* Correspondence:
Albert Stuart Reece
A leading perspectives piece in the New England Journal of Medicine recently observed the salience of assessing drug safety in children and emphasized that effects experienced in childhood can have long lasting impacts as they interfere with maturation and growth of the organism into later life. Senior researchers from the National Institute of Drug Abuse have frequently drawn attention to the implications of adolescent cannabis exposure. The effects of gestational exposure are even more far reaching. These factors are given further urgency by studies showing 25% of Californian teenage mothers in California use cannabis.
Cannabis-related neuroteratology appears to clearly fall on a spectrum of deficits.
With the obvious caveats that many of the longitudinal studies of prenatal cannabis exposure (PCE) have been conducted in very different populations, that it is not easy to control for other sociodemographic factors frequently associated with drug use, and that the concentration of cannabis commonly used in the older studies was much lower, findings which together engender a fair degree of heterogeneity in the published reports, a remarkably consistent thread runs through the PCE literature. Three major longitudinal studies have followed children exposed prenatally from white middle class Ottawa from the late 1970’s; from predominantly African-American Pittsburgh from 1982; and from the Netherlands from 2001. Reductions in birth weight of 200-300g, slightly smaller head circumferences (2.8mm), and body length are reported in weekly users with several studies reporting dose-response effects.
In terms of neurobehavioural functioning increased neonatal startle response were seen, with specific cognitive defects in grade school, increased impulsivity, hyperactivity and depression at age 10, poor school achievement, adolescent delinquency, increased violence and aggression amongst girls, increased use of tobacco and cannabis in teens, and in the early 20’s in the longest running study, deficits in short term memory, visuospatial memory and motor impulse control. These defects have been linked with ADHD and with autism. Microcephaly was also noted in a large Hawaiian study. Increased neonatal startle and later cognitive defects are also seen in rodents after PCE.
These findings are clinically significant, and may assume public health significance when one notes that autism is increasing in all USA states where it is measured, paralleling rising rates of cannabis use across the country.
Two reports from C.D.C. indicate an almost doubling of the rate of anencephaly following PCE R.R.=1.9 (95%C.I. 1.1-3.2). In the context of the foregoing findings this major datum implies that cannabis has the unusual distinction of being a neurotoxin which interferes with brain development to the point of chemically amputating the forebrain. Hence there is clear evidence of a graded spectrum of deficits following PCE from subtle ASD- and ADHD- like neurobehavioural defects, to smaller heads, to microcephaly and to anencephaly including foetal neurological and neonatal death.
In the context of indicative epidemiology consideration of pathophysiological mechanisms is pertinent to address the Hill principles of causality.
There are numerous compelling mechanisms by which PCE can be related to subsequent teratogenic outcomes.
Importantly the cerebellum, midbrain, diencephalon and forebrain express moderate to high levels of type 1 cannabinoid receptors (CB1R) from early in gestation.
It was recently powerfully demonstrated that opposing gradients of the ligand-receptor guidance pairs slit-Roundabout (robo) and the notch ligand dll control and determine mammalian corticogenesis in diverse organisms including snakes, birds, mice and human organoids by controlling the switch for cortical neurogenesis from directly via radial glia cells to a more indirect and proliferative pathway via intermediate progenitors (Figure 1). Cannabinoids have been shown to reverse this natural gradient for dll, and acting via a 2AG / CB2R / slit2 / Robo1 / 2AG / CB1R / JNK / ERK pathway to stimulate robo.
Neurexin-neuroligin is a trans-synaptic ligand-receptor pair which directly induces and maintains synapse formation, and has been shown to be inhibited by cannabinoids.
Axon guidance is also controlled by robo-slit and by stathmin-induced tubulin polymerization, which are sensitive to cannabinoids.
White matter disconnection is well documented following adolescent and prenatal cannabis use, and in autism, and oligodendrocytes have CB1R’s and CB2R’s.
Mitochondria possess both CB1R’s and cannabinoid signal transduction machinery and are known to be highly sensitive to cannabinoids and interact with DNA maintenance pathways by several routes.
Cannabinoids have also been shown to alter signaling via the neurotransmitters: glutamate, GABA, opioids, dopamine, serotonin and enkephalin.
Cannabinoids have demonstrated intergenerational epigenetic effects on the medium spiny neurons of the nucleus accumbens and amygdala and also on immune cells which sculpt dendritic networks and prune synapses.
Acting via CB1R, GPR55, and vanilloid type 1 receptors cannabis has been linked with arteritis with likely downstream actions on neurogenic and other stem cell niches.
Endocardial cushions also carry high levels of CB1R’s and the American Academy of Pediatrics has a position statement noting the increased incidence of Ebstein’s syndrome and ventricular septal defect (VSD) after PCE. Both syncytiotrophoblast and placental arteries carry high concentrations of CB1R’s and abnormalities of uterine blood flow have been documented.
Cannabinoids interfere with tubulin polymerization and mitotic spindle function and thereby act as indirect genotoxins. The implication of cannabis with four inheritable cancers implies malignant teratogenicity and genotoxicity.
Colorado reports dramatic rises of total congenital anomalies, microcephaly, VSD, ASD, Down’s syndrome and chromosomal defects, all of which are relatively straightforward to quantify.
Colorado legislators have also moved to declare a state of crisis related to an autism rate presently growing by 30% 2012-2014. Similarly in northern California a coincident hotspot of cannabis use, gastroschisis and autism has been reported. In New Jersey 4.5% of 8 year old boys are autistic.
The above findings comprehend both positive and negative association along with multiple plausible biological pathways linking causality.
As rising rates of community cannabis use augment rising cannabis concentrations and intersect often asymptotic cannabinoid dose-response genotoxicity curves, increased clinical teratogenesis is to be expected. Of these anomalies the neurobehavioural teratology will likely be the most common, is arguably the most costly and severe, and is also most difficult to quantify.
Are we prepared?
Source: Paper by Albert Stuart Reese sent to Elinore.Mccance-katz@samhsa.hhs.gov 2018