Combined exposure to alcohol and cannabis during development: Mechanisms and outcomes

Highlights

• Cannabis is the most frequently used illicit drug among pregnant women.

• Half of pregnant women who report cannabis use, also report the consumption of alcoholic beverages.

• Early alcohol and cannabis exposure is linked to worse developmental outcomes than exposure to either drug alone.

• Alcohol and cannabinoids exert a synergistic effect during early development through the endocannabinoid system.

Abstract

Exposure to substances of abuse during pregnancy can have long-lasting effects on offspring. Alcohol is one of the most widely used substances of abuse that leads to the most severe consequences. Recent studies in the United States, Canada, and the United Kingdom showed that between 1% and 7% of all children exhibit signs and symptoms of fetal alcohol spectrum disorder (FASD). Despite preventive campaigns, the rate of children with FASD has not decreased during recent decades. Alcohol consumption often accompanies exposure to such drugs as tobacco, cocaine, opioids, and cannabis. These interactions can be synergistic and exacerbate the deleterious consequences of developmental alcohol exposure. The present review focuses on interactions between alcohol and cannabis exposure and the potential consequences of these interactions.

Introduction

Substance use during pregnancy endangers the fetus and may alter neurodevelopment, causing life-long consequences. Cannabis products are the most frequently used illicit drugs among pregnant women, and recent legalization in many states in the United States increased their use during the last decade (Substance Abuse and Mental Health Services Administration, 2020). Marijuana is commonly used as an anti-nausea remedy during early stages of pregnancy (Dickson et al., 2018). Interestingly, half of pregnant women who report drinking alcohol also report consuming cannabis (Center for Behavioral Health Statistics and Quality, 2015). Despite the high prevalence of simultaneous drug use, little is known about its effects on the maternal and fetal central nervous systems. The cannabis legalization process for medical and recreational use in various countries globally requires a better understanding of the effects of cannabis during pregnancy.

The consequences of alcohol exposure on the developing child are well-documented (Mattson, Bernes, & Doyle, 2019; May et al., 2020; Riley & McGee, 2005; Wozniak, Riley, & Charness, 2019) and are considered the leading cause of avoidable developmental disabilities (Abel & Sokol, 1986). Physical, cognitive, and neurobiological consequences in the fetus following gestational alcohol consumption are collectively known as fetal alcohol spectrum disorder (FASD). The most devastating outcome of FASD is fetal alcohol syndrome (FAS), which is associated with craniofacial and ocular dysmorphology and growth and cognitive deficits. An increasing number of studies demonstrate FAS-like physical alterations after gestational cannabis exposure (Boa-Amponsem, Zhang, Mukhopadhyay, Ardrey, & Cole, 2019; Carty, Thornton, Gledhill, & Willett, 2018; Fish et al., 2019; Gilbert et al., 2016). This literature suggests common mechanisms and pathways by which both alcohol and cannabis exert teratogenic effects on the developing central nervous system. Both alcohol and cannabis are known as neuroinhibitory drugs. When alcohol is consumed together with other inhibitory drugs (e.g., cannabis, opioids, or γ-hydroxybutyric acid [GHBA]) it synergistically increases its effect (Singh, 2019). However, the mechanisms that underlie the interaction between these two substances and how this interaction leads to specific physical and behavioral features remain to be elucidated. The results of the few studies on this subject indicate the involvement of the endocannabinoid system with an important role of the cannabinoid-1 (CB₁) receptor and sonic hedgehog pathway. The present review synthesizes recent findings from animal models that were prenatally exposed simultaneously to alcohol and cannabinoids, with a focus on mechanisms and behavioral and physical outcomes.