Cannabidiol potentiates phenobarbital-induced cell death in the developing brain

Epilepsy, affecting about 1 % of the global population, is more prevalent in children. The primary treatment is antiseizure medications (ASMs), with phenobarbital (PB) being the most common for pediatric cases. However, PB is effective in only two-thirds of patients and can cause side effects like cell death in developing brains. Early-life epilepsy treatment is particularly challenging, as many patients continue to experience poorly controlled seizures. Due to the limitations of current ASMs, cannabidiol (CBD) has emerged as a promising alternative, offering fewer side effects, neuroprotective properties, and efficacy in treatment-resistant cases. However, its impact on the developing brain remains unclear. In this study, we evaluated the safety profile of CBD in immature rodent brains, with particular attention to possible neurodegenerative effects as detected by Fluoro-Jade C histochemical staining (a sensitive marker of neuronal degeneration. CBD was administered at doses of 2, 20, and 200 mg/kg to postnatal day 7 wistar rats (male and female), with neuronal cell death assessed 24 h later. Results showed no overall increase in cell death compared to controls, suggesting comparable cell viability across doses. Notably, combining CBD 30 mg/kg with PB 75 mg/kg significantly increased neuronal death, with the PB+CBD group showing over twice the neurodegeneration of PB alone. These findings indicate that CBD may exacerbate PB-induced neurotoxicity, countering its expected neuroprotective benefits at certain doses. This highlights the need for caution when combining CBD with PB in pediatric epilepsy treatment.