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

Abstract

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.

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

“…The involvement of key developmental processes Wnt, HoxA, and sonic hedgehog in the above results explains for stroke the implication of cannabinoids in a wide variety of teratogenic, developmental, and neurodevelopmental congenital anomalies, as documented in Colorado, Hawaii, the USA, Canada, Australia, and Europe (27-29, 191-205, 207). This description fits well with the wide variety of congenital anomalies that have been linked with cannabis, including those of the cardiovascular, central nervous, gastrointestinal, chromosomal, limb, uronephrological, body wall, and orofacial systems, as well as in the general embryo (27)(28)(29)(191)(192)(193)(194)(195)(196)(197)(198)(199)(200)(201)(202)(203)(204)(205). Congenital anomalies that have been linked to cannabis exposure in the USA were anophthalmia/microphthalmia, anotia/microtia, aortic valve stenosis, atrial septal defect, biliary atresia, bladder extrophy, choanal atresia, cleft palate alone, cleft lip alone, cleft lip with cleft palate, cleft lip with or without cleft palate, cloacal extrophy, club foot, coarctation of the aorta, common truncus, congenital cataract, congenital dislocation of the hip, congenital posterior urethral valve, deletion of 22q11.2, diaphragmatic hernia, Ebstein's anomaly, encephalocele, epispadias, esophageal atresia with or without tracheesophageal atresia, Hirschsprung's disease, congenital megacolon, hydrocephalus without spina bifida, hypospadias, interrupted aortic arch, microcephalus, obstructive genitourinary defect, omphalocele, patent ductus arteriosus, pulmonary valve atresia, pulmonary valve atresia and stenosis, rectal and large intestinal atresia and stenosis, reduction deformity upper limbs, reduction deformity lower limbs, renal agenesis and hypoplasia, small intestinal atresia/stenosis, trisomy 13, trisomy 18, trisomy 21 (Down's syndrome), Turner's syndrome, and ventricular septal defect (192,202,205).…”

“…. Twenty stigmata of aging in cannabis dependence Fifteen hallmarks of aging have been described in cannabis dependence, including (1) increased acute and chronic physical and mental illness (138), (2) acceleration of cardiovascular and organismal age (15), (3) endocrine disruption, particularly of the hypothalamo-pituitary-gonadal axis (139, 140), (4) mitochondrial inhibition (141-144), (5) DNA hypomethylation and advanced epigenetic age (14,(145)(146)(147), ( 6) neuroinflammation accompanying cannabis-associated mental illnesses (148-173), (7) cirrhosis (174-176), (8) degeneration of oocytes and sperm (177,178), (9) increased carcinogenesis (28, [179][180][181][182][183][184][185][186][187][188][189][190], (10) heightened rates of many congenital anomalies and teratologic syndromes (27)(28)(29)(191)(192)(193)(194)(195)(196)(197)(198)(199)(200)(201)(202)(203)(204)(205)(206)(207), (11) telomerase inhibition (11,208), (12) chromosomal damage (2,4,8,<...…”

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 ].…”

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

“…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 ].…”