# VIP (Aviptadil): Evidence, Mechanism, Dosing & Legal Status

> A clinical monograph on vasoactive intestinal peptide (VIP) and its synthetic form aviptadil (Zyesami/RLF-100) — a mechanistically compelling neuropeptide whose largest, best-controlled human trials in COVID-19/ARDS failed.

*Published 2026-06-30 · Updated 2026-07-01 · By Marcus Feld, PharmD, BCPS*

The short answer
VIP/aviptadil is the textbook case of a *mechanistically beautiful* peptide that repeatedly failed to prove clinical benefit when tested rigorously. The biology is real — Gs/cAMP vasodilation, surfactant support, and a genuine tolerogenic shift toward regulatory T cells — but the **highest-quality human evidence is negative**: the independent NIH TESICO RCT (n=461) showed no benefit and no survival improvement in COVID-19/ARDS, and the FDA twice declined an Emergency Use Authorization.[1](https://peptidevox.com/#r1)[17](https://peptidevox.com/#r17)

Vasoactive intestinal peptide (VIP) is a naturally occurring 28-amino-acid neuropeptide and potent vasodilator/immunomodulator; its synthetic counterpart **aviptadil** (Zyesami, RLF-100) reached late-stage human trials in COVID-19 respiratory failure on the rationale that VIP protects alveolar type II cells, upregulates surfactant, and dampens inflammatory cytokines.[1](https://peptidevox.com/#r1) Its popularity in the wellness and peptide community — chiefly for off-label intranasal "mold illness" use — far outruns its proof. This monograph separates the two.

*This article is informational and editorial content for research and educational purposes only. It is not medical advice, not a protocol to follow, and not a sourcing guide. VIP/aviptadil is not an FDA-approved drug for any indication discussed; it is investigational and compounded. Dosing figures are reported strictly as seen in the published literature and clinical trials for completeness — not as recommendations. Consult a licensed clinician before any health decision.*

## What is VIP and how does it work?

VIP is a 28-residue peptide (sequence HSDAVFTDNYTRLRKQMAVKKYLNSILN, molecular formula C147H237N43O43S, CAS 37221-79-7), a member of the secretin/glucagon peptide superfamily closely related to PACAP and GLP-1.[12](https://peptidevox.com/#r12)[10](https://peptidevox.com/#r10) The synthetic INN **aviptadil** was assigned by the WHO in 1997 and is the identical 28-amino-acid molecule.[12](https://peptidevox.com/#r12)

The core mechanism centers on two class-B (secretin-family) G-protein-coupled receptors, **VPAC1 and VPAC2**, which bind VIP and PACAP with comparable high affinity. Both VPAC receptors are Gs-coupled, so activation raises intracellular cAMP via adenylate cyclase — the proximal driver of VIP's downstream effects.[10](https://peptidevox.com/#r10)[11](https://peptidevox.com/#r11) VPAC1 is widely distributed (CNS, lung, liver, intestine, T-lymphocytes), while VPAC2 predominates in CNS, pancreas, smooth and cardiac muscle, and kidney.[10](https://peptidevox.com/#r10) Physiologically this produces vasodilation (systemic and selective pulmonary), increased cardiac output, bronchodilation, smooth-muscle relaxation, and intestinal water and electrolyte secretion — the last being the basis of VIPoma watery diarrhea.[12](https://peptidevox.com/#r12) In human sarcoidosis lung, VIP reduced TNF-alpha and increased regulatory T cells, the proof-of-concept for its tolerogenic immune effect.[9](https://peptidevox.com/#r9)

A defining pharmacologic obstacle dominates everything: native VIP has an **extremely short plasma half-life of under two minutes**, which has historically forced continuous IV infusion or repeated inhaled/intranasal dosing.[10](https://peptidevox.com/#r10) On the lung surface, inhaled VIP is rapidly inactivated by neutral endopeptidase (NEP), shortening inhaled efficacy.[7](https://peptidevox.com/#r7) There is no meaningful oral bioavailability.

## What is the evidence by indication?

Bottom line up front: VIP has a compelling mechanism but a thin, largely negative clinical record. The largest, best-controlled trials failed; the positive signals come from small, often open-label or single-investigator studies. The full registry of the pivotal COVID-19 program can be reviewed at [ClinicalTrials.gov (TESICO/ACTIV-3b, NCT04843761)](https://clinicaltrials.gov/study/NCT04843761).

  VIP/aviptadil evidence by indication

    IndicationBest evidenceGrade / direction

    COVID-19 / ARDS (IV aviptadil)NIH TESICO RCT (n=461), placebo-controlledA — NEGATIVE (no benefit, stopped for futility)
    COVID-19 (inhaled/nebulized)Turkish Phase II RCT (n=80): faster dischargeB — mixed/preliminary
    Pulmonary (arterial) hypertensionSingle inhaled 100 ug dose in 20 patients: transient vasodilation; chronic RCT negativeB — small, acute, transient
    SarcoidosisOpen-label Phase II (n=20): reduced TNF-alpha, increased regulatory T cellsB — open-label proof-of-concept
    CIRS / mold illness (intranasal)Single-investigator open-label cohorts (Shoemaker)C-D — weak, uncontrolled
    Immune support / longevity (wellness)None — mechanistic/anecdotal onlyD

The headline evidence is the COVID-19/ARDS program, where human RCTs exist and are definitive on the negative side. The NIH-sponsored **TESICO (ACTIV-3b)** randomized, placebo-controlled trial across 28 US sites enrolled 461 patients in the aviptadil comparison. On the Day-90 six-category ordinal primary outcome, aviptadil did not differ from placebo (OR 1.11, 95% CI 0.80-1.55, p=0.54); 90-day mortality was 38% (aviptadil) versus 36% (placebo), and the trial was stopped early for futility, with the authors concluding there is "no evidence to suggest aviptadil has a therapeutic role" in this population.[1](https://peptidevox.com/#r1)[2](https://peptidevox.com/#r2)[3](https://peptidevox.com/#r3) An earlier company-sponsored 60-day RCT missed its primary endpoint, producing only a post-hoc/secondary survival signal that the independent TESICO trial did not replicate.[4](https://peptidevox.com/#r4) A small Turkish Phase II RCT of inhaled aviptadil (n=80) reported faster discharge (7.8 vs 10 days, p=0.049) — a modest single signal, with no large confirmatory RCT establishing a hard-outcome benefit.[5](https://peptidevox.com/#r5)[6](https://peptidevox.com/#r6)

The positive signals are smaller and softer. In 20 patients with pulmonary hypertension, a single inhaled 100-microgram dose of aviptadil produced small but significant, selective and temporary pulmonary vasodilation during right-heart catheterization — but a subsequent Phase II RCT of chronic inhaled VIP in PAH was negative, undercutting durable benefit.[7](https://peptidevox.com/#r7)[8](https://peptidevox.com/#r8) In an open-label Phase II sarcoidosis study, 20 patients receiving nebulized VIP for four weeks had reduced bronchoalveolar TNF-alpha and increased alveolar regulatory T cells — the first human demonstration of VIP's tolerogenic effect, but uncontrolled and never advanced to a confirmatory RCT.[9](https://peptidevox.com/#r9)

Proven vs hyped
Proven: transient pulmonary vasodilation and short-term lung immunomodulation in tiny studies, plus an approved ED combination product (Invicorp) abroad. Hyped: survival/recovery benefit in respiratory failure (disproven in RCT) and "mold-illness cure" (unproven, single-investigator). The CIRS/intranasal use is the dominant consumer application yet rests on the weakest evidence in the file.[15](https://peptidevox.com/#r15)

## Is intranasal VIP a real treatment for CIRS or mold illness?

This is the dominant consumer/peptide-community use, almost entirely associated with Ritchie Shoemaker. The supporting literature is small, uncontrolled, and overwhelmingly single-investigator: an IRB-approved open-label cohort reported mean symptom scores falling roughly 74% and transcriptomic shifts across about 700 genes, plus a before/after grey-matter-volume report — but these are open-label, with the patient as his own control, not randomized.[13](https://peptidevox.com/#r13)[14](https://peptidevox.com/#r14) An independent 2024 review of CIRS-treatment evidence found that nearly all positive data originate from Shoemaker or close collaborators; the intranasal-VIP studies specifically were open-label (n~35) or small case series (n~14) with no independent RCTs, and CIRS itself is not a broadly accepted mainstream diagnosis.[15](https://peptidevox.com/#r15) From a functional/integrative root-cause standpoint, VIP's immunoregulatory biology is plausible and the safety record in this setting appears acceptable — but plausibility and uncontrolled symptom scores are not proof of efficacy, and this use must be labeled unproven (Grade C-D).

## What doses appear in the literature?

Reported strictly as information, not a protocol. In the COVID/ARDS RCTs, IV aviptadil was given as an escalating regimen — 600 pmol/kg (day 1), 1,200 pmol/kg (day 2), 1,800 pmol/kg (day 3) — delivered as a 12-hour infusion daily for three days, with the rate paused or slowed for hypotension or diarrhea.[1](https://peptidevox.com/#r1) Inhaled/nebulized dosing used single 100-microgram doses for acute pulmonary vasodilation, with nebulized aviptadil 100 micrograms up to three times daily studied in COVID and over four weeks in sarcoidosis.[7](https://peptidevox.com/#r7)[9](https://peptidevox.com/#r9) The off-label CIRS protocol uses compounded intranasal VIP at 50 micrograms per spray, roughly four to eight sprays per day — compounded, off-label, and based on uncontrolled data.[13](https://peptidevox.com/#r13) Because VIP is degraded rapidly in blood and on the lung surface, all dosing schedules are built around its under-two-minute half-life and NEP inactivation.[10](https://peptidevox.com/#r10)[7](https://peptidevox.com/#r7)

## How safe is VIP/aviptadil?

The dominant, dose-limiting side effects are hypotension and diarrhea, mechanistically expected because they mirror the VIPoma syndrome (watery diarrhea plus vasodilation).[12](https://peptidevox.com/#r12) In TESICO, infusion reactions were far more frequent with aviptadil than placebo (86.6% vs 57.4%, p<0.001), driven by hypotension (58.4% vs 41.3%) and diarrhea (39.8% vs 11.3%), plus facial flushing (14.7% vs 6.1%) and tachycardia; mean arterial pressure ran 5-7 mmHg lower during infusion, resolving within about two hours.[1](https://peptidevox.com/#r1) No new safety signal beyond the expected vasodilatory/GI effects emerged, and IV aviptadil "was generally well tolerated" with effects managed by protocol.[1](https://peptidevox.com/#r1)[18](https://peptidevox.com/#r18) The dominant theoretical concern is mechanistic: VIP/VPAC signaling is mitogenic and pro-angiogenic in some tissues, and VPAC receptors are overexpressed on several cancers, raising a theoretical tumor/angiogenesis caution with chronic exogenous VIP — not demonstrated in the short human trials.[11](https://peptidevox.com/#r11) Additive hypotension is expected with vasodilators and antihypertensives; caution applies in hypovolemia, baseline hypotension, or hemodynamic instability. There are no human reproductive safety data, so pregnancy and lactation should be avoided.[1](https://peptidevox.com/#r1)

## What is the FDA and regulatory status in 2026?

VIP/aviptadil is not FDA-approved for any respiratory or immune indication. Aviptadil (Zyesami) remains investigational and has never received full approval, accelerated approval, or an EUA.[16](https://peptidevox.com/#r16) The FDA declined an EUA in November 2021 (insufficient benefit/risk data) and declined again in July 2022 for a remdesivir-refractory subgroup based on a post-hoc analysis, and had also declined Breakthrough Therapy designation; aviptadil did hold Fast Track status and was studied with NIH/BARDA/DoD support.[17](https://peptidevox.com/#r17)[16](https://peptidevox.com/#r16) After the TESICO futility result, the developer pivoted away from the program.[18](https://peptidevox.com/#r18)

For off-label use, VIP is supplied through 503A compounding pharmacies, and the broader compounded-peptide regulatory environment is in active flux: the FDA moved roughly 19 peptides into restrictive Category 2 (Sept 2023-Dec 2024), issued interim guidance in January 2025, and on April 15, 2026 removed 11 peptides from Category 2 pending a PCAC hearing (July 23-24, 2026) and formal rulemaking that could take more than a year.[20](https://peptidevox.com/#r20)[19](https://peptidevox.com/#r19) Anyone relying on compounded intranasal VIP should verify its current list status, as availability can change with these proceedings. For completeness, aviptadil combined with phentolamine (Invicorp) is an approved ED therapy in the UK, Denmark and New Zealand — the lone approved aviptadil product, in an unrelated indication.[12](https://peptidevox.com/#r12) VIP/aviptadil is not specifically named on the WADA Prohibited List and is not a recognized ergogenic class, though athletes should confirm against the current list.

**Bottom line.** VIP/aviptadil pairs a mechanistically beautiful profile with a thin, largely negative clinical record. The highest-quality human evidence is negative in COVID-19/ARDS; the pulmonary-hypertension and sarcoidosis signals are small, transient and open-label; and the widely promoted intranasal CIRS/mold use is Grade C-D, uncontrolled, single-investigator, and resting on a contested diagnosis. Net: investigational, not approved, mechanistically interesting, and clinically unproven for its popular uses. Regulatory facts here are current as of June 2026; the July 23-24, 2026 PCAC outcome was pending at the time of writing and should be re-verified after that date.

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Source: https://peptidevox.com/peptide-encyclopedia/vip
Index: https://peptidevox.com/llms.txt · Full text: https://peptidevox.com/llms-full.txt