NOT FOR HUMAN CONSUMPTION

Vasoactive intestinal peptide (VIP) is a naturally occurring 28–amino-acid neuropeptide widely expressed in the enteric nervous system, peripheral nerves, immune cells, and the CNS. It functions as a neurotransmitter/neuromodulator and immunoregulatory peptide, with prominent roles in vasodilation, smooth-muscle relaxation, epithelial secretion, and immune “tone.”

Clinically, most “VIP therapy” discussions involve aviptadil, a synthetic VIP (often formulated for IV or inhaled delivery in investigational programs).

2) Molecular pharmacology and receptor biology

2.1 Receptors

VIP signals primarily through class B GPCRs:

• VPAC1 (VIPR1)

• VPAC2 (VIPR2)

Both are activated by VIP (and also by PACAP), whereas PAC1 is PACAP-preferring and has low affinity for VIP.

2.2 Canonical signaling

VPAC receptor activation typically couples to Gs → adenylyl cyclase → cAMP → PKA/CREB. Depending on cell type and receptor context, VIP signaling can also engage additional pathways (e.g., β-arrestin-linked regulation, other G-protein coupling, receptor oligomerization/regulation).

2.3 Systems-level physiology (why VIP “hits many organs”)

VIP’s pleiotropy comes from receptor distribution across:

• Vascular smooth muscle & endothelium → vasodilation

• Airways → bronchodilation, immunomodulation

• GI tract → secretion, motility, smooth muscle relaxation

• Immune cells → cytokine modulation and inflammatory regulation

3) Immunology and inflammation: what VIP tends to do

VIP is often characterized as anti-inflammatory / immune-modulating in many contexts, including suppression of pro-inflammatory cytokine programs and shaping immune cell responses. This is a major reason it has been explored in inflammatory disease and lung injury settings.

4) Pharmacokinetics and delivery constraints (a key limitation)

A central translational problem is that native VIP is degraded very rapidly in plasma, with a reported half-life on the order of ~1–2 minutes.

This is why development work has emphasized:

• local delivery (e.g., inhalation for lung-targeted effects),

• stabilized analogs, and

• formulation systems to reduce systemic side effects and extend activity.

5) Clinical and translational evidence (what’s most studied)

5.1 Pulmonary vascular disease / pulmonary hypertension (inhaled VIP/aviptadil)

Inhaled aviptadil has been studied as a pulmonary vasodilator with the aim of producing lung-selective hemodynamic effects while limiting systemic hypotension; published clinical work in pulmonary hypertension reported modest and short-lived pulmonary vasodilation without major side effects in that study.

5.2 ARDS and COVID-19 (aviptadil programs)

VIP biology (alveolar/immune modulation + vascular effects) motivated multiple ARDS/COVID programs, including inhaled aviptadil trials. Clinical trial registrations remain the best canonical source for what was tested and the endpoints.
A 2025 peer-reviewed report in hospitalized COVID-19 pneumonia described inhaled aviptadil as well tolerated and associated with faster recovery in that study setting.

Regulatory nuance: “Orphan Drug Designation” has been granted for certain aviptadil development programs (e.g., ARDS/sarcoidosis), but that is not the same as approval.

5.3 Migraine/vascular headache biology

VIP is vasoactive in cranial circulation and has been used experimentally to probe neurovascular mechanisms (e.g., infusion paradigms assessing vasodilation and headache responses).

6) Safety and tolerability (mechanism-predictable)

Because VIP is a strong vasodilator/secretagogue, systemic exposure is commonly associated with dose- and route-dependent adverse effects such as:

• decreased blood pressure, tachycardia/palpitations, cutaneous flushing

• GI effects, including diarrhea/watery-diarrhea syndrome in some contexts

These predictable effects are a major reason inhaled delivery and lung-targeted formulations have been explored.

7) Current status (practical summary)

• VIP is an endogenous peptide with strong mechanistic rationale across pulmonary, vascular, and immune biology.

• Native VIP is hard to use systemically due to very rapid degradation and vasodilatory side effects.

• Most real-world “VIP as a drug” efforts center on aviptadil and delivery strategies (especially inhaled) in pulmonary indications and ARDS/COVID-related trials.

Selected references (high-yield)

• VPAC receptor biology and signaling:

• Physiology overview (VIP/PACAP receptors and GI/vascular roles):

• Immunology + PK/side-effect constraints (half-life; hypotension/tachycardia/flushing/diarrhea):

• Pulmonary delivery rationale + lung-selective effects:

• ARDS/COVID trial registry and 2025 inhaled study