Toxicity of Cannabigerol: Examination of Long-Term Toxicity and Lifespan in Caenorhabditis elegans and 14-Day Study in Sprague Dawley Rats

Introduction: Cannabigerol (CBG) is becoming widely available despite little being known about its potential toxicity or long-term effects. Materials and Methods: The present investigation involved two distinct studies. The first study explored acute and long-term effects of CBG on toxicity, lifespan, and aging in adult Caenorhabditis elegans (C. elegans). Animals were treated with CBG (0.075 mu M-3.75 mM) to determine acute toxicity, mortality, and motility. Acute heat-induced stress survival (thermotolerance; 37 degrees C for 4 h) following CBG administration (0.075-3.75 mM) was measured. Long-term toxicity of lifelong CBG administration (7.5, 75, or 375 mu M CBG) was determined through changes in motility and lifespan duration. In the second study, healthy, adult, Sprague Dawley rats received 0, 35, 70, or 140 mg/kg-bw/day CBG (n = 5 per sex per group) daily for 14 days via oral gavage. Signs of gross toxicity and changes in behavior, body weight, food consumption, and serum chemistry were monitored. Liver, kidney, and adrenal gland weights were recorded, and histopathology of select tissues was examined. Results: CBG treatment did not result in acute or long-term toxicity in C. elegans. CBG-treated animals demonstrated increased thermotolerance, with maximal effect (127.7%) observed following 75 mu M CBG. Lifelong CBG exposure significantly increased the percentage of highly active animals at multiple timepoints, resulting in a similar to 160% increase in late-stage motility across treatment groups (p <= 0.011). While there was no change in maximum lifespan (23-24 days across all groups), lifelong CBG administration resulted in mean lifespan extension of 13.9%-19.1% (all p <= 0.0008). No treatment-related deaths or clinical signs were observed in rats following CBG treatment. Significant increases in alkaline phosphatase (p <= 0.001 and 0.05 for males and females, respectively) and chloride (males only; p <= 0.05) were observed in the high dose group, but these changes were of low magnitude and incidence, and therefore determined not to be toxicologically relevant. Absolute and relative liver weights were statistically increased in females of the high dose group compared to control animals; however, mean liver weights in this group (7.8 g) were within historical control values. No test substance-related macroscopic or microscopic findings were observed in the organs evaluated. Conclusions: These data will assist in dose selection for future studies investigating the long-term safety and tolerability of CBG.