VIP
Vasoactive Intestinal Peptide · Aviptadil · RLF-100
28-amino-acid neuropeptide; the definitive aviptadil COVID-19 trial (TESICO) showed no benefit
Overview
Vasoactive Intestinal Peptide (VIP) is a 28-amino-acid neuropeptide distributed throughout the nervous system, gut, and lungs, where it signals through the VPAC1 and VPAC2 receptors to produce vasodilation, smooth-muscle relaxation, secretion, and broad immune modulation. Its synthetic counterpart is called aviptadil (also known by the development codes RLF-100 and the brand Zyesami).
VIP is extremely short-lived in the bloodstream — degraded by plasma endopeptidases within roughly one to two minutes — which is why it cannot be taken orally and why every practical route works around that instability. Community interest centers almost entirely on intranasal use, popularized as the final step of Ritchie Shoemaker's protocol for Chronic Inflammatory Response Syndrome (CIRS, 'mold illness'), typically dosed at about 50 mcg per nostril up to four times daily from a pharmacy-compounded spray. A separate subcutaneous research format dosed in micrograms also exists; the two products are not interchangeable.
It is important to keep the routes and their evidence separate. The strongest clinical data are for intravenous aviptadil in critical illness, and they are negative: the NIH-run ACTIV-3b/TESICO trial found no benefit over placebo for COVID-19-associated respiratory failure and was stopped for futility, after which FDA emergency authorization was declined. The intranasal CIRS evidence is limited to small open-label studies from a single group with no placebo-controlled confirmation. A real, recurring safety signal across uses is pancreatic irritation (rising lipase), so lipase monitoring is standard. The figures below summarize this evidence for research reference only.
Key parameters
- Dose range
- 50 mcg/nostril intranasal (community); 50–200 mcg SC; IV aviptadil in trials
- Frequency
- Intranasal up to 4× daily, or SC 1–2× daily (community)
- Half-life
- Very short (~1–2 minutes in plasma)
- Route
- Intranasal (community); intravenous as aviptadil in trials
- Vial sizes
- 5 mg
- Regulatory status
- Not approved as a standalone drug in the US. The synthetic form aviptadil (RLF-100/Zyesami) is investigational and was studied intravenously for COVID-19; aviptadil plus phentolamine (Invicorp) is licensed in some European countries for erectile dysfunction. Compounded intranasal VIP is used off-label under enforcement discretion; supplied research material is labeled for laboratory use only.
Mechanism of action
VPAC1 / VPAC2 receptor agonism
VIP binds the G-protein-coupled VPAC1 and VPAC2 receptors, raising intracellular cyclic AMP and driving vasodilation, smooth-muscle relaxation, and secretory and immune effects across many tissues.
Anti-inflammatory / immune modulation
Shifts immune responses toward a less inflammatory profile in preclinical models — for example favoring regulatory over pro-inflammatory T-cell activity — which is the rationale behind its use in chronic inflammatory conditions.
Pulmonary surfactant and Type II alveolar cell support
VIP receptors are concentrated on alveolar Type II cells; aviptadil was developed for lung injury on the premise that it protects these cells and upregulates surfactant, though the pivotal COVID-19 trial did not show clinical benefit.
Circadian / suprachiasmatic signaling
VIP is a key neurotransmitter in the suprachiasmatic nucleus, the brain's master clock, contributing to circadian regulation.
Dosing protocol & phases
| Phase | Weeks | Dose | Notes |
|---|---|---|---|
| Intranasal (community / CIRS) | Ongoing | ~50 mcg per nostril, up to 4× daily | The Shoemaker CIRS paradigm; dispensed pre-compounded by a pharmacy, with the first dose given in-clinic and lipase monitored. |
| Subcutaneous start (community) | Weeks 1–2 | 50 mcg once daily | Conservative introduction to assess blood-pressure and GI tolerability before increasing. |
| Subcutaneous standard (community) | Ongoing | 100 mcg 1–2× daily (up to 200 mcg) | Most frequently discussed SC research range; divided dosing reflects the very short half-life. |
Reconstitution guide
For educational and research reference only. Not intended for human consumption, not medical advice. Compounds discussed are sold and used for laboratory research purposes only.
5 mg vial + 1 mL bacteriostatic water
Concentration5,000 mcg/mL · 5 mg/mL
| Target dose | Draw volume | U-100 units |
|---|---|---|
| 50 mcg | 0.01 mL | 1 |
| 100 mcg | 0.02 mL | 2 |
| 200 mcg | 0.04 mL | 4 |
Higher-strength mix; subcutaneous draws are very small, so a fine 0.3 mL U-100 barrel helps.
5 mg vial + 2 mL bacteriostatic water
Concentration2,500 mcg/mL · 2.5 mg/mL
| Target dose | Draw volume | U-100 units |
|---|---|---|
| 50 mcg | 0.02 mL | 2 |
| 100 mcg | 0.04 mL | 4 |
| 200 mcg | 0.08 mL | 8 |
More dilute mix that doubles the draw volume for easier measurement of small subcutaneous doses.
Reconstitution calculator
Pre-filled with VIP's vial sizes. Adjust the water volume and target dose to see the exact draw, with warnings for doses that are hard to measure or won't fit a syringe.
At 5,000 micrograms per millilitre, a 50 microgram dose is 0.01 millilitres, or 1 units on a U-100 syringe, giving 100 doses per vial.
This draw is only 1 units — small volumes are hard to measure accurately. Consider using less bacteriostatic water to make each dose a larger, easier-to-read draw.
Supplies needed
Affiliate disclosure: we may earn a commission from supplier links, at no extra cost to you. For research and educational use only.
Recommended supply
VIP — research vial
From our verified partner Dynotides, with a third-party certificate of analysis per batch.
Injection supplies
- View
Bacteriostatic water
Diluent for reconstituting lyophilized vials.
- Buy
Insulin syringes (U-100)
0.3–0.5 mL, 29–31 G for accurate small draws.
- Buy
Alcohol prep pads
Sterile swabs for the vial stopper and site.
- Buy
Sharps container
Safe disposal of used needles.
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Storage fridge
Keeps reconstituted vials at 2–8 °C.
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Insulated travel case
Cooled, TSA-friendly case for travel.
Missed-dose guidance
No approved-label guidance exists. Because VIP is cleared within minutes, a missed intranasal or subcutaneous dose is simply skipped and the schedule resumed at the next interval — there is no benefit to doubling up. For investigational intravenous aviptadil, dosing is fully clinician-managed.
Side effects & safety
| Category | Effect | Trial incidence |
|---|---|---|
| Cardiovascular | Flushing, lightheadedness, low blood pressureDirect consequence of VIP's vasodilatory action; orthostatic instability is a contraindication. | — |
| Gastrointestinal | Loose stools / diarrhea | — |
| Pancreatic | Elevated lipase / pancreatic irritationThe key safety signal: lipase is checked before starting, ~2 weeks in, and after dose increases; abdominal pain or a rising lipase means stop and seek care. | — |
| Neurological | Mild headache | — |
Clinical trials & evidence
ACTIV-3b / TESICO (IV aviptadil for COVID-19)
Phase 3 (RCT)Through day 90 · Adults with COVID-19-associated acute hypoxemic respiratory failure
No improvement in clinical outcomes versus placebo; the data and safety monitoring board stopped the aviptadil arm for futility and FDA emergency authorization was declined.
NCT04843761 ↗Intranasal VIP in CIRS (Shoemaker)
Open-label (uncontrolled)Varies · ~15–20 patients with chronic inflammatory response syndrome
Small open-label studies reported restored grey-matter nuclear volumes and symptom improvement, but there is no placebo-controlled confirmation.
Trial identifier needs verification
Storage & handling
- Lyophilized
- Store lyophilized powder frozen at −20 °C for long-term stability; refrigerate at 2–8 °C protected from light for shorter-term use.
- Reconstituted
- Refrigerate at 2–8 °C and use within ~28 days; do not freeze. Compounded nasal spray follows its pharmacy-specific labeling. Discard if cloudy.
Comparisons
| Vs. | Target | Half-life | Dosing | Efficacy | Status |
|---|---|---|---|---|---|
| Thymosin Alpha-1 | VPAC1/VPAC2 agonism (vascular + immune) vs thymic immune modulation | ~1–2 min vs ~2 h | Intranasal/SC daily vs ~2× weekly | Negative pivotal IV trial; open-label CIRS use vs approved abroad for hepatitis B/immune support | Investigational vs approved in some countries |
| KPV | VPAC neuropeptide (systemic) vs alpha-MSH fragment (local anti-inflammatory) | ~1–2 min vs short | Intranasal/SC vs SC/oral daily | Vascular + immune signaling vs gut/skin anti-inflammatory | Both research-only in the US |
Sources & references
Frequently asked questions
What is the difference between VIP and aviptadil?
Aviptadil is the synthetic form of vasoactive intestinal peptide and has the same 28-amino-acid sequence. The name is generally used for the pharmaceutical/intravenous product (RLF-100/Zyesami), whereas 'VIP' is the term used for compounded intranasal and research-use material.
Did aviptadil work for COVID-19?
No. The definitive NIH-run ACTIV-3b/TESICO trial found that intravenous aviptadil did not improve outcomes versus placebo through 90 days, the arm was stopped for futility, and FDA emergency authorization was declined.
Why is lipase monitored with VIP?
VIP can irritate the pancreas and raise lipase. Standard practice is to check lipase before starting, around two weeks in, and after any dose increase; new abdominal pain or a rising lipase is a signal to stop and seek medical care.
Related protocols
Thymosin Alpha-1
Tα1
Immune-modulating thymic peptide; 1.6 mg twice weekly is the typical Zadaxin regimen
KPV
Lys-Pro-Val
Tripeptide C-terminal fragment of alpha-MSH studied for anti-inflammatory activity (preclinical)
Looking to match this protocol to a verified research vial? Our partner supplier publishes a certificate of analysis per batch.
For educational and research reference only. Not intended for human consumption, not medical advice. Compounds discussed are sold and used for laboratory research purposes only.