Abstract
BackgroundCannabinoids 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.MethodsState 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.ResultsData 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).ConclusionsData 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.
Highlights
Cannabinoids including cannabidiol have recognized genotoxic activities but their significance has not been studied broadly epidemiologically across the teratological spectrum
Similar warnings occur on the labelling of “Hemp Oil” which is made freely accessible to the Australian public on supermarket shelves. Such overt warnings relating to acknowledged genotoxicity by the distributors and marketers of cannabinoids, and mandated warnings required by official drug regulators on both sides of the Atlantic directly imply that the genotoxicity of these agents is acknowledged in laboratory and preclinical studies and is in truth an established fact of science
We demonstrate how inverse probability weighting can be employed in multivariable regression models and use spatiotemporal models to investigate causal relationships formally and in a space-time context as an analytical pathway proof of concept for subsequent detailed studies across all congenital anomalies
Summary
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. Major authorities and several smaller convenience sample series claim that the use of cannabis in pregnancy is associated with increased prematurity, smaller head circumference, increased small for gestational age, low birth weight and relative infertility in male and female users [3,4,5] This view which enjoys widespread currency in the medical profession, is clearly at odds with the official governmental view endorsed in the requirements on registered product information for the medical profession and consumers, but is typical of the communitywide confusion relating to much of the information on cannabis and cannabinoids
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