hormone — sold for a narrow, single-investigator gray-market niche. This entry is a study in contrast. Three threads: (1) VIP is a real endogenous neuropeptide with huge, well-established physiology — it's literally a master regulator of the brain's circadian clock; (2) yet its gray-market use is almost entirely one thing — a nasal spray in the "CIRS / mold-illness" protocol of a single physician (Ryan Shoemaker), where nearly all the human data come from that one investigator; (3) the honest gap between "fundamentally important molecule" and "proven niche therapy" is the whole lesson — plus a regulatory twist: the FDA has moved to remove VIP from the list of compoundable drugs.
Status note: watch: FDA compounding status, and whether any independent (non-Shoemaker) controlled trial of intranasal VIP in CIRS or inflammatory disease appears — that would be decisive

Sources:
Hamnett R, et al. Vasoactive intestinal peptide controls the suprachiasmatic circadian clock network via ERK1/2 and DUSP4. Nat Commun. 2019 (circadian master-clock role).
Smalley SG, Barrow PA, Foster N. Immunomodulation of innate immune responses by VIP: therapeutic potential in inflammatory disease. Clin Exp Immunol. 2009 (PMID 19604262).
Shoemaker RC, et al. VIP corrects chronic inflammatory response syndrome (CIRS) acquired following exposure to water-damaged buildings. Health. 2013 (open-label, 20 patients) — the primary CIRS reference; plus RNA-Seq (Med Res Arch 2016) and grey-matter-volume (Internal Medicine Review 2017). ⚠ Predominantly single-investigator, open-label, unreplicated.
Vu JP, et al. Regulation of appetite, body composition, and metabolic hormones by VIP. J Mol Neurosci. 2015.
FDA compounding-list action re: VIP (removal announced); aviptadil (RLF-100) ARDS/COVID trials (context). CIRS is a contested diagnosis in mainstream medicine.