VIPvasoactive intestinal peptide — the body's own anti-inflammatory vasodilator
VIP is a natural 28-amino-acid hormone your own body makes, found throughout the gut, lungs, brain, blood vessels, and immune system. It relaxes blood vessels and airways, calms inflammation, and helps set the body's daily clock. Its lab-made form, aviptadil, is an approved component of an erectile-dysfunction injection in some countries and has been studied (with mixed and ultimately disappointing late-stage results) for severe COVID-19 lung failure. Most "VIP peptide" uses sold online — like intranasal sprays for chronic inflammatory illness — are off-label and not proven.
An endogenous neuropeptide of the secretin/glucagon superfamily acting at the Gs-coupled VPAC1 and VPAC2 receptors (and weakly PAC1), driving cAMP and producing vasodilation, bronchodilation, gut secretion, surfactant/ATII protection, and a broad anti-inflammatory (Th1→Th2, Treg-promoting) program. Synthetic VIP (aviptadil) is approved as part of Invicorp for ED; it carried FDA orphan/Fast-Track status in COVID-ARDS but the definitive TESICO RCT was negative. Half-life is only ~1–2 minutes, which shapes every delivery question.
VIP — HSDAVFTDNYTRLRKQMAVKKYLNSILN (C₁₄₇H₂₃₇N₄₃O₄₃S, MW ≈ 3326.8 Da, CAS 37221-79-7; aviptadil acetate CAS 40077-57-4, PubChem CID 16132300) — isolated 1970 by Said & Mutt from porcine duodenum; encoded by the human VIP gene (also yielding PHM-27); central α-helix (Val5–Asn24) with disordered termini. It shares ~70% homology with PACAP and binds VPAC1/VPAC2 with a Gs/adenylyl-cyclase/cAMP mechanism; the entire 28-residue chain is required for receptor engagement.
A real hormone with real — and overstated — therapeutic claims.
Unlike most experimental peptides, VIP is a genuine endogenous human hormone with decades of physiology behind it and a partially approved drug form. That makes the honesty task different: the biology is solid, but the marketing around "VIP therapy" often races far ahead of the evidence. Below, the established physiology is separated from the one approved indication (ED, as part of Invicorp), the investigational uses (lung injury — where the pivotal trial failed), and the off-label/unproven uses (intranasal for chronic inflammatory illness).
🩸
Core physiology
Vasodilation
A potent non-adrenergic vasodilator and smooth-muscle relaxant acting through VPAC1/VPAC2 → cAMP. Grade A (physiology).
🛡️
Immune role
Anti-inflammatory
A potent endogenous anti-inflammatory factor — shifts Th1→Th2, promotes regulatory T cells, lowers TNFα. Grade B/P.
🫁
Lung biology
ATII protection
Bronchodilates, protects alveolar type-II cells, and supports surfactant production — the rationale for ARDS trials. Grade B/P.
💊
Approved use
ED (Invicorp)
Aviptadil 25 µg + phentolamine 2 mg (Invicorp) is approved for erectile dysfunction (UK, 2000). Grade A.
🦠
COVID-ARDS
Negative trial
The definitive TESICO RCT of IV aviptadil in COVID-19 respiratory failure was negative despite Fast-Track status. Grade B.
⏱️
Pharmacokinetics
~1–2 min
Very short plasma half-life with renal elimination — the central obstacle to any oral or once-daily use. Grade B.
👃
Intranasal / CIRS
Off-label
Intranasal VIP for chronic inflammatory response syndrome rests on open-label, single-group reports — not approved or RCT-proven. Grade C/D.
🧬
Family
VIP / PACAP
Shares ~70% homology with PACAP and the VPAC1/VPAC2 receptors; both are secretin/glucagon-superfamily peptides. Grade A.
02 · Mechanism of action
How VIP signals across so many systems.
VIP's reach comes from one elegant fact: its receptors (VPAC1, VPAC2) sit on vascular smooth muscle, airway smooth muscle, epithelial and immune cells, neurons, and pancreatic islets alike — all coupled to Gs and cAMP. The same second-messenger switch therefore produces vasodilation in vessels, bronchodilation in airways, an anti-inflammatory program in immune cells, and insulin secretion in islets. The receptor biology is established physiology (Grade A/B); the disease-treatment translations below it are far more variable.
Grade A
🔌
1 · VPAC1 / VPAC2 → Gs → cAMP
VIP works through two G-protein-coupled receptors that raise the intracellular signal cAMP.
Clinical significance: VPAC1 and VPAC2 are stimulatory (Gs) GPCRs; activating them raises cAMP and drives nearly all of VIP's downstream effects. VPAC1 is the dominant receptor for most of VIP's biological activity and is broadly expressed across gut, lung, liver, and immune cells. Tissue-specific receptor distribution explains why one peptide has so many effects.
Molecular detail: The receptors belong to the secretin/glucagon (class B) GPCR superfamily, shared with PACAP. VIP first binds the receptor N-terminus then other domains, requiring the entire 28-residue chain; alanine-scanning identified ~14 of 28 positions important for VPAC1 affinity/potency, and a triple mutant [Ala11,22,28]VIP yielded the first >1000-fold VPAC1-selective agonist.
Grade A
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2 · Vasodilation & smooth-muscle relaxation
VIP relaxes blood-vessel and other smooth muscle — its original namesake effect.
Clinical significance: VIP is a potent non-adrenergic vasodilator of systemic and pulmonary vessels. In ex-vivo pulmonary artery it is substantially more potent at muscle relaxation than prostacyclin, and the effect is endothelium-independent. This underlies its use in the ED combination and its pulmonary-hypertension rationale.
Molecular detail: cAMP/PKA signaling lowers smooth-muscle Ca²⁺ sensitivity and tone. VPAC1/VPAC2 are expressed on vascular smooth muscle and dura-mater vessels; VIP also exerts coronary vasodilation with positive inotropic/chronotropic effects on the heart.
Grade B/P
🛡️
3 · Immunomodulation (Th1→Th2, Treg)
VIP is one of the body's built-in brakes on inflammation.
Clinical significance: VIP dampens pro-inflammatory signaling and steers immunity toward tolerance. It promotes a Th1→Th2 shift, generates CD4⁺CD25⁺ regulatory T cells, raises IL-10, and lowers TNFα — the basis for interest in sarcoidosis, autoimmune, and cytokine-driven disease.
Molecular detail: Acting largely via VPAC1 on macrophages and T cells, VIP suppresses NF-κB-driven cytokines and modulates p38 MAPK. VIP and PACAP enhance macrophage IL-10 and generate Tregs in vivo; VIP receptors are anti-inflammatory in models of lethal endotoxic shock.
Grade B/P
🫁
4 · Lung protection & surfactant
VIP protects the cells that keep alveoli open and producing surfactant.
Clinical significance: VIP targets the alveolar type-II (ATII) cell, the surfactant factory and stem cell of the alveolus. It prevents ATII apoptosis (via Granzyme/Fas pathways), increases surfactant protein A and phosphatidylcholine production, and is protective in animal ARDS models — the entire mechanistic case for the COVID-ARDS program.
Molecular detail: VIP acts at VPAC1 on ATII cells; surfactant effects run through PKC/c-Fos, and VIP decreases myofibroblast proliferation in post-injury models. Mechanistic strength here contrasts with the negative pivotal clinical trial — a textbook case of strong biology not translating.
Grade B/P
🍬
5 · Glucose-dependent insulin secretion (VPAC2)
Through VPAC2, VIP helps the pancreas release insulin when glucose is high.
Clinical significance: VIP stimulates glucose-dependent insulin secretion preferentially via VPAC2, without driving hypoglycemia. It also promotes islet β-cell proliferation (FoxM1 pathway), motivating VPAC2-selective agonists as candidate type-2-diabetes drugs. Native VIP's short half-life limits direct use.
Molecular detail: VPAC2 on β-cells couples to cAMP-potentiated insulin release. VPAC2-selective agonists are being developed to separate the insulinotropic effect from VIP's vasodilatory/immune actions, since unselective VIP hits many tissues at once.
Grade B/P
🕒
6 · Circadian, gut & neuroendocrine roles
VIP helps run the brain's master clock and tunes gut secretion and motility.
Clinical significance: VIP neurons in the suprachiasmatic nucleus synchronize the circadian clock; in the gut VIP stimulates water/electrolyte secretion, relaxes enteric smooth muscle, and inhibits gastric acid. Excess VIP from a pancreatic tumor (VIPoma) causes profuse secretory diarrhea — VIP's most distinctive clinical fingerprint.
Molecular detail: VIP is widely distributed across CNS, autonomic, digestive, respiratory, and reproductive systems as a co-transmitter. It also acts as a neurodevelopmental and neuroprotective factor; the same cAMP signaling underlies SCN coupling, intestinal secretion, and pituitary-axis regulation.
L3 · Core signaling
One receptor switch, many organs
🧬 VIP / aviptadil
ligand
→
🔌 VPAC1 / VPAC2
class-B GPCR
→
⚡ ↑ cAMP / PKA
second messenger
→
🩸 Vasodilation
+ bronchodilation
→
🛡️ Anti-inflammatory
+ lung / islet / clock
L3 · Receptor map
VIP's three receptors at a glance
Receptor
VIP affinity
Key tissues
Notable role
VPAC1 (VIPR1)
High
Gut, lung, liver, immune cells
Most of VIP's biology; ATII protection
VPAC2 (VIPR2)
High
β-cells, vascular/airway smooth muscle, SCN
Insulin secretion; smooth-muscle tone
PAC1 (ADCYAP1R1)
Low
CNS, trigemino-autonomic
Mainly a PACAP receptor
L3 · VIP vs PACAP
The VIP / PACAP relationship
Feature
VIP
PACAP
Length
28 residues
27 or 38 residues
Homology
~70% shared sequence
Shared receptors
VPAC1, VPAC2
VPAC1, VPAC2, PAC1 (high)
Vasodilation duration
Shorter
Longer (migraine-relevant)
Superfamily
Secretin / glucagon
03 · Clinical & dosing context
Dosing exists — but only in specific, supervised settings.
VIP is the rare atlas entry with genuine human dosing data — because aviptadil is an actual drug. But those doses live in tightly defined contexts: an intracavernosal ED injection, hospital IV/inhaled infusions in trials, and an off-label intranasal protocol. None is a "wellness" regimen, and the ~1–2 minute half-life means VIP cannot be dosed like a typical self-administered peptide. The route panels below give the documented numbers with the setting that makes them meaningful; the calculator handles reconstitution arithmetic only.
Approved in one narrow indication; investigational or off-label everywhere else
Synthetic VIP (aviptadil) is approved only as part of Invicorp — 25 µg aviptadil + 2 mg phentolamine, intracavernosal, for erectile dysfunction. IV and inhaled aviptadil for lung injury are investigational, and the pivotal COVID-19 trial was negative. Intranasal VIP for chronic inflammatory illness is off-label and unproven. VIP is not a self-care peptide; any therapeutic use belongs with a qualified clinician.
The half-life problem
IV aviptadil has a plasma half-life of only ~1–2 minutes, a volume of distribution ~14 mL/kg, and is renally eliminated (≈35% in 4 h, ≈90% in 24 h). This is why VIP is delivered by continuous infusion, local injection, or inhalation rather than as a daily shot — and why every delivery route is really a question about overcoming rapid clearance.
This is the one approved VIP indication. It must be prescribed and used per the product label; intracavernosal injection is a clinical procedure, not a self-experiment. Grade A.
Approved-use anchor
Invicorp at a glance
Element
Detail
VIP component
Aviptadil 25 µg
Co-agent
Phentolamine 2 mg (α-blocker)
Route
Intracavernosal injection
Status
Approved for ED
IV infusion — investigational (lung injury)
Hospital / trial setting only
Grade B
Trial dosing
COVID-ARDS trials infused IV aviptadil at escalating 50→150 pmol/kg/hr over 12 h; an early sepsis-ARDS series used 50–100 pmol/kg/hr.
Pivotal result
The TESICO randomized trial of IV aviptadil in COVID-19 respiratory failure was negative — no established benefit.
Setting
ICU continuous infusion with hemodynamic monitoring — never an outpatient route.
Investigational only, and the definitive trial failed. Pmol/kg/hr ICU dosing is not convertible to any self-administered regimen. Grade B.
Investigational history
IV aviptadil — what was tried
Context
Dose
Outcome
Sepsis-ARDS (2005, n=8)
50–100 pmol/kg/hr × 12 h
Small open-label series
COVID-ARDS (RLF-100-001)
50→150 pmol/kg/hr
Mixed early signals
TESICO RCT (2023)
IV aviptadil vs placebo
Negative
Inhaled / nebulized — investigational
Lung-directed delivery
Grade B/C
Rationale
Direct airway delivery to VPAC1-rich ATII cells, bypassing rapid systemic clearance.
Studied in
Nebulized VIP in a Phase II sarcoidosis study (20 patients, 4 weeks) was safe, well-tolerated, and reduced inflammatory markers; inhaled aviptadil was trialed in COVID-19 (e.g. AVICOVID-2, HOPE).
Status
Investigational across asthma, COPD, sarcoidosis, pulmonary hypertension, COVID — no approval.
Monitoring
Cough, bronchospasm, flushing, blood pressure.
Promising mechanism and tolerability signals, but efficacy is unproven; inhaled use should occur only in a trial or under specialist care. Grade B/C.
Inhaled programs
Where inhaled VIP has been studied
Indication
Stage
Note
Sarcoidosis
Phase II
Safe; ↓ inflammation
COVID-19
Trials (AVICOVID-2, HOPE)
Investigational
Asthma / COPD / PAH
Orphan designations
Not approved
Intranasal — off-label (CIRS)
Unproven; open-label reports only
Grade C/D
Reported use
Compounded intranasal VIP has been prescribed off-label for chronic inflammatory response syndrome (CIRS), typically as a multi-dose-per-day nasal spray after a sequential treatment protocol.
Evidence
Support comes from small open-label, single-group studies (e.g. ~20 patients) reporting symptom and biomarker changes — no randomized controlled trials.
Status
Not FDA-approved for CIRS; CIRS itself is not a universally accepted diagnosis. Compounded product quality varies.
Monitoring
Blood pressure, nasal irritation, GI symptoms; the source protocol advises checking lipase before starting.
This is the use most often marketed online and the least evidence-supported. It should only be considered, if at all, under a knowledgeable clinician — not self-directed. Grade C/D.
Honest framing · CIRS
What the intranasal evidence is — and isn't
Claim
Evidence level
Symptom/biomarker improvement
Open-label, uncontrolled
Grey-matter volume restoration
Single-group imaging reports
Randomized controlled efficacy
None
Regulatory approval for CIRS
None
Research / laboratory
In vitro & animal use
Grade P
Use
Receptor pharmacology (VPAC1/VPAC2 binding, adenylyl-cyclase assays), immunology, and physiology models; analogs include VPAC1- and VPAC2-selective agonists.
Reconstitution
Per supplier; the calculator below handles mg→µg/mL working-concentration math.
Research-reagent context; not a human dosing route. Grade P.
Tool peptides
Selective VIP-family tools
Tool
Selectivity
[Ala11,22,28]VIP
>1000-fold VPAC1-selective agonist
VIP(6–28)
VPAC antagonist fragment
VPAC2-selective agonists
Diabetes candidates
Dose context · by setting
Documented VIP/aviptadil amounts by use (context, not a self-dosing menu)
This calculator validates concentration and draw-volume arithmetic only — the same mg→mL math used throughout the atlas. It is not a VIP dosing recommendation. VIP's approved use (Invicorp) is a fixed-dose ED product; its investigational uses are weight-based ICU infusions in pmol/kg/hr; and intranasal CIRS use is off-label. Therapeutic VIP belongs with a clinician, not self-administration. Verify any product's identity, purity, and sterility.
Concentration
—
Draw volume
—
Units (U-100)
—
Aliquots/vial
—
Basis
—
04 · Combinations
Combinations — one approved, the rest contextual.
VIP's most important "combination" is a real, approved one: aviptadil with phentolamine for ED. Beyond that, the pairings below are mechanistic or protocol-level context, not validated regimens. Because VIP is a potent vasodilator and immune modulator, the dominant caution across combinations is additive hypotension and the risk of layering an unproven peptide onto serious disease that needs proper treatment.
Aviptadil + Phentolamine (Invicorp)
Approved combination
Aviptadil (VIP)PhentolamineED
The one approved VIP combination: VIP's vasodilation plus phentolamine's α-blockade produces erection. Invicorp pairs 25 µg aviptadil with 2 mg phentolamine for intracavernosal ED treatment. This is a finished, regulated product — not something to recreate. Grade A.
Agent
Role
Grade
Aviptadil (VIP)
Vasodilation (cAMP)
A
Phentolamine
α-adrenergic blockade
A
VIP + Sequential CIRS Protocol
Off-label protocol context
Intranasal VIPCIRS protocol
In the off-label CIRS setting, intranasal VIP is positioned as a final step after a sequence of other interventions (mold avoidance, binders, MARCoNS treatment, etc.). The protocol places VIP after antecedent steps that themselves provided benefit. This is a single-clinician protocol with open-label support, not a validated combination. Grade C/D.
Step
Role
Evidence
Antecedent CIRS steps
Prerequisite per protocol
Open-label
Intranasal VIP
Final "replacement" step
C/D
VIP + Standard ARDS / ICU Care
Investigational adjunct
IV aviptadilICU standard of care
In trials, IV aviptadil was studied as an add-on to maximal intensive care, not a replacement. The TESICO RCT added IV aviptadil to standard care and found no benefit. Any future role would be strictly investigational and hospital-based. Grade B.
Element
Status
Grade
Standard ICU care
Foundation
A
Aviptadil add-on
Investigational · negative trial
B
VIP + Other Vasodilators
Caution · additive hypotension
VIP / aviptadilNitrates / PDE5iAntihypertensives
VIP is a potent vasodilator, so co-use with nitrates, PDE5 inhibitors, or antihypertensives risks additive hypotension. Reported adverse effects of aviptadil include hypotension, flushing, and diarrhea. This is a caution, not a recommended stack. Grade B/P.
Co-agent
Concern
Nitrates / PDE5i
Additive hypotension
Antihypertensives
BP drop
Clinical note — The only validated VIP combination is the approved Invicorp ED product. Everything else is either an investigational hospital protocol (where the pivotal trial failed) or an off-label single-clinician protocol with open-label support only. As a potent vasodilator, VIP's main interaction hazard is additive blood-pressure lowering. Serious conditions — respiratory failure, sarcoidosis, complex chronic illness — require proper medical management; VIP is not a substitute for it.
05 · Safety & contraindications
Generally well tolerated in studied settings — with predictable vasodilator effects.
Because VIP is endogenous and has been given in several trials, more is known about its safety than for most atlas peptides. In supervised use, aviptadil has generally been well tolerated, with adverse effects that follow directly from its biology: vasodilation (hypotension, flushing) and gut stimulation (diarrhea). The larger real-world risks are contextual — unverified compounded product, off-label use for unproven indications, and using VIP in place of established treatment for serious disease.
Safety signals & cautions
Generally well tolerated (supervised)Across several Phase II evaluations aviptadil was well tolerated, with mostly mild effects. Grade B.
HypotensionVasodilation can lower blood pressure — the most predictable effect, especially IV. Reported with aviptadil. Grade B.
FlushingCutaneous vasodilation; common and benign. Documented. Grade B.
DiarrheaVIP stimulates intestinal secretion — the same mechanism that makes VIPoma cause diarrhea. Mechanistically expected. Grade B.
Priapism (ED route)Intracavernosal vasodilators can cause prolonged erection requiring urgent care. Grade B.
Unverified compounded productOff-label/compounded VIP varies in purity and sterility — a real-world hazard beyond the molecule itself.
Pregnancy / lactationInsufficient data — avoid outside clear medical need. Grade D.
Treatment substitutionUsing VIP instead of proven therapy for serious disease (e.g. respiratory failure) is the most consequential risk. Grade D.
Practical safety framework
Hemodynamics first
Because VIP is a potent vasodilator, blood pressure is the key monitoring parameter, especially for IV use and when combined with nitrates, PDE5 inhibitors, or antihypertensives. Flushing is common and usually benign.
Setting matters more than the molecule
The approved ED use is a clinical procedure; investigational lung use is ICU-only; intranasal CIRS use is off-label and unproven. Match the level of supervision to the route — none of these is a casual self-care peptide.
Don't displace real care
The biggest danger isn't a side effect — it's using VIP in place of established treatment for serious conditions, or trusting unverified compounded product. Serious disease needs a clinician and proven therapy.
Check status with anti-doping authority before use
Verify
06 · Evidence base
A deep physiology base — and a humbling clinical record.
VIP has one of the richest basic-science foundations of any peptide here: 50+ years of receptor pharmacology, immunology, and organ physiology since its 1970 discovery. Its clinical translation is more sobering. There is one approved use (ED), tolerability data from multiple trials, and a strong mechanistic case in lung injury — but the pivotal COVID-ARDS RCT was negative, and the popular intranasal CIRS use rests on uncontrolled reports. The honest verdict: established as physiology and as an ED component; unproven as a broad therapeutic.
Discovery · 1970
Said & Mutt
Isolated from porcine duodenum; named for its vasodilatory effect. Foundational.
Approved · 2000
Invicorp (ED)
Aviptadil + phentolamine approved for erectile dysfunction. Grade A.
Pivotal · 2023
TESICO ✗
IV aviptadil in COVID-19 respiratory failure: negative randomized trial. Lancet Respir Med.
Nicole et al. 2000 — VIP residues for VPAC1/VPAC2 & a selective agonist
Alanine-scanning across all 28 residues mapped which positions drive VPAC1/VPAC2 binding and adenylyl-cyclase activation, and combining mutations at positions 11, 22 and 28 produced [Ala11,22,28]VIP — the first >1000-fold VPAC1-selective agonist. A cornerstone of VIP receptor pharmacology.
Characterized VPAC1 as the dominant VIP receptor across the GI tract (colon > ileum > jejunum), establishing where VIP-based therapies would act and reinforcing the Gs/cAMP signaling model common to VIP and PACAP. VPAC1 GI distribution.
Delgado & Ganea — VIP as an endogenous anti-inflammatory & Treg inducer
A body of immunology work showing VIP (and PACAP) shift Th1→Th2, enhance macrophage IL-10, generate CD4⁺CD25⁺ regulatory T cells in vivo, and protect against lethal endotoxic shock — the mechanistic basis for VIP's anti-inflammatory therapeutic interest.
Lung-explant and ATII-cell models show VIP prevents ATII apoptosis (Granzyme/Fas), increases surfactant protein A and phosphatidylcholine (PKC/c-Fos), reduces myofibroblast proliferation, and is protective in animal ARDS — the full mechanistic rationale behind the aviptadil lung program.
Brown et al. 2023 (TESICO) — IV aviptadil was negative
The multicenter ACTIV-3b/TESICO randomized, placebo-controlled trial of IV aviptadil for COVID-19-associated hypoxemic respiratory failure did not show benefit — the definitive clinical test, and a negative one, despite strong preclinical lung biology.
Invicorp (aviptadil + phentolamine) — approved for ED
Aviptadil 25 µg with phentolamine 2 mg, intracavernosal, approved in the UK (2000) and marketed in several countries as an alternative ED therapy — the single approved VIP indication and the one Grade-A clinical use.
Nebulized VIP in sarcoidosis — safe, anti-inflammatory
An open-label Phase II study of nebulized VIP in 20 sarcoidosis patients over 4 weeks found it safe and well tolerated with a significant reduction in inflammatory activity — supporting the immunomodulatory rationale while remaining investigational.
Reviews VIP's glucose-dependent insulin secretion and β-cell proliferation (FoxM1) via VPAC2, and the development of VPAC2-selective agonists as hypoglycemia-sparing diabetes candidates — illustrating how selectivity engineering addresses VIP's broad, short-lived action.
Pharmacology reviews document IV aviptadil's very short half-life (~1–2 min), small volume of distribution (~14 mL/kg), and renal elimination (~35% at 4 h, ~90% at 24 h), with no significant drug-drug interactions — the constraints that force infusion/local/inhaled delivery.
Shoemaker — intranasal VIP in CIRS (open-label series)
Open-label, single-group reports describe intranasal VIP in CIRS reducing symptoms and biomarkers (MMP9, TGF-β1, C4a), raising VEGF, and restoring grey-matter volume on imaging. These are uncontrolled and not RCT-validated — the basis for off-label use, and the weakest evidence tier on the page.
VIP-secreting pancreatic tumors cause profuse secretory (watery) diarrhea, hypokalemia, and achlorhydria — the Verner-Morrison syndrome. This natural over-expression experiment is VIP's most distinctive clinical signature and explains the diarrhea seen with therapeutic dosing. Verner-Morrison / VIPoma.
Human infusion studies show VIP produces cranial vasodilation but, unlike PACAP, only modestly provokes migraine and cannot sustain long vasodilation — clarifying the functional difference between the two closely related peptides at shared receptors. VIP cranial infusion.
GRADE summary — Evidence strength is high (Grade A) for VIP's core physiology and receptor pharmacology and for the approved ED combination; moderate (Grade B) for tolerability and for the mechanistic lung rationale; but the pivotal COVID-ARDS RCT (TESICO) was negative, and the popular intranasal CIRS use is supported only by open-label, uncontrolled reports (Grade C/D). Honest positioning: "a thoroughly characterized endogenous hormone and a real ED-drug component, whose broader therapeutic promise has so far outrun its controlled-trial evidence." Strong biology, short half-life, and a humbling clinical record all coexist here.
07 · Compare & contrast
VIP among the secretin/glucagon-superfamily peptides.
VIP belongs to a family of class-B GPCR peptides — its closest relative is PACAP (shared receptors, ~70% homology), and it sits alongside secretin, glucagon, and the incretins GLP-1/GIP in the broader superfamily. What distinguishes VIP is its combination of vasodilation and broad immunomodulation through VPAC1/VPAC2, plus its very short half-life — features that shape both its uses and its delivery problem.
L1 · Consumer — VIP is a natural hormone your body makes that relaxes blood vessels and airways and calms inflammation. Its lab-made version (aviptadil) is an approved part of an erectile-dysfunction injection in some countries and was tested for severe COVID-19 lung failure, where the big trial did not work. The intranasal "VIP spray" sold for chronic inflammatory illness is off-label and not proven. VIP is a real drug in specific medical settings — not a casual self-care peptide.
L2 · Clinical — VIP is an endogenous secretin/glucagon-superfamily neuropeptide acting at Gs-coupled VPAC1/VPAC2 receptors to drive vasodilation, bronchodilation, anti-inflammation, surfactant/ATII protection, and glucose-dependent insulin secretion. Synthetic VIP (aviptadil) is approved for ED (Invicorp), investigational for lung injury (the pivotal TESICO RCT was negative), and used off-label intranasally for CIRS on open-label evidence. Its ~1–2 minute half-life dictates infusion, local, or inhaled delivery.
L3 · Research — VIP (HSDAVFTDNYTRLRKQMAVKKYLNSILN; C₁₄₇H₂₃₇N₄₃O₄₃S, ~3326.8 Da) engages VPAC1/VPAC2 (and weakly PAC1) via Gs/adenylyl-cyclase/cAMP; the full 28-residue chain is needed for binding, and alanine-scanning yielded the >1000-fold VPAC1-selective [Ala11,22,28]VIP. It shares ~70% homology with PACAP. Therapeutic engineering focuses on overcoming its rapid clearance and on receptor-selective analogs (e.g. VPAC2 agonists for diabetes), since native VIP acts broadly and briefly across many organ systems.
08 · References & evidence
Source register.
Evidence grades reflect the strength of support for the specific claim cited, not the prestige of the journal. For VIP, the firmest sources establish receptor pharmacology and core physiology (Grade A), the approved ED indication (Grade A), and trial-level tolerability and the negative COVID RCT (Grade B); the intranasal CIRS literature is open-label and uncontrolled (Grade C/D). The mix is unusually broad because VIP spans textbook physiology, an approved drug, failed trials, and off-label use all at once.