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

Abstract

Introduction. Since high rates of congenital anomalies (CAs), including facial CAs (FCAs), causally attributed to antenatal and community cannabis use have been reported in several recent series, it was of interest to examine this subject in detail in Europe. Methods. CA data were taken from the EUROCAT database. Drug exposure data were downloaded from the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Income was taken from the World Bank’s online sources. Results. On the bivariate maps of both orofacial clefts and holoprosencephaly against resin, the Δ9-tetrahydrocannabinol concentration rates of both covariates increased together in France, Bulgaria, and the Netherlands. In the bivariate analysis, the anomalies could be ranked by the minimum E-value (mEV) as congenital glaucoma > congenital cataract > choanal atresia > cleft lip ± cleft palate > holoprosencephaly > orofacial clefts > ear, face, and neck anomalies. When nations with increasing daily use were compared to those without, the former had generally higher rates of FCAs (p = 0.0281). In the inverse probability weighted panel regression, the sequence of anomalies—orofacial clefts, anotia, congenital cataract, and holoprosencephaly—had positive and significant cannabis coefficients of p = 2.65 × 10−5, 1.04 × 10−8, 5.88 × 10−16, and 3.21 × 10−13, respectively. In the geospatial regression, the same series of FCAs had positive and significant regression terms for cannabis of p = 8.86 × 10−9, 0.0011, 3.36 × 10−8, and 0.0015, respectively. Some 25/28 (89.3%) E-value estimates and 14/28 (50%) mEVs were >9 (considered to be in the high range), and 100% of both were >1.25 (understood to be in the causal range). Conclusion. Rising cannabis use is associated with all the FCAs and fulfils the epidemiological criteria for causality. The data indicate particular concerns relating to brain development and exponential genotoxic dose-responses, urging caution with regard to community cannabinoid penetration.

Cannabis- and Substance-Related Carcinogenesis in Europe: A Lagged Causal Inferential Panel Regression Study

“…The main results of this study reveal that cannabis is indeed related to the incidence of many cancers in both bivariate- and multivariable-adjusted models and strongly confirm results, which have been previously described elsewhere, particularly in the USA [ 17 , 18 , 44 , 167 , 168 , 169 , 211 , 212 , 213 , 214 , 215 ].…”

“…It is therefore highly relevant that tripling levels of community cannabis exposure have been linked with a tripling of total birth defect rates in Canada’s northern provinces, and increased levels of cannabis exposure have been linked with higher rates of dozens of congenital anomalies in Hawaii, Colorado, Australia and the USA [ 44 , 45 , 46 , 47 , 48 , 49 ], affecting most major organ systems (cardiovascular, gastrointestinal, genitourinary, respiratory, neurological and body wall), including limbs and chromosomal anomalies, trisomies and monosomy [ 44 , 45 , 46 , 47 , 48 , 49 ]. Much data have come to light recently as a result of large studies of national and transnational datasets on this subject [ 44 , 46 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ].…”

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

“…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.…”

“…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 ].…”

Perturbation of 3D nuclear architecture, epigenomic dysregulation and aging, and cannabinoid synaptopathy reconfigures conceptualization of cannabinoid pathophysiology: part 1–aging and epigenomics

“…For these reasons, it is envisaged that the triple confluence of rising cannabis prevalence rates, intensity of use rates, and cannabinoid potency will manifest relatively abruptly as steep rises in adverse mental health, as well as teratologic, carcinogenic, and age-related outcomes, as are indeed being observed and documented in several jurisdictions ( 16 , 25 , 27 – 32 , 179 – 187 , 189 – 205 , 207 , 232 , 234 – 237 , 321 , 342 – 345 ).…”