Subchronic Exposure to Low-Dose Cannabidiol (CBD) and Δ9-Tetrahydrocannabinol (Δ9-THC) Nanoemulsions Suggests Low Renal Toxicity: A Preliminary Study.

Guedes Pinto T.; Rosario B.; de Aquino P.; Viana G.; Ricardo N.; Silveira E.; Brito D.; Zampieri D.; Viana M.; Ribeiro D. · Pathophysiology : the official journal of the International Society for Pathophysiology · 2026

**Background & Methods** This preliminary study evaluated renal toxicity of cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) nanoemulsions in 40 male Wistar rats allocated to five groups receiving daily oral gavage for 21 consecutive days. Groups received vehicle control, CBD alone (2.5 or 5 mg/kg), or CBD+THC combination (2.5 or 5 mg/kg), with kidney tissue analyzed via histopathology and immunohistochemistry markers (Ki-67, GST-P, and cleaved caspase-3). **Key Findings** • High-dose groups (5 mg/kg) demonstrated marked renal histopathological damage including tubular and glomerular injury, hemorrhagic areas, inflammatory infiltration, and necrosis, with significantly elevated Ki-67 and cleaved caspase-3 immunoexpression compared to controls. • Low-dose groups (2.5 mg/kg) showed no significant pathological changes, suggesting a dose-dependent response pattern. • GST-P expression (phase II detoxification enzyme marker) was significantly increased only in the CBD 5 mg/kg group, indicating potential metabolic stress at higher doses. **Dosage & Administration** CBD 2.5 mg/kg and 5 mg/kg; CBD+THC 2.5 mg/kg and 5 mg/kg. All treatments administered daily via oral gavage for 21 consecutive days in male Wistar rats. **Safety & Adverse Effects** High-dose cannabinoid nanoemulsions (5 mg/kg) produced dose-dependent renal toxicity manifested as tubular and glomerular damage, hemorrhagic areas, inflammatory infiltration, and tissue necrosis. Molecular markers indicated increased cellular proliferation and apoptosis at high doses. Low-dose exposure (2.5 mg/kg) produced no observed adverse effects. **Evidence Quality** This is a preliminary animal study with significant limitations including small sample size (n=8/group), short treatment duration (21 days), single species and sex evaluation, and lack of functional renal parameters (serum creatinine, blood urea nitrogen). The nanoemulsion formulation studied may not directly translate to clinical cannabinoid preparations. No human data presented. Study provides foundational evidence for dose-dependent renal effects but requires confirmation through longer-term investigations, multiple animal models, functional assessments, and mechanistic studies before clinical implications can be established.

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