Effects of cannabis on congenital limb anomalies in 14 European nations: A geospatiotemporal and causal inferential study

2022

IJERPH

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Introduction. Of the many congenital anomalies (CAs) recently linked with community cannabis exposure, arguably the most concerning are neurological CAs (NCAs). We therefore conducted a detailed study of this in fourteen European nations. Methods. Congenital anomaly data were from Eurocat. Drug exposure data were from European Monitoring Centre for Drugs and Drug Addiction. Income from World bank. Results. The Netherlands, Spain, France and Bulgaria reported increasing rates of many NCAs. The NCA rate (NCAR) was higher in nations with increasing daily cannabis use when compared to those without (p = 0.0204, minimum E-value (mEV) = 1.35). At bivariate analysis, the mEVs of the following NCAs were significantly cannabis related: severe microcephaly 2.14 × 1013, craniosynostosis 5.27 × 1011, nervous system 4.87 × 1011, eye 2.73 × 107, microphthalmos 4.07 × 106, anencephalus 710.37, hydrocephalus 245.64, spina bifida 14.86 and neural tube defects 13.15. At inverse probability, weighted panel regression terms including cannabis were significantly related to the following series of anomalies: nervous system, anencephalus, severe microcephalus, microphthalmos, neural tube defect and spina bifida from p = 5.09 × 10−8, <2.2 × 10−16, <2.2 × 10−16, 4.84 × 10−11, <2.2 × 10−16 and 9.69 × 10−7. At geospatial regression, this same series of anomalies had terms including cannabis significant from p = 0.0027, 1.53 × 10−7, 3.65 × 10−6, 2.13 × 10−8, 0.0002 and 9.76 × 10−12. 88.0% of 50 E-value estimates and 72.0% of mEVs > 9. This analysis therefore demonstrates both close association of cannabis exposure with multiple NCAs across space-time and also fulfills the quantitative criteria of causal inferential analysis. Conclusions. Nine NCARs on bivariate and six NCARs on multivariable regression were cannabis related and fulfilled quantitative epidemiological criteria for causality and are consistent with other series. Particular concerns relate to exponential dose–response effects demonstrated in the laboratory and epidemiological studies. Great caution with community cannabinoid penetration is warranted. Data indicate that cannabis is a significant environmental teratogen and thus imply that cannabinoids should be regulated similarly to the manner in which all other important genotoxins are carefully controlled by communities for their self-sustaining longevity and the protection of generations yet to come.

Section: Generalizabilitysupporting

confidence: 90%

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

2022

IJERPH

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“…There are various strengths and limitations to the present conceptualization. The strengths include the remarkable consistency across the many epidemiological studies, which clearly demonstrates the genotoxic harms of cannabis exposure in several different international jurisdictions, in relation to both the congenital anomalies [ 28 , 36 , 37 , 40 , 45 , 46 , 49 , 51 , 71 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 ] and cancer [ 22 , 23 , 24 , 25 , 26 , 30 , 41 , 232 ], and, indeed, now also in aging [ 53 , 54 ]. Similar results in many different studies are clearly mutually supportive and strengthen the overall quality of the body of evidence.…”

Section: Mechanisms Of Cannabinoid Genotoxicitymentioning

confidence: 98%

“…For the reader who is unfamiliar with this epidemiological literature, it should be pointed out that most of the modern epidemiological studies referred to are not just observational ecological studies of convenience which happen to show a particular association. Many of the best studies used a formal space–time analysis and the quantitative tools of causal inference to introduce a pseudo-randomized quasi-experimental paradigm from which it is entirely appropriate to invoke causal associations [ 28 , 36 , 37 , 40 , 45 , 51 , 71 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 ].…”

Section: Introductionmentioning

confidence: 99%

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

2023

IJERPH

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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.

“…Many papers demonstrate that the dose-response relationship of cannabinoids with both genomic mutagenicity and mitochondrial toxicity is strongly exponential [52][53][54][55][56]. Moreover, this exponentiation of the dose-response effect has been extended to epidemiological studies where it has been repeatedly demonstrated that the passage from the fourth to fifth quintile of cannabinoid exposure is accompanied by a discontinuous quantum jump in congenital anomaly rates [5,[57][58][59][60].…”

Section: Introductionmentioning

confidence: 98%

Congenital Gastrointestinal Anomalies in Europe 2010–2019: A Geo-Spatiotemporal and Causal Inferential Study of Epidemiological Patterns in Relationship to Cannabis- and Substance Exposure

Gastroenterology Insights

2023

Introduction: Congenital anomalies (CA’s) of most of the gastrointestinal tract have been linked causally with prenatal or community cannabis exposure. Therefore, we studied this relationship in Europe. Methods: CA data were from Eurocat. Drug-use data were sourced from the European Monitoring Centre for Drugs and Drug Addiction. Income data were taken from the World Bank. Results: When countries with increasing rates of daily cannabis use were compared with those which were not, the overall rate of gastrointestinal CA’s (GCA’s) was higher in the former group (p = 0.0032). The five anomalies which were related to the metrics of cannabis exposure on bivariate analysis were bile duct atresia, Hirschsprungs, digestive disorders, annular pancreas and anorectal stenosis or atresia. The following sequence of GCA’s was significantly linked with cannabis metrics at inverse-probability-weighted-panel modelling, as indicated: esophageal stenosis or atresia, bile duct atresia, small intestinal stenosis or atresia, anorectal stenosis or atresia, Hirschsprungs disease: p = 1.83 × 10−5, 0.0046, 3.55 × 10−12, 7.35 × 10−6 and 2.00 × 10−12, respectively. When this GCA series was considered in geospatial modelling, the GCA’s were significantly cannabis-related from p = 0.0003, N.S., 0.0086, 6.652 × 10−5, 0.0002, 71.4% of 35 E-value estimates and 54.3% minimum E-values (mEVv’s) > 9 (high zone) and 100% and 97.1% > 1.25 (causality threshold). The order of cannabis sensitivity by median mEVv was Hirschsprungs > esophageal atresia > small intestinal atresia > anorectal atresia > bile duct atresia. Conclusions: Seven of eight GCA’s were related to cannabis exposure and fulfilled the quantitative criteria for epidemiologically causal relationships. Penetration of cannabinoids into the community should be carefully scrutinized and controlled to protect against exponential and multigenerational genotoxicity ensuing from multiple cannabinoids.