VIP (vasoactive intestinal peptide)

Human, and the only application here with a marketing approval behind it. The product is a fixed intracavernosal injection of aviptadil (synthetic VIP) 25 µg with phentolamine mesylate 1–2 mg, marketed as Invicorp for moderate-to-severe erectile dysfunction. The pairing is rational rather than arbitrary: VIP acts on the veno-occlusive mechanism with little effect on arterial inflow, while phentolamine, an α-adrenergic antagonist, increases arterial inflow — complementary halves of an erection ^{11Reference 11Dinsmore WW · 2008ReviewVasoactive intestinal polypeptide/phentolamine for intracavernosal injection in erectile dysfunction — reviewView study →}. The product has a long and slow development history — aviptadil was under investigation for erectile dysfunction by its original developer (Senatek) well before it acquired its COVID-era reputation ^{12Reference 12Keijzers GB · 2001ReviewAviptadil (Senatek) — reviewView study →}. A 2019 systematic review of intracavernosal injectables states the regulatory position plainly: approval of ICI agents is mainly limited to alprostadil, “with the recent addition of aviptadil/phentolamine combination therapy in a select few geographical regions” ^{13Reference 13Duncan C et al. · 2019Systematic reviewErectile dysfunction: a global review of intracavernosal injectables — systematic reviewView study →}. That is the approval, and it is narrow.

The efficacy numbers deserve care, because two sources disagree and the more optimistic one is the less independent. A 2008 narrative review written from within the product’s development orbit reported effectiveness in ≥80% of men with very low penile pain and negligible priapism risk ^{11Reference 11Dinsmore WW · 2008ReviewVasoactive intestinal polypeptide/phentolamine for intracavernosal injection in erectile dysfunction — reviewView study →}.

The largest independent dataset is a 2025 retrospective single-center series of 308 men referred specifically because they had failed or could not tolerate alprostadil: 59% overall resumed penetrative sexual activity, and the result split sharply by why they were referred — 76% among men who had found alprostadil too painful, versus 36% among men who had failed maximal-dose alprostadil ^{14Reference 14Al-Mitwalli A et al. · 2025Intracavernosal injection of aviptadil and phentolamine for refractory erectile dysfunction — human (retrospective series, n=308)View study →}.

Facial flushing occurred in 22.5%, and ischemic priapism in one patient (0.3%) ^{14Reference 14Al-Mitwalli A et al. · 2025Intracavernosal injection of aviptadil and phentolamine for refractory erectile dysfunction — human (retrospective series, n=308)View study →}.

So the tolerability advantage over alprostadil looks real; the ≥80% efficacy figure does not survive contact with contemporary practice in a refractory population.

Gap: Every efficacy figure belongs to the combination, and no trial randomized VIP alone — its independent contribution is unknown. The best contemporary dataset is retrospective, single-center, and uncontrolled, in a pre-selected refractory population. There is no US approval. And all of this is intracavernosal injection: none of it transfers to inhaled, intranasal or systemic VIP.

Human RCTs — and the headline result is negative. Synthetic VIP (aviptadil, branded Zyesami/RLF-100) was developed for COVID-19 hypoxemic respiratory failure on a lung-protective rationale: VIP concentrates in alveolar type-II cells, upregulates surfactant and suppresses cytokine synthesis ^{3Reference 3Youssef JG et al. · 2022RCTThe use of IV vasoactive intestinal peptide (aviptadil) in patients with critical COVID-19 respiratory failure: results of a 60-day randomized controlled trial — human (RCT, n=196)View study →}. This produced the largest human clinical program any peptide here has, so the null it delivered is unusually well-earned.

The first substantial trial randomized 196 patients 2:1 to three days of IV aviptadil or placebo. Its primary endpoint — alive and free of respiratory failure at day 60 — was not met (OR 1.6, 95% CI 0.86–3.11). A secondary 60-day survival analysis reached significance (OR 2.0, 95% CI 1.1–3.9, p=0.035), and the authors argued from it, but their own stated conclusion on the primary was that “there was no difference between Aviptadil versus placebo” ^{3Reference 3Youssef JG et al. · 2022RCTThe use of IV vasoactive intestinal peptide (aviptadil) in patients with critical COVID-19 respiratory failure: results of a 60-day randomized controlled trial — human (RCT, n=196)View study →}.

The definitive test was TESICO (NCT04843761), a NIH-funded, randomized, placebo-controlled trial across 28 US sites. Among 461 patients in the modified intention-to-treat analysis, the odds ratio for a better outcome on the primary ordinal endpoint at day 90 was 1.11 (95% CI 0.80–1.55, p=0.54); cumulative 90-day mortality was 38% on aviptadil versus 36% on placebo (HR 1.04, 95% CI 0.77–1.41, p=0.78). The data and safety monitoring board recommended stopping the aviptadil arm for futility in May 2022 ^{4Reference 4Brown SM et al. · 2023RCTIntravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial — human (RCT, n=461 analysed; stopped for futility)View study →}.

A separate, smaller line of work used the inhaled route: a multicenter double-blind RCT in 80 hospitalized patients reported a mean time to discharge of 7.8 versus 10 days (p=0.049) and greater day-28 CT improvement (p=0.028) ^{5Reference 5Esendagli D et al. · 2025RCTInhaled aviptadil is a new hope for recovery of lung damage due to COVID-19 — human (RCT, n=80)View study →}.

That is a single small positive trial against a large negative one, and the 2025 systematic review and meta-analysis is the fairest summary: pooling the randomized evidence gave a survival odds ratio of 1.01 (95% CI 0.72–1.42, p=0.93) — no significant benefit ^{6Reference 6Udupa AA et al. · 2025Meta-analysisAviptadil therapy in acute respiratory distress syndrome patients: a systematic review and meta-analysis — meta-analysis of human studiesView study →}.

Note that the pooled RCT evidence in that meta-analysis is the same two trials described above, so it is a re-analysis of this data, not additional confirmation of it.

Aviptadil is not approved for COVID-19 or ARDS anywhere. Public reporting and sponsor announcements describe the FDA declining Emergency Use Authorization; those are company and regulator statements rather than indexed literature, so they are noted here without a reference number.

Gap: This is a well-evidenced null, not an untested idea. The remaining uncertainty is narrow: whether the inhaled route behaves differently from intravenous infusion, which rests on one 80-patient trial that has never been confirmed at scale. All human data are in critically ill hospitalized inpatients receiving supervised IV or nebulized dosing.

Human, but open-label and biomarker-only — and this is native VIP, not an analogue. Twenty patients with histologically proven active pulmonary sarcoidosis inhaled nebulized VIP for four weeks in an open phase II study. Treatment was safe and well tolerated and produced a coherent immunoregulatory shift within the lung: significantly reduced TNF-α production by cells isolated from bronchoalveolar lavage fluid, and increased numbers of bronchoalveolar CD4⁺CD127⁻CD25⁺ regulatory T cells with demonstrable suppressive activity on effector T cells. Parallel in-vitro work showed VIP converting naïve CD4⁺CD25⁻ T cells into FoxP3⁺ regulatory T cells ^{1Reference 1Prasse A et al. · 2010Inhaled vasoactive intestinal peptide exerts immunoregulatory effects in sarcoidosis — human (open-label phase II, n=20)View study →}. The authors describe it as the first demonstration of an immunoregulatory effect of VIP in humans, which it plausibly is.

What it is not is a demonstration that patients got better. There was no control group, no blinding, no randomization, twenty participants, and the endpoints were immune-cell measurements rather than lung function, symptoms or disease progression. Sixteen years on it has not been replicated or followed by a controlled trial.

Gap: One small uncontrolled study with surrogate endpoints. No randomized trial, no clinical-outcome data, no replication.

Human RCT — but of a different molecule. Endogenous VIP is a potent airway bronchodilator, and reviews have long framed inhaled VIP agonists as a plausible respiratory therapy while flagging the half-life as the practical obstacle ^{7Reference 7Mathioudakis A et al. · 2013ReviewVasoactive intestinal peptide inhaled agonists: potential role in respiratory therapeutics — reviewView study →}. That obstacle is why the human asthma data are for a stabilized analogue, not VIP: Ro 25-1553, a cyclic VPAC2-selective agonist.

In a double-blind, randomized, placebo-controlled crossover study in 24 patients with moderate stable asthma, inhaled Ro 25-1553 600 µg produced rapid bronchodilation — a geometric mean FEV₁ increase over placebo of 6% (95% CI 4–9) within three minutes, comparable to formoterol’s 8% (95% CI 5–10). Maximum effect over 24 hours was similar too (7% versus 10%). The difference was duration: the Ro 25-1553 effect was attenuated by five hours, while formoterol was still bronchodilating at twelve ^{10Reference 10Lindén A et al. · 2003RCTBronchodilation by an inhaled VPAC(2) receptor agonist in patients with stable asthma — human (randomised placebo-controlled crossover, n=24; analogue Ro 25-1553)View study →}.

Neither produced clinically relevant side effects. Related stable analogues relax airway and pulmonary vasculature in mouse and rat lungs ^{19Reference 19Yin J et al. · 2013AnimalVasodilatory effect of the stable vasoactive intestinal peptide analog RO 25-1553 in murine and rat lungs — animal (mouse, rat)View study →}.

Gap: The human efficacy belongs to an analogue, not to VIP, and the analogue was weaker and much shorter-acting than an existing standard drug — which is why it was not developed further. Native VIP is not a viable inhaled asthma therapy on pharmacokinetic grounds alone.

One small open-label human study, and a follow-up program that never reported. The rationale is a deficiency argument: patients with primary pulmonary hypertension were found to have reduced VIP in serum and lung tissue with compensatory upregulation of VPAC receptors. On that basis, eight patients received VIP and showed decreased mean pulmonary artery pressure, increased cardiac output and increased mixed venous oxygen saturation, without reported side effects ^{9Reference 9Petkov V et al. · 2003Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension — human (open-label, n=8)View study →}. The authors themselves framed it as providing “enough proof for further investigation” — an explicitly preliminary claim, from an uncontrolled study of eight people.

What happened next is worth stating precisely, because it is easy to describe wrongly in either direction. The follow-up was pemziviptadil (PB1046), a long-acting sustained-release VIP analogue designed to solve the half-life problem; its phase 2 trial in pulmonary arterial hypertension (NCT03556020, n=35) was terminated — but for study-drug resupply delays during COVID-19, not for futility or harm. A second pemziviptadil trial (NCT04433546) was terminated because the company was “no longer pursuing” the indication. So the correct statement is not that controlled work disproved the idea; it is that the controlled work was abandoned before it produced an efficacy readout. Current reviews treat VIP’s role in pulmonary disease as unproven and pharmacokinetically constrained ^{8Reference 8Zhong HL et al. · 2023ReviewThe role of vasoactive intestinal peptide in pulmonary diseases — reviewView study →}.

Gap: The only positive human data are an uncontrolled n=8 study from 2003. No randomized trial has ever reported, no VIP-based therapy is approved for PAH, and the analogue program that would have answered the question was discontinued for commercial and supply reasons.

Animal only — and the gap here is total. VIP is a genuine endogenous immunomodulator: it shifts Th1/Th2 balance, induces regulatory T cells and dampens innate inflammation through VPAC1 and VPAC2 ^{15Reference 15Martínez C et al. · 2019ReviewA clinical approach for the use of VIP axis in inflammatory and autoimmune diseases — reviewView study →}. Administered exogenously, it is protective across a wide spread of rodent models — collagen-induced arthritis, the K/BxN autoimmune arthritis model, colitis, and lupus-like disease ^{15,16Reference 15Martínez C et al. · 2019ReviewA clinical approach for the use of VIP axis in inflammatory and autoimmune diseases — reviewView study →Reference 16Leceta J et al. · 2021AnimalMechanism of immunoregulatory properties of vasoactive intestinal peptide in the K/BxN mice model of autoimmune arthritis — animal (mouse)View study →}. The mechanism is well characterized and the preclinical results replicate across laboratories, which is more than many entries here can say.

What does not exist is any human efficacy data whatsoever. There is no randomized trial of VIP in rheumatoid arthritis, inflammatory bowel disease, lupus, or any other autoimmune indication, and the one-minute half-life is the obvious reason no one has attempted one with native peptide. The sarcoidosis study above is the closest thing to human evidence for VIP as an immunomodulator, and it measured immune cells rather than disease.

Gap: Animal-only for efficacy. Consistent rodent benefit and a clear mechanism do not make a human result. Anyone citing “VIP is anti-inflammatory” as a reason to take it is citing mouse data and receptor biology.

This is deliberately left un-scored, and the reason is that there is nothing to score. Intranasal VIP is promoted within the “chronic inflammatory response syndrome” (CIRS) / biotoxin-illness community, principally as a late step in the Shoemaker protocol for people with reported water-damaged-building exposure. It is supplied as a compounded prescription nasal spray, and for many people it is the only context in which they have encountered VIP at all.

Two things can be said neutrally. First, CIRS is not an established diagnostic entity in mainstream medicine — it does not appear as a recognized diagnosis in standard classifications, and the framework around it is largely maintained outside conventional clinical research. Second, and separately from that dispute: a search of ClinicalTrials.gov returns no registered trial of VIP for CIRS, mold illness or biotoxin illness of any design — not a randomized trial, not an open-label one. The available human material is case reports. That is not a criticism of anyone’s experience; it is a statement about what has and has not been measured.

The practical consequence is that the intranasal route — the one actually being sold and used for this purpose — is also the route with the least evidence behind it. Every scored application above used intracavernosal, nebulized or intravenous administration. No study here establishes what an intranasal dose of VIP does in a human being.

Gap: Everything. No controlled trial, no dose-finding, no pharmacokinetic characterization of the intranasal route, and no safety data for chronic intranasal use.