Immune-modulating effects of dietary cannabinoid-receptor 2 agonist beta-caryophyllene and cooling frequency in dairy cows under environmental heat load.

Hubner L.; Silva P.; Butenko Y.; Shattenstein B.; Portnick Y.; Dogot T.; Marcus L.; Nasser A.; Samara M.; Bradford B. et al. · Frontiers in immunology · 2026

**Background & Methods** This 2026 randomized controlled trial examined 40 mid-lactation Holstein dairy cows under environmental heat stress assigned to a 2×2 factorial design comparing dietary beta-caryophyllene (BCP) supplementation versus control with either 3 or 6 daily cooling sessions. At week 5, six cows per group underwent intra-mammary lipopolysaccharide (LPS) challenge to assess immune response, with measurements of milk production, feed intake, behavior, vaginal temperature, and blood biomarkers for stress and immune function. **Key Findings** - BCP supplementation reduced peak fever response during LPS-challenge, with lowest temperatures observed in the BCP-6CS group; plasma cortisol area under the curve tended to be lower in BCP-6CS versus CTL-3CS, suggesting stress-mitigating effects. - BCP-supplemented cows demonstrated immune-modulating effects including lower blood monocyte percentages post-LPS challenge and increased mean platelet volume and mass compared to controls. - Prior to LPS challenge, BCP increased resting bout duration and reduced eating time without affecting overall milk production or feed intake; increased cooling frequency (6 versus 3 sessions daily) improved thermoregulation with longer rumination time, reduced panting, and lower respiratory rate. **Dosage & Administration** Beta-caryophyllene was administered at 5 mg/kg body weight as a dietary supplement. Cooling interventions consisted of either 3 or 6 sessions daily during the experimental period. **Safety & Adverse Effects** Not reported. The study did not document adverse effects or safety concerns related to BCP supplementation or cooling frequency in the studied population. **Evidence Quality** This review-type publication presents a controlled experimental design with adequate sample size (n=10 per group) and appropriate randomization stratification. However, limitations include the relatively short intervention period, use of a single inflammatory challenge model (intra-mammary LPS) that may not reflect natural disease processes, and lack of long-term follow-up. The study is specific to dairy cattle, limiting direct translational applicability to other species or contexts. Some findings showed only tendencies toward significance (cortisol AUC), suggesting modest effect sizes. The 2×2 factorial design strengthens evidence for main effects but increases experimental complexity.

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