Prenatal cannabis exposure – The “first hit” to the endocannabinoid system, Kimberlei A. Richardson et al., 2016,

Prenatal cannabis exposure – The “first hit” to the endocannabinoid system

Kimberlei A. Richardson, Allison K. Hester, Gabrielle L. McLemore

Neurotoxicology and Teratology, 2016, 58, 5-14.

DOI : 10.1016/

© 2016 Elsevier Inc. All rights reserved

Abstract :

As more states and countries legalize medical and/or adult recreational marijuana use, the incidences of prenatal cannabis exposure (PCE) will likely increase. While young people increasingly view marijuana as innocuous, marijuana preparations have been growing in potency in recent years, potentially creating global clinical, public health, andworkforce concerns. Unlike fetal alcohol spectrumdisorder, there is no phenotypic syndrome associated with PCE. There is also no preponderance of evidence that PCE causes lifelong cognitive, behavioral, or functional abnormalities, and/or susceptibility to subsequent addiction.

However, there is compelling circumstantial evidence, based on the principles of teratology and fetal malprogramming, suggesting that pregnant women should refrain fromsmoking marijuana. The usage of marijuana during pregnancy perturbs the fetal endogenous cannabinoid signaling system (ECSS), which is present and active from the early embryonic stage, modulating neurodevelopment and continuing this role into adulthood. The ECSS is present in virtually every brain structure and organ system, and there is also evidence that this systemis important in the regulation of cardiovascular processes.

Endocannabinoids (eCBs) undergird a broad spectrum of processes, including the early stages of fetal neurodevelopment and uterine implantation. Delta-9-tetrahydrocannabinol (THC), the psychoactive chemical in cannabis, enters maternal circulation, and readily crosses the placental membrane. THC binds to CB receptors of the fetal ECSS, altering neurodevelopment and possibly rewiring ECSS circuitry.

In this review, we discuss the Double-Hit Hypothesis as it relates to PCE.We contend that PCE, similar to a neurodevelopmental teratogen, delivers the first hit to the ECSS,which is compromised in such away that a second hit (i.e., postnatal stressors)will precipitate the emergence of a specific phenotype. In summary, we conclude that perturbations of the intrauterine milieu via the introduction of exogenous CBs alter the fetal ECSS, predisposing the offspring to abnormalities in cognition and altered emotionality. Based on recent experimental evidence thatwewill reviewhere,we argue that young women who become pregnant should immediately take a “pregnant pause” from using marijuana.

Keywords : Prenatal cannabis exposure, Marijuana, Maternal cannabis exposure, Neurodevelopment, Fetal malprogramming, Fetal neurodevelopment, Epigenetics, Double hit hypothesis