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 lM to 4 mM) and assessing mortality and motility compared to control animals. Thermotolerance was examined by treating adult animals with CBD (0.4 lM 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 lM 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 lM CBD. The thermotolerance study showed that 40 lM 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 lM CBD revealed a maximum life extension of 18% observed at 40 lM 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.

Cannabidiol regulates CB1‐pSTAT3 signaling for neurite outgrowth, prolongs lifespan, and improves health span in Caenorhabditis elegans of Aβ pathology models

“…elegans Aβ 1‐42 model although a recent pilot study showed some moderate increase of lifespan in wild‐type C . elegans after CBD administration 19 . These Aβ strains have been used for various behavioral assays and pharmacological screens, including the identification of novel compounds for treating neurodegeneration 20,21 …”

“…17,18 No study was carried out to examine if CBD can be used to extend lifespan and improve health span in C. elegans Aβ 1-42 model although a recent pilot study showed some moderate increase of lifespan in wild-type C. elegans after CBD administration. 19 These Aβ strains have been used for various behavioral assays and pharmacological screens, including the identification of novel compounds for treating neurodegeneration. 20,21 This study aimed to reveal the mechanism of action of CBD on Aβ-induced neurite degeneration, lifespan, and health span using in vitro and in vivo models of Aβ.…”

Cannabidiol induces autophagy and improves neuronal health associated with SIRT1 mediated longevity

“…Although increasing evidence has shown the beneficial effects of CBD in different models of aging and age-associated disease [ 17 – 19 , 49 ], the molecular mechanism of how CBD affects neuronal aging remains elusive. In C. elegans , many physiological changes at the tissue, cellular, and molecular levels occur that are closely related to the effects of aging [ 22 ].…”

“…Cannabidiol (CBD), a non-intoxicating cannabinoid from Cannabis sativa , exhibits a broad spectrum of beneficial pharmacological effects, including antipsychotic [ 13 ], pro-cognitive [ 14 ], anti-inflammatory [ 15 ], and antioxidant [ 16 ] properties. Recently, CBD treatment has been shown to increase lifespan and improve healthspan in different models, such as the nematode worm ( Caenorhabditis elegans ) [ 17 , 18 ] and zebrafish ( Danio rerio ) [ 19 ]. However, the exact mechanism through which CBD modulates lifespan is unclear.…”

Galleria mellonella as a novel eco-friendly in vivo approach for the assessment of the toxicity of medicinal plants

“…In this context, invertebrate models appear as a very promising alternative and have seen a gain in popularity in recent years [37][38][39][40][41]. The most used invertebrate models for toxicity trials among others are Artemia salina, Daphnia magna, Drosophila melanogaster, soil invertebrate Folsomia candida, the nematode Caenorhabditis elegans, and the Greater Wax Moth Galleria mellonella [38,[42][43][44]. Among all these in vivo insects' models, G. mellonella has several attractive benefits due to its practicality, in particular its low cost, ease of acquisition and handling (no specialist training or equipment is required), ability to survive at 37°C (unlike many other non-mammalian hosts), they are large enough (2 cm in length and weigh approximately 250 mg) for accurate dosing (unlike commonly used invertebrate models such as C. elegans and D. melanogaster) which make it possible to handle individual larvae and administer test compounds directly into each individual (which is not always possible with other smaller invertebrate models) and enhances the reproducibility of assays conducted using this model [37,38,45].…”