Abstract
Cannabis and cannabinoids are implicated in multiple genotoxic, epigenotoxic and chromosomal-toxic mechanisms and interact with several morphogenic pathways, likely underpinning previous reports of links between cannabis and congenital anomalies and heritable tumours. However the effects of cannabinoid genotoxicity have not been assessed on whole populations and formal consideration of effects as a broadly acting genotoxin remain unexplored. Our study addressed these knowledge gaps in USA datasets. Cancer data from CDC, drug exposure data from National Survey of Drug Use and Health 2003–2017 and congenital anomaly data from National Birth Defects Prevention Network were used. We show that cannabis, THC cannabigerol and cannabichromene exposure fulfill causal criteria towards first Principal Components of both: (A) Down syndrome, Trisomies 18 and 13, Turner syndrome, Deletion 22q11.2, and (B) thyroid, liver, breast and pancreatic cancers and acute myeloid leukaemia, have mostly medium to large effect sizes, are robust to adjustment for ethnicity, other drugs and income in inverse probability-weighted models, show prominent non-linear effects, have 55/56 e-Values > 1.25, and are exacerbated by cannabis liberalization (P = 9.67 × 10–43, 2.66 × 10–15). The results confirm experimental studies showing that cannabinoids are an important cause of community-wide genotoxicity impacting both birth defect and cancer epidemiology at the chromosomal hundred-megabase level.
Highlights
Cannabis and cannabinoids are implicated in multiple genotoxic, epigenotoxic and chromosomal-toxic mechanisms and interact with several morphogenic pathways, likely underpinning previous reports of links between cannabis and congenital anomalies and heritable tumours
It was adjusted to include estimates of early termination of pregnancy for anomaly (ETOPFA) taken from the published l iterature[64,65,66]. These datasets were matched with drug use data from NSDUH at Substance Abuse and Mental Health Services Administration (SAMHSA) for the period 2003–201767 so that the fifteen years 2003–2017 became the period of analysis
The present study examined the bivariate and multivariate relationships of the principal components of five chromosomal pathologies and five cancers to substance exposure, income and ethnicity covariates in a quantitative causal analysis framework
Summary
Cannabis and cannabinoids are implicated in multiple genotoxic, epigenotoxic and chromosomal-toxic mechanisms and interact with several morphogenic pathways, likely underpinning previous reports of links between cannabis and congenital anomalies and heritable tumours. An elegant and incisive molecular dissection of the cannabidiol-related genotoxic mechanisms was recently published by the Parnell group which indicated that cannabidiol-hedgehog signalling and cannabinoid receptor type 1 (CB1R)—smoothened receptor heterodimerization was a key molecular mediator of developmental malformations including orofacial cleft palate and lip deformities, exencephaly and microphthalmia/anophthalmia in mice and z ebrafish[27]. These authors noted that since the hedgehog pathway is a key developmental mechanism implicated in many oncogenic pathways it could be expected to implicated in the growth and promotion of several cancers. Promiscuous heterodimerization of the CB1R with many other G-protein receptors has been reported including notch and C
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