VIP Research

Vasoactive intestinal peptide is a 28-residue neuropeptide found in mammalian nerve and gut tissue. ^[22] Aviptadil is the international nonproprietary name for synthetic VIP. ^[22] The research splits into two threads that share a molecule and share almost nothing else. One produced an authorized combination product for erectile dysfunction. ^[20] The other tested aviptadil in COVID-19 respiratory failure, and its two largest trials failed. ^[1][3] Collapsing the two is a common error, so this article keeps them apart.

What VIP and aviptadil are

Aviptadil is not an analogue of VIP but synthetic VIP itself, sequence-identical to the endogenous human peptide. ^[22] The 2025 meta-analysis calls it a synthetic analogue, and that is inaccurate. ^[5]

Two CAS numbers circulate for one structure, 37221-79-7 against vasoactive intestinal peptide generally and 40077-57-4 against the name aviptadil. ^[22] Both resolve to the same InChIKey on PubChem, so the two records describe one molecule. ^[22]

Both also give the formula and mass of the C-terminal free acid, and that is a trap. ^[22] Authentic VIP and authentic aviptadil are C-terminally amidated instead. ^[22] A specification block copied from PubChem therefore describes a different species from the one a certificate of analysis should report. ^[22] VIP should be checked against its own certificate, not a database record.

Regulatory status, stated precisely

The line usually applied to research peptides, that a compound is not approved for human therapeutic use, is false here. ^[20] Aviptadil is an authorized active substance, and its authorization is narrow in four ways. ^[16][20] It holds only in fixed combination with phentolamine mesylate, only for erectile dysfunction, only by intracavernosal injection, and only under individual national marketing authorizations. ^[16][20] No aviptadil product is approved for any respiratory, inflammatory or systemic indication in the United States or the European Union. ^[24][25]

The product is long established. ^[20] UK marketing approval was granted in October 2000, and New Zealand approval is recorded by April 2000. ^[20] An independent 2019 review says approval in this class is mainly limited to alprostadil, with the aviptadil combination added in a few regions. ^[16] There is no centralized European authorization and no European Public Assessment Report. ^[25] No centralized application record was found either, so nothing here should be read as an EMA refusal. ^[25]

Drugs@FDA holds no aviptadil record, and the only US listings are bulk-ingredient registrations carrying no application number. ^[24] The FDA declined two separate emergency use authorization requests for aviptadil in COVID-19, in November 2021 and July 2022. ^[23] Those were agency decisions rather than sponsor withdrawals. ^[23]

Aviptadil was also granted European orphan designations for acute lung injury, sarcoidosis and ARDS. ^[25] The agency's register lists all three with a positive designation status. ^[25] Designation is a development incentive rather than an approval, and the agency says so on those pages. ^[25] The two oldest designations have produced no authorized product in roughly nineteen years. ^[25]

US development stalled early, with all clinical trials placed on hold in August 1999 and the FDA moving to a partial hold in July 2000. ^[20] The underlying safety signal came from rodent data on a competitor's phentolamine product, not from aviptadil itself. ^[20]

Mechanism, and who produced the evidence for it

The human anti-inflammatory evidence is one uncontrolled study, in which Prasse and colleagues gave inhaled VIP to 20 patients with sarcoidosis. ^[17] It was open-label phase 2, with no control arm and no clinical efficacy endpoint. ^[17] TNF-alpha production by bronchoalveolar lavage cells fell, and lavage regulatory T cells rose. ^[17] The same paper reported in vitro conversion of naive human T cells into FoxP3-positive regulatory T cells. ^[17] Its author list includes staff of the sponsor that held the two oldest orphan designations. ^[17]

The second pillar is a pulmonary hypertension deficiency story. ^[19] Petkov and colleagues reported low VIP in human serum and lung tissue, alongside claimed hemodynamic improvement on substitution. ^[19] That was eight human patients, uncontrolled and unblinded. ^[19] A later human single-dose study called the pulmonary vasodilating effect modest and short-lived. ^[18] Only 6 of 20 patients achieved a fall in pulmonary vascular resistance greater than 20%. ^[18] That paper's co-authors also included personnel from the same sponsor. ^[18] Both mechanistic pillars therefore rest on uncontrolled human work with one commercially interested sponsor behind it. ^[17][18][19]

VIP research in COVID-19 and ARDS

A PubMed search restricted to the randomized controlled trial publication type returns exactly three aviptadil trials. ^[26] Two are null and the third is small and contested. ^[1][3][7]

TESICO is the decisive one, and it was NIH-funded. ^[1] It randomized 471 human patients at 28 US sites, 461 in the modified intention-to-treat analysis. ^[1] The day-90 primary ordinal outcome gave an odds ratio of 1.11 (95% CI 0.80 to 1.55, p=0.54). ^[1] Mortality to day 90 was 38% on aviptadil against 36% on placebo (HR 1.04, 95% CI 0.77 to 1.41, p=0.78). ^[1] The day-5 safety composite ran numerically the wrong way, at 63% against 56% (OR 1.40, 95% CI 0.94 to 2.08, p=0.10). ^[1] An independent monitoring board recommended stopping the aviptadil comparison for futility. ^[1] The journal published an independent editorial alongside it, titled as a negative trial. ^[2]

The sponsor trial came first, and much of the circulating positive claim for intravenous aviptadil traces back to its secondary results. ^[3] Youssef and colleagues randomized 196 human patients and missed the primary endpoint, at an odds ratio of 1.6 (95% CI 0.86 to 3.11). ^[3] Its own conclusions state that there was no difference between aviptadil and placebo. ^[3] They then recommend the compound on a secondary survival endpoint and unadjusted subgroups. ^[3] One author is affiliated with the company commercializing it. ^[3] The journal ran a critical editorial in the same issue. ^[4] TESICO was roughly 2.4 times larger and did not reproduce those secondary findings. ^[1][3]

A 2025 systematic review covered nine human studies and 665 patients to October 2025. ^[5] Its pooled survival odds ratio against placebo, which rests on the two randomized trials, was 1.01 (95% CI 0.72 to 1.42, p=0.93). ^[5] Its authors state that current evidence does not indicate a significant survival benefit, and they declare no conflict of interest. ^[5] The companion editorial asks whether aviptadil in ARDS is promise or mirage. ^[6] The uncontrolled case series inside that review cannot support any efficacy claim, and one covered six human patients. ^[5][21]

One human inhaled trial was positive, and Esendagli and colleagues randomized 80 patients across nine centers. ^[7] Mean time to discharge was 7.8 days on aviptadil against 10 days on placebo (p=0.049). ^[7] Day-7 dyspnea scores and day-28 CT improvement also favored aviptadil. ^[7] Both measures were null at their earlier timepoints, with dyspnea no different at day 3 (p=0.090) and CT damage no different at day 1 (p=0.962). ^[7] The lower death rate, 5.1% against 12.2%, was a raw proportion given with no test and no confidence interval. ^[7]

Two published letters responded to that trial in the same journal. ^[8][9] Gao and Lu note that the sample size was calculated on oxygen saturation while the declared primary endpoint was time to discharge. ^[8] They also note that patients who deteriorated and needed intensive care were excluded after randomization, which they argue could omit failures of therapy and inflate efficacy. ^[8] The authors' reply confirms both the oxygen-saturation calculation and the post-randomization exclusions, and defends them. ^[28] Charles and colleagues, writing more favorably, record that the dyspnea benefit was not significant at day 28. ^[9]

The program registered on ClinicalTrials.gov beyond those three trials is largely unreported. ^[29] Two sponsor trials of inhaled aviptadil were terminated or withdrawn by sponsor decision, one after 144 enrollments and one at zero. ^[29] An investigator-led Swiss inhaled trial was terminated for recruitment failure. ^[29] A randomized aviptadil arm in the I-SPY COVID platform trial is closed. ^[29] None of those four has published a result. ^[29]

The erectile dysfunction evidence in humans

The registration-era data are one program reported twice rather than two independent trials. ^[12][13] Two 1999 human placebo-controlled reports share doses, device, several investigators and near-identical response rates two months apart. ^[12][13] Roughly 75% and 66% of men responded to the two combination presentations, against 12% and 18% on placebo. ^[12] Transient facial flushing was the principal adverse event in both, accompanying 40% of 1,711 injections in the first report and 33.9% of 2,770 in the second. ^[12][13] An earlier open-label human salvage series in 70 men whose other injectables had failed reported 47 usable erections, with facial flushing in 53%. ^[14]

Independent practice data are more sober, and a 2025 retrospective human series of 308 men at one referral center found 59% overall effectiveness. ^[10] That split sharply by indication, at 76% in men switched for intolerable alprostadil pain against 36% in men who had failed maximal-dose alprostadil (p<0.0001). ^[10] Facial flushing occurred in 22.5% of them, and ischemic priapism in one patient. ^[10] A commercially linked 2008 review had asserted effectiveness in at least 80% of men. ^[15] That review names the then licensee, and its co-author worked at a pharmaceutical consultancy. ^[15]

The only head-to-head randomized human comparison favored alprostadil on efficacy in its dose-finding phase, at 83% against 73% for the VIP combination (p=0.002). ^[11] Patients in that phase still preferred the VIP combination, 69% against 31% (p=0.011). ^[11] In the second phase the efficacy gap disappeared, with 83 to 85% of injections producing an adequate erection across all three presentations. ^[11] The reason for the preference is tolerability, and it is a trade rather than a clean win. ^[11] Pain accompanied 28% of alprostadil injections against 3% of VIP combination injections. ^[11] Facial flushing ran the other way, at 3% for alprostadil against 16 to 17% for the VIP combination (p<0.001). ^[11]

Where controlled human evidence is absent

Intranasal VIP replacement appears in the chronic inflammatory response syndrome and mold illness literature. ^[27] A PubMed search pairing vasoactive intestinal peptide or aviptadil with that syndrome returns two records, and neither is a trial of VIP. ^[26] One is a single-patient case report describing intranasal VIP alongside biotoxin removal, dental extractions and a relaxation program, so it cannot attribute any outcome to VIP. ^[27] The other is a retrospective human cohort that measured VIP as a biomarker rather than administering it. ^[26] No controlled human trial of VIP in that indication is indexed in PubMed. ^[26]

Conclusion

Aviptadil is a genuinely authorized active substance, and its authorization is narrow and specific. ^[16][20] The erectile dysfunction evidence is real, and it describes a tolerability trade rather than superior efficacy. ^[10][11] The independent practice data are more sober than the registration-era figures. ^[10][12] The respiratory evidence is null wherever it has been tested at scale and independently, and the one positive randomized trial is small and contested. ^[1][5][7] VIP sold as research-grade material is not a medicine and is not for human consumption.

Frequently Asked Questions

Is aviptadil approved for human use anywhere? Yes, but only in a narrow form. It is authorized only in fixed combination with phentolamine mesylate, only for erectile dysfunction, only by intracavernosal injection, and only under national marketing authorizations. ^[16][20] No aviptadil product is approved for any respiratory or systemic indication in the United States or the European Union. ^[24][25]

Is aviptadil the same molecule as VIP, or an analogue of it? It is the same molecule. ^[22] Aviptadil is the international nonproprietary name for synthetic VIP, sequence-identical to the endogenous human peptide. ^[22] The 2025 meta-analysis describes it as a synthetic analogue, and that description is inaccurate. ^[5]

Did aviptadil work in COVID-19? Not in the intravenous trials, which are the largest ones. ^[1][3] The NIH-funded trial returned an odds ratio of 1.11 on its day-90 primary outcome (p=0.54) and was stopped for futility. ^[1] The 2025 pooled analysis returned a survival odds ratio of 1.01 against placebo (p=0.93). ^[5] One small inhaled trial did report a positive result, and two published letters responded to it. ^[7][8][9]

Has the positive inhaled trial been replicated? Not in the indexed literature so far. ^[26] A PubMed search restricted to randomized controlled trials returns three aviptadil trials in total, and only the 80-patient inhaled trial was positive. ^[7][26] One letter challenged its power calculation and its post-randomization exclusions, and the authors' reply confirmed both. ^[8][28]

References

1. 1

   Brown SM, et al. Lancet Respiratory Medicine, 2023;11(9):791-803. PMID 37348524.; DOI: 10.1016/S2213-2600(23)00147-9. Registry record NCT04843761.
2. 2

   Lee WL, Slutsky AS. Lancet Respiratory Medicine, 2023;11(9):759-760. PMID 37348523.; DOI: 10.1016/S2213-2600(23)00218-7. Comment on reference 1.
3. 3

   Youssef JG, et al. Critical Care Medicine, 2022;50(11):1545-1554. PMID 36044317.; DOI: 10.1097/CCM.0000000000005660. Registry record NCT04311697.
4. 4

   Auld SC. Critical Care Medicine, 2022;50(11):1662-1664. PMID 36227034.; DOI: 10.1097/CCM.0000000000005686. Comment on reference 3.
5. 5

   Udupa AA, et al. Indian Journal of Critical Care Medicine, 2025;29(11):942-953. PMID 41368449.; DOI: 10.5005/jp-journals-10071-25084. Declaration read from the PMC full text, PMC12683555: "Source of support: Nil. Conflict of interest: None."
6. 6

   Chanchalani G. Indian Journal of Critical Care Medicine, 2025;29(11):895-896. PMID 41368453.; DOI: 10.5005/jp-journals-10071-25095.
7. 7

   Esendagli D, et al. Medical Principles and Practice, 2025;34(2):191-200. PMID 39870064.; DOI: 10.1159/000543773. Registry record NCT04844580.
8. 8

   Gao C, Lu X. Medical Principles and Practice, 2026;35(1):90-91. PMID 40928995.; DOI: 10.1159/000548272. Letter on reference 7; full text read from PMC12885511.
9. 9

   Charles EJ, et al. Medical Principles and Practice, 2026;35(1):95-96. PMID 40675136.; DOI: 10.1159/000547366. Letter on reference 7; full text read from PMC12885515.
10. 10

    Al-Mitwalli A, et al. Journal of Sexual Medicine, 2025;22(5):726-730. PMID 40192471.; DOI: 10.1093/jsxmed/qdaf067.
11. 11

    Shah PJ, et al. Current Medical Research and Opinion, 2007;23(10):2577-83. PMID 17875241.; DOI: 10.1185/030079907X233232.
12. 12

    Dinsmore WW, et al. BJU International, 1999;83(3):274-9. PMID 10233493.; DOI: 10.1046/j.1464-410x.1999.00935.x.
13. 13

    Sandhu D, et al. International Journal of Impotence Research, 1999;11(2):91-7. PMID 10356669.; DOI: 10.1038/sj.ijir.3900388.
14. 14

    Dinsmore WW, et al. British Journal of Urology, 1998;81(3):437-40. PMID 9523666.; DOI: 10.1046/j.1464-410x.1998.00564.x.
15. 15

    Dinsmore WW, Wyllie MG. BJU International, 2008;102(8):933-7. PMID 18485029.; DOI: 10.1111/j.1464-410X.2008.07764.x.
16. 16

    Duncan C, et al. World Journal of Urology, 2019;37(6):1007-1014. PMID 30895359.; DOI: 10.1007/s00345-019-02727-5.
17. 17

    Prasse A, et al. American Journal of Respiratory and Critical Care Medicine, 2010;182(4):540-8. PMID 20442436.; DOI: 10.1164/rccm.200909-1451OC.
18. 18

    Leuchte HH, et al. European Respiratory Journal, 2008;32(5):1289-94. PMID 18978135.; DOI: 10.1183/09031936.00050008.
19. 19

    Petkov V, et al. Journal of Clinical Investigation, 2003;111(9):1339-46. PMID 12727925.; DOI: 10.1172/JCI17500.
20. 20

    Keijzers GB. Current Opinion in Investigational Drugs, 2001;2(4):545-9. PMID 11566015.
21. 21

    Sampley S, et al. Indian Journal of Critical Care Medicine, 2024;28(1):70-74. PMID 38510776.; DOI: 10.5005/jp-journals-10071-24594.
22. 22

    NCBI PubChem, PUG-REST, retrieved 28 August 2026. CAS 37221-79-7 resolves to CID 53314964 and CAS 40077-57-4 to CID 16132300. Both records return C147H237N43O43S, MW 3326.8, InChIKey VBUWHHLIZKOSMS-RIWXPGAOSA-N, which is the C-terminal free acid. The amidated peptide is C147H238N44O42S.
23. 23

    FDA emergency use authorization declines of November 2021 and 1 July 2022, announced by the sponsor and reported independently across trade coverage, including BioSpace, Pharmafile and BioBuzz. Rechecked 28 August 2026. No primary FDA letter was located, and decline letters of this kind are not routinely published by the agency, so this entry rests on secondary reporting.
24. 24

    US Food and Drug Administration, openFDA. Field-qualified queries of drugsfda and drug/label on substance name, generic name, brand name and active ingredient return no aviptadil record. The three aviptadil NDC entries are bulk-ingredient registrations with no application number. Retrieved 28 August 2026.
25. 25

    European Medicines Agency. Orphan designation pages EU/3/06/395 (acute lung injury, granted 28 August 2006), EU/3/07/473 (sarcoidosis, granted 14 September 2007) and EU/3/26/3200 (ARDS, granted 23 February 2026), read live on ema.europa.eu on 28 August 2026. Each carries the field "Orphan designation status: Positive", and the ARDS page states that designation "does not mean the medicine is available or authorised for use". No centralized marketing authorization and no European Public Assessment Report for aviptadil was found.
26. 26

    NCBI PubMed, E-utilities esearch, re-run 28 August 2026. `aviptadil AND randomized-controlled-trial[pt]` returns 3 records (39870064, 37348524, 36044317). A phrase-qualified search for vasoactive intestinal peptide or aviptadil with "chronic inflammatory response syndrome" returns 2 records: 27165859, printed as reference 27, a single-patient case report; and 42077435 (DiTulio M, Navarro-Torres CA, Front Endocrinol 2026;17:1728408; DOI: 10.3389/fendo.2026.1728408), a retrospective observational cohort of 188 adults in which VIP was one of three measured biomarkers and was not administered. Neither is a trial of VIP in that indication.
27. 27

    Gunn SR, et al. American Journal of Case Reports, 2016;17:320-5. PMID 27165859.; DOI: 10.12659/ajcr.896949.
28. 28

    Esendagli D, et al. Medical Principles and Practice, 2026;35(1):92-94. PMID 40652932.; DOI: 10.1159/000547370. Author reply to reference 8; full text read from PMC12885512.
29. 29

    ClinicalTrials.gov, API v2, retrieved 28 August 2026. NCT04360096 TERMINATED, whyStopped "Sponsor decision", enrollment 144. NCT05137795 WITHDRAWN, whyStopped "Sponsor decision", enrollment 0. NCT04536350 TERMINATED for recruitment difficulty, enrollment 83, lead sponsor Prof. Dr. Jorg Leuppi. NCT04488081 lists an arm "Aviptadil + Standard of Care (CLOSED)"; no publication covering that arm was located.