Geotemporospatial and causal inference epidemiological analysis of US survey and overview of cannabis, cannabidiol and cannabinoid genotoxicity in relation to congenital anomalies 2001–2015

Abstract

Background Cannabinoids including cannabidiol have recognized genotoxic activities but their significance has not been studied broadly epidemiologically across the teratological spectrum. We examined these issues including contextual space-time relationships and formal causal inferential analysis in USA. Methods State congenital anomaly (CA) rate (CAR) data was taken from the annual reports of the National Birth Defects Prevention Network 2001–2005 to 2011–2015. Substance abuse rates were from the National Survey of Drug Use and Health a nationally representative longitudinal survey of the non-institutionalized US population with 74.1% response rate. Drugs examined were cigarettes, monthly and binge alcohol, monthly cannabis and analgesic and cocaine abuse. Early termination of pregnancy for abortion (ETOPFA) rates were taken from the published literature. Cannabinoid concentrations were from Drug Enforcement Agency. Ethnicity and income data were from the US Census Bureau. Inverse probability weighted (IPW) regressions and geotemporospatial regressions conducted for selected CAs. Results Data on 18,328,529 births from an aggregated population of 2,377,483,589 for mid-year analyses 2005–2013 comprehending 12,611 CARs for 62 CAs was assembled and ETOPFA-corrected (ETOPFACAR) where appropriate. E-Values for ETOPFACARs by substance trends were elevated for THC (40 CAs), cannabis (35 CAs), tobacco (11 CAs), cannabidiol (8 CAs), monthly alcohol (5 CAs) and binge alcohol (2 CAs) with minimum E-Values descending from 16.55, 1.55x107, 555.10, 7.53x1019, 9.30 and 32.98. Cardiovascular, gastrointestinal, chromosomal, limb reductions, urinary, face and body wall CAs particularly affected. Highest v. lowest substance use quintile CAR prevalence ratios 2.84 (95%C.I. 2.44, 3.31), 4.85 (4.08, 5.77) and 1.92 (1.63, 2.27) and attributable fraction in exposed 0.28 (0.27, 0.28), 0.57 (0.51, 0.62) and 0.47 (0.38, 0.55) for tobacco, cannabis and cannabidiol. Small intestinal stenosis or atresia and obstructive genitourinary defect were studied in detail in lagged IPW pseudo-randomized causal regressions and spatiotemporal models confirmed the causal role of cannabinoids. Spatiotemporal predictive modelling demonstrated strongly sigmoidal non-linear cannabidiol dose-response power-function relationships (P = 2.83x10−60 and 1.61x10−71 respectively). Conclusions Data implicate cannabinoids including cannabidiol in a diverse spectrum of heritable CAs. Sigmoidal non-linear dose-response relationships are of grave concern. These transgenerational genotoxic, epigenotoxic, chromosomal-toxic putatively causal teratogenic effects strongly indicate tight restrictions on community cannabinoid penetration.

Epidemiology of Δ8THC-Related Carcinogenesis in USA: A Panel Regression and Causal Inferential Study

“…The full implications of this profound and far-reaching result have yet to be fully explored. They have an obvious relevance and concordance with the results reported both in this study and in similar reports [27,[79][80][81][96][97][98]. Several classical studies have provided clear evidence of chromosomal breaks [9,10,13], end-to-end fusions [9,10], and chromosomal bridge formations in telophase [11,12,99] following cannabis exposure.…”

“…The link between cancer and cannabinoids is complex and multifactorial and has recently been reviewed in several recently published works [10,[14][15][16]27,31,32,34,35,[41][42][43]71,72,75,[78][79][80][81][82][83][84][85][86][87][88][89][90][91][92]. Our intention here is to introduce the way in which these general observations may relate to some specific cancer types.…”

“…Trisomies (of chromosomes 13, 18 and 21) and monosomies (of chromosome X, Turners syndrome) have been well-documented following cannabis exposure [44,46,47,81,102], where chromosomal mis-segregation is clearly a major feature of cannabis-related genotoxicity. Moreover, male disomy of chromosome X (Kleinfelters syndrome) has also been observed in association with cannabis exposure in the European data (manuscript submitted).…”

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

“…The relationship between body wall congenital anomalies (BWCAs) and cannabis exposure has been documented by researchers over many years. The relationship between omphalocele, a condition whereby the rapid elongation of the gut and increased liver size in the early stage of gestation reduces intra-abdominal space and forces the intestinal loops or other internal organs to protrude outside out of the abdominal cavity, and cannabis exposure was initially identified in animals [ 1 , 2 , 3 ] and has since been noted in several human studies [ 4 , 5 , 6 , 7 , 8 ]. Gastroschisis has been linked with cannabis use by many series [ 9 , 10 , 11 , 12 , 13 , 14 , 15 ], and in several large national and state-level epidemiological series [ 4 , 6 , 7 , 11 , 16 ].…”

“…The relationship between omphalocele, a condition whereby the rapid elongation of the gut and increased liver size in the early stage of gestation reduces intra-abdominal space and forces the intestinal loops or other internal organs to protrude outside out of the abdominal cavity, and cannabis exposure was initially identified in animals [ 1 , 2 , 3 ] and has since been noted in several human studies [ 4 , 5 , 6 , 7 , 8 ]. Gastroschisis has been linked with cannabis use by many series [ 9 , 10 , 11 , 12 , 13 , 14 , 15 ], and in several large national and state-level epidemiological series [ 4 , 6 , 7 , 11 , 16 ]. Diaphragmatic hernia has been linked with cannabis exposure in the USA by researchers from the Center for Disease Control [ 17 ] and more recently with patterns of US cannabidiol exposure [ 6 ].…”