A 13-week oral toxicity and toxicokinetic study of cannabidiol in Sprague Dawley rats with a 4-week recovery period

Cannabidiol (CBD) is widely marketed as a health and wellness product. However, evidence for its effectiveness and safety remains limited. This study assessed the toxicity and toxicokinetic profile of CBD in Sprague Dawley rats over 13 weeks at low (5 mg/kg/day), mid (15 mg/kg/day), and high (150 mg/kg/day) doses, followed by a 4-week recovery period. Toxicokinetic analyses revealed no marked sex differences in systemic exposure to CBD or its metabolite 6-OH-CBD; however, female rats had slightly higher exposure to metabolites 7-OH-CBD and 7-COOH-CBD. Accumulation of CBD and its metabolites was observed following repeated oral administration of CBD. No CBD-related effects on mortality, clinical observations, or ophthalmoscopy were observed during the study. Higher food consumption was observed in rats treated with the high CBD dose group; however, this did not correlate with a statistically significant increase in body weight. A slightly higher fold increase in serum alanine aminotransferase (∼1.4-fold to 1.5-fold) was observed in the CBD high group, which was determined to be reversible. Histopathological analyses showed hepatocyte hypertrophy, but this effect was not accompanied by inflammatory changes or other microscopic lesions and resolved over the recovery period. Hypertrophy of pars distalis cells in pituitary gland and cortical cell vacuolation in adrenal glands were determined to be adaptive changes and reversible during the recovery period. The no-observed effect level was considered to be lower than the lowest tested dose (5 mg/kg/day) and no-observed adverse effect level to be the highest tested dose (150 mg/kg/day).