VIP (Vasoactive Intestinal Peptide); Aviptadil (synthetic VIP); ZYESAMI; RLF-100
Vasoactive Intestinal Peptide (VIP); Vasoactive Intestinal Polypeptide; Aviptadil (INN for synthetic VIP)
VIP is a 28-amino acid endogenous neuropeptide and high-affinity agonist at VPAC1 (EC50 0.02-0.03 nM) and VPAC2 (EC50 0.05-0.087 nM) receptors. Acts via cAMP signaling to produce potent vasodilation, anti-inflammatory immunomodulation, and neuroprotection. Synthetic VIP (aviptadil) is investigational for ARDS/respiratory failure but the largest independent RCT (TESICO, n=471) was NEGATIVE for primary endpoints (PMID 37348524). Used off-label in functional medicine for CIRS/mold illness protocols.
Last updated: 2026-03-13
Safety Summary
The safety profile of VIP/aviptadil is generally benign in available clinical data. No dose-limiting toxicities were identified in Phase I studies or the 60-day RCT (PMC9555831; NCT00004494). The TESICO trial reported no excess SAEs vs placebo (PMC10278994; PMID 37348524). Flushing, hypotension, and headache are the most commonly reported effects. No established drug-drug interactions are documented (Drugs.com aviptadil entry, DrugBank DB18634). No CYP-mediated metabolism (proteolytic clearance). No tolerance, tachyphylaxis, or withdrawal effects documented in studies up to 60 days (PMC9555831; IJCCM systematic review; FDA NDA multidisciplinary review). Animal chronic toxicity at supratherapeutic doses: mild dose-dependent histologic findings (renal interstitial inflammation, hepatic vacuolization, cardiac muscle fiber changes) generally absent at therapeutic exposures (PMC6982157; Frontiers Pharmacol 2021 doi:10.3389/fphar.2021.638128). No cancer signal in FAERS or WHO VigiBase surveillance. Long-term human safety data are limited. Note: PLUVICTO (lutetium Lu 177 vipivotide tetraxetan) is completely unrelated to VIP therapy despite sharing the acronym.
Known Side Effects
common
common (dose-dependent)
common
uncommon
common (intranasal users)
uncommon
uncommon
Who Should NOT Use This
Standard contraindication for any biologic peptide. Hypersensitivity/anaphylaxis is a recognized theoretical risk for protein therapeutics.
Exogenous VIP administration would be counterproductive in patients with endogenous VIP excess. VIPomas produce watery diarrhea, hypokalemia, and achlorhydria (WDHA syndrome) (PMC6743256).
VIP is a potent vasodilator that can reduce mean arterial pressure by 10-15% during infusion (PMID 3687785). Patients with baseline hypotension should use with extreme caution. BP monitoring recommended.
Clinical trials excluded pregnant individuals. No specific pregnancy safety data exist. Benefits/risks must be individually assessed.
Talk to Your Doctor
Before considering VIP (Vasoactive Intestinal Peptide); Aviptadil (synthetic VIP); ZYESAMI; RLF-100, discuss it with your healthcare provider. Ask about potential interactions with your current medications, whether it is appropriate for your health conditions, and what monitoring may be needed.
Sources: [1-12]
Evidence Assessment
Evidence tier 3 (multiple clinical trials with mixed/negative results). Aviptadil has undergone Phase 2b/3 and Phase 3 RCTs, placing it beyond Phase I/limited evidence. However, the largest independent RCT (TESICO, n=471, PMID 37348524; PMC10278994) was stopped for futility -- NEGATIVE for primary endpoints. The sponsor Phase 2b/3 trial (n=196, PMC9555831) missed its primary endpoint though showed a significant secondary outcome. The FDA declined EUA. There are no FDA-approved indications for VIP/aviptadil as of March 2026. EMA orphan designations exist for sarcoidosis and PAH but no marketing authorization. Safety/PK data are well-characterized but efficacy evidence is weak-to-negative from the definitive trial. Community use for CIRS/mold illness is based on practitioner protocols, not RCT evidence.
1Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trialNCT04536350PMID 37348524
Brown SM et al. - Lancet Respiratory Medicine (2023) - Phase 3 RCT (independent, NIH ACTIV-3b) - n=471
NEGATIVE. Stopped for futility. Ordinal recovery/survival day-90 OR 1.40 (95% CI 0.94-2.08, p=0.10). No significant benefit of aviptadil over placebo when added to remdesivir for COVID-19 hypoxemic respiratory failure. No excess SAEs.
Limitations: COVID-19-specific; may not generalize to other respiratory conditions. Conducted during evolving standard of care. Addition of remdesivir in both arms may have reduced observable treatment effect.
2The Use of IV Vasoactive Intestinal Peptide (Aviptadil) in Patients With Critical COVID-19 Respiratory Failure: Results of a 60-Day Randomized Controlled Trial
Youssef JG et al. - Critical Care Medicine (2022) - Phase 2b/3 RCT (sponsor-conducted) - n=196
Primary endpoint missed: alive and free of respiratory failure at day 60, OR 1.6 (95% CI 0.86-3.11). Significant secondary endpoint: survival from respiratory failure OR 2.0 (95% CI 1.05-3.88, p=0.035). No tolerance/tachyphylaxis over 60 days. Acceptable safety profile.
Limitations: Industry-sponsored by NRx Pharma. Primary endpoint not met. Small sample. COVID-19-specific. Not independently replicated in larger TESICO trial.
3VIP in the Treatment of Critical COVID-19 With Respiratory Failure: A Prospective Externally-Controlled Trial
Youssef JG et al. - SSRN preprint (2020) - Prospective externally-controlled - n=45 (21 treated, 24 controls)
Day-60 survival 81% vs 21% (HR 0.15, 95% CI 0.05-0.45). Respiratory recovery 55% vs 10%. IL-6 reduced ~75% in treated patients. TNF-alpha decreased in 5/6 measured.
Limitations: External (non-randomized) control group introduces significant selection bias. Very small sample. Preprint, not peer-reviewed. Industry-sponsored.
4Understanding VPAC receptor family peptide binding and selectivity
Piper SJ, Wootten D et al. - Nature Communications (2022) - Structural biology / receptor pharmacology (cryo-EM) - N/A (in vitro)
Elucidated structural basis of VIP and PACAP binding to VPAC1/VPAC2 using cryo-EM. Revealed two-domain binding mechanism and key selectivity determinants.
Limitations: In vitro structural study; clinical translation not directly addressed.
5Cardiovascular effects of vasoactive intestinal peptide in healthy subjectsPMID 3687785
Frase LL et al. - American Journal of Cardiology (1987) - Human experimental infusion study - Small (healthy volunteers)
IV VIP infusion produced marked vasodilation with forearm vascular resistance decrease ~65%, MAP reduction ~10-15%, and acute heart rate increases.
Limitations: Small sample of healthy volunteers; acute infusion only.
6Vasoactive intestinal peptide in man: pharmacokinetics, metabolic and circulatory effectsPMID 730072
Domschke S et al. - Gut (1978) - Human PK/PD study - Small (healthy volunteers)
Established fundamental PK parameters: plasma disappearance half-time ~1 minute, volume of distribution ~14 mL/kg, clearance ~9 mL/kg/min. Dose-dependent vasodilation.
Limitations: Early study; small sample; IV route only. Remains the primary human PK reference.
7Two-hour infusion of vasoactive intestinal polypeptide induces delayed headache and extracranial vasodilation in healthy volunteersNCT03989817
Ghanizada H et al. - Cephalalgia (2020) - RCT (double-blind, placebo-controlled crossover) - 12 healthy volunteers
VIP infusion produced temporal artery dilation (p<0.001) and delayed headache (p=0.003 incidence; p=0.034 intensity) vs placebo.
Limitations: Small sample; healthy volunteers; mechanism-focused study.
8A Clinical Approach for the Use of VIP Axis in Inflammatory and Autoimmune Diseases
Martinez C et al. - International Journal of Molecular Sciences / Frontiers in Immunology (2020) - Review - N/A
Comprehensive review of VIP's immunomodulatory potential. Animal chronic toxicity at supratherapeutic doses showed mild, dose-dependent organ histologic changes. VIP promotes Treg differentiation and inhibits Th1/Th17 responses.
Limitations: Review article; limited direct clinical trial data for autoimmune indications.
9Therapeutic potential of vasoactive intestinal peptide and its receptor VPAC2 in type 2 diabetes
Various - Frontiers in Endocrinology (2022) - Review / translational - N/A
VIP/VPAC2 agonism enhances glucose-stimulated insulin secretion without driving insulin release at low glucose. VPAC2-selective agonists in early development for T2DM.
Limitations: Mostly preclinical data; human RCT evidence for metabolic indications lacking.
10Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions
Delgado M et al. - Review (2013) - Review - N/A
Comprehensive review of VIP immune functions: suppresses TNF-alpha, IL-6, IL-12; promotes IL-10, TGF-beta; inhibits Th1/Th17; promotes Treg and M2 macrophage phenotypes via cAMP/PKA.
Limitations: Primarily preclinical evidence.
11A Synthetic Agonist to Vasoactive Intestinal Peptide Receptor-2 Induces Regulatory T Cell Neuroprotective Activities in Models of Parkinson's Disease
Various - Frontiers in Cellular Neuroscience (2019) - Preclinical (rodent PD models) - Animal models
VPAC2-selective agonist (LBT-3627) reduced microglial inflammation, increased Treg activity, protected dopaminergic neurons, and improved motor/behavioral endpoints in PD models.
Limitations: Preclinical only; no human efficacy data.
12Recent advances in vasoactive intestinal peptide physiology and pathophysiology: focus on the gastrointestinal system
Iwasaki M et al. - F1000Research (2019) - Review - N/A
VIP is a principal enteric neurotransmitter. Acts at VPAC1 and VPAC2 to regulate chloride/water secretion, smooth muscle relaxation, epithelial barrier integrity. Altered VIP signaling associated with motility disorders.
Limitations: Mechanistic review; limited direct therapeutic RCT data.