Martina V. Kovács, Helenice Charchat-Fichman, J. Landeira-Fernandez, Alexandre E. Medina, Thomas E. Krahe, Combined exposure to alcohol and cannabis during development: mechanisms and outcomes, Alcohol, 2023, ISSN 0741-8329,
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.
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 Use 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 (see Figure A, Figure B, Figure C, Figure D).
The consequences of alcohol exposure on the developing child are well documented (Riley & McGee, 2005; May et al., 2020; Mattson et al., 2019; Wozniak et al., 2019) and 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 (Gilbert et al., 2016; Carty et al., 2018; Boa-Amponsem et al., 2019; Fish et al., 2019). 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.
Despite preventive campaigns in recent decades, substance use during pregnancy is still relatively frequent. According to the 2019 National Survey on Drug use and Health, 5.4% of pregnant women declared past-month marijuana use and 9.5% declared past-month alcohol use in the United States (Substance Abuse and Mental Health Services Administration, 2020). The survey reported a significant increase in marijuana use but a slight decrease in alcohol use among pregnant women compared with past
Alcohol-induced impairments are well documented in the literature with various types of timing and frequency of alcohol exposure (Sulik et al., 1981). Alcohol is highly neurotoxic and easily crosses the placenta and blood-brain barrier, causing changes in gene expression, neuronal proliferation (Luo & Miller, 1998), migration (Delatour et al., 2019), oligodendrocyte number, and white matter integrity (Newville et al., 2017). It also interferes with growth factors and synaptogenesis and disrupts
Actions of alcohol and cannabis on the endocannabinoid system in the developing central nervous system
Studies of animal models of FASD have been developed in recent decades to shed light on the mechanisms of alcohol-induced teratogenic effects in the developing central nervous system. These studies have reported epigenetic modifications (for review, see Basavarajappa & Subbanna, 2016), alterations of neuroplasticity (Granato & Daring, 2018; Medina, 2011), and alterations of signaling pathways (Shukrun et al., 2019; Kumar et al., 2010; Zhang et al., 2013). Alcohol exerts effects on the
Endocannabinoid signaling mechanisms
The endocannabinoid signaling system plays distinct roles and has different mechanisms during fetal development and in the adult brain. The endocannabinoid signaling system plays an important role during neurodevelopment, including neurogenesis, proliferation, migration, axonal pathfinding, and the formation of synaptic connections (Wu et al., 2011; Bukiya, 2019). The endocannabinoid system may exert effects even before conception because it is present in reproductive tissues and affects sperm
Simultaneous alcohol and cannabis exposure: neurodevelopmental consequences and mechanisms
The first studies that investigated the combined effects alcohol and cannabis use observed cross-tolerance between the two substances. Heavy marijuana users became less intoxicated from alcohol consumption than non-marijuana users. They also exhibited fewer alcohol-induced neuropsychological deficiencies after co-administration (Jones & Stone, 1970). Participants who simultaneously used both substances exhibited alterations of sleep patterns (Zarcone, 1973), deficits in cognitive and
First-trimester co-exposure to alcohol and cannabis
Co-exposure to cannabinoids and alcohol is linked to holoprosencephaly spectrum defects during early developmental stages. Even low doses of alcohol that are administered together with cannabinoids have similar negative outcomes on the central nervous system as high doses of alcohol exposure alone. In zebrafish and mouse embryos, the teratogenic effects of alcohol and cannabinoids converge through the sonic hedgehog signaling pathway and induce ocular and facial dysmorphology (Fish et al., 2019
The development of the fetal brain vasculature system, the neural stem cell self-renewal and differentiation occur during the second-trimester of gestation. Emerging evidence shows that simultaneous alcohol and cannabis (CP-55940, synthetic cannabinoid) exposure may induce premature neural stem cell growth, alter cell proliferation, and has been associated with acute and delayed decrease in fetal-directed blood flow (Rouzer et al., 2022).
During the third trimester of gestation, the central nervous system undergoes rapid growth (brain growth spurt) by making and breaking synaptic connections, which lasts until late adolescence. Exposure to drugs during this period may interrupt neuronal plasticity and alter the formation and refinement of neural circuits (Medina, 2011). Developmental studies of mouse embryos reported that alcohol increases AEA levels in postsynaptic neurons through transcriptional activation of the NAPE-PLD and
Potential therapeutic implications
Preclinical studies indicate that a CB1 receptor antagonist, SR141716A, may have a protective effect against the effects of combined exposure to alcohol and cannabinoids during development such as behavioral deficits (Boa-Amponsem et al., 2019), morphological phenotypes (Fish et al., 2019), and neurodegeneration (Hansen et al., 2008). Shh mRNA overexpression has a similar effect, as it rescues normal juvenile behavior (Boa-Amponsem et al., 2019), blocks development of microphthalmia phenotype
Substance use during pregnancy is associated with alterations in neurodevelopment and long-lasting deficits in offspring. The most used substances by pregnant women are alcohol and cannabis (Substance Abuse and Mental Health Services Administration, 2020), which are frequently consumed together. Accumulating evidence shows that alcohol and cannabis, when administered together, synergistically alter neurodevelopment from the earliest stages of gestation (Boa-Amponsem et al., 2019; Boa-Amponsem