In a recent review published in Experimental Neurology, researchers presented the effects of simultaneous alcohol and cannabinoid (SAC) usage during gestation on fetal brain development.
Cannabis and alcohol are the most highly consumed psychoactive substances by expecting women, both of which have been independently associated with lifelong harmful effects on fetal development. SAC usage amplifies the pharmacodynamic effects of and craving for both drugs. However, data on polysubstance usage in the prenatal period by humans and non-human species are limited.
About the review
In the present review, researchers reported on maternal SAC outcomes on fetal development.
SAC implications on offspring development
In rats and mice, SAC elevated the rates of reabsorption, and notably, the combined administration showed greater or synergistic effects on pup reabsorption in comparison to the additive effects of individual drug exposures. Additionally, SAC has been associated with considerable reductions in pup body weight. In the presence of a cannabinoid, the rate of alcohol metabolism could be impeded, and SAC litters experienced greater impairments in motor coordination compared to those exposed to alcohol only, especially in the female offspring.
Both drugs influenced each other’s bioavailability by increasing each other’s plasma concentrations and prolonging the duration of fetal interactions when simultaneously consumed. In humans, SAC children showed elevated lowered hippocampal neurogenesis, increased hippocampal memory impairments, and altered hippocampal structure and function.
Cannabinoid receptor 1 (CB1) receptors located in the brain mediate profound neurotoxicity after SAC exposure. In zebrafish, SAC has disrupted Shh (sonic hedgehog) signaling pathways among vertebrates, which is essential for the healthy development of the embryo, especially for craniofacial development and NSC (neural crest cell) survival. SAC, in low doses, has led to ophthalmic and cranial defects, symptomatic of FASD (fetal alcohol spectrum disorder). Prenatal alcohol exposure (PAE) has reportedly led to fetal growth restrictions, microcephaly, and reduced blood flow to the brain.
Studies have reported that PAE impairs uterine and embryonic vasculature formation, hindering nutrient delivery to the fetus and, therefore, resulting in impaired fetal growth. Further, PAE in mice has reportedly lowered the velocity of fetal blood flow in cerebral arteries and the umbilical cord of the fetus. PAE had also led to fetal middle cerebral artery dilation, mediated by cannabinoid receptors.
Regular prenatal marijuana usage has led to fetal growth restrictions, elevated umbilical artery systolic: diastolic ratios, and absent or reversed the end-diastolic flow of blood in the umbilical arteries. Cannabinoid use has also been associated with lowered cerebroplacental ratios (CPR), oligohydramnios, low fetal birth weight, and greater intensive care unit (ICU) admissions.
Prenatal murine exposure to 2.0 mg/kg of CP55940, a synthetically obtained cannabinoid, has lowered fetal cerebral vessel diameter, length, and density. SAC has also lowered VEGF (vascular endothelial growth factor) expression and inhibited cellular proliferation and angiogenesis. Ethanol has reportedly reduced the neurogenic and self-renewal abilities of fetal NSCs and resulted in microcephaly.
Murine exposure to CP-55940, a synthetically obtained cannabinoid agonist, led to holoprosencephaly, exencephaly, and cortical dysplasia, indicative of the vulnerability of fetal preliminary neural tube stem cells to cannabinoids. Prenatal cannabinoid exposure (PCE) might interfere with the endocannabinoid system by synaptic pruning inhibition.
Cannabinoids mimic neurotransmitters and act as anandamides to inhibit neurotransmitter release. PAE has been associated with elevated extracellular GABA (gamma-aminobutyric acid) concentrations, GABAA receptor upregulation and lower potassium-evoked GABA release in the embryonic neocortex of rodent animals. Prenatal THC (delta-9-tetrahydrocannabinol) exposure has reduced CB1 concentrations and the number of CCK-INTs (cholecystokinin-expressing interneurons) in the hippocampus region of the fetal brain.
Excessive alcohol exposure has reportedly reduced cortical AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) GluR1 (glutamate ionotropic receptor AMPA type subunit 1) and GluR2 levels by 50% and 33%, respectively, in comparison to controls. PCE has lowered cerebellar AMPA GluR1 in glial cells and GluR2/3 expression in Purkinje neurons of the fetus. PAE has reduced NMDA (N-methyl-d-aspartate) receptor function and expression, and NR2A (subunit NMDA receptor 2A) and NR2B expression in the fetal hippocampus.
PCE has persistently altered systems that regulate glutamatergic release from the feta brain cortex. In rats, prenatal exposure to 5.0 mg/kg THC equivalents has led to significant decreases in hippocampal glutamatergic neurotransmission in the male offspring, associated with lower glutamate uptake, and lower expression of glutamate transporter1 (GLT1) and GLAST in hippocampal synaptosomes.
Conclusions and future directions
To conclude, based on the review findings, SAC use leads to altered fetal brain development. While designing future preclinical studies of SAC outcomes, the patterns of SAC consumption and different exposure models including the timing and method of administration, and drug concentrations must be considered.
Researchers must determine the cannabinoid to be researched upon, such as the exact substance (THC or CBD), or mechanism-driven substances such as CB1 agonists. Further, standardized measures such as growth metrics and maternal blood alcohol/THC concentrations must be used to assess SAC outcomes. Furthermore, SAC-associated preterm delivery and spontaneous abortions must be reported for precise inferences.
S.K. Rouzer, J. Gutierrez, K.V. Larin, et al. (2023). Alcohol & cannabinoid co-use: Implications for impaired fetal brain development following gestational exposure, Experimental Neurology. doi: https://doi.org/10.1016/ j.expneurol.2023.11431 https://www.sciencedirect.com/science/article/pii/S001448862300002X