Cannabinoids Exacerbate Alcohol Teratogenesis (Alcohol & Cannabis Toxic Combination for Developing Babies)

Scientific Reports volume 9, Article number: 16057 (2019)

Abstract: We tested whether cannabinoids (CBs) potentiate alcohol-induced birth defects in mice and zebrafish, and explored the underlying pathogenic mechanisms on Sonic Hedgehog (Shh) signaling. The CBs, Δ9-THC, cannabidiol, HU-210, and CP 55,940 caused alcohol-like effects on craniofacial and brain development, phenocopying Shh mutations. Combined exposure to even low doses of alcohol with THC, HU-210, or CP 55,940 caused a greater incidence of birth defects, particularly of the eyes, than did either treatment alone. Consistent with the hypothesis that these defects are caused by deficient Shh, we found that CBs reduced Shh signaling by inhibiting Smoothened (Smo), while Shh mRNA or a CB1 receptor antagonist attenuated CB-induced birth defects. Proximity ligation experiments identified novel CB1-Smo heteromers, suggesting allosteric CB1-Smo interactions. In addition to raising concerns about the safety of cannabinoid and alcohol exposure during early embryonic development, this study establishes a novel link between two distinct signaling pathways and has widespread implications for development, as well as diseases such as addiction and cancer.

Fetal Alcohol Spectrum Disorder (FASD) is common; recent conservative prevalence rates range from 1–5%1. Binge alcohol drinking (i.e. more than 4 or 5 drinks in two hours for women and men, respectively) is increasingly popular among young people, and is especially damaging to the embryo during the third to fourth weeks of pregnancy, when most pregnancies are unrecognized2,3. Alcohol exposure during this period causes characteristic craniofacial malformations of Fetal Alcohol Syndrome (FAS) including small palpebral fissures (micropthalmia), a smooth philtrum, and brain malformations in the holoprosencephaly spectrum3.

ffMarijuana use is also rising4, and about 4% of pregnancies are marijuana-exposed5, through either recreational use or as an anti-nausea self-medication. However, some subgroups of pregnancies have considerably more exposure6,7 and nearly 20% of a cohort of pregnant women in California, aged 18–24, report marijuana use8. As marijuana and other cannabinoids (CBs), such as cannabidiol (CBD), become increasingly legalized for medical or recreational purposes, and they remain perceived as low-risk substances9 safe to use during pregnancy, the incidence of CB-exposed pregnancies will rise even further. A recent study of births in Colorado found that the incidence of several birth defects has risen in the state during the period of marijuana legalization10.

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