VIP (Vasoactive Intestinal Peptide)
Aviptadil, RLF-100, ZYESAMI, vasoactive intestinal polypeptide, VIP 28
The Ground Truth Score
four plain questions, never one numberReal human RCTs exist, but they're negative, and the popular nasal-spray use is a different, near-unproven story
Bottom line
VIP is an endogenous peptide with a genuine drug-development history (the IV form, aviptadil, ran through Phase 3 RCTs that mostly failed), but the intranasal/subcutaneous "CIRS / mold-recovery" use that drives consumer interest rests almost entirely on one clinic's small, uncontrolled studies and should be treated as unproven.
Does the science back it?
Do real people feel it?
Is it safe?
Could it be placebo?
Can you legally get it?
CompoundablePrescription, compoundedNo FDA-approved product, but a lawful route exists: a prescriber can order it from a 503A or 503B compounding pharmacy. That means a licensed facility and a real prescription, which is a genuinely different world from a research-chemical vendor, though a compounded drug is still not an FDA-reviewed one.
FDA lists vasoactive intestinal peptide in Category 1 of its 503A interim list (substances under evaluation, list updated May 14, 2026), so compounding pharmacies may prepare it under FDA's interim policy. That is enforcement discretion, not inclusion on the bulks list and not an approval; NAD+ sits on the same list. Aviptadil has never been FDA-approved, and FDA denied Emergency Use Authorization for it in critical COVID-19 twice (Nov 2021 and July 2022). The popular intranasal CIRS use rests on small uncontrolled studies.
Legal status as of 2026-10-12. This is a separate axis from the grades above, and it does not move them. A vote about who may legally prepare a compound is not evidence that the compound works.
"Do real people feel it?" is anecdote, not proof, weighted up because the science is thin, never because it beats a trial. And "could it be placebo?" is not an insult: if you feel better, that's real to you. The point is only to know whether you're paying peptide prices for an expectation.
Why is the evidence this thin? It's mostly economics →
Dose at a glance
full dosing ↓REPORTED, not prescribed.
Reported, not prescribed. Verify your vial and your math.
First documented human use
Human pharmacokinetic and physiologic studies of infused VIP date to the late 1970s (e.g., a 1978 study of VIP in man characterizing its metabolic and circulatory effects). The synthetic form aviptadil entered formal FDA-authorized human trials beginning ~2001. So unlike most gray-market peptides, controlled human trials HAVE been completed, but the largest and most rigorous ones (COVID-19 respiratory failure) were negative on their primary endpoints. No controlled human trial supports the popular intranasal CIRS/anti-aging use specifically beyond small open-label cohorts.
The pitch
What people claim it does
Stated plainly and neutrally, exactly as you'll hear it. We grade each one below.
- A 28-amino-acid peptide naturally produced in the human body (gut, nerves, immune cells) that signals through VPAC1/VPAC2 receptors to raise cAMP, broadly producing vasodilation and anti-inflammatory effects.
- Marketed in compounding/wellness circles mainly as an intranasal spray to 'reset' chronic inflammation in mold-illness / CIRS, and to normalize biomarkers like TGF-beta1, MMP-9, C4a and VEGF.
- The intravenous form, aviptadil (RLF-100/ZYESAMI), was developed as a pharmaceutical and tested in large COVID-19 respiratory-failure trials and earlier in pulmonary hypertension and sarcoidosis.
- Investigated for its immunoregulatory effect on cytokines such as TNF-alpha and IL-6 in inflammatory lung disease.
The data behind each bullet
What actually backs it
The largest, most rigorous human trial, the NIH-run TESICO/ACTIV-3b RCT (28 US sites), found NO benefit of IV aviptadil for COVID-19 hypoxaemic respiratory failure versus placebo. This is the single most important data point and it is negative.
Randomized, placebo-controlled multicenter RCT published in The Lancet Respiratory Medicine (Sept 2023); explicitly concluded no evidence aviptadil improved clinical outcomes.
Brown et al. 2023, TESICO, IV aviptadil and remdesivir in COVID-19 respiratory failure (Lancet Respir Med) ↗An earlier sponsor-affiliated Phase 2b/3 RCT (196 patients, 2:1 IV aviptadil vs placebo) MISSED its primary endpoint (alive and free from respiratory failure at day 60; OR 1.6, 95% CI 0.86-3.11). It reported a secondary survival signal (OR ~2.0) and reduced IL-6, but a missed primary endpoint plus sponsor involvement makes this hypothesis-generating, not confirmatory.
Randomized, double-blind, placebo-controlled trial published in Critical Care Medicine (2022); primary endpoint not statistically significant by the authors' own report.
PubMed: IV aviptadil critical COVID-19 60-day RCT (PMID 36044317) ↗The FDA twice DECLINED Emergency Use Authorization for aviptadil (ZYESAMI) in critical COVID-19 (Nov 2021 and again July 2022), citing insufficient benefit/risk data; aviptadil has never been FDA-approved for any indication.
FDA EUA decisions; company press releases and trade coverage. Confirms regulators did not find the human efficacy data adequate.
DailyMed / FDA search: aviptadil ↗In pulmonary hypertension, a single inhaled aviptadil dose in 20 patients produced only a small, short-lived pulmonary vasodilation, and no longer randomized trial is found in PubMed or ClinicalTrials.gov.
Single-dose study (100 mcg inhaled, 20 patients) from 2008; a modest, short-lived effect and no side effects reported. No later randomized trial found, so there is no efficacy evidence in this indication.
Leuchte et al. 2008, inhaled VIP in pulmonary hypertension (Eur Respir J) ↗In sarcoidosis, a small open-label Phase II study (20 patients, 4 weeks nebulized VIP) was safe and reduced TNF-alpha in bronchoalveolar lavage, a real but early immunoregulatory signal, not an efficacy outcome.
Open-label human pilot study; biomarker change only, no controlled clinical-outcome endpoint.
Prasse et al. 2010, inhaled VIP in sarcoidosis (Am J Respir Crit Care Med) ↗The popular intranasal CIRS / 'gray-matter restoration' use rests on small (~20-patient), open-label, UNCONTROLLED studies from a single clinical network (Shoemaker), reporting biomarker normalization and MRI changes. No independent replication or controlled trial exists for this indication.
Open-label case series without control groups, largely from one research ecosystem; flagged as a key limitation. This is the weakest evidence in the profile and underlies the most common consumer use.
Dooley et al. 2024, CIRS review of treatment evidence (Ann Med Surg) ↗A small multicenter RCT of inhaled aviptadil in 80 hospitalized COVID-19 patients found a shorter time to discharge (7.8 vs 10 days) and a better day-28 CT score than placebo.
Randomized, double-blind, placebo-controlled, 9 centers, n=80; a single small trial, not replicated, and its methods were questioned in 2025-2026 correspondence. Inhaled, not the intranasal or injected use sold for wellness.
Esendagli et al. 2025, Med Princ Pract ↗A 2025 meta-analysis of the two IV aviptadil RCTs in COVID-19 respiratory failure found no survival benefit versus placebo (odds ratio 1.01, 95% CI 0.72-1.42).
Systematic review of 9 studies (2 RCTs, 7 case series, 665 patients).
Udupa et al. 2025, Indian J Crit Care Med ↗Prove it
Can you tell if it's working?
The honest test: if it's working, is there any objective way to see it, a blood marker, a scan, a wearable? For a lot of peptides the answer is no, and that's worth knowing before you spend on labs or gear.
The one objective non-blood readout is exercise (stress-echo) pulmonary artery systolic pressure, VIP's signature claimed effect, but it rests entirely on uncontrolled, single-network data and cannot isolate VIP from the rest of the CIRS protocol.
Bloodwork
Nothing on a routine panel confirms this one. Anyone who says otherwise is guessing.
VIP is an endogenous neuropeptide with a ~1-2 minute plasma half-life that acts locally via VPAC1/VPAC2 receptors and cAMP; it is not measured on any routine panel, and its therapeutic effects (bronchodilation, pulmonary/systemic vasodilation, anti-inflammatory immune modulation, subjective CIRS/mold-illness symptom relief) do not move any standard LabCorp/Quest analyte.
Read this before you spend on labs
You cannot confirm VIP is working with routine bloodwork. The CIRS/mold-illness protocol built around VIP nasal spray tracks a panel (C4a, TGF-beta1, MMP-9, VEGF, and MSH/ADH), but these are specialty send-outs, not routine labs; several are notoriously assay- and lab-dependent (C4a and MSH especially), and their link to VIP efficacy rests on a single contested Shoemaker protocol rather than established evidence. TNF-alpha and IL-6 are neither routine nor specific enough to serve as an efficacy proxy, and the sarcoidosis signal was measured in bronchoalveolar lavage (a research assay), not blood. The rigorous IV aviptadil trials for COVID respiratory failure, pulmonary hypertension, and sarcoidosis were largely negative. VIP's real endpoints are symptomatic and anti-inflammatory, and its very short half-life means the peptide itself is undetectable on standard panels, so there is no routine blood marker to draw a baseline or retest against.
Other ways to track it
Stress (exercise) echocardiography, pulmonary artery systolic pressure (PASP) at rest and during exercise
A working result shows exercise-induced pulmonary artery systolic pressure falling back toward the normal range; normalizing exercise PASP is the one objective functional endpoint claimed in the CIRS/VIP literature, consistent with VIP acting as a pulmonary vasodilator. Expect nothing in a person without exercise-induced pulmonary hypertension, and note that any change cannot be cleanly attributed to VIP because the full CIRS protocol runs alongside it.
VIP raises cAMP at VPAC receptors and dilates the pulmonary vasculature, and the popular CIRS use claims it normalizes elevated pulmonary artery pressure during exercise. Caveat, load-bearing: this endpoint comes only from small, open-label, uncontrolled Shoemaker case series from a single clinical network. Controlled evidence on VIP analogs is weak-to-negative, IV aviptadil (RLF-100/Zyesami) failed its primary endpoint in randomized COVID respiratory-failure trials, and early small aviptadil pulmonary-hypertension studies that were positive were never replicated in controlled trials. So the measurement is objective, but it neither validates the compound nor isolates it.
Bottom line
VIP's popular intranasal CIRS use rests on small, open-label, uncontrolled case series from a single clinical network; the nearest objective non-blood readout is normalization of pulmonary artery systolic pressure during exercise on a stress echocardiogram, VIP's signature claimed effect, but that endpoint exists only in that uncontrolled data and cannot be attributed to VIP alone because the whole protocol runs with it. Controlled evidence on VIP analogs is not supportive, IV aviptadil failed its primary endpoint in randomized COVID respiratory-failure trials, and there is no clean positive (or clean negative) randomized aviptadil trial for pulmonary hypertension, only unreplicated small positive studies. VCS (visual contrast sensitivity) is objective but is a whole-protocol CIRS marker, not VIP-specific, so it is not a tracking channel here. No validated efficacy readout exists on urine, stool, CGM, DEXA, sleep/wearable, VO2max, or genetic testing, and it does not show on any routine blood panel. Treat any tracked change as suggestive, not proof.
Logging baseline vs retest is the whole game. The Truth Tracker is our free log for bloodwork, DEXA, genetics, and wearable data, bring your own numbers.
How to track it →Mechanism
How it's assumed to work
Assumed mechanism (well-characterized for the endogenous peptide, but efficacy for the marketed uses is not established): VIP binds the G-protein-coupled receptors VPAC1 and VPAC2, raising intracellular cAMP. This drives smooth-muscle relaxation and vasodilation (including pulmonary and systemic vessels) and shifts immune cells toward an anti-inflammatory profile, lowering pro-inflammatory cytokines (TNF-alpha, IL-6) and modulating regulatory T cells. In CIRS theory it is claimed to re-regulate a dysfunctional innate-immune/neuroendocrine axis (TGF-beta1, MMP-9, C4a, VEGF, MSH), but that downstream clinical claim is theoretical, not proven.
Dosing & handling
What users and clinicians report
REPORTED, not prescribed. The most common consumer protocol is intranasal compounded spray, 50 mcg per metered spray, often up to ~4 sprays/day, run for an initial ~30 days and sometimes extended 12+ weeks. Some practitioners report subcutaneous protocols (e.g., ~50 mcg AM/PM). The pharmaceutical IV form (aviptadil) used very different, weight-based infused dosing in a monitored hospital setting, those numbers do not translate to at-home use.
Do not equate the supervised IV aviptadil doses from trials with at-home intranasal/subQ microdosing, they are different routes, formulations, and risk settings. Because VIP drops blood pressure, dose escalation should be conservative and any lightheadedness, flushing, or palpitations is a signal to stop. Intranasal CIRS dosing in the literature is prescriber-directed and sequenced after other treatments; using it first, or sourcing it gray-market, departs from even the limited evidence that exists.
Timing & food
Reported intranasal CIRS dosing is typically split through the day (e.g., morning and later doses, up to ~4x/day) rather than a single bolus, because the peptide's half-life is minutes. It is generally used independent of food. In the CIRS protocol the more important "timing" is sequence, not time-of-day: it is intended only after binders, MARCoNS eradication and environmental remediation, on the theory that giving it before the inflammatory drivers are removed wastes it. A first-dose blood-pressure check is prudent given the vasodilatory effect.
Half-life
Very short, roughly 1 to 2 minutes in plasma, cleared by rapid enzymatic degradation (and shortened further in inflammatory states by complement and protease activity) plus renal clearance. This extremely brief half-life is why the IV drug required continuous/repeated infusion and why intranasal or sustained-release approaches are pursued; it also undercuts simple assumptions about how long any systemic effect lasts.
Reconstitution sensitivity
As a peptide, VIP is heat- and protease-sensitive and prone to degradation. Lyophilized product should be stored cold; reconstituted with bacteriostatic or sterile water, kept refrigerated, protected from light, freeze-thaw cycles and agitation avoided. Compounded nasal sprays are similarly perishable and short-dated. Gray-market lyophilized vials carry real risk of degraded or mis-identified peptide, since the molecule does not tolerate poor handling.
Real-world signal
What people actually report
Anecdote, not proof, weighted because the science is thin. Here's the record, graded on volume, consistency, and how credible the sources are.
Volume
Moderate but niche and concentrated. Online discussion clusters heavily in the mold-illness/CIRS community (where it is the protocol's capstone) and in longevity/peptide forums; it is far less broadly discussed than BPC-157 or GLP-1 peptides. Much of the visible "information" is vendor and clinic marketing rather than independent user reports.
Consistency
Mixed and polarized. Within the CIRS community some users report meaningful gains in energy, cognition and inflammation; others report little change, intolerance (headache, BP drops, nasal irritation), high cost, or symptom return after stopping. Because it is always given last in a long protocol, even enthusiastic reports rarely isolate VIP itself.
Source credibility
Low to moderate. The most favorable claims trace back to a single clinical ecosystem (Shoemaker/SurvivingMold) and to vendors selling the product, both of which have incentives. Independent, skeptical, hard-outcome reports are sparse. The credible human evidence that does exist (the IV RCTs) is largely negative and is about a different route and indication than what consumers buy.
- Anecdote, not proof: within the mold-illness/CIRS community, a subset describe a noticeable lift in energy, mental clarity and reduced 'inflamed' feeling once VIP nasal spray is added as the final protocol step, but typically after months of binders and remediation, so attribution is muddy.
- Anecdote: many users report the vasodilatory effects directly, flushing, warmth, lightheadedness or a blood-pressure dip, headache, and nasal irritation/runny nose, especially on early doses; some find this limits how much they can use.
- Anecdote: a recurring theme is cost and access frustration (prescription compounding, short shelf life) and reports that benefits fade after stopping, fueling debate over whether it is 'replacement' or just transient.
- Anecdote: outside CIRS, longevity/peptide users tend to report it as subtle or unremarkable compared with the hype, and more skeptical voices note the failed COVID and pulmonary-hypertension trials when pushing back on marketing claims.
Placebo risk, High
Rated High for the popular intranasal/wellness use because the headline benefits people chase, more energy, clearer thinking, "less inflamed," better mood, are subjective and expectancy-prone, the product is expensive and effortful (raising commitment/justification bias), and it is administered at the emotional finish line of a long, hard recovery protocol when people most expect to feel better. The objective biomarker and MRI claims come from uncontrolled studies, so they cannot offset the placebo concern. (Placebo risk is lower in the supervised IV trial setting, where outcomes were hard and measured, and there the drug largely failed.)
Risk panel
What could go wrong
Adverse events
VIP is a potent vasodilator, so the consistent acute adverse effects are dose-dependent hypotension (sometimes with compensatory tachycardia), facial flushing/warmth, headache, dizziness, and GI effects (nausea, cramping, diarrhea). Intranasal use commonly causes nasal irritation and rhinorrhea. In the IV COVID and sarcoidosis trials these were generally mild and transient, and no drug-related SERIOUS adverse events were reported, a genuinely reassuring signal for short-course supervised IV use.
Theoretical concerns
Mechanistically, broad VPAC-receptor agonism affects vasculature, immune signaling, secretion and smooth muscle well beyond any single target tissue. The blood-pressure-lowering effect is the main acute hazard (caution with hypotension, hypovolemia, or concurrent vasodilators/antihypertensives). VIP also has growth/proliferative and pro-secretory signaling roles, so chronic unsupervised dosing in people with hormone-sensitive or proliferative conditions is a theoretical concern. Because the gut-hormone VIPoma tumor causes severe secretory diarrhea via VIP excess, very high or sustained exogenous exposure is biologically non-trivial.
Contraindications
Avoid or use only under close supervision in anyone with low baseline blood pressure, hemodynamic instability, hypovolemia, or significant cardiovascular disease, and be cautious with antihypertensives, nitrates, PDE5 inhibitors, or other vasodilators (additive hypotension). The IV form is an ICU/monitored drug for a reason. Pregnancy, breastfeeding, active malignancy, and pediatric use are uncharacterized for the wellness/intranasal context and should be treated as contraindications absent a prescriber's judgment.
Honest unknowns
The single biggest unknown is long-term safety of repeated intranasal/subcutaneous self-dosing over months, there is no controlled dataset for the CIRS/anti-aging pattern of use, only one clinic's open-label follow-up claiming durability. Product identity and purity from gray-market sources is unverified (real content, endotoxin, correct sequence). Whether nasal-delivered VIP reaches the brain or systemic targets at claimed doses, and whether the reported MRI/biomarker changes replicate independently, are open. Drug-interaction and chronic-use data outside short supervised IV courses are essentially absent.
Confound watch
In CIRS/mold protocols VIP is deliberately the LAST step, taken only after binders (cholestyramine/welchol), MARCoNS nasal antibiotic eradication, antifungals, correction of MSH/ADH and removal from the moldy environment. That means almost everything a user attributes to VIP is layered on top of months of other interventions plus environmental remediation, making clean attribution nearly impossible. Wellness users also frequently stack VIP with BPC-157, thymosin/TA1, NAD+, methylation support, and lifestyle changes. The strong subjective, energy/cognition-based nature of the reported benefits compounds this.
History
Discovery → first use → status
- 1970VIP isolated from porcine small intestine (Said & Mutt); a 28-amino-acid peptide of the secretin/glucagon superfamily.
- 1978Pharmacokinetic/physiologic studies of infused VIP in humans characterize its very short plasma half-life and circulatory effects.
- ~2001Synthetic VIP (aviptadil) granted FDA authorization for human trials; later studied in pulmonary hypertension and sarcoidosis.
- ~2008-2010Inhaled VIP studies in pulmonary hypertension (single-dose, modest effect) and open-label sarcoidosis (biomarker signal).
- 2013Shoemaker open-label case series popularizes intranasal VIP (50 mcg/spray) as the final step of the CIRS / water-damaged-building protocol.
- 2020-2021Aviptadil (RLF-100/ZYESAMI) fast-tracked for COVID-19 respiratory failure; sponsor reports a met primary endpoint in one Phase 2b/3 readout amid controversy.
- Nov 2021 & July 2022FDA declines Emergency Use Authorization for ZYESAMI in critical COVID-19 (twice).
- Sept 2023NIH TESICO/ACTIV-3b RCT published in Lancet Respiratory Medicine: no benefit of IV aviptadil, the definitive negative result.
- 2026VIP sits in Category 1 (substances under evaluation) of FDA's 503A interim list, updated May 2026. It was not among the seven peptides the PCAC heard on July 23-24, 2026, nor among the five FDA lists for its next meeting before the end of February 2027.
Verification
The COA standard, applied
Cross-checked the PubMed-indexed Critical Care Medicine RCT (PMID 36044317, primary endpoint NOT significant, OR 1.6, CI 0.86-3.11) and the Lancet Respiratory Medicine TESICO RCT (negative) directly; confirmed FDA twice declined EUA and there is no FDA approval; confirmed half-life via the 1978 human PK study; confirmed the CIRS evidence is small open-label single-network work. Discounted vendor/affiliate peptide sites (peptide catalogs, clinic marketing pages), which uniformly overstate efficacy and omit the negative Phase 3 results.
The full verification standard →Sources
Where this comes from
- IV aviptadil critical COVID-19 RCT. Critical Care Medicine (PMID 36044317) ↗· 196-pt randomized double-blind trial; PRIMARY ENDPOINT NOT significant (OR 1.6, 95% CI 0.86-3.11); secondary survival signal; sponsor-affiliated.
- Brown et al. 2023, TESICO / ACTIV-3b aviptadil RCT (Lancet Respir Med; PMID 37348524) ↗· NIH multicenter placebo-controlled RCT, Lancet Respiratory Medicine 2023; found NO benefit of IV aviptadil, the definitive negative result.
- Leuchte et al. 2008, inhaled VIP in pulmonary hypertension (Eur Respir J; PMID 18978135) ↗· Single 100 mcg inhaled dose in 20 patients; small, short-lived pulmonary vasodilation. No longer randomized trial found.
- Prasse et al. 2010, inhaled VIP in sarcoidosis (Am J Respir Crit Care Med; PMID 20442436) ↗· Open-label 20-pt pilot; safe, reduced TNF-alpha in BAL; biomarker only, no clinical outcome.
- Dooley et al. 2024, CIRS review of treatment evidence (Ann Med Surg; PMID 39649915) ↗· Review of the CIRS literature. The popular intranasal use rests on small (~20-pt) open-label, uncontrolled, single-network case series, not independently replicated; the key Shoemaker series is not PubMed-indexed, so this review is a stand-in, not independent confirmation.
- FDA: 503A categories list (Category 1, substances under evaluation), updated May 14, 2026 ↗· Lists Vasoactive Intestinal Peptide in Category 1; no route restriction is listed. Not inclusion on the bulks list.
- VIP human pharmacokinetics in man, 1978 (PubMed) ↗· Early human PK; documents the ~1-minute plasma half-life and circulatory effects.
- FDA / DailyMed search, aviptadil ↗· Confirms no FDA-approved aviptadil label; FDA declined EUA for ZYESAMI twice (2021, 2022).
- ClinicalTrials.gov, aviptadil studies ↗· Trial registry across COVID-19 (incl. TESICO/ACTIV-3b) and other indications; useful to see what was tested and how it ended.
The four lenses reflect the evidence and the real-world record as of the last review and will change as data arrives. Real-world signal and reported feedback are anecdote, not proof. Nothing here is medical advice or a prescription.