Geotemporospatial and causal inferential epidemiological overview and survey of USA cannabis, cannabidiol and cannabinoid genotoxicity expressed in cancer incidence 2003–2017: part 3 – spatiotemporal, multivariable and causal inferential pathfinding and exploratory analyses of prostate and ovarian cancers

Abstract

Background The epidemiology of cannabinoid-related cancerogenesis has not been studied with cutting edge epidemiological techniques. Building on earlier bivariate papers in this series we aimed to conduct pathfinding studies to address this gap in two tumours of the reproductive tract, prostate and ovarian cancer. Methods Age-standardized cancer incidence data for 28 tumour types (including “All (non-skin) Cancer”) was sourced from Centres for Disease Control and National Cancer Institute using SEER*Stat software across US states 2001–2017. Drug exposure was sourced from the nationally representative household survey National Survey of Drug Use and Health conducted annually by the Substance Abuse and Mental Health Services Administration 2003–2017 with response rate 74.1%. Federal seizure data provided cannabinoid concentration data. US Census Bureau provided income and ethnicity data. Inverse probability weighted mixed effects, robust and panel regression together with geospatiotemporal regression analyses were conducted in R. E-Values were also calculated. Results 19,877 age-standardized cancer rates were returned. Based on these rates and state populations this equated to 51,623,922 cancer cases over an aggregated population 2003–2017 of 124,896,418,350. Inverse probability weighted regressions for prostate and ovarian cancers confirmed causal associations robust to adjustment. Cannabidiol alone was significantly associated with prostate cancer (β-estimate = 1.61, (95%C.I. 0.99, 2.23), P = 3.75 × 10− 7). In a fully adjusted geospatiotemporal model at one spatial and two temporal years lags cannabidiol was significantly independently associated with prostate cancer (β-estimate = 2.08, (1.19, 2.98), P = 5.20 × 10− 6). Cannabidiol alone was positively associated with ovarian cancer incidence in a geospatiotemporal model (β-estimate = 0.36, (0.30, 0.42), P < 2.20 × 10− 16). The cigarette: THC: cannabidiol interaction was significant in a fully adjusted geospatiotemporal model at six years of temporal lag (β-estimate = 1.93, (1.07, 2.78), P = 9.96 × 10− 6). Minimal modelled polynomial E-Values for prostate and ovarian cancer ranged up to 5.59 × 1059 and 1.92 × 10125. Geotemporospatial modelling of these tumours showed that the cannabidiol-carcinogenesis relationship was supra-linear and highly sigmoidal (P = 1.25 × 10− 45 and 12.82 × 10− 52 for linear v. polynomial models). Conclusion Cannabinoids including THC and cannabidiol are therefore important community carcinogens additive to the effects of tobacco and greatly exceeding those of alcohol. Reproductive tract carcinogenesis necessarily implies genotoxicity and epigenotoxicity of the germ line with transgenerational potential. Pseudoexponential and causal dose-response power functions are demonstrated.

Anti-Cancer Activity of Cannabis sativa Phytocannabinoids: Molecular Mechanisms and Potential in the Fight against Ovarian Cancer and Stem Cells

“…A note should be given to the publication [ 69 ] that suggested, based on an epidemiological overview and survey of USA cannabis and cannabinoid users, that CBD might be considered a community carcinogen, additive to the effects of tobacco. Due to the considerable effect of CBD on cancer-associated genetic pathways, adverse effects from activating these pathways are possible.…”

“…As a result, the actual cannabis molecules and their combination(s) that might be active against OC markers have not been identified. In contrast, an epidemiological overview and survey of cannabis and phytocannabinoid users in the USA between 2003 and 2017 on the occurrence of prostate and ovarian cancers suggested that CBD might be considered a community carcinogen, additive to the effects of tobacco [ 69 ].…”

European Epidemiological Patterns of Cannabis- and Substance-Related Body Wall Congenital Anomalies: Geospatiotemporal and Causal Inferential Study

“…The concern is that this relatively abrupt launching of parts of the continent into higher cannabinoid exposure zones will continue to see an increasing number of severe genotoxic outcomes such as those described above for amelia. Particularly when this report is read in conjunction with other reports on cannabinoid teratogenicity [ 4 , 5 , 6 , 7 , 11 , 16 , 108 , 130 , 131 ], cannabinoid cancerogenicity [ 95 , 96 , 97 , 99 , 100 , 102 , 103 , 104 , 106 , 108 ], cannabinoid accelerated aging [ 102 , 132 , 133 ], heritable mutagenic and carcinogenic disease [ 98 , 99 , 100 , 108 , 134 , 135 , 136 ], and heritable neurotoxicity [ 107 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 ], it becomes clear that rational policies in this area would tightly restrict and control community exposure to genotoxic and neurotoxic cannabinoids for multiple public health indications as has always been the community’s response to known serious genotoxic xenobiotics. The prospect of continued contamination of the food chain and increasing population exposure, incurring avoidable genetic and epigenetic damage to the heritable material of the population for multiple generations to come, is most serious indeed.…”

“…As outlined in the introduction, the mechanisms of cannabis genotoxicity are many and complex and have been reviewed elsewhere [ 4 , 5 , 6 , 7 , 16 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 ]. For our present purposes, we wish to focus on two pathways of particular importance, these being the disruption of key morphogen gradients and the epigenomic perturbations.…”

Clinical Epigenomic Explanation of the Epidemiology of Cannabinoid Genotoxicity Manifesting as Transgenerational Teratogenesis, Cancerogenesis and Aging Acceleration

“…Contrariwise, strong epidemiological evidence from many jurisdictions showed the likely involvement of cannabinoids in many cancers, dozens of serious birth defects and cellular and organismal aging [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. Moreover, there is a remarkably close uniformity between the findings from different jurisdictions [ 38 , 39 ], which not only confirms the findings of single studies but also, according to the established Hill criteria of causality, lends formal credence to the likely causal relationship between epidemiologically assessed cannabis exposure and the observed morbidity.…”