Vasoactive Intestinal Peptide (VIP)
Summary
VIP is a 28-amino-acid neuropeptide made by gut, brain, and immune cells that suppresses inflammatory cytokines and dilates blood vessels. Its synthetic version, aviptadil, was tested in a 196-patient trial in critical COVID-19: the primary endpoint missed, while a secondary survival analysis favored treatment. It remains unapproved in the US, though an aviptadil-phentolamine combination is licensed in the UK for erectile dysfunction. Its plasma half-life is about one minute.
Also known as: VIP, Aviptadil, RLF-100, Zyesami
Key Findings at a Glance
- • VIP was isolated from small intestine in 1970 and reclassified from gut hormone to broadly distributed neuropeptide signaling through VPAC1/VPAC2 receptors.
- • Human pharmacokinetics show a disappearance half-time of about one minute after IV infusion, forcing multi-hour infusion or inhaled delivery in trials.
- • In a 196-patient critical COVID-19 RCT, aviptadil missed its primary endpoint but showed two-fold odds of 60-day survival in a secondary analysis, with no drug-related serious adverse events.
- • VIP both prevented and treated experimental arthritis by downregulating autoimmune and inflammatory components simultaneously (Nature Medicine 2001).
Vasoactive Intestinal Peptide (VIP) Overview & Molecular Profile
Vasoactive intestinal peptide was isolated from porcine small intestine in 1970 by Said and Mutt, who named it for its potent vasodilatory activity. A member of the secretin/glucagon peptide family, VIP is produced by neurons throughout the gut and brain, by immune cells, and by airway epithelium, and it signals through two Gs-coupled receptors, VPAC1 and VPAC2, defined in the IUPHAR receptor review. Its research footprint spans three domains. In immunology, VIP suppressed both the autoimmune and inflammatory components of experimental arthritis in a landmark Nature Medicine study, and inhaled VIP reduced TNF-alpha output from lung macrophages in an open phase II sarcoidosis trial. In critical care, synthetic VIP (aviptadil) was infused in a 196-patient randomized trial in critical COVID-19 respiratory failure: the primary endpoint did not reach significance, though a secondary analysis showed two-fold odds of 60-day survival. In neurology, VIP neurons pace circadian rhythms in the suprachiasmatic nucleus, and compounded intranasal VIP circulates in off-label protocols for mold-related chronic illness, an application whose key supporting study is not indexed in PubMed and remains unverified by controlled replication. Where thymosin alpha-1 research centers on T-cell maturation, VIP research centers on damping inflammatory cytokine output.
Mechanism of Action: Immunomodulation & Antimicrobial Activity
VIP binds VPAC1 and VPAC2 receptors with similar affinity; both couple to G-alpha-s, raising adenylyl cyclase activity, cAMP, and PKA signaling, while the related PAC1 receptor prefers PACAP over VIP. In immune cells this cascade suppresses production of TNF-alpha, IL-6, and IL-12, shifts T-helper balance away from Th1 and Th17 and toward regulatory T cells, and was sufficient to prevent and treat experimental arthritis in mice. In lung, VIP supports surfactant production by type II alveolar cells, relaxes airway and vascular smooth muscle, and inhibits inflammatory cytokine release, the composite rationale for aviptadil in respiratory failure. VIP is degraded within minutes by neutral endopeptidases and trypsin-like enzymes; human infusion work measured a disappearance half-time of about one minute, which is why trial protocols use multi-hour escalating infusions rather than bolus dosing.
Research-Observed Effects
Immunomodulation and Cytokine Suppression
Moderate ResearchVIP is an endogenous immunomodulatory signal rather than a simple vasodilator. Through VPAC1/VPAC2-driven cAMP signaling it suppresses TNF-alpha, IL-6, and IL-12 production, reduces Th1 and Th17 activity, and expands regulatory T cells. Human evidence comes from an open phase II study in 20 sarcoidosis patients, where 4 weeks of inhaled VIP was safe and significantly reduced TNF-alpha production by alveolar macrophages while increasing regulatory T cells in bronchoalveolar lavage (PMID: 20442436). The mechanistic and early human data are consistent, but no placebo-controlled immunology trial has been run.
Lung Protection in Respiratory Failure (Aviptadil)
Moderate ResearchSynthetic VIP (aviptadil) was developed for acute respiratory failure on the rationale that VIP supports surfactant production, protects type II alveolar cells, and inhibits cytokine synthesis. In a 196-patient multicenter randomized trial in critical COVID-19 respiratory failure, three days of escalating IV aviptadil missed the primary endpoint (alive and free of respiratory failure at day 60; OR 1.6, 95% CI 0.86-3.11), but a prespecified secondary analysis showed two-fold odds of 60-day survival (OR 2.0, 95% CI 1.1-3.9; p=0.035), with a 10-fold survival odds signal in the mechanically ventilated subgroup and reduced IL-6 by day 3 (PMID: 36044317). A negative primary endpoint with a positive secondary signal leaves the clinical benefit unresolved.
Vasodilation and Circulatory Effects
Extensive ResearchVIP earned its name from its vasodilatory potency, and the human pharmacology was mapped early: graded IV infusions of 0.6-3.3 pmol/kg/min in healthy volunteers produced dose-related plasma levels, cutaneous flushing, increased pulse rate, and widened blood-pressure amplitude at the highest dose, with a disappearance half-time of about one minute and a metabolic clearance rate of roughly 9 mL/kg/min (PMID: 730072). The same study concluded that VIP does not function as a circulating hormone under physiological conditions, consistent with its role as a locally acting neuropeptide.
Experimental Autoimmune Disease Suppression
Preliminary ResearchIn the collagen-induced arthritis model, VIP both prevented disease onset and treated established arthritis, downregulating the autoimmune component (reduced autoreactive T-cell responses and autoantibodies) and the inflammatory component (reduced cytokines and joint destruction) simultaneously (PMID: 11329057). Related models extend the pattern to other autoimmune settings, positioning VIP and VPAC agonists as candidate immune-resetting agents. All of this evidence is preclinical; the only human autoimmune-adjacent data are the open sarcoidosis inhalation study.
Circadian Rhythm Regulation
Preliminary ResearchVIP is the principal neurotransmitter of the ventrolateral suprachiasmatic nucleus, where VIP-expressing neurons synchronize cellular clocks across the master circadian pacemaker; receptor pharmacology and CNS distribution are catalogued in the IUPHAR review of VIP/PACAP receptors (PMID: 22289055). This circadian role underlies research interest in VIP for sleep and jet-lag biology, but it remains physiology-level evidence without human interventional trials.
Safety & Tolerability
VIP's human safety record is thinner than its clinical-trial history suggests. The pivotal aviptadil trial reported no drug-related serious adverse events, but it missed its primary endpoint and remains unapproved; early infusion studies documented flushing and circulatory effects at high doses; and compounded intranasal VIP sits outside any controlled evidence base.
Human data: Human data exist from a 196-patient randomized IV trial, a 20-patient open inhaled study, and small pharmacokinetic infusion series. There is no approved product and no long-term safety database, and intranasal compounded use has no controlled-trial support.
Regulatory status: Not approved by the FDA for any indication as of 2026, and the aviptadil COVID-19 program did not progress to approval after the pivotal trial missed its primary endpoint. Aviptadil is not unapproved everywhere, however: Invicorp, a fixed combination of aviptadil 25 micrograms with phentolamine mesilate 2 mg, holds a UK marketing authorisation as a prescription-only injection for erectile dysfunction (PL 20623/0018, granted April 2015), with equivalent national authorisations in several other markets.
- PubMed 36044317
In the 196-patient COVID-19 RCT, aviptadil produced no drug-related serious adverse events over 60 days, but the primary endpoint was not met - the survival benefit was a secondary analysis, so the trial does not establish clinical efficacy.
Human trial - PubMed 730072
Graded IV VIP infusions in healthy volunteers caused flushing, increased pulse rate, and widened blood-pressure amplitude at the highest dose, consistent with potent vasodilation; disappearance half-time was about one minute.
Human PK - PubMed 20442436
Nebulized VIP over 4 weeks in 20 sarcoidosis patients was reported safe and well tolerated in an open phase II study without placebo control.
Human trial - PubMed 11329057
VIP suppresses TNF-alpha, IL-6, and IL-12 while promoting regulatory T cells; sustained systemic immunosuppression of this kind is a theoretical risk for infection surveillance and tumor immunity that has never been studied with chronic human dosing.
Theoretical
Research Protocol Doses Reported in Published Literature
Research Disclaimer: Doses reported below are from published preclinical research protocols. Vasoactive Intestinal Peptide (VIP) is not approved by the US FDA for human use; regulatory status can differ in other countries, so see the regulatory status note in the safety section of this page. This information is provided for research reference only and does not constitute a dosing recommendation.
| Route | Dose | Frequency | Notes |
|---|---|---|---|
| Intravenous (hospital RCT) | 50/100/150 pmol/kg/hr (graduated) | Three 12-hour infusions on successive days | Youssef 2022 aviptadil trial in critical COVID-19; primary endpoint not met |
| Nebulized inhalation | Protocol-defined (open phase II) | Daily x 4 weeks | Prasse 2010 sarcoidosis study; well tolerated, reduced alveolar TNF-alpha |
| Intravenous (human PK) | 0.6-3.3 pmol/kg/min | 30-minute infusion | Domschke 1978; disappearance half-time about 1 minute; flushing at the highest dose |
| Intranasal (compounded, off-label) | 50 mcg per spray | Multiple times daily in community protocols | No controlled-trial basis; CIRS protocol use only |
All doses above are reported from published research protocols using laboratory subjects. Refer to the cited studies in the Research Studies section above for original source data.
Research Studies & References
Polypeptide with broad biological activity: isolation from small intestine
Said SI, Mutt V
Science (1970)
The discovery paper. Said and Mutt isolated a 28-amino-acid peptide from porcine small intestine with potent vasodilatory and hypotensive activity, naming it vasoactive intestinal peptide. The work founded the secretin/glucagon/VIP peptide family field; VIP was subsequently localized to neurons throughout the gut, brain, and airways, reclassifying it from a gut hormone to a broadly distributed neuropeptide.
Vasoactive intestinal peptide in man: pharmacokinetics, metabolic and circulatory effects
Domschke S, Domschke W, Bloom SR, et al.
Gut (1978)
The reference human pharmacokinetic study. Graded VIP infusions of 0.6, 1.3, and 3.3 pmol/kg/min over 30 minutes in four healthy volunteers produced dose-related plasma levels reaching the range seen in Verner-Morrison syndrome. After infusion, plasma VIP fell by first-order kinetics with an average disappearance half-time of one minute, a metabolic clearance rate of about 9 mL/kg/min, and a distribution volume of about 14 mL/kg. The highest dose caused flushing, increased pulse rate, and widened blood-pressure amplitude. The authors concluded VIP does not act as a circulating hormone under physiological conditions.
Vasoactive intestinal peptide prevents experimental arthritis by downregulating both autoimmune and inflammatory components of the disease
Delgado M, Abad C, Martinez C, Leceta J, Gomariz RP
Nature Medicine (2001)
A landmark preclinical study in the collagen-induced arthritis model. VIP prevented disease onset when given early and treated established arthritis when given later, simultaneously downregulating the autoimmune component (autoreactive T-cell responses and autoantibodies) and the inflammatory component (pro-inflammatory cytokines and joint destruction). The paper established VIP's dual immunomodulatory profile and motivated two decades of VPAC-agonist research in autoimmunity.
Inhaled vasoactive intestinal peptide exerts immunoregulatory effects in sarcoidosis
Prasse A, Zissel G, Lutzen N, et al.
American Journal of Respiratory and Critical Care Medicine (2010)
An open phase II study in 20 patients with active sarcoidosis treated with nebulized VIP for 4 weeks. Inhaled VIP was safe and well tolerated, significantly reduced TNF-alpha production by cells isolated from bronchoalveolar lavage, and increased bronchoalveolar CD4+CD127-CD25+ regulatory T cells with functional suppressive activity. The study provides direct human evidence that inhaled VIP exerts immunoregulatory effects in inflamed lung, though without placebo control.
Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1
Harmar AJ, Fahrenkrug J, Gozes I, et al.
British Journal of Pharmacology (2012)
The definitive receptor-pharmacology review for the VIP/PACAP family. It defines VPAC1 and VPAC2 as Gs-coupled receptors binding VIP and PACAP with similar affinity, and PAC1 as the PACAP-preferring receptor, catalogues their tissue distribution across brain, gut, lung, and immune system, and summarizes the cAMP/PKA signaling, physiological functions (including circadian regulation in the suprachiasmatic nucleus), and therapeutic opportunities and challenges for this receptor family.
The 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, Lavin P, Schoenfeld DA, et al.
Critical Care Medicine (2022)
A multicenter, placebo-controlled trial randomizing 196 patients with critical COVID-19 respiratory failure across ten US hospitals to three 12-hour IV infusions of aviptadil at graduating doses (50, 100, 150 pmol/kg/hr) or placebo. The primary endpoint - alive and free from respiratory failure at day 60 - did not reach significance (OR 1.6, 95% CI 0.86-3.11). A secondary analysis found two-fold odds of 60-day survival (OR 2.0, 95% CI 1.1-3.9; p=0.035), with a 10-fold survival odds signal in mechanically ventilated patients and significantly reduced IL-6 by day 3. No drug-related serious adverse events were reported. The primary-endpoint miss means clinical benefit remains unproven despite the survival signal.
Frequently Asked Questions
Is VIP the same thing as aviptadil?
Aviptadil is the pharmaceutical name for synthetic human vasoactive intestinal peptide - the identical 28-amino-acid sequence made synthetically for clinical use. RLF-100 and Zyesami are development and brand names for the intravenous aviptadil program tested in critical COVID-19. When research refers to VIP it may mean the endogenous neuropeptide, the synthetic drug, or compounded intranasal preparations; the clinical trial data apply specifically to IV aviptadil.
Did aviptadil actually work in COVID-19?
The honest answer is unresolved. In the 196-patient randomized trial in critical COVID-19 respiratory failure, aviptadil missed its primary endpoint (alive and free of respiratory failure at day 60; OR 1.6, not significant). A prespecified secondary analysis showed two-fold odds of 60-day survival (p=0.035), and the mechanically ventilated subgroup showed a 10-fold survival odds signal, with IL-6 reduced by day 3 and no drug-related serious adverse events (PMID: 36044317). A negative primary endpoint with a positive secondary signal is hypothesis-generating, not proof, and no approval followed.
Is VIP nasal spray proven for mold illness (CIRS)?
No. Compounded intranasal VIP is used off-label in chronic inflammatory response syndrome protocols, but the key supporting study was published in a journal not indexed in PubMed, involves a small uncontrolled case series, and has never been tested in a randomized, placebo-controlled trial. The protocol's lab-monitoring practices (such as tracking lipase and TGF-beta1) likewise have no controlled-evidence basis. Anyone considering it should treat it as unproven and discuss it with a physician, particularly given VIP's vasodilatory potency.
What are VPAC1 and VPAC2?
VPAC1 and VPAC2 are the two receptors that mediate VIP's effects. Both are Gs-coupled G-protein-coupled receptors that raise cAMP when activated, and both bind VIP and the related peptide PACAP with similar affinity, while a third receptor, PAC1, prefers PACAP. Their distribution - VPAC1 broadly across lung, gut, liver, and immune cells; VPAC2 more prominent in smooth muscle and certain brain regions - explains VIP's combined vascular, immune, and neurological profile, as defined in the IUPHAR receptor review (PMID: 22289055).
Why is VIP given by multi-hour infusion instead of a single injection?
Human pharmacokinetic work showed that VIP disappears from plasma by first-order kinetics with an average half-time of about one minute after IV infusion, with a metabolic clearance rate of roughly 9 mL/kg/min (PMID: 730072). A bolus injection therefore produces only a brief pulse of exposure. Clinical trials compensate with sustained delivery: the aviptadil COVID-19 trial used three 12-hour continuous infusions on successive days, and pulmonary studies use repeated inhalation or intranasal dosing to maintain local levels.
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