CB1R Expression Key to Understanding Cannabis Teratology

 

In an era when 24% of teenage Californian mothers test cannabis-positive it is unfortunate that the vast and conflicting literature on cannabis teratology has created professional confusion on the important subject of cannabis teratology.  An appreciation of overarching patterns can contribute to clarity in this field.

There is considerable agreement in the literature that cannabis interferes with foetal development including earlier birth, higher rates of prematurity, and lifelong smaller heads – which obviously necessarily implies lifelong smaller brains as well 1.  Moreover the National Birth Defects Prevention Network coordinated by CDC have issued two papers documenting increased rates of anencephaly with R.R. = 1.7 (95%C.I. 0.9-3.4) and RR=1.9 (95% C.I. 1.1-3.2) respectively 2.   And there is very close agreement from the three major longitudinal studies from Ottawa, Pittsburgh and Netherlands of brain growth and intellectual development in children after prenatal cannabis exposure (PCE) which clearly document impaired executive functioning, poorer attention, difficulty in school work increased rates of addiction, persisting through all grades of school and into young adult life as long as the early 20’s 3.   Other studies have shown reduced frontal cortical thickness and increased white matter tract disconnections approaching 90% in key executive and computational cortical areas.  It is known that the foetal brain stem is low in cannabinoid type 1 receptors (CB1R’s) but many parts of the rest of the brain, including cerebral, hippocampal, orbitofrontal and cerebellar cortices, the limbic system and parts of the midbrain have moderate to high density CB1R’s.

This pattern of CB1R distribution forms both the greatest strength of cannabis and also its greatest weakness.  It is often – although clearly wrongly – said that cannabis cannot kill patients because the brain stem is low in CB1R’s so direct respiratory depression cannot occur as occurs from opioids.  The tag line about cannabis not causing death, though thoroughly deserving of “urban myth” status is demonstrably erroneous as cannabis is now well linked with cardiac arrest, psychosis, testicular cancer, chronic lung disease and unemployment – amongst many others – all of which are greatly elevate mortality.  As in adult life, so in foetal life the largely supratentorial distribution of CB1R’s implies that perturbation of the endogenous endocannabinoid system could conceivably interfere with the development of the supratentorial brain.  This pattern is well displayed by anencephaly in which the brain stem is often more or less intact.  It can be argued that the remainder of the neuroteratological manifestations of PCE reflect the pattern of distribution and expression of CB1R’s which occur with development.   This implies that cannabis neuroteratology actually reflects a continuum with subtle forms of neurobehavioral teratology at one end of the spectrum, microcephaly and smaller heads in an intermediate position and anencephaly at the most severe end.  This continuum can be further extended to include neurologically induced foetal loss and spontaneous and therapeutically induced terminations.

Moreover high density CB1R’s have been demonstrated on brain mitochondria where they subserve numerous key brain functions including thinking, attention, memory and wakefulness 4.  Their inhibition is directly linked with stimulating aging processes via mitonuclear crosstalk, induction of the mitochondrial stress response and impaired DNA repair.  The implications of accelerated molecular and neuronal aging at the foetal stage have not been properly considered.

The American Heart Association and the American Academy of Pediatrics issued a statement as long ago as 2007 that found two heart defects, ventricular septal defect (VSD) and Ebsteins anomaly, were known to be related to cannabis use on the basis of two studies 5.  Importantly both the atrioventricular valves and parts of the membranous interventricular septum are derived from the endocardial cushions which are known to be high in CB1R’s from as early as 9 weeks of gestation.  The Colorado experience also fits here with a 35% increase in VSD rates and a 262% increase in atrial septal defect rates 2000-2013 (Figure 1).  This early appearance of cardiovascular CB1R’s is important as many women are unsure of their pregnancy at this time; and given the very long half-life of cannabis in fat stores of several months immediate cessation would not protect a developing foetus during critical periods of organogenesis.  Studies show that paternal exposure is more significant than maternal exposure for several defects including transposition of the great arteries.  CB1R is a key regulator of the neurovascular neural stem cell niche.

Gastroschisis incidence has also risen, and reflects vasoactive drug exposure.  High density CB1R’s on foetal arteries, CB1R-mediated vasospasm and cannabis arteritis imply that the demonstrated vasoactive properties of cannabis have been largely overlooked 6.  Seven studies uniformly document on univariate testing increased incidence of gastroschisis after cannabis exposure and a further two studies show increased severity.  Carefully adjusted Canadian studies show a threefold elevation of gastroschisis risk.

Δ9-Tetrahydrocannabinol also interferes with nuclear actin and tubulin polymerization directly interfering with the processes of DNA repair and cell division respectively 7.  Hence Down’s syndrome, which is one of the chromosomal mis-segregation disorders has been linked with PCE.

Government reports from Canada show a clear association of high congenital anomaly rates for total defects, cardiovascular defects, orofacial clefts and gastroschisis with areas of high cannabis consumption.  Similar evidence is also available for high cannabis use areas in Northern New South Wales in Australia.  USA state level epidemiology replicates these same patterns.

As the second most common cannabinoid present in cannabis it is important to appreciate that the above-cited neonatal epidemiology also implicates cannabidiol which also binds to CB1R’s at high doses and has demonstrated genotoxicity, epigenotoxicity and mitochondrial toxicity.

These observations show that the CB1R, the dominant cannabinoid endoreceptor, well explains much of the neurobehavioural and cardiovascular teratology which is now relatively well described.

Importantly such an understanding, together with the non-linear asymptotic cannabinoid-genotoxic dose-response curve, predicts that increased community exposure to cannabis both by prevalence and by the high concentrations widely available will necessarily imply severe brain damage which can safely be said to approach 100% for significant in utero or paternal exposure, a congenital defect from which recovery is not possible as brain growth is permanently compromised.

Source:  Paper by Prof. Dr. Stuart Reece to DrugWatch International  July 2018

References

Volkow ND, Compton WM, Wargo EM. The Risks of Marijuana Use During Pregnancy. JAMA. 2017;317(2):129-130.Van Gelder MMHJ, Donders ART, Devine O, Roeleveld N, Reefhuis J.

Using bayesian models to assess the effects of under-reporting of cannabis use on the association with birth defects, national birth defects prevention study, 1997-2005. Paediatric and perinatal epidemiology. 2014;28(5):424-433.

Brents L. Correlates and consequences of Prenatal Cannabis Exposure (PCE): Identifying and Characterizing Vulnerable Maternal Populations and Determining Outcomes in Exposed Offspring In: Preedy V.R., ed. Handbook of Cannabis and Related Pathologies: Biology, Pharmacology, Diagnosis and Treatment. Vol 1. London: Academic Press; 2017:160-170.

Hebert-Chatelain E, Desprez T, Serrat R, et al. A cannabinoid link between mitochondria and memory. Nature. 2016;539(7630):555-559.

 

Jenkins KJ, Correa A, Feinstein JA, et al. Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation. 2007;115(23):2995-3014.

Pacher P, Steffens S, Hasko G, Schindler TH, Kunos G. Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the ugly. Nat Rev Cardiol. 2018;15(3):151-166.

Reece AS, Hulse GK. Chromothripsis and epigenomics complete causality criteria for cannabis- and addiction-connected carcinogenicity, congenital toxicity and heritable genotoxicity. Mutat Res. 2016;789:15-25.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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