Section 01
What it's used for
Pulmonary Hypertension
In human clinical trials, inhaling VIP, vasoactive intestinal peptide, lowered blood pressure in the lung arteries and improved how well the right side of the heart worked, the chamber most strained by this lung condition.
▸Clinical wording
Inhaled VIP reduces pulmonary artery pressure and improves right heart function. Clinical trials have been conducted.
COVID-19 Lung Failure (ARDS)
Aviptadil, a synthetic VIP, was tested in people with severe COVID-19 lung failure, without FDA emergency approval. Small trials showed better oxygen; the biggest trial, TESICO, found no survival benefit (OR 1.01, P=.93), per a 2025 review.
▸Clinical wording
Aviptadil (synthetic VIP) was studied for COVID-19-related ARDS under Fast Track/emergency IND status but did not receive FDA emergency use authorization. Improved oxygenation has been reported in smaller trials and case series, but the largest randomized controlled trial (TESICO) found no significant survival benefit (OR 1.01, P=.93), a result echoed by a 2025 meta-analysis.
Autoimmune Disease Models
In animal models of rheumatoid arthritis, multiple sclerosis, type 1 diabetes, and inflammatory bowel disease, VIP showed effects before any human testing. These are preclinical, pre-human, results only, not evidence it works in people.
▸Clinical wording
Preclinical efficacy in rheumatoid arthritis, multiple sclerosis, type 1 diabetes, and inflammatory bowel disease models.
Nerve Cell Protection
VIP has been shown to guard nerve cells against excitotoxicity, a kind of damage from overactive chemical signaling that can kill neurons, and to encourage neural stem cells to mature into new nerve cells for repair.
▸Clinical wording
VIP protects against excitotoxicity and promotes neural stem cell differentiation.
Section 02
Mechanism of Action
Two receptors, different organs, one messenger
- This 28-unit peptide works through two receptors that it shares with a related peptide.
- Both mainly raise the internal messenger cAMP and act through the kinase PKA.
- The two receptors sit in different organs, which is why one peptide gives tissue-specific readouts.
- In mouse brain-clock slices lacking them, about half the neurons lost their daily rhythm.
▸Clinical wording
VPAC1 and VPAC2 receptor coupling to cAMP and PKA
VIP is a 28-residue peptide that signals through two class B1 G protein-coupled receptors it shares with PACAP: VPAC1 and VPAC2. Both couple preferentially to Gas, so occupancy raises adenylate cyclase activity and cAMP, with protein kinase A as the dominant effector; secondary coupling to Gai, Gaq and Gbg adds inositol phosphates, calcium, PKC, ERK, PI3K/Akt and CaMK, and internalised receptors continue signalling through beta-arrestin. Distribution is uneven — VPAC1 predominates in small intestine, colon, liver and brain, VPAC2 in stomach, pancreas, lung and brain — which is why one ligand produces tissue-specific readouts (Langer et al., 2022). VPAC2 is also the coupling point for circadian pacemaking: in mouse suprachiasmatic slices lacking Vip or Vipr2 roughly half the neurons lost circadian firing and the remainder desynchronised, and a VPAC2-selective agonist restored rhythmicity in 71% of arrhythmic Vip-/- neurons but did nothing in Vipr2-/- tissue (Aton et al., 2005).
Two brakes on inflammatory gene switching
- In mouse macrophages it cut nitric oxide output by lowering the enzyme that makes it.
- One arm blocks a master inflammation switch from binding the gene's control region.
- A second, messenger-dependent arm blocks a different gene-activating factor instead.
- In the same groups' wider work, several inflammation messengers fell while calming ones rose.
▸Clinical wording
Transcriptional brake on NF-kB and IRF-1 in macrophages
In mouse peritoneal macrophages and RAW 264.7 cells, VIP and PACAP reduced nitric oxide output dose- and time-dependently by lowering iNOS mRNA and protein. Two separable arms were resolved: a cAMP-independent arm that blocks NF-kB binding to the iNOS promoter, and a cAMP-dependent arm that preferentially inhibits IRF-1 transactivation (Delgado et al., 1999). Across the wider literature from the same groups the pattern extends to TNF-alpha, IL-12, IL-6 and IL-1beta, with MAPK and AP-1 also downregulated and IL-10 and TGF-beta1 rising, alongside reduced phagocytic activity and free-radical production in cultured macrophages, monocytes, dendritic cells and neutrophils (Pozo et al., 2007; Delgado et al., 2004).
Expanding the immune system's peacekeepers
- Given with an antigen to engineered mice, it expanded calming regulatory T cells.
- Those cells suppressed other T cells more strongly per cell and transferred suppression to untreated mice.
- They also prevented graft-versus-host disease in irradiated mice given foreign bone marrow.
- In an open 20-patient sarcoidosis trial, inhaled peptide raised lung regulatory T cells and cut TNF-alpha.
▸Clinical wording
Tolerogenic dendritic cells and regulatory T cell expansion
Administering VIP together with specific antigen to TCR-transgenic mice expanded CD4+CD25+ T cells expressing Foxp3 and neuropilin-1. On a per-cell basis these were more potent suppressors of responder T cell proliferation than the baseline population; they transferred suppression to naive animals, inhibited delayed-type hypersensitivity and prevented graft-versus-host disease in irradiated hosts reconstituted with allogeneic bone marrow (Delgado et al., 2005). The human counterpart is a four-week open phase II trial of nebulised VIP in 20 patients with active sarcoidosis, in which bronchoalveolar lavage cells showed increased regulatory T cells, conversion of naive CD4+ cells to a regulatory phenotype, and significantly reduced TNF-alpha production (Prasse et al., 2010).
Relaxing the muscle in vessel walls
- In rat vessel muscle it opened a potassium channel, and blocking that channel weakened the relaxation.
- In isolated rat lungs it widened constricted vessels, an effect abolished by blocking nitric oxide production.
- In 20 patients with pulmonary hypertension one inhaled dose gave small, brief, lung-selective widening.
- That dose did not change systemic blood pressure.
▸Clinical wording
Smooth muscle relaxation via KATP channels and nitric oxide
In rat mesenteric vascular smooth muscle VIP activated the vascular Kir6.1/SUR2B KATP channel isoform with half-maximal activation near 10 nM; activation was blocked by the PKA inhibitor Rp-cAMP, and in isolated artery rings VIP produced concentration-dependent relaxation that glibenclamide attenuated, tying hyperpolarisation directly to the vasodilator response (Yang et al., 2007). A second arm is endothelium-linked: in isolated rat lungs VIP dilated the constricted pulmonary bed dose-dependently, an effect abolished by nitric oxide synthase inhibition and restored by L-arginine (Iwabuchi et al., 1997). In 20 patients with pulmonary hypertension, a single 100 ug inhaled dose of VIP produced small, transient but selective pulmonary vasodilation without systemic blood pressure change (Leuchte et al., 2008).
Protecting neurons through support cells
- Its neuroprotection runs largely through astrocytes, the brain's support cells.
- In rat astrocyte cultures it regulated a protective protein, with direction depending on culture age.
- In newborn mice with white-matter injury it did not prevent the lesion but drove later repair.
- In mouse neuron cultures its boost to a growth factor vanished when glutamate receptors were blocked.
▸Clinical wording
Glia-dependent neuroprotection through BDNF and ADNP
VIP's neuroprotection is largely indirect and routed through astrocytes. In rat astrocyte cultures VIP regulated activity-dependent neuroprotective protein (ADNP) expression via the VPAC2 receptor, with the direction of the effect depending on culture age (Zusev and Gozes, 2004). In postnatal day-5 mice given intracerebral ibotenate — a model of preterm excitotoxic white-matter injury — VIP did not prevent the initial lesion but induced secondary axonal regrowth and repair of the white-matter cyst; the pathway ran through an atypical VPAC2 receptor and astrocytic PKC, with BDNF released by astrocytes acting on neuronal MAPK and PKC (Passemard et al., 2011). In mouse cortical neurone cultures VIP and PACAP raised BDNF mRNA, but NMDA receptor antagonists abolished the effect, indicating potentiation of tonic glutamate signalling rather than direct induction (Pellegri et al., 1998).
Section 03
Biological Pathways
- VPAC1/VPAC2 → Gs → cAMP → PKAVIP activates VPAC1 and VPAC2, class B GPCRs coupling mainly to Gs, raising cAMP and PKA; VPAC1 predominates in gut, liver and brain, VPAC2 in stomach, pancreas and lung, giving tissue-specific vasodilation.
- NF-κB/IRF-1 suppression in macrophagesIn macrophages VIP lowers iNOS and nitric oxide via cAMP-independent NF-κB blockade and cAMP-dependent IRF-1 inhibition, cutting TNF-α, IL-12, IL-6 and IL-1β while raising IL-10 and TGF-β1.
- Tolerogenic DCs and Treg inductionVIP with antigen expands Foxp3+ regulatory T cells that suppress proliferation and block graft-versus-host disease in mice; a human sarcoidosis trial found nebulised VIP raised regulatory T cells and cut TNF-α.
- KATP channel and NO-mediated vasodilationVIP opens vascular Kir6.1/SUR2B KATP channels via PKA, relaxing smooth muscle in a glibenclamide-blockable way, and dilates pulmonary vessels via nitric oxide; inhaled VIP eased pulmonary hypertension in one trial.
- Glial BDNF/ADNP neuroprotectionVIP acts on astrocytic VPAC2 to regulate ADNP and BDNF; in a mouse white-matter injury model this astrocyte-neuron signalling supported axonal regrowth via MAPK and PKC, indirect rather than direct neuroprotection.
Section 04
Dosage Information
HSDAVFTDNYTRLRKQMAVKKYLNSILN-NH2| Route / system | Context | Range studied | Limitation |
|---|---|---|---|
| Intravenous — aviptadil (synthetic VIP) | COVID-19 trials in respiratory failure | 50, then 100, then 150 pmol/kg/hr as three 12-hour infusions — 600, 1200 and 1800 pmol/kg a day, in all about 0.8–1.1 mg at 70–90 kg | No benefit at day 90: odds ratio 1.11, p = 0.54. Low blood pressure in 58%, diarrhoea in 40% of infusions, a third paused for side effects — in intensive care. |
| Inhaled — nebulised aviptadil | Phase 2 sarcoidosis trial; two terminated COVID-19 trials | Sarcoidosis: 200 µg a day (4 × 50 µg), 4 weeks, 20 patients. COVID-19: 100 µg three times daily; 67 µg three times daily for 10 days. | In sarcoidosis everyone knew what they got: 20 patients, immune markers in lung fluid, no clinical result. Both COVID-19 trials stopped without answering. |
| Intracavernosal — approved combination | Invicorp, licensed in the UK for erectile dysfunction | Aviptadil 25 µg with phentolamine mesilate 2 mg, one injection into the penis, no more than one in 24 hours | The erectile effect is largely the phentolamine's. Even 25 µg into one organ flushes the face in 22–53% of injections, and none of it transfers to systemic use. |
| Intranasal — self-administration | Circulating CIRS protocol, outside any trial | 50 µg per spray four times a day, nostrils alternating; 100 µg four times a day in month two — 200 to 400 µg a day | No controlled trial of VIP in the nose exists, and none is registered for this use. Numbers come from one clinician's protocol and an uncontrolled case series. |
Results
Syringe Fill Level (100u syringe)
Set positive values for: Recommended dose per kg.
Research Use Only. This information is for educational and research purposes only. Not intended for medical advice or self-medication.
Section 05
Protocols
No protocols featuring this peptide yet. Browse All Protocols
Section 06
Stability & Storage
Lyophilised powder
Stored lyophilised at −20 °C. VIP is extremely sensitive to degradation once in serum, with a half-life under 1 minute, which underlines the need for careful handling of any solution made from it.
After reconstitution
Reconstituted solutions must be used quickly rather than stored, since the peptide breaks down rapidly in solution; no extended in-use period is established for it.
Section 07
Side Effects & Precautions
Transient hypotension and tachycardia (vasodilation). Diarrhea (stimulates intestinal secretion). Flushing and warmth. Hypoglycemia risk at high doses. Limited human safety data for chronic systemic use.
Section 08
Regulatory Status
FDA / United States
Not approved as a standalone drug
Neither VIP nor aviptadil holds an approved NDA or BLA for any indication in the US; FDA's Orphan Drug Designations for ARDS and pulmonary arterial hypertension are a research incentive, not an approval.
COVID-19 emergency use
FDA declined emergency authorisation twice
The agency refused aviptadil's (Zyesami/RLF-100) Emergency Use Authorization request for critical COVID-19 respiratory failure in November 2021 and again in July 2022, citing insufficient efficacy data; an expanded-access protocol still let individual patients receive it.
Compassionate use abroad
Some countries authorised it outside the US process
Georgia authorised emergency use of intravenous aviptadil for critical COVID-19 in July 2021, and Hungary agreed a compassionate-care pathway for the region in December 2021 — decisions made by national regulators, not FDA.
UK, Denmark, New Zealand
Approved there for erectile dysfunction
Aviptadil combined with phentolamine (Invicorp) is an approved second-line intracavernosal injection in these countries for men who don't respond to oral PDE5 inhibitors — a different formulation and indication from the COVID-19 programme.
WADA
Not on the Prohibited List
VIP and aviptadil are not named among the peptide hormones or growth factors banned under category S2, so no anti-doping restriction currently applies.
Approvals for VIP-related compounds are narrow, indication-specific and still evolving — an orphan designation, an expanded-access protocol or a foreign compassionate-use decision is not the same as a marketing approval. Regulatory status differs between jurisdictions and changes over time — check the current documents of your own regulator before relying on any of this.
Section 09
Research Studies
- [1]Signal Transduction by VIP and PACAP ReceptorsLanger I, Jeandriens J, Couvineau A, Sanmukh S, Latek D. · Biomedicines · 2022
- [2]Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neuronsAton SJ, Colwell CS, Harmar AJ, Waschek J, Herzog ED. · Nature Neuroscience · 2005
- [3]Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide prevent inducible nitric oxide synthase transcription in macrophages by inhibiting NF-kappa B and IFN regulatory factor 1 activationDelgado M, Munoz-Elias EJ, Gomariz RP, Ganea D. · Journal of Immunology · 1999
- [4]Tuning immune tolerance with vasoactive intestinal peptide: a new therapeutic approach for immune disordersPozo D, Gonzalez-Rey E, Chorny A, Anderson P, Varela N, Delgado M. · Peptides · 2007
- [5]The significance of vasoactive intestinal peptide in immunomodulationDelgado M, Pozo D, Ganea D. · Pharmacological Reviews · 2004
- [6]Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivoDelgado M, Chorny A, Gonzalez-Rey E, Ganea D. · Journal of Leukocyte Biology · 2005
- [7]Inhaled vasoactive intestinal peptide exerts immunoregulatory effects in sarcoidosisPrasse A, Zissel G, Lutzen N, Schupp J, Schmiedlin R, Gonzalez-Rey E, et al. · American Journal of Respiratory and Critical Care Medicine · 2010
- [8]PKA-dependent activation of the vascular smooth muscle isoform of KATP channels by vasoactive intestinal polypeptide and its effect on relaxation of the mesenteric resistance arteryYang Y, Shi Y, Guo S, Zhang S, Cui N, Shi W, Zhu D, Jiang C. · Biochimica et Biophysica Acta · 2007
- [9]Vasoactive intestinal peptide causes nitric oxide-dependent pulmonary vasodilation in isolated rat lungIwabuchi S, Ono S, Tanita T, Koike K, Fujimura S. · Respiration · 1997
- [10]Inhalation of vasoactive intestinal peptide in pulmonary hypertensionLeuchte HH, Baezner C, Baumgartner RA, Bevec D, Bacher G, Neurohr C, Behr J. · European Respiratory Journal · 2008
- [11]Differential regulation of activity-dependent neuroprotective protein in rat astrocytes by VIP and PACAPZusev M, Gozes I. · Regulatory Peptides · 2004
- [12]VIP-induced neuroprotection of the developing brainPassemard S, Sokolowska P, Schwendimann L, Gressens P. · Current Pharmaceutical Design · 2011
- [13]VIP and PACAP potentiate the action of glutamate on BDNF expression in mouse cortical neuronesPellegri G, Magistretti PJ, Martin JL. · European Journal of Neuroscience · 1998
Section 10
Frequently Asked Questions
VIP is a 28-amino-acid neuropeptide made throughout the nervous system, gut and immune system, acting as a neurotransmitter and immunomodulator through two receptors, VPAC1 and VPAC2. It has vasodilatory, anti-inflammatory and neuroprotective effects, which is why it has been investigated for conditions ranging from pulmonary hypertension to autoimmune disease.
No confirmed benefit: the largest randomized trial (TESICO) found no significant survival difference (odds ratio 1.01, P=.93), a result a 2025 meta-analysis echoed. Earlier, smaller trials and case series had reported improved oxygenation, but aviptadil never received FDA emergency authorization for this use.
This use has no controlled trial behind it and is not registered anywhere as a studied treatment. The circulating protocol, sprayed several times a day, comes from one clinician's regimen and uncontrolled case reports, not from a trial measuring whether it works.
Because VIP is a vasodilator, transient low blood pressure and a fast heart rate are common, along with flushing and diarrhea from its effect on intestinal secretion. In one intravenous COVID-19 trial, low blood pressure occurred in 58% of infusions and diarrhea in 40%, with a third of infusions paused for side effects — human safety data for chronic, long-term use are still limited.
VIP itself is not approved as a standalone drug anywhere. Its synthetic form, aviptadil, was studied under emergency and investigational authorizations for COVID-19 ARDS but was never granted emergency use authorization. It is not on the WADA prohibited list.
The lyophilized powder is stored at −20 °C. Once dissolved it is far less stable — VIP breaks down in blood serum with a half-life under one minute — so any reconstituted solution needs to be used right away rather than stored.
Aviptadil is the synthetic, manufactured version of VIP used in clinical trials such as the COVID-19 and pulmonary hypertension studies, while VIP itself refers to the naturally occurring peptide. They share the same amino-acid sequence, so trial results for aviptadil describe VIP's own pharmacology, not a separate drug.