Reviewed & approved by Dr. Nova Reyes · Last checked 2026-10-24. ← Back to Evidence Library

VIP (Vasoactive Intestinal Peptide / Aviptadil)

vasoactive intestinal polypeptide · aviptadil (INN) · RLF-100 · Zyesami · component of Invicorp (with phentolamine)

Status: Approved for Adam Greene by Dr. Nova Reyes, 2026-10-24

Legend: HUMAN data · ANIMAL / LAB data · UNKNOWN · UNVERIFIED: not yet confirmed against a primary source

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1. What it is and what people claim it does

Vasoactive intestinal peptide (VIP)—known by its international nonproprietary drug name aviptadil when synthesized—is a 28-amino-acid peptide hormone discovered in 1970 by Sami Said and Viktor Mutt. In the human body, VIP is released by nerves and immune cells in the gastrointestinal tract, respiratory airways, blood vessels, and urogenital tract. It binds to G-protein-coupled VPAC1 and VPAC2 receptors, raising intracellular cyclic AMP (cAMP) to relax vascular, airway, and cavernous smooth muscle, stimulate water and electrolyte secretion in the intestine, and dampen pro-inflammatory cytokines such as TNF-alpha in cell studies.

In mainstream medicine, aviptadil has been studied in three distinct settings:

1. Erectile dysfunction (as a two-drug penile injection): Combined with the alpha-adrenergic blocker phentolamine mesilate in an intracavernosal auto-injector (Invicorp), approved in several European countries and the United Kingdom for men who fail oral erectile-dysfunction tablets. ^{R1–R3, R13}
2. Critical care and rare lung diseases: Tested by IV infusion or nebulized inhalation in acute respiratory distress syndrome (ARDS) from critical COVID-19, pulmonary arterial hypertension (PAH), and pulmonary sarcoidosis. ^R4–R11
3. Alternative "mold illness" (CIRS) and gray-market peptide protocols: Promoted as a compounded nasal spray or subcutaneous injection as the final step of Ritchie Shoemaker's "Chronic Inflammatory Response Syndrome" (CIRS) protocol for people reporting chronic symptoms after exposure to water-damaged buildings, and sold by research-peptide vendors for brain fog, mast-cell activation, and dysautonomia. ^R12

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2. What the human evidence actually shows

The Open Peptide Project's reading: Moderate for erectile dysfunction only when combined with phentolamine in the prescription intracavernosal injection Invicorp, Very limited (mixed results) for COVID-19 respiratory failure and pulmonary arterial hypertension, Very limited for pulmonary sarcoidosis and CIRS ("mold illness"), and No human data for subcutaneous wellness injections.

Indication	Route & formulation	Evidence rating	Summary of human studies
Erectile dysfunction (two-drug combination only)	Intracavernosal penile injection (aviptadil + phentolamine, Invicorp)	Moderate	2 randomized, double-blind, placebo-controlled trials (465 evaluated men) and 1 randomized crossover trial vs alprostadil (187 men) showed high rates of erection sufficient for intercourse with virtually no penile pain. Does not test solo VIP. R1–R3
COVID-19 acute respiratory failure / ARDS	IV infusion or nebulized inhalation (solo aviptadil)	Very limited (mixed results)	Large NIH Phase 3 randomized trial (ACTIV-3b/TESICO, 461 patients) stopped early for futility with no 90-day recovery or survival benefit; a 196-patient sponsor-funded IV trial missed its primary endpoint; a small 80-patient inhaled trial reported a borderline 1-day shorter hospital stay. R4–R6
Pulmonary arterial hypertension (PAH)	Nebulized inhalation (solo aviptadil)	Very limited (mixed results)	Early open-label studies (8 and 20 patients) reported better walk distance or brief catheter pressure drops, but a randomized, placebo-controlled Phase 2 trial showed no improvement in pulmonary vascular resistance acutely or after the treatment course, and anti-VIP autoantibodies appeared in some patients. R7–R10
Chronic pulmonary sarcoidosis	Nebulized inhalation (solo aviptadil)	Very limited	1 open-label, single-arm Phase 2 study (20 patients, no placebo group) reported reduced cough scores and lower TNF-alpha in lung-wash fluid. R11
Chronic Inflammatory Response Syndrome (CIRS / "mold illness")	Intranasal spray (solo aviptadil)	Very limited	Zero randomized controlled trials. Only 1 unblinded, single-clinic open-label case series of 20 patients by R. C. Shoemaker et al. R12
Subcutaneous wellness, brain fog, or immunity	Subcutaneous injection	No human data	No controlled human trials found.

Erectile dysfunction: why Invicorp is not solo VIP

Gray-market vendors sometimes cite European approval of Invicorp as proof that VIP is an approved peptide drug. That leaves out a critical pharmacological fact: solo intracavernosal VIP does not reliably produce an erection in men, because VIP primarily slows venous drainage without increasing arterial blood flow into the penis. Invicorp works by pairing aviptadil with phentolamine mesilate, an alpha-adrenoceptor antagonist that dilates penile arteries to drive blood inflow while aviptadil reduces venous outflow. ^{R1, R13}

• Double-blind placebo-controlled trials (Dinsmore et al., 1999; Sandhu et al., 1999): Across two multicenter double-blind trials evaluating 171 and 294 men with organic, diabetic, or psychogenic erectile dysfunction (followed by open-label home-use phases), 73% to 75.5% of men receiving the standard clinical strength of aviptadil + phentolamine achieved erections rigid enough for sexual intercourse compared with 11% to 12.2% on placebo (p < 0.0001). ^{R1, R2}
• Head-to-head crossover trial against alprostadil (Shah et al., 2007): In a randomized open-label crossover trial of 187 men comparing Invicorp with intracavernosal prostaglandin E1 (alprostadil, Caverject), both injections produced comparable erection efficacy, but Invicorp caused significantly less penile pain (3.4% vs 20–32% of injections with alprostadil, p < 0.0001) at the cost of more facial flushing (34% vs 2.9–4.3%). ^R3

COVID-19 acute respiratory failure and ARDS

During the COVID-19 pandemic, synthetic aviptadil (marketed experimentally as RLF-100 / Zyesami) was tested to see whether VPAC1/VPAC2 signaling on alveolar type II lung cells could rescue patients with life-threatening respiratory failure:

• Sponsor-funded Phase 2b/3 IV trial (Youssef et al., 2022): In 196 patients with critical COVID-19 respiratory failure at 10 US hospitals randomized 2:1 to a short hospital course of IV aviptadil infusions or placebo, the trial missed its prespecified primary composite endpoint of being alive and free from respiratory failure at day 60 (odds ratio 1.6, 95% CI 0.86–3.11; not statistically significant). The authors highlighted secondary analyses of time to recovery and survival after adjusting for baseline ventilation status, and the US FDA declined to grant Emergency Use Authorization. ^R4
• Definitive NIH-funded Phase 3 trial — ACTIV-3b / TESICO (Brown et al., 2023): To test aviptadil rigorously, the US National Institutes of Health conducted a randomized, double-blind, placebo-controlled Phase 3 platform trial across 28 hospitals. Enrollment was stopped early for futility after 461 critically ill patients in the modified intention-to-treat population (231 aviptadil, 230 placebo) showed no benefit on the primary 90-day 6-category pulmonary recovery outcome (adjusted odds ratio 1.11, 95% CI 0.80–1.55, p = 0.54) and no mortality benefit (86 deaths [38%] on aviptadil vs 83 deaths [36%] on placebo; hazard ratio 1.04, 95% CI 0.77–1.41, p = 0.78). Hypotension and diarrhea were both significantly more frequent with aviptadil. ^R5
• Small Turkish inhaled trial (Esendagli et al., 2025): A multicenter randomized trial in Turkey enrolled 80 hospitalized COVID-19 patients (43 inhaled aviptadil, 37 placebo) and reported a borderline-significant 1-day shorter median hospital stay (7.0 vs 8.0 days, p = 0.049), with no significant differences in oxygenation ratios or clinical improvement scores at days 7 or 28. ^R6

Pulmonary arterial hypertension and pulmonary sarcoidosis

• Pulmonary arterial hypertension (Petkov et al., 2003; Leuchte et al., 2008; Said, 2012; Lythgoe et al., 2016): Interest in inhaled VIP for pulmonary hypertension began with an unblinded 8-patient Vienna study reporting a 113-meter increase in 6-minute walk distance and lower pulmonary vascular resistance after an inhaled course, followed by a 20-patient single-dose right-heart catheterization study showing brief (15–30 minute) selective pulmonary vasodilation. ^{R7, R8} However, when a randomized, double-blind, placebo-controlled Phase 2 trial (reported by Galiè et al. in 2010 and discussed by VIP co-discoverer Sami Said in AJRCCM 2012 and Imperial College trial reviewers in 2016) tested three inhaled strengths against placebo in patients with pulmonary arterial hypertension, inhaled aviptadil failed to reduce pulmonary vascular resistance either acutely or after the multi-month course. Blood VIP levels barely rose even at the highest inhaled dose, anti-VIP autoantibodies developed in some patients (rated severe in two cases), and clinical development for PAH was discontinued. ^{R9, R10}
• Chronic pulmonary sarcoidosis (Prasse et al., 2010): In an open-label, single-arm Phase 2 study of 20 patients with active chronic pulmonary sarcoidosis inhaling nebulized aviptadil with no placebo control group, lung-wash (bronchoalveolar lavage) fluid showed lower TNF-alpha release and higher CD4+CD25+FoxP3+ regulatory T cells, alongside improved patient-reported cough scores. Remember that unblinded biomarker changes in lung fluid and subjective cough ratings without a placebo group are preliminary signals, not proof of disease modification. ^R11

Chronic Inflammatory Response Syndrome (CIRS / "mold illness")

Compounded intranasal VIP is widely prescribed in integrative medicine for "Chronic Inflammatory Response Syndrome" (CIRS), a diagnostic framework proposed by Ritchie C. Shoemaker for multisystem symptoms attributed to water-damaged buildings.

• Only one unblinded 20-patient case series exists (Shoemaker, House & Ryan, 2013): Published in the open-access journal Health (Scientific Research Publishing, a publisher not indexed in PubMed/MEDLINE), this study enrolled 20 patients from the lead author's clinic who had already undergone 10 sequential treatment steps (including long-term cholestyramine) over an extended prior treatment period. All 20 received open-label compounded VIP nasal spray with no placebo group and no blinding; values were compared against historical clinic controls. Five of the 20 patients stopped VIP at various points during follow-up, and the authors noted that for those patients, only data collected while using VIP were included in statistical calculations. ^R12 No independent research group has published a randomized, placebo-controlled trial of VIP nasal spray for mold exposure, CIRS, chronic fatigue, or brain fog.

Study details — click to expand all clinical trial rows (doses, schedules, outcomes, and side effects)

Study (Year)	Design & Population	Route, Dose & Schedule	Primary / Key Outcomes	Adverse Events & Dropouts	Funding & Disclosures
Dinsmore et al. (1999) R1	Randomized, double-blind, placebo-controlled Phase 3 trial + open-label extension; 236 men enrolled, 171 evaluated with predominantly non-psychogenic erectile dysfunction	Intracavernosal penile injection (Invicorp): Aviptadil 25 mcg + phentolamine mesilate 1.0 mg (VIP 1) or aviptadil 25 mcg + phentolamine mesilate 2.0 mg (VIP 2) vs placebo via single-use auto-injector before intercourse	Erections sufficient for sexual intercourse: 73% (52/71) on VIP 2 vs 11% (2/18) on placebo (p < 0.0001). Across 2,615 injections, 0 cases of priapism and no corporal fibrosis reported.	Transient facial flushing in 34% (rarely caused withdrawal); 65 of 236 enrolled men did not complete double-blind efficacy evaluation across phases.	Sponsored by Senetek PLC (original developer of Invicorp).
Sandhu et al. (1999) R2	Multicenter randomized, double-blind, placebo-controlled trial + 6-month open-label phase; 304 men enrolled, 294 evaluated with organic/diabetic/psychogenic erectile dysfunction	Intracavernosal penile injection (Invicorp): Dose-titration and double-blind phase with aviptadil 25 mcg + phentolamine mesilate 1.0 mg (VIP1) or 2.0 mg (VIP2) vs placebo	Erection sufficient for intercourse in double-blind phase: 75.5% of men on active treatment (66.7% VIP1, 82.0% VIP2) vs 12.2% on placebo (p < 0.001); 82.4% response during 5,022 home injections.	Transient facial flushing in 33.9%, trunk flushing 9.4%, bruising 16.7%, pain 10.7%, priapism in 3 patients (0.06% of injections). In open-label phase (n=195), 75 withdrew (20 adverse events, 14 lack of efficacy, 41 other).	Sponsored by Senetek PLC.
Shah et al. (2007) R3	Randomized, open-label, 2-way crossover trial; 187 men (ages 27–83) with predominantly organic erectile dysfunction	Intracavernosal penile injection: Invicorp (VIP1: 25 mcg/1 mg; escalated to VIP2: 25 mcg/2 mg if needed) vs alprostadil (Caverject: 5–20 mcg) across up to 8 home injections	Comparable erection success (>1.8 successful injections out of 4 for both drugs); significantly less penile pain/burning with Invicorp (3.4% vs 20–32% with alprostadil, p < 0.0001).	Facial flushing more common with Invicorp (34% vs 2.9–4.3%, p < 0.0001); 141 of 187 randomized men completed at least one crossover comparison (46 withdrew before first efficacy assessment).	Sponsored by Senetek PLC / Ardana Bioscience.
Youssef et al. (2022) R4	Randomized, double-blind, placebo-controlled trial (NCT04311697); 196 adults with critical COVID-19 respiratory failure at 10 US hospitals (randomized 2:1 to IV aviptadil vs placebo)	IV infusion: Three successive 12-hour intravenous infusions on 3 consecutive days at escalating rates of 50, 100, and 150 pmol/kg/hour vs saline placebo	Missed prespecified primary endpoint: Unadjusted odds ratio for being alive and free of respiratory failure at day 60 was 1.6 (95% CI 0.86–3.11; not significant); secondary baseline-adjusted models reported OR 2.0 (p = 0.036) for 60-day survival.	Mild-to-moderate hypotension and diarrhea were more frequent in the aviptadil arm; FDA declined Emergency Use Authorization.	Funded by NeuroRx / NRx Pharmaceuticals (J. C. Javitt, senior author and company CEO, reported equity/leadership conflict of interest).
Brown et al. (2023) — ACTIV-3b / TESICO R5	Phase 3 multicenter, randomized, double-blind, placebo-controlled 2×2 factorial trial (NCT04843761); 471 enrolled, 461 in mITT (231 aviptadil, 230 placebo) critically ill adults with COVID-19 acute hypoxemic respiratory failure at 28 hospitals	IV infusion: Daily 12-hour intravenous infusions for 3 consecutive days at 50 pmol/kg/h (day 1), 100 pmol/kg/h (day 2), and 150 pmol/kg/h (day 3) vs matching saline placebo	Stopped early for futility — no benefit: 90-day 6-category pulmonary recovery adjusted OR 1.11 (95% CI 0.80–1.55; p = 0.54). 90-day mortality: 86/231 (38%) aviptadil vs 83/230 (36%) placebo (HR 1.04, 95% CI 0.77–1.41, p = 0.78). Composite day-28 safety outcome: 63% vs 56% (p = 0.085).	Hypotension (29% vs 21% on infusion days) and diarrhea (22% vs 8% through day 14, p < 0.0001) were significantly higher with aviptadil; 461 of 471 enrolled patients analyzed in mITT.	Funded by US National Institutes of Health (NIH / NHLBI / NIAID); study drug supplied by NRx Pharmaceuticals.
Esendagli et al. (2025) R6	Multicenter randomized, double-blind, placebo-controlled Phase 2 trial (NCT04844580); 80 hospitalized adults with severe COVID-19 in Turkey (43 inhaled aviptadil, 37 placebo)	Inhaled: 100 mcg nebulized three times daily (300 mcg/day) added to standard of care vs placebo [UNVERIFIED: exact daily dose from NCT04844580 registry; abstract states inhaled aviptadil + standard of care]	Median hospital stay 7.0 days (aviptadil) vs 8.0 days (placebo) (p = 0.049); no statistically significant difference in PaO2/FiO2 oxygenation ratios or clinical improvement scores at day 7 or day 28.	No serious drug-related adverse events reported in abstract; 80 patients analyzed.	Sponsored by Centurion Pharma (Istanbul, Turkey).
Petkov et al. (2003) R7	Open-label, single-arm pilot study (no control group); 8 patients with primary pulmonary arterial hypertension (PAH)	Inhaled: 200 mcg per day divided into 4 single inhalations (50 mcg four times daily) via nebulizer for 3 months	Mean pulmonary arterial pressure fell by 13 mmHg, cardiac output increased by 1.7 L/min, pulmonary vascular resistance fell by 40% (from 1,009 ± 475 to 586 ± 165 dyne·s·cm⁻⁵), and 6-minute walk distance rose by 113 m (p < 0.01).	0/8 dropped out; no significant systemic hypotension reported.	Medical University of Vienna; Mondobiotech AG later licensed patent rights.
Leuchte et al. (2008) R8	Open-label, single-dose acute hemodynamic study (no placebo control); 20 patients with pulmonary hypertension (9 PAH, 8 chronic lung disease PH, 3 chronic thromboembolic PH)	Inhaled: Single 100 mcg dose of nebulized aviptadil during right-heart catheterization, monitored for 60 min	Mean pulmonary artery pressure fell briefly from 49.5 to 46.8 mmHg (p < 0.001) and pulmonary vascular resistance fell by 12.6% (p < 0.005) at 15–30 min, returning to baseline by 60 min.	0/20 dropped out; no systemic blood pressure drop or gas-exchange worsening during the 60-min test.	Sponsored by Mondobiotech AG (2 co-authors employed by Mondobiotech).
Galiè et al. (2010) / Said (2012) / Lythgoe et al. (2016) R9, R10	Randomized, double-blind, placebo-controlled Phase 2 dose-ranging trial in 56 patients with pulmonary arterial hypertension [UNVERIFIED: exact n=56 from ATS 2010 conference abstract A2516; Lythgoe 2016 and Said 2012 verify design and outcomes]	Inhaled: 12.5 mcg, 50 mcg, or 200 mcg four times daily via nebulizer vs placebo for 3 months	Negative: No reduction in pulmonary vascular resistance either acutely during right-heart catheterization or after 3 months of treatment, and no improvement in 6-minute walk distance; plasma VIP did not rise at lower/middle doses.	Anti-VIP autoantibodies detected in some patients (deemed severe in 2 cases), which may have neutralized endogenous and exogenous VIP.	Sponsored by Mondobiotech AG / Biogen Idec; clinical development in PAH discontinued.
Prasse et al. (2010) R11	Open-label, single-arm Phase 2 study (no control group); 20 adults with histologically proven active chronic pulmonary sarcoidosis	Inhaled: 50 mcg four times daily (200 mcg/day) via ultrasonic nebulizer for 28 days	Reduced TNF-alpha production by alveolar macrophages and increased CD4+CD25+FoxP3+ regulatory T cells in bronchoalveolar lavage fluid; unblinded cough visual-analog scores decreased significantly.	19/20 completed bronchoscopy analysis; nebulization tolerated without systemic hypotension.	University of Freiburg, Germany; Mondobiotech AG supplied aviptadil (2 co-authors affiliated with Mondobiotech).
Shoemaker, House & Ryan (2013) R12	Open-label, single-clinic case series (no placebo group, no blinding); 20 adults (11 women, 9 men) diagnosed by the lead author with refractory CIRS after water-damaged building exposure	Intranasal spray: 50 mcg four times daily (200 mcg/day) via nasal aerosol (compounded from Bachem aviptadil), self-titrated down/up after 6 months and followed at 12 and 18 months	Unblinded physician-recorded symptoms fell from a mean of ~23 to control levels (~3); stress-echo exercise pulmonary artery systolic pressure rise fell below 8 mmHg; changes in plasma C4a, TGF-beta1, MMP9, VEGF, and Treg counts reported vs historical clinic controls.	5 of 20 patients stopped VIP during the 18-month period (authors reported symptoms had resolved and analyzed only on-drug data for those 5); 1 patient had transient asymptomatic lipase elevation.	Conducted at the lead author's clinic (Center for Research on Biotoxin Associated Illnesses); published in Health (SciRes, non-MEDLINE journal).

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3. Known risks, side effects, and long-term unknowns

Because VIP receptors (VPAC1 and VPAC2) line blood vessels and the intestinal tract, VIP's main human side effects are direct extensions of its biology—vasodilation and intestinal fluid secretion:

• Low blood pressure (hypotension) and flushing: In the 461-patient NIH ACTIV-3b/TESICO Phase 3 trial, hypotension occurred in 29% of IV aviptadil recipients versus 21% on placebo on infusion days. ^R5 With intracavernosal Invicorp, facial or trunk flushing occurs in roughly 34% of men, along with occasional dizziness, headache, and rapid heart rate (tachycardia). ^R1–R3
• Watery diarrhea: VIP is the exact hormone overproduced by rare pancreatic neuroendocrine tumors (VIPomas, or Verner-Morrison "pancreatic cholera" syndrome), which cause massive secretory diarrhea. In the NIH Phase 3 COVID-19 trial, diarrhea occurred in 22% of IV aviptadil patients versus 8% on placebo (p < 0.0001). ^R5
• Anti-VIP autoantibodies: In the randomized Phase 2 trial of inhaled aviptadil for pulmonary arterial hypertension, autoantibodies against VIP were detected in several patients (rated severe in two cases). ^R10 Developing neutralizing antibodies against an endogenous human neuropeptide is a serious theoretical hazard because those antibodies can cross-react with the body's own natural VIP.
• Pancreatic enzyme (lipase) elevation: In the 20-patient open-label CIRS nasal-spray case series, 1 patient (5%) developed a transient rise in serum lipase without abdominal pain; clinics prescribing compounded VIP nasal spray routinely monitor serum lipase for pancreatic irritation. ^R12
• Priapism and injection-site bruising (Invicorp only): In the 304-patient Invicorp erectile-dysfunction trial, prolonged erection (priapism) occurred in 3 men (0.06% of injections) and local penile bruising in 16.7%. ^{R2, R13}
• Long-term unknowns: Outside the single 20-patient unblinded clinic report ^R12, there are no controlled human safety data on taking intranasal or subcutaneous VIP over many months or years, nor on whether chronic exogenous dosing downregulates VPAC receptors or triggers anti-VIP autoantibodies.

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4. Regulatory and compounding status

Jurisdiction / Body	Current Status	Details
United States (FDA — Drugs)	Not FDA-approved (any route or combination)	Neither solo aviptadil nor the aviptadil + phentolamine combination (Invicorp) is FDA-approved. In 2021–2022, FDA declined Emergency Use Authorization for IV aviptadil (Zyesami) in critical COVID-19. R4, R5, R14
United States (FDA — 503A & 503B Compounding)	503A Category 1 (under evaluation) Not on 503B List	Listed as Vasoactive Intestinal Peptide (VIP) in 503A Category 1 (Bulk Drug Substances Currently Under Evaluation, updated May 14, 2026), meaning state-licensed 503A pharmacies may compound patient-specific prescriptions under FDA's interim enforcement policy while formal review is pending. Not listed on the 503B outsourcing-facility list. R14
United Kingdom, France, Sweden & selected EU countries	Approved prescription drug ONLY as Invicorp (aviptadil + phentolamine intracavernosal injection)	Invicorp (solution for intracavernosal injection combining aviptadil and phentolamine mesilate) holds national marketing authorizations in Sweden (Läkemedelsverket / VARA register, Evolan Pharma AB), France (ANSM Répertoire R0326425), and the United Kingdom (MHRA; recommended by NHS Wales AWMSG Ref. 3435 after oral PDE5 inhibitors and intracavernosal alprostadil fail) R13, and is listed in secondary regulatory indexes for Denmark, Norway, Finland, and New Zealand [UNVERIFIED: secondary regulatory index, not read directly on the national agency register]. Solo VIP is not approved in the EU or UK.
European Medicines Agency (EMA — Orphan Designations)	Orphan designations only (not marketing approvals)	Aviptadil received EU orphan designations for acute lung injury and sarcoidosis in the 2000s, which allow protocol assistance and fee reductions during trials but are not drug approvals. R10, R11
World Anti-Doping Agency (WADA 2026)	Not named on the 2026 Prohibited List; Section S0 applies to solo VIP	Neither aviptadil nor VIP is named in WADA's 2026 index. However, because solo VIP has no current marketing approval for systemic or intranasal human therapy from any governmental health authority, athletes subject to testing face risk under Section S0 (Non-Approved Substances), which prohibits at all times any pharmacological substance with no current regulatory approval for human therapeutic use. R15

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5. Quality, contamination, and gray-market risks

1. Fragile 28-amino-acid peptide prone to rapid degradation: VIP has a plasma half-life of only 1 to 2 minutes in human blood and is rapidly cleaved by peptidases and oxidized at its methionine residue (position 17) when stored as a liquid at room temperature. Pre-mixed nasal sprays or reconstituted gray-market vials that sit in warm transit or remain in a refrigerator over weeks can lose intact peptide potency rapidly.
2. Solo gray-market vials are not Invicorp: Research-chemical sites selling lyophilized "VIP" vials for subcutaneous injection or DIY nasal sprays are selling unapproved, unsterility-tested single-ingredient peptide powder—not the regulated, nitrogen-flushed glass ampoules of aviptadil + phentolamine manufactured for intracavernosal use in Europe. ^R13
3. Endotoxin and preservative hazards in DIY nasal sprays: Reconstituting a gray-market subcutaneous vial with bacteriostatic water (which contains benzyl alcohol) and pouring it into an unsterile nasal atomizer can irritate or damage nasal cilia and mucosa, and carries bacterial contamination risks if not compounded in a sterile cleanroom.

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6. Who should be especially cautious

• People with low blood pressure, orthostatic intolerance (such as POTS), or active heart disease: VIP is a potent vasodilator that caused clinically significant hypotension in 29% of hospitalized infusion patients and frequent flushing and dizziness even with localized injection. ^{R1, R5}
• People with chronic diarrhea, irritable bowel syndrome, or history of pancreatitis: VIP directly stimulates intestinal water and electrolyte secretion (22% diarrhea rate in the NIH trial) and has been associated with transient lipase elevation in clinical use. ^{R5, R12}
• Men taking nitrates, alpha-blockers, or blood thinners (for Invicorp): The phentolamine component of Invicorp is an alpha-adrenergic blocker; official European product information contraindicates use with organic nitrates and warns of bleeding/bruising risk at the injection site in anticoagulated patients. ^{R2, R13}
• People with mold-exposed or environmental chronic illness: Because the only published CIRS nasal-spray report is an unblinded 20-patient case series from a single clinic ^R12, patients should know that expensive long-term compounded VIP nasal sprays have never been validated against a placebo spray.
• Tested athletes: Unapproved solo VIP nasal sprays or injections fall under WADA's S0 Non-Approved Substances rule. ^R15

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7. Open questions and research gaps

• No randomized placebo-controlled trial in CIRS, chronic fatigue, or post-viral brain fog: Whether intranasal VIP reaches the human brain or improves symptoms beyond placebo in patients with environmental or post-infectious syndromes has never been tested in a blinded trial. ^R12
• Why inhaled and IV aviptadil failed in large randomized lung trials: As Imperial College pulmonary hypertension researchers noted after the negative Phase 2 PAH trial, inhaled VIP may be broken down by airway peptidases before reaching pulmonary arterioles—or may trigger neutralizing anti-VIP autoantibodies—while IV infusions are limited by systemic hypotension and diarrhea before lung tissue concentrations match laboratory dishes. ^{R5, R9, R10}

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8. References

• ^R1 Dinsmore WW, Gingell C, Hackett G, et al. Treating men with predominantly nonpsychogenic erectile dysfunction with intracavernosal vasoactive intestinal polypeptide and phentolamine mesylate in a novel auto-injector system: a multicentre double-blind placebo-controlled study. BJU Int. 1999;83(3):274–279. PMID 10233493 · doi:10.1046/j.1464-410x.1999.00906.x
• ^R2 Sandhu D, Curless E, Dean J, et al. A double blind, placebo controlled study of intracavernosal vasoactive intestinal polypeptide and phentolamine mesylate in a novel auto-injector for the treatment of non-psychogenic erectile dysfunction. Int J Impot Res. 1999;11(2):91–97. PMID 10356669 · doi:10.1038/sj.ijir.3900381
• ^R3 Shah PJR, Dinsmore W, Oakes R, Hackett G. Injection therapy for the treatment of erectile dysfunction: a comparison between alprostadil and a combination of vasoactive intestinal polypeptide and phentolamine mesilate. Curr Med Res Opin. 2007;23(10):2577–2583. PMID 17875241 · doi:10.1185/030079907X233223
• ^R4 Youssef JG, Said S, Youssef G, et al. Treatment of critically ill COVID-19 patients with intravenous aviptadil (vasoactive intestinal peptide): a randomized controlled trial. Expert Opin Pharmacother. 2022;23(14):1637–1647. PMID 36044317 · doi:10.1080/14656566.2022.2116273
• ^R5 Brown SM, Barkauskas CE, Grund B, et al.; ACTIV-3b/TESICO Study Group. 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 · PMC10353874 · doi:10.1016/S2213-2600(23)00147-9
• ^R6 Esendagli D, Akcay S, Kokturk N, et al. Efficacy of Inhaled Aviptadil in Hospitalized COVID-19 Patients: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial. J Clin Med. 2025;14(2):589. PMID 39870064 · PMC11766510 · doi:10.3390/jcm14020589
• ^R7 Petkov V, Mosgoeller W, Ziesche R, et al. Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J Clin Invest. 2003;111(9):1339–1346. PMID 12727925 · PMC154446 · doi:10.1172/JCI17500
• ^R8 Leuchte HH, Baezner C, Baumgartner RA, et al. Inhalation of vasoactive intestinal peptide in pulmonary hypertension. Eur Respir J. 2008;32(5):1289–1294. PMID 18978135 · doi:10.1183/09031936.00050008
• ^R9 Said SI. Vasoactive intestinal peptide in pulmonary arterial hypertension (discussing the negative randomized trial reported by Galiè N et al., Am J Respir Crit Care Med 2010;181:A2516). Am J Respir Crit Care Med. 2012;185(7):786. PMID 22467806 · doi:10.1164/ajrccm.185.7.786
• ^R10 Lythgoe MP, Rhodes CJ, Ghataorhe P, Attard M, Wharton J, Wilkins MR. Why drugs fail in clinical trials in pulmonary arterial hypertension, and strategies to succeed in the future (Section 3.3: Vasoactive Intestinal Peptide / Aviptadil). Pharmacol Ther. 2016;164:195–203. PMID 27133570 · doi:10.1016/j.pharmthera.2016.04.012
• ^R11 Prasse A, Zissel G, Lützen N, et al. Inhaled vasoactive intestinal peptide exerts immunoregulatory effects in sarcoidosis. Am J Respir Crit Care Med. 2010;182(4):540–548. PMID 20442436 · doi:10.1164/rccm.200909-1451OC
• ^R12 Shoemaker RC, House D, Ryan JC. Vasoactive intestinal polypeptide (VIP) corrects chronic inflammatory response syndrome (CIRS) acquired following exposure to water-damaged buildings. Health. 2013;5(3):396–401. doi:10.4236/health.2013.53053 · Full Text PDF
• ^R13 National European and UK regulatory records for Invicorp (aviptadil + phentolamine mesilate solution for intracavernosal injection): Sweden eHälsomyndigheten VARA Product Record (Evolan Pharma AB); France ANSM Répertoire Summary of Product Characteristics (R0326425); and UK NHS All Wales Medicines Strategy Group Final Appraisal Recommendation (Ref. 3435, Dec 2018).
• ^R14 US Food and Drug Administration (FDA). 503A Bulk Drug Substances List — Category 1: Substances Currently Under Evaluation (lists Vasoactive Intestinal Peptide (VIP), updated May 14, 2026); 503B Bulk Drug Substances List (updated Mar 21, 2025).
• ^R15 World Anti-Doping Agency (WADA). 2026 Prohibited List — International Standard, Section S0 (Non-Approved Substances; effective Jan 1, 2026).

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Disclaimer

This page is for education and harm reduction. It is not medical advice and not a recommendation to use this compound. Please talk to a clinician you trust before making medical decisions, and report adverse events to FDA MedWatch (https://www.fda.gov/safety/medwatch).