Formulation-specific dose-response in the serum proteome of healthy dogs following cannabidiol administration

Cannabidiol (CBD) is increasingly being used in veterinary medicine; however, its systemic molecular effects in dogs remain poorly characterized. This study employed label-free quantitative proteomics to compare the serum proteomic responses of healthy dogs (<i>n</i> = 18) after 30 days of oral CBD delivery via three distinct matrices: hemp by-product feed pellets (F), CBD-infused oil (O), and semi-solid treat (SN). The verified chronic doses differed among the groups. Multivariate analysis revealed distinct formulation-specific proteomic signatures, with the F group clustered separately from the O and SN groups. Despite dose and matrix variations, all groups shared a core metabolic response characterized by downregulation of apolipoproteins (APOA4, APOC3, APOC1, and APOH) and upregulation of hemoglobin subunits (HBA and HBB), indicating CBD-mediated modulation of lipid metabolism and redox homeostasis. The high-exposure groups (O, SN) uniquely exhibited upregulation of proteins involved in vascular integrity and tissue scaffolding (e.g., TGFB1, PDGFRB, and VWF), while the SN group also showed induction of immunomodulatory and cytoprotective markers, such as clusterin (CLU). These findings demonstrate that the CBD delivery matrix critically influences systemic bioavailability and the scope of proteomic remodeling. Although all formulations engage core metabolic pathways, high-bioavailability formats induce additional signatures suggestive of vascular stabilization and stress resilience, providing a molecular rationale for optimizing CBD-based therapeutic formulations in canine medicine.