VIP.

VIP is a research compound.

Its biological effect is described in the mechanism section.

It draws interest for various research areas.

C-tier evidence: some human evidence exists but isn't definitive.

What it is

VIP (vasoactive intestinal peptide, also called vasoactive intestinal polypeptide) is a 28-amino-acid neuropeptide first isolated from porcine intestine in the early 1970s. It is highly conserved across mammals and belongs to the secretin/glucagon peptide superfamily, sharing close homology with PACAP (pituitary adenylate cyclase-activating polypeptide). It is widely distributed in the central and peripheral nervous systems and in the gut, and is notably enriched in lung tissue. The synthetic form used in human trials is known as aviptadil.

How it works

VIP signals through two class B G-protein-coupled receptors, VPAC1 and VPAC2, both of which bind VIP and PACAP with high affinity (a related receptor, PAC1, is PACAP-selective). Receptor activation couples primarily to adenylate cyclase, raising intracellular cAMP, with secondary coupling to phospholipase C in some contexts. Downstream effects include smooth-muscle relaxation and vasodilation, bronchodilation, stimulation of exocrine and electrolyte secretion, glucose-dependent insulin secretion (largely via VPAC2), and broad immunomodulatory/anti-inflammatory actions that shift cytokine balance away from pro-inflammatory mediators. In the lung, VIP receptors are concentrated on alveolar type II cells, which is part of the rationale for studying it in acute lung injury.

What the evidence shows

Human evidence is mixed and, for most systemic indications, limited. The strongest, most rigorous human data come from TESICO (ACTIV-3b), a randomized, placebo-controlled trial of intravenous aviptadil in COVID-19-associated hypoxaemic respiratory failure published in Lancet Respiratory Medicine (2023); it enrolled ~471 randomized participants and was stopped for futility, finding no improvement in clinical outcomes versus placebo. The earlier enthusiasm rested largely on small open-label series and preclinical/animal models of acute lung injury and cytokine suppression, which did not translate into proven benefit in the controlled setting. The best-established human use is local, not systemic: aviptadil combined with phentolamine (Invicorp) is an approved intracavernosal injection for erectile dysfunction in several countries. VIP has also held orphan-drug designations for pulmonary hypertension and sarcoidosis, but those indications lack confirmatory pivotal trial evidence.

Safety considerations

As an endogenous vasodilator, systemic VIP/aviptadil can cause hypotension, flushing, and diarrhea, and intravenous infusion has been associated with these effects in trials. Excess endogenous VIP, as seen in VIPoma tumors, produces severe secretory (watery) diarrhea, hypokalemia, and dehydration, illustrating its potent secretory pharmacology. For intracavernosal use, the combination product is reported to carry low rates of penile pain and priapism relative to some other injectables. Long-term safety of systemic administration is not well characterized, and the controlled COVID-19 data did not establish a net clinical benefit; safety beyond the studied settings remains uncertain.

Regulatory status

VIP itself is not an FDA-approved drug; intravenous aviptadil is investigational in the United States and was studied under FDA mechanisms including orphan-drug designations (pulmonary hypertension, sarcoidosis) and emergency COVID-19 trials. The aviptadil/phentolamine combination (Invicorp) is approved for erectile dysfunction in several countries including the UK, Denmark, and New Zealand, but not broadly in the US.

1. [1]Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR Review 1 — British Journal of Pharmacology, 2012; PMID 22289055
2. [2]Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial — Lancet Respiratory Medicine, 2023; PMID 37348524
3. [3]Vasoactive intestinal polypeptide/phentolamine for intracavernosal injection in erectile dysfunction (Invicorp) — Drugs, 2008; PMID 18485029
4. [4]Therapeutic potential of vasoactive intestinal peptide and its receptor VPAC2 in type 2 diabetes — Frontiers in Endocrinology, 2022; PMC9531956

• Not FDA-approved for most discussed uses; investigational.
• Can cause flushing/blood-pressure effects; medical context matters.

Stack fit

Why not B: held back by safety clarity, regulatory clarity, practical relevance.

Why not D: supported by mechanism confidence.

What would move it up: Larger controlled human trials, clearer long-term safety, replicated findings, and regulatory progress.

What would move it down: Failed confirmatory trials, new safety signals, or evidence that popular claims don't translate.

• VIP is not FDA-approved for human use; it is discussed in a research context.

• Whether observed effects reliably translate to humans at large.
• Long-term safety in healthy users, and full drug-interaction risk.
• Optimal studied parameters outside any approved indication.
• Claim-by-claim verdicts — these are authored against verified sources and shown when complete.
• Quality and purity of material from non-pharmaceutical sources.

1. What it is
2. The preclinical evidence lane
3. Why Early, and not higher or lower
4. Proven lane vs speculative lane
5. What people report
6. Regulatory status
7. What changed recently