Toxicological Evaluation and Pain Assessment of Four Minor Cannabinoids Following 14-Day Oral Administration in Rats

Introduction: Despite growing consumer interest and market availability, the safety of minor cannabinoids, generally present in low concentrations in Cannabis sativa L., is not well understood. Materials and Methods: Cannabichromene (CBC; 3.2, 10, 17, 22, 32, or 100 mg/kg-bw/day), cannabinol (CBN; 1, 3.2, 10, 17, 32, or 100 mg/kg-bw/day), delta-8-tetrahydrocannabinol (D8-THC; 0.32, 1, 3.2, or 10 mg/kg-bw/day), tetrahydrocannabivarin (THCV; 3.2, 10, 17, 22, 32, or 100 mg/kg-bw/day), and vehicle (medium-chain triglyceride oil) preparations were administered via oral gavage once daily for 14 days to Sprague Dawley rats. Changes in behavior, body weight, food consumption, clinical pathology, organ weights, body temperature, and thermal pain sensitivity (tail flick assay) were assessed. Select organ tissues were collected at terminal necropsy and fixed for histopathological examination. Results: No treatment-related deaths were observed throughout the study, and cannabinoids were generally well tolerated. While some significant trends in body weight differences from controls (increases and decreases) were observed, these occurred independently of food consumption. Overall, differences in serum chemistry and hematology parameters between cannabinoid groups and their respective control groups were considered to occur due to biological variation among rats. No treatment-related gross abnormalities were observed in examined organs. Significant changes in absolute and relative organ weights occurred primarily in males and were generally of negligible magnitude. There were no biologically significant histopathological observations. While pain tolerance was significantly improved in animals treated with D8-THC (3.2 and 10 mg/kg-bw/day, day 14), results across minor cannabinoids were inconsistent and warrant further study. Conclusion: Minor cannabinoids were well tolerated across 14 days of daily oral administration at the doses assessed. Modest, dose-dependent trends in relative organ weights and serum chemistry parameters warrant exploration at higher oral doses. These data will assist in dose selection for future studies investigating the long-term safety and effects of CBC, CBN, D8-THC, and THCV.