Division of Psychiatry, University of Western Australia, Crawley, WA 6009, Australia.
School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia.
Int J Environ Res Public Health. 2023 Feb 14;20(4):3360. doi: 10.3390/ijerph20043360.
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.
随着全球对大麻及其衍生物在治疗某些疾病方面的治疗潜力的兴趣日益增加，为了正确评估治疗风险与效益之间的平衡，必须彻底了解大麻素的毒性特征。包括加拿大、澳大利亚、美国和欧洲在内的许多司法管辖区的现代研究证实，一些关于先天性异常和癌症诱导的最令人担忧和严重的历史报告实际上低估了多系统、兆碱基规模的跨代遗传损伤。这些来自致畸和致癌文献的研究结果得到了最近的数据支持，这些数据显示，在接触大麻的患者中，慢性疾病的加速模式和先进的 DNA 甲基化表观遗传时钟年龄。总之，多系统致癌、致畸和加速衰老强烈表明，与大麻素相关的遗传毒性比人们普遍认为的更为重要，因此对公共健康和多代人的影响非常大。最近报道的纵向全基因组关联研究以相当大的方法学复杂性优雅地解释了许多这些观察到的影响，包括正常染色体分离和 DNA 修复的多个抑制途径、DNA 甲基化的基本表观遗传机制的抑制以及表观遗传启动子超甲基化的端粒酶加速，这些特征都与衰老有关。对于癌症，还发现了 810 个靶点。观察到的恶性肿瘤类型都有流行病学记录。对大脑、心脏、面部、泌尿生殖、胃肠道和四肢发育进行了详细的表观基因组解释，充分解释了观察到的畸形模式，包括关键形态发生梯度的抑制。因此，这些主要的表观基因组见解构成了一系列强有力的新论据，既增进了我们对多系统多代大麻素遗传毒性下游后果的理解，又由于机制是因果关系的关键，强烈倾向于证明这种关系的因果性质。在这个介绍性的概念概述中，我们介绍了这个新的综合范式框架的各个方面。这些概念不仅提出了，而且确实指出了许多领域需要进一步研究和基础科学研究，以推进生物学、临床医学和人口健康领域的许多重要问题的探索。有鉴于此，我们必须正确评估每种潜在大麻应用的风险效益比，考虑到药物效力、疾病严重程度、人类发育阶段和使用时间。
