VIP Peptide: Immunomodulator, CIRS Agent and ADNP Precursor

Vasoactive intestinal peptide (VIP) is a 28-amino-acid neuropeptide belonging to the glucagon/secretin superfamily of peptide hormones (PubChem CID 53314964, molecular formula C₁₄₇H₂₃₇N₄₃O₄₃S). Despite its name implying a gut-specific role, VIP is one of the most widely distributed signalling molecules in the human body, functioning as a neurotransmitter, neuromodulator, and immunoregulatory peptide across multiple organ systems.

VIP was first isolated in 1970 by Sami Said and Viktor Mutt from porcine small intestine, published in Science as a polypeptide with broad biological activity that decreased systemic arterial pressure and increased heart rate, stroke volume, and blood flow. The vasodilatory property that first drew attention became the source of the name, but within a decade researchers discovered VIP in the central nervous system, lungs, heart, pancreas, thyroid, genitourinary tract, and immune tissue. Said, who later became professor of medicine at Stony Brook University, continued VIP research for over four decades until his death in 2013, making him one of the longest-serving investigators of a single peptide in modern pharmacology.

The synthetic pharmaceutical formulation of VIP is called aviptadil (also known as RLF-100). Aviptadil holds both FDA and EU orphan drug designations for the treatment of acute respiratory distress syndrome (ARDS), pulmonary hypertension, and sarcoidosis, held by Relief Therapeutics.

Property	Detail
Full name	Vasoactive intestinal peptide (VIP)
Sequence	His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH2
Length	28 amino acids (C-terminal amidation required for activity)
PubChem CID	53314964
Discovery	Sami Said and Viktor Mutt, 1970, porcine small intestine
Receptors	VPAC1 (immune, lungs, liver) and VPAC2 (CNS, smooth muscle, immune)
Plasma half-life	Approximately 1-2 minutes (rapid enzymatic degradation)
Pharmaceutical form	Aviptadil (synthetic VIP, orphan drug status FDA + EU)
Superfamily	Glucagon/secretin (related to PACAP, PHI, secretin, glucagon, GHRH)

VIP is part of a broader cluster of nootropic and neuropeptide compounds covered on this site. For the cross-category overview of cognitive-enhancing peptides, see the nootropic and neuropeptide compounds hub.

The bottom line: VIP is an endogenous 28-amino-acid neuropeptide with one of the broadest distribution profiles of any signalling molecule in the body, acting through two identified G-protein-coupled receptors across the nervous, immune, cardiovascular, and gastrointestinal systems.

VIP exerts its biological effects primarily through two class B G-protein-coupled receptors: VPAC1 and VPAC2. VPAC1 is widely expressed in the immune system, lungs, and liver. VPAC2 is concentrated in the central nervous system, smooth muscle, and immune cells. Both receptors activate adenylate cyclase through Gs-protein coupling, raising intracellular cAMP, though the downstream consequences differ by tissue.

Immunomodulation

VIP’s immunomodulatory function is arguably its most clinically relevant property. VIP suppresses pro-inflammatory cytokine release (TNF-alpha, IL-6, IL-12) from macrophages and dendritic cells while promoting anti-inflammatory mediators (IL-10). In preclinical models, VIP generates CD4+CD25+Foxp3+ regulatory T cells, shifting the immune balance toward tolerance. This type 2 immune bias, combined with its ability to modulate both innate and adaptive immunity, has led researchers to describe VIP as functioning more like a cytokine than a conventional neuropeptide.

Neuroprotection and circadian function

VIP is expressed in a distinct subtype of inhibitory interneuron across multiple brain regions. In the hypothalamus, VIP-expressing neurons in the suprachiasmatic nuclei (SCN) play a central role in circadian rhythm synchronisation. VIP also shows neuroprotective activity in preclinical models, likely mediated through BDNF-independent pathways involving cAMP-PKA signalling and anti-apoptotic gene expression.

A 2025 Neuroscience Bulletin study (Huang et al.) identified a previously unrecognised role for SCN VIP neurons: mediating light-induced transient forgetting. Acute bright light exposure selectively impaired trace fear memory by activating VIP neurons in the SCN, and the research group mapped the responsible circuitry to a SCN-to-PVT (paraventricular nucleus of the thalamus) VIP neuronal pathway using optogenetic and chemogenetic manipulation. This extends VIP’s known SCN function beyond timekeeping into active memory modulation – a finding with no equivalent in any other neuropeptide in this cluster.

The VIP-ADNP-NAP drug development lineage

One of VIP’s most significant but least discussed contributions to neuroscience lies not in VIP itself but in a protein it regulates. VIP signalling drives expression of activity-dependent neuroprotective protein (ADNP), a transcription factor essential for brain formation that regulates over 400 genes. The Gozes laboratory at Tel Aviv University discovered that ADNP contains an eight-amino-acid neuroprotective snippet – NAPVSIPQ, known as NAP – which became the drug candidate davunetide (also AL-108 and CP201).

Davunetide proceeded to clinical trials for progressive supranuclear palsy, schizophrenia (where MRS imaging showed neuroprotective effects), and amnestic mild cognitive impairment. De novo ADNP mutations cause the ADNP syndrome, an autism-spectrum condition with global developmental delays. The entire drug development lineage – from VIP as the upstream regulatory signal, through ADNP as the effector protein, to NAP/davunetide as the clinical candidate – represents perhaps the clearest example of a neuropeptide spawning a multi-decade pharmaceutical programme, and it traces back to VIP’s signalling cascade.

Bone metabolism

VPAC1 and VPAC2 receptors are expressed on both osteoblasts and osteoclasts, with receptor subtype expression shifting during the bone cell differentiation timeline. Preclinical studies from the late 1990s onward (Lundberg et al. 1999, 2000, 2001) established that VIP stimulates osteoblastic activity – including alkaline phosphatase expression and calcium accumulation in mineralised nodules – while inhibiting osteoclastogenesis through upregulation of osteoprotegerin and downregulation of RANKL, the primary osteoclast-activating ligand.

A 2024 BioFactors study (Castro-Vazquez et al.) confirmed this bone-protective effect in human mesenchymal stem cells for the first time, demonstrating that VIP promoted osteogenic differentiation and significantly reduced the RANKL/OPG ratio. A separate 2019 cross-sectional study (Wang et al.) found that serum VIP levels were inversely correlated with the severity of postmenopausal osteoporosis in human patients. These findings position VIP as a potential regulatory molecule in bone homeostasis – an angle largely absent from the compound’s clinical discussion outside specialist neuro-osteology literature.

Pulmonary function

VIP receptors are densely distributed in lung tissue, including alveolar walls, bronchial epithelium, and pulmonary artery smooth muscle. VIP acts as one of the major non-adrenergic, non-cholinergic (NANC) inhibitory neurotransmitters in the lung, mediating bronchodilation and pulmonary vasodilation. This pulmonary role forms the basis for aviptadil’s orphan drug designations and the COVID-19 ARDS clinical trials.

Gastrointestinal function

In the gut, VIP stimulates water and electrolyte secretion, relaxes enteric smooth muscle, dilates peripheral blood vessels, stimulates pancreatic bicarbonate secretion, and inhibits gastrin-stimulated gastric acid secretion. It also stimulates pepsinogen secretion from chief cells. VIP signalling is upregulated in inflammatory bowel conditions including Crohn’s disease, where mast cell-VIP communication appears to be dysregulated.

The bottom line: VIP operates through VPAC1/VPAC2 receptors with overlapping but distinct tissue distributions, generating effects across the immune, nervous, pulmonary, and gastrointestinal systems that make it one of the most pleiotropic neuropeptides yet characterised.

CIRS and the Shoemaker protocol

VIP’s highest-profile clinical application is as the final step (Step 11) in the Shoemaker protocol for chronic inflammatory response syndrome (CIRS), a multi-system illness attributed to exposure to biotoxins from water-damaged buildings. In CIRS patients, endogenous VIP levels are frequently suppressed, and the protocol uses compounded intranasal VIP to restore immune regulation after earlier protocol steps (binder therapy, MARCoNS eradication, inflammatory marker correction) have been completed.

Ritchie Shoemaker, who developed the protocol, published an IRB-approved study and a peer-reviewed paper (Health, 2013) reporting that intranasal VIP reduced elevated inflammatory markers (MMP-9, TGF beta-1, C4a), raised suppressed VEGF levels, normalised clotting abnormalities including acquired von Willebrand’s, and returned regulation to pituitary-adrenal and ADH-osmolality axes. A subsequent NeuroImage-based study reported that intranasal VIP safely restored volume to multiple grey matter nuclei in CIRS patients. Over 300 physicians have prescribed intranasal VIP for CIRS patients, with more than 90% reporting symptom reduction, according to Shoemaker’s clinical data.

Aviptadil in acute respiratory distress syndrome

The clinical evidence for aviptadil (synthetic VIP) in ARDS spans two eras: pre-COVID and pandemic. In the mid-2000s, Youssef, Said, and colleagues treated 8 patients with septic ARDS with intravenous VIP at 50-100 pmol/kg/hr. Six of eight survived, which appeared favourable for septic ARDS, but the study was open-label with no control group and was never scaled due to the senior author’s retirement.

During the COVID-19 pandemic, aviptadil entered multiple clinical pathways. Youssef and colleagues studied 21 patients under an expanded access programme (EAP), reporting 90% four-week survival including successful decannulation of 4 of 5 ECMO patients, though this was against non-randomised concurrent controls. A randomised controlled trial (NCT04311697) enrolled 196 patients with preliminary results suggesting 71-72% 28-day survival in both aviptadil and placebo groups, with exploratory signals of possible benefit in the high-flow nasal cannula subgroup. The DSMB identified no important safety concerns. The ACTIV-3b/TESICO programme (NCT06729606) represents the most rigorous ongoing evaluation.

Pulmonary hypertension and sarcoidosis

Inhaled aviptadil has been studied in patients with pulmonary arterial hypertension (reduction in pulmonary artery pressure, improved cardiac output and mixed venous oxygen) and in a Phase II open-label study of 20 sarcoidosis patients (significant reduction in TNF-alpha and increment of CD4+CD127-CD25+ T cells in bronchoalveolar lavage fluid over 4 weeks). Five Phase II trials have been conducted under European regulatory authority, establishing the general safety profile at doses up to 300 mcg inhaled daily.

Preclinical evidence

Research area	Key findings	Evidence tier
Immunomodulation	Treg generation, cytokine suppression, anti-inflammatory bias in multiple rodent models	Preclinical (robust)
ARDS / lung protection	Reduced lung inflammation, improved oxygenation in animal models; 7/8 human septic ARDS patients survived (Phase I)	Phase I/II human (small, open-label)
Circadian regulation	VIP-expressing SCN neurons essential for circadian synchronisation in animal models	Preclinical
COVID-19 ARDS	Expanded access: 90% 4-week survival (21 patients). RCT (196 patients): no clear benefit vs placebo at primary endpoint	Phase II/III human (mixed results)
Neuroprotection	Anti-apoptotic, anti-inflammatory effects in neuronal injury models	Preclinical
CIRS / mold illness	Intranasal VIP normalised biomarkers, restored grey matter volume (Shoemaker group)	Clinical observations (open-label, no independent RCT)
COVID-19 viral entry	VIP reduced ACE2 and TMPRSS2 surface expression in stimulated epithelial cells (Gutzler 2025 IJMS)	In vitro
Bone metabolism	Osteoinductive effect confirmed in human MSCs (Castro-Vazquez 2024). Serum VIP inversely correlated with osteoporosis severity in postmenopausal women (Wang 2019)	Preclinical/cross-sectional human
ADNP/NAP drug lineage	VIP regulates ADNP, from which davunetide (NAP) was derived. Davunetide reached Phase II/III trials for PSP, schizophrenia, MCI	Downstream clinical (Phase II/III)
Memory modulation	SCN VIP neurons mediate light-induced transient forgetting via SCN-to-PVT pathway (Huang 2025 Neurosci Bull)	Preclinical (optogenetic/chemogenetic)

The bottom line: VIP has the broadest evidence base of any compound in this cluster, spanning preclinical immunology, small-scale human ARDS data, Phase II pulmonary trials, the Shoemaker CIRS protocol, bone metabolism research, the ADNP/davunetide drug development lineage, and emerging SCN memory modulation data, but no large independently conducted RCT has demonstrated efficacy for any single indication in which VIP itself is the administered compound.

VIP has an unusual regulatory history compared to other research peptides. As of the FDA’s updated April 22, 2026 document for bulk drug substances nominated for use in compounding under section 503A, vasoactive intestinal peptide appears in Category 1, meaning the FDA has not identified significant safety risks and is exercising enforcement discretion to permit compounding while the substance remains under evaluation.

This status has a complicated backstory. The FDA’s Pharmacy Compounding Advisory Committee first reviewed VIP in 2016 and decided there was insufficient information to move it onto the positive 503A bulks list. In September 2019, the FDA released a proposed rule explicitly proposing that VIP not be included on that list. Despite this, VIP was not moved to Category 2 (the restricted category), meaning compounding pharmacies with valid prescriptions have continued to prepare it throughout the ongoing evaluation period.

Separately, aviptadil (the pharmaceutical-grade synthetic VIP) holds FDA and EU orphan drug designations for ARDS, pulmonary hypertension, and sarcoidosis. Relief Therapeutics holds a US patent and proprietary manufacturing processes. This means VIP occupies two regulatory tracks simultaneously: the compounding pathway and the drug-development pathway (orphan drug).

Jurisdiction	Status
FDA (USA)	Not approved for any indication. Category 1 on interim 503A bulks list (compoundable under enforcement discretion). Orphan drug designation for aviptadil (ARDS, PH, sarcoidosis)
MHRA (UK)	Not licensed
TGA (Australia)	Not approved
EMA (EU)	Orphan drug designation for aviptadil. Five Phase II trials conducted under EU regulatory authority
WADA	Not individually listed. Possible S0 blanket prohibition as non-approved peptide hormone

For how different countries regulate peptide compounds more broadly, see the guides for the US, the UK and Australia.

The bottom line: VIP’s Category 1 status makes it one of the few peptides in the cognitive/neuropeptide cluster that can currently be legally compounded under FDA enforcement discretion, though this is an interim position and not equivalent to formal approval.

VIP’s safety profile draws from multiple data sources: five Phase II aviptadil trials conducted under European regulatory authority, the COVID-19 expanded access and RCT data, and the Shoemaker group’s CIRS clinical experience.

Aviptadil has demonstrated a 20-year history of use in Phase II trials for sarcoidosis, pulmonary fibrosis, bronchospasm, and ARDS. Numerous healthy volunteer studies have shown that IV infusion is well tolerated. The most commonly reported side effects across all data sources are hypotension (reflecting VIP’s vasodilatory activity), flushing, and diarrhoea. In the largest COVID-19 randomised trial, hypotension was uncommon and did not generally require changes to the infusion. Mild-to-moderate diarrhoea occurred in approximately one-third of patients. In the expanded access programme, hypotension occurred in 5 of 21 (24%) patients.

For intranasal VIP in the CIRS context, the Shoemaker group reports possible side effects of headaches, dizziness, palpitations, and irritability, which generally pass quickly. The 1.5-year safety study reported that intranasal VIP was safe at the doses used in the protocol.

VIP’s very short half-life (1-2 minutes in plasma) is a double-edged pharmacological property: it limits the duration of any adverse effects but also limits therapeutic action, requiring either continuous infusion (for IV aviptadil) or frequent intranasal administration (for CIRS protocols). The rapid clearance is primarily renal, with 35% eliminated in the first 4 hours and 90% within 24 hours.

The bottom line: VIP has a relatively favourable safety profile across two decades of Phase II data and CIRS clinical use, with hypotension, flushing, and diarrhoea as the primary side effects, though no large-scale long-term safety study exists and the CIRS data comes from the Shoemaker group’s own clinical observations.

VIP belongs to the glucagon/secretin superfamily and shares structural homology and some receptor overlap with pituitary adenylate cyclase-activating polypeptide (PACAP). PACAP binds VIP receptors with similar affinity yet does not reproduce all of VIP’s neuroprotective or immunomodulatory effects, a distinction that highlights how small structural differences within a peptide family can produce meaningfully different pharmacological profiles.

Within the cognitive and neuropeptide cluster on this site, VIP occupies a distinctive niche. Unlike Semax (ACTH-derived, primarily neurotrophic and nootropic) or Selank (tuftsin-derived, primarily anxiolytic and immunomodulatory), VIP’s clinical trajectory is driven by immunomodulation and pulmonary function rather than direct cognitive enhancement. Its inclusion in the neuropeptide cluster reflects its endogenous role as a neurotransmitter and neuromodulator rather than its primary research applications. For details on how to evaluate purity of any peptide product, see the certificate of analysis guide.

The bottom line: VIP’s primary clinical interest lies in immunomodulation and pulmonary function rather than direct cognitive enhancement, distinguishing it from other compounds in the neuropeptide cluster.