VIP
Vasoactive intestinal peptide, made synthetically as aviptadil and tested in COVID-19 respiratory failure, where the largest trial was stopped for futility
Vasoactive intestinal peptide (VIP) is a 28-amino-acid signalling peptide found in nerves throughout the gut and lungs. Its synthetic form, aviptadil, was tested in COVID-19 respiratory failure: the largest trial, TESICO, was stopped for futility, while a smaller one reported better survival on a secondary measure. Infused into people with migraine, VIP itself brings attacks on.
What is it?
VIP is released by nerves in the gut, lungs and elsewhere, where it relaxes smooth muscle, widens blood vessels and damps inflammation. In lung tissue it has been reported to increase surfactant and reduce inflammatory signalling, which is what drew attention to it during the pandemic.
Two COVID-19 trials point different ways, and the bigger one is the more reliable. TESICO randomised 461 patients with COVID-19 respiratory failure, 94% of them in intensive care, to intravenous aviptadil or placebo; the trial was stopped for futility, the odds of a better outcome at day 90 were 1.11 and 38% against 36% had died. An earlier 196-patient trial missed its own primary end point but reported twice the odds of survival at day 60 as a secondary finding. A small trial of inhaled aviptadil in 80 hospitalised patients reported discharge about two days sooner than placebo.
Pooling has not rescued it. A 2025 meta-analysis of aviptadil in acute respiratory distress syndrome found the two randomised trials gave a survival odds ratio of 1.01, no benefit, while uncontrolled case series kept reporting better oxygen levels. That gap between case series and trials is the main lesson of the VIP record so far.
Outside COVID-19, a two-hour infusion of VIP triggered migraine attacks in 15 of 21 people with migraine against 1 on placebo, which makes it a tool for studying migraine rather than a treatment for it. VIP is not approved in the US, where aviptadil remains investigational. It also dilates vessels locally: injected into the penis with phentolamine, aviptadil worked for 59% of 308 men who had failed most other treatments.
As a measurement, VIP is mainly used to look for VIPomas, tumours that secrete it and cause severe watery diarrhoea. A 2026 review warns that a mildly raised level rarely means a VIPoma, with a positive predictive value of 12% at the usual threshold. Lower levels have been reported in Parkinson's disease with depression, multiple sclerosis and diabetic bladder dysfunction, all small cross-sectional studies.
Mechanism of Action
VIP is a neuropeptide released by nerves in the gut, lungs and elsewhere; it relaxes smooth muscle, widens blood vessels and damps inflammation.
Vasodilation
VIP widens blood vessels, which explains flushing on infusion, its use in erectile dysfunction injections and its ability to provoke migraine.
Lung
In lung tissue it has been reported to increase surfactant and reduce inflammatory signalling, the rationale for aviptadil in respiratory failure.
Gut secretion
Excess VIP from tumours drives profuse watery diarrhoea and low potassium, which is how VIPomas present.
Published Research
These are the studies that describe VIP and aviptadil, read from their PubMed abstracts: four human trials, three of them in COVID-19.
TESICO: 461 patients with COVID-19 respiratory failure
Intravenous aviptadil as a 12-hour infusion for 3 days, or placebo, in patients mostly in intensive care. The trial was stopped for futility: the odds of a better day-90 outcome were 1.11, and 38% against 36% had died by day 90.
Critical COVID-19: 196 patients
Three days of intravenous aviptadil or placebo. The primary end point, alive and free of respiratory failure at day 60, was not met (odds ratio 1.6). Survival at day 60 was better as a secondary measure (odds ratio 2.0), with less interleukin-6 release by day 3.
Inhaled aviptadil: 80 hospitalised patients
Inhaled aviptadil or placebo on top of standard care. Mean time to discharge was 7.8 days against 10.0, breathlessness scores were lower at day 7 and CT lung damage improved more by day 28. Deaths were 5.1% against 12.2%; the trial was small.
A two-hour infusion in people with migraine: 21 patients
VIP or placebo on two separate days. Migraine attacks followed VIP in 15 of 21 people against 1 of 21 on placebo, resembling their usual attacks, with greater headache intensity and artery widening.
Provoking cluster headache
In active cluster headache, VIP infusion triggered attacks in a third to half of patients, as PACAP38 did; neither did in remission.
Inhaled in sarcoidosis
In sarcoidosis, inhaled VIP was well tolerated, lowered lung-cell TNF-alpha and raised regulatory T cells.
Severe viral ARDS, six patients
In a retrospective series of 6 ICU patients with severe viral ARDS given aviptadil, oxygen saturation and the SpO2/FiO2 ratio improved over 3 days of infusion, with no adverse effects noted and no control group.
Erectile dysfunction injections
In 308 men who had failed most non-surgical treatments, intracavernosal aviptadil with phentolamine worked for 59% overall (76% with partial and 36% with full prior failure); flushing affected 22.5% and priapism 1 man.
High VIP rarely means VIPoma
In a retrospective review, a VIP result above the usual 75 pg/mL threshold had a positive predictive value for VIPoma of only 12%; the optimal threshold was 442 pg/mL, and the authors advise testing only in specific clinical scenarios.
A VIPoma in practice
A woman with chronic diarrhoea and potassium of 2.1 mmol/L had an 8 cm pancreatic neuroendocrine tumour with serum VIP eight times normal; a somatostatin analogue and surgery resolved her symptoms.
VIP-secreting tumours in children
Two children with chronic secretory diarrhoea had VIP-secreting neuroblastic tumours that were metastatic and inoperable at diagnosis, one fatal; the authors urge earlier consideration of the diagnosis.
Unchanged by anti-CGRP treatment
In migraine patients treated with anti-CGRP antibodies, plasma VIP and PACAP stayed stable and did not distinguish responders, while galcanezumab lowered CGRP.
Parkinson's disease mood
People with Parkinson's disease had lower serum VIP than healthy controls, and lower again with anxiety and depression; VIP distinguished those with affective symptoms with an AUC of 0.89.
Diabetic bladder
VIP and serotonin were reduced in diabetic neurogenic bladder, fell with severity and rose with treatment alongside urodynamic improvement.
Aviptadil in ARDS: meta-analysis
Across 9 studies with 665 patients, the two randomised trials showed no survival benefit (odds ratio 1.01), while the seven case series reported better oxygenation and 48 of 54 survivors; the authors call for larger trials.
A marker in multiple sclerosis?
A systematic review of 7 studies found VIP often lower in MS but inconsistently, with no genetic association and too much bias to support it as a biomarker.
Cartilage cells
In 3D cultures from human osteoarthritis models, VIP increased cell proliferation and matrix production and reduced complement C1R and the enzymes MMP1 and MMP13.
Bone cells
In co-cultures of human osteoblasts, osteocytes and osteoclasts, VIP lowered the RANKL/OPG ratio and sclerostin expression, an osteoprotective pattern.
Dosing Data
VIP is not approved in the US. Trials infused aviptadil intravenously; research studies have used short infusions to provoke headache.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
Side Effects & Contraindications
Reported Side Effects
From the trials above.
Contraindications & Cautions
VIP has no US label. These cautions follow from its trial record.
Legal Status
VIP is investigational in the US as aviptadil.
Frequently Asked Questions
?What is VIP?
Vasoactive intestinal peptide, a 28-amino-acid signalling peptide from nerves in the gut and lungs that relaxes smooth muscle and damps inflammation.
?Did aviptadil work in COVID-19?
The largest trial, TESICO, was stopped for futility and found no difference at day 90. A smaller trial missed its primary end point but reported better day-60 survival as a secondary measure.
?Why is it infused?
VIP is cleared from plasma within minutes, so the trials gave it as long infusions or inhaled it.
?Does VIP cause migraine?
In people who already get migraine, a two-hour infusion brought on attacks in 15 of 21, against 1 of 21 on placebo.
?What is a VIPoma?
A tumour that secretes VIP, such as the pancreatic neuroendocrine tumour in a 2026 case report, causing severe watery diarrhoea and low potassium. A mildly raised VIP level rarely means one: at the usual threshold only 12% of positives had a VIPoma in a 2026 review.
?Is VIP used for erectile dysfunction?
Aviptadil combined with phentolamine has been injected into the penis; in 308 men who had failed most other treatments it worked for 59%, with flushing in 22.5%.
References
- [fda] FDA. Drugs@FDA (openFDA): no approved application for aviptadil (vasoactive intestinal peptide). Read September 30, 2026.
- [pubmed] Brown SM, et al. "Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial." Lancet Respir Med, 2023;11(9):791-803. PMID: 37348524.
- [pubmed] Youssef JG, et al. "The Use of IV Vasoactive Intestinal Peptide (Aviptadil) in Patients With Critical COVID-19 Respiratory Failure: Results of a 60-Day Randomized Controlled Trial." Crit Care Med, 2022;50(11):1545-1554. PMID: 36044317.
- [pubmed] Esendagli D, et al. "Inhaled Aviptadil Is a New Hope for Recovery of Lung Damage due to COVID-19." Med Princ Pract, 2025;34(2):191-200. PMID: 39870064.
- [pubmed] Pellesi L, et al. "Effect of Vasoactive Intestinal Polypeptide on Development of Migraine Headaches: A Randomized Clinical Trial." JAMA Netw Open, 2021;4(8):e2118543. PMID: 34357396.
- [pubmed] Delgado M, et al. "Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions." Amino Acids, 2013;45(1):25-39. PMID: 22139413.
- [clinicaltrials] ClinicalTrials.gov NCT04311697: COVID-AIV, intravenous aviptadil for critical COVID-19 with respiratory failure, completed (registry record read September 30, 2026).
- [clinical-trial] Vollesen ALH, et al. "The effect of pituitary adenylate cyclase-activating peptide-38 and vasoactive intestinal peptide in cluster headache." Cephalalgia, 2020;40(13):1474-1488. PMID: 32962406.
- [pubmed] Prasse A, et al. "Inhaled vasoactive intestinal peptide exerts immunoregulatory effects in sarcoidosis." Am J Respir Crit Care Med, 2010;182(4):540-8. PMID: 20442436.
- [pubmed] Udupa AA, et al. "Aviptadil Therapy in Acute Respiratory Distress Syndrome Patients: A Systematic Review and Meta-analysis." Indian J Crit Care Med, 2025;29(11):942-953. PMID: 41368449.
- [pubmed] Sampley S, et al. "Effect of Aviptadil, a Novel Therapy, on Clinical Outcomes of Patients with Viral-related Severe ARDS: A Retrospective Observational Study." Indian J Crit Care Med, 2024;28(1):70-74. PMID: 38510776.
- [pubmed] Al-Mitwalli A, et al. "Intracavernosal injection of aviptadil and phentolamine for refractory erectile dysfunction." J Sex Med, 2025;22(5):726-730. PMID: 40192471.
- [pubmed] Korleski J, et al. "Elevated vasoactive intestinal peptide concentrations poorly predict VIPoma." Endocr Relat Cancer, 2026;33(1). PMID: 41498509.
- [pubmed] Stafl L, et al. "Severe hypokalaemia and secretory diarrhoea secondary to a vasoactive intestinal peptide-secreting tumour (VIPoma)." BMJ Case Rep, 2026;19(7). PMID: 42409425.
- [pubmed] Barbar M, et al. "Vasoactive Intestinal Peptide (VIP)-Secreting Neuroblastic Tumors in Children Presenting With Chronic Secretory Diarrhea: A Report of Two Cases." Cureus, 2026;18(7):e112564. PMID: 42591963.
- [pubmed] Chiasserini D, et al. "CGRP, VIP and PACAP plasmatic levels in migraine patients before and after anti-CGRP(R) monoclonal antibodies treatment." Cephalalgia, 2026;46(6):3331024261429802. PMID: 42307444.
- [pubmed] Li L, et al. "Serum VIP and IL-1β Levels Are Associated With Anxiety and Depression in Patients With Parkinson's Disease: A Cross-Sectional Study." Brain Behav, 2026;16(9):e71742. PMID: 42677804.
- [pubmed] Shi L, et al. "Clinical implications of vasoactive intestinal peptide and 5-hydroxytryptamine in diabetic neurogenic bladder and their relationship with post-void residual." J Med Biochem, 2026;45(2):429-437. PMID: 42769828.
- [pubmed] Cabrera-Martín A, et al. "Vasoactive intestinal Peptide as a diagnostic or prognostic biomarker in multiple sclerosis: A systematic review." Mult Scler Relat Disord, 2026;113:107377. PMID: 42447728.
- [pubmed] Tecza K, et al. "Vasoactive intestinal peptide advances chondrogenesis and modulates pathogenic mediators in human osteoarthritis." J Mol Med (Berl), 2026;104(1). PMID: 42178419.
- [pubmed] Castro-Vázquez D, et al. "Osteoprotective effects of the neuropeptide VIP: insights from triple cultures of human osteocytes, osteoblasts, and osteoclasts." Transl Res, 2026;292:40-51. PMID: 42013997.
Sources & Citations
Studies were read from their PubMed abstracts; aviptadil has no US label. Read October 7, 2026.
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