Effect of Cannabidiol on the Long-Term Toxicity and Lifespan in the Preclinical Model Caenorhabditis elegans.

ABSTRACT

Introduction: Despite widespread use of cannabidiol (CBD), no lifelong toxicity study has been published to date. Caenorhabditis elegans is often used in preclinical lifelong toxicity studies, due to an estimated 60-80% of their genes having a human ortholog, and their short lifespan of ∼2-3 weeks. In this study, we examined both acute and long-term exposure studies of CBD at physiologically relevant concentrations. Materials and Methods: Acute toxicity was determined by treating day 1 adults with a wide range of CBD concentrations (0.4 µM to 4 mM) and assessing mortality and motility compared to control animals. Thermotolerance was examined by treating adult animals with CBD (0.4 µM to 4 mM) and exposing them to 37°C for 4 h, and then scoring for the number of alive animals treated with CBD compared to controls. Long-term toxicity was assessed by exposing day 1 adults to 10, 40, and 100 µM CBD until all animals perished. Control animals had no active drug exposure. Results: We report both acute and long-term exposure studies of CBD to adult C. elegans at physiologically relevant concentrations. Acute toxicity results showed that no animal died when exposed to 0.4-4000 µM CBD. The thermotolerance study showed that 40 µM CBD, but not other treatment levels, significantly increased resistance to heat stress by 141% compared to the untreated controls. Notably, whole-life exposure of C. elegans to 10-100 µM CBD revealed a maximum life extension of 18% observed at 40 µM CBD. In addition, motility analysis of the same groups revealed an increase in late-stage life activity by up to 206% compared to controls. Conclusion: These results serve as the only CBD lifelong exposure data in an in vivo model to date. While further research into the lifelong use of CBD should be carried out in mammalian models, the C. elegans model indicates a lack of long-term toxicity at physiologically relevant concentrations.