Abstract
As global interest in the therapeutic potential of cannabis and its' derivatives for the management of selected diseases increases, it is increasingly imperative that the toxic profile of cannabinoids be thoroughly understood in order to correctly assess the balance between the therapeutic risks and benefits. Modern studies across a number of jurisdictions, including Canada, Australia, the US and Europe have confirmed that some of the most worrying and severe historical reports of both congenital anomalies and cancer induction following cannabis exposure actually underestimate the multisystem thousand megabase-scale transgenerational genetic damage. These findings from teratogenic and carcinogenic literature are supported by recent data showing the accelerated patterns of chronic disease and the advanced DNA methylation epigenomic clock age in cannabis exposed patients. Together, the increased multisystem carcinogenesis, teratogenesis and accelerated aging point strongly to cannabinoid-related genotoxicity being much more clinically significant than it is widely supposed and, thus, of very considerable public health and multigenerational impact. Recently reported longitudinal epigenome-wide association studies elegantly explain many of these observed effects with considerable methodological sophistication, including multiple pathways for the inhibition of the normal chromosomal segregation and DNA repair, the inhibition of the basic epigenetic machinery for DNA methylation and the demethylation and telomerase acceleration of the epigenomic promoter hypermethylation characterizing aging. For cancer, 810 hits were also noted. The types of malignancy which were observed have all been documented epidemiologically. Detailed epigenomic explications of the brain, heart, face, uronephrological, gastrointestinal and limb development were provided, which amply explained the observed teratological patterns, including the inhibition of the key morphogenic gradients. Hence, these major epigenomic insights constituted a powerful new series of arguments which advanced both our understanding of the downstream sequalae of multisystem multigenerational cannabinoid genotoxicity and also, since mechanisms are key to the causal argument, inveighed strongly in favor of the causal nature of the relationship. In this introductory conceptual overview, we present the various aspects of this novel synthetic paradigmatic framework. Such concepts suggest and, indeed, indicate numerous fields for further investigation and basic science research to advance the exploration of many important issues in biology, clinical medicine and population health. Given this, it is imperative we correctly appraise the risk-benefit ratio for each potential cannabis application, considering the potency, severity of disease, stage of human development and duration of use.