Protective effects of cannabidiol against acute stress: behavioral responses and corticosterone concentrations in female Wistar rats.

Uršič M.; Karaer M.; Gregorič A.; Vake T.; Snoj T. · Frontiers in pharmacology · 2026

**Background & Methods** This animal study evaluated cannabidiol's (CBD) protective effects against acute restraint stress in 36 female Wistar rats randomly assigned to six groups: four CBD-treated groups (2, 10, 20, and 100 mg/kg doses) and two placebo control groups (vehicle medium-chain triglycerides). Following CBD or placebo administration, stressed groups underwent 60 minutes of restraint stress, with all animals subsequently tested in an open field arena for 30 minutes and blood samples collected for corticosterone analysis via ELISA. **Key Findings** • CBD-treated rats demonstrated anxiolytic-like behavior, spending significantly more time in the center of the open field arena compared to stressed control rats, indicating reduced anxiety-like responses to acute stress. • Distance traveled in the open field differed significantly between groups overall; however, CBD showed no significant effects on locomotor activity across the tested dose range (2-100 mg/kg). • Plasma corticosterone concentrations showed no significant differences between CBD-treated and untreated groups at either timepoint (60 minutes post-administration and 90 minutes after stress onset), suggesting CBD's anxiolytic effects may operate through mechanisms independent of acute corticosterone suppression. **Dosage & Administration** CBD was administered at four doses: 2, 10, 20, and 100 mg/kg. Route of administration and vehicle delivery method were not explicitly specified beyond reference to medium-chain triglycerides as the placebo vehicle. Administration occurred 60 minutes prior to stress exposure. **Safety & Adverse Effects** Not reported. The study did not document adverse effects, behavioral toxicity, or safety concerns across the tested dose range. **Evidence Quality** This preclinical animal model study presents moderate evidence quality with several limitations. The use of female Wistar rats limits generalizability to human populations; sex-specific responses may not translate across species or genders. The lack of dose-dependent effects (no significant differences among CBD doses) is noteworthy and raises questions about optimal dosing. The absence of corticosterone suppression despite observed anxiolytic behavior suggests incomplete mechanistic understanding. The study's primary limitation is inability to definitively establish CBD's mechanism of action. The authors appropriately acknowledge need for further investigation. Applicability to clinical settings requires additional human trials examining dose-response relationships and mechanistic pathways.

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