Emerging understanding of the effects of cannabis use during pregnancy.

Abstract

The negative effects of the use of marijuana (Cannabis sativa) on pregnancy outcomes is an area that urgently needs to be brought to the attention of the public and requires more and continuous research. The urgency is justified by the rapidly increasing approvals of many states and countries to allow medicinal and recreational use of marijuana and its individual components. While the legalization and decriminalization of the use of marijuana and associated compounds benefit society in many respects (Mitchell, 2016), full understanding of the potential risks is lagging. Nonetheless, based on the information that is available, use of marijuana or associated compounds is not recommended before, during, and after pregnancy even through adolescence. The Food and Drug Administration (FDA), the U.S. Surgeon General, and various scientific and medical societies (American Association of Pediatrics, ACOG, etc.) warn against maternal marijuana use during pregnancy and breastfeeding (FDA, 2019). Δ9-Tetrahydrocannabinol (Δ9-THC) is the main psychoactive component of marijuana and can pass through the mother's system to the developing embryo and fetus undeterred by the placenta (Abrams et al., 1985; Bailey, Cunny, Paule, & Slikker Jr., 1987; Grotenhermen, 2003; Martin, Dewey, Harris, & Beckner, 1977). Animal studies suggest that the plasma levels in embryos and fetuses can reach 10% of maternal levels and decrease slowly (Bailey et al., 1987; Grant, Petroff, Isoherranen, Stella, & Burbachert, 2017; Hutchings, Martin, Gamagaris, Miller, & Fico, 1989). The compounds can also be transferred from the mother to the infant through breast milk (Grotenhermen, 2003; Perez-Reyes & Wall, 1982). THC is detectable in breast milk even 6 weeks after the mother is exposed (Perez-Reyes & Wall, 1982; Wymore et al., 2021). Cannibidiol (CBD) is the nonpsychoactive component present in marijuana and available as a supplement. The U.S. FDA has approved one prescription CBD product for the treatment of rare severe seizure disorders in children (FDA [US] consumer fact sheet). Where sale of cannabis products is allowed, CBD-containing products may be sold as beneficial for a variety of conditions, but none of these products or uses have been evaluated or approved by FDA and their safety is unknown. Smoking marijuana also comes with similar risks to those associated with smoking tobacco in any form, both to the individual user and to those who are exposed to second-hand smoke (Moir et al., 2008). Increased risks for lung cancer and respiratory diseases (e.g., COPD) are well-known consequences. Marijuana is often taken with alcohol or other drugs. The combinations can have synergistic negative effects. Popular means of cannabis exposure are: smoking [joints, bongs, bowls, blunts], vaping, dabbing, and ingesting (CDC, 2020 and Hasin, 2018). The need for more research is clear. The marijuana available now has a very different composition and strength compared with what was available during the 1960s or even a decade ago (OEHHA, 2019). This means that the findings from the past studies might not reflect and reveal the current risks to offspring when exposed before and after birth. Long-term effects of early exposure are just beginning to be understood (Bara et al, 2021). The more recently acknowledged effects of these compounds on the adolescent brain are also alarming, given that the disruption of the last steps of brain development may alter the maturation of higher cognitive function. The adolescent brain passes through a vulnerable developmental window during which myelination and remodeling of connections are highly active and if disturbed can lead to life-long neurodevelopmental consequences affecting neurobehavioral functions, especially cognition, emotions, psychoses, and addiction. These functions impact many aspects of the individual's career, social life, and overall health (Dow-Edwards et al., 2019). At a meeting on December 11, 2019, California's Developmental and Reproductive Toxicant Identification Committee (DARTIC) voted to add cannabis smoke and Δ9-THC to the Proposition 65 list as causing reproductive toxicity (developmental endpoint). As the lead Agency for California's Proposition 65, staff of the Office of Environmental Health Hazard Assessment compiled, summarized, and reviewed the available evidence for consideration by the DARTIC. The evidence they considered included mechanistic data, epidemiological data, and studies of somatic and neurobehavioral developmental effects in experimental animals. The supporting evidence is presented in this issue. This BDR focus includes three reviews that describe the animal-derived data on effects of marijuana/cannabis exposure during pregnancy that will bring you up to date on evaluation of cannabis smoke and Δ9-THC in California since legalization there. In addition, this special issue features an original research article on how CBD affects neural tube closure. These papers explain the potential mechanisms for how marijuana disrupts many aspects of normal development, particularly through interference with the many functions of the endogenous cannabinoids (ECs). In Part I of three reviews, Dr. Campbell and colleagues introduce the endocannabinoid (EC) system, discuss how Δ9-THC interferes with several systems of somatic development, and summarize the results of whole animal studies conducted by several routes of exposure. The EC system is comprised of ECs and their receptors (CBRs). The EC system has a role in many aspects of development, from implantation to morphogenesis. Exogenous cannabinoids, including Δ9-THC, can bind CBRs, leading to interference with critical developmental processes. Understanding how ECs and their receptors serve many critical functions in normal development was key to determining the biological plausibility of Δ9-THC-induced developmental effects. The data indicate that Δ9-THC can interfere with the EC system's role in critical events such as implantation, immune system development, bone growth, and neurodevelopment. While somatic development is covered in Part I, Parts II and III focus on the developmental neurotoxicity of Δ9-THC and the mechanisms specific to developmental neurotoxicity outcomes. Experimental evidence indicates a role for the EC system in development of early cleavage stage embryos, as well as in implantation. Δ9-THC can interfere directly with these processes, causing failure of continued embryonic development or preventing implantation. Adverse effects on the immune system include decreased cellularity of the developing thymus, and significant immune dysregulation observed postnatally following prenatal Δ9-THC exposure. The EC system is also involved in regulating bone growth, as characterized in long bones, with Δ9-THC exposure leading to inhibition of chondrocyte differentiation and resulting in significantly reduced bone growth. Guideline-type, whole animal developmental toxicity studies were performed using cannabis smoke, or by oral or injection exposure to Δ9-THC. While most of these studies were somewhat limited in methodology and reporting, overall results were consistent with an effect on both pre- and postnatal growth after prenatal exposure to cannabis smoke. Oral or injected Δ9-THC gave similar results, including increased offspring mortality and decreased fetal or birth weights. Dr. Iyer and colleagues inform us in Part II, that animal studies include neurodevelopmental effects after cannabis exposure during pregnancy. Changes in locomotor and exploratory behavior were observed. Cognitive effects included impairment of memory and learning, attention deficits, alterations in response to visual stimuli, and time taken to complete tasks. Emotionality was reported in rodents as an increase in separation-induced ultrasonic vocalizations, reduced social interaction and play behavior, and increased generalized anxiety. Of particular significance is the increased proclivity to addiction, possibly mediated through epigenetic mechanisms. Increased rate of acquisition of morphine self-administration and/or enhanced sensitivity toward the rewarding effects of morphine or heroin was observed in adult animals that were prenatally exposed to Δ9-THC. Along with behavioral parameters that were examined, this review also covers cellular and molecular mechanisms such as the expression of cannabinoid receptors. Neurochemical effects on specific brain regions and neurotransmitter systems seen in these animal studies appear to impact cognitive function, motor activity, and drug sensitivity. Many different types of neurotransmitters are affected by the endocannabinoid system and Δ9-THC also appears to affect the production of those neurotransmitters. Altered mRNA levels of genes relevant to synaptic plasticity in the nucleus accumbens (the brain region associated with compulsivity, addiction vulnerability, and reward sensitivity) were noted. Together with findings in the accompanying third review, the mechanistic studies provide evidence for the biological plausibility of the effects reported. Findings in zebra fish studies were consistent with effects in mammalian models. Additionally, studies examined how cannabis exposure can cause changes that affect the way genes work, that is, changes on how the body reads a DNA sequence without changing the DNA sequence itself. These epigenetic effects include changes in DNA methylation, for example, lower methylation levels were reported in human sperm DNA; and differentially methylated regions were reported in rat sperm DNA. Also, alterations in dopamine receptor associated methylation, gene expression, and protein expression, specifically altered dopamine receptor gene expression in some brain regions, were reported in animals and humans (aborted fetuses). The epigenetic findings appear to have cross-generational effects and were a result of paternal exposure to Δ9-THC prior to conception. Dr. Niknam and colleagues in Part III inform us that mechanistic studies supporting neurobehavioral outcomes seen in whole animal experiments after exposure to Δ9-THC affect many pathways during development. These pathways are part of the endocannabinoid system comprised of cannabinoid receptors and are crucial in the process of proper neurodevelopment. The role of various receptors involved with the EC system such as CBRs and their modulation of other receptor types are outlined (Figure 1). In addition, the authors discuss how altered mechanisms involved in the modulation of these receptors (including GABA, GIRK, RyRs, TRPVs, and dopamine) can perturb signaling in the EC system to produce cognitive and behavioral impairments. Findings from studies using Δ9-THC as well as synthetic cannabinoids are included. Locomotor and musculoskeletal perturbations may be a result of interactions with various receptors in the CNS and PNS. Several mechanisms, including epigenetics, appear to be involved in outcomes such as drug-seeking behavior. The role of mechanistic studies in bridging the gaps between molecular initiating events and apical neurodevelopmental endpoints is explored. In the primary research paper, Drs. Gheasuddin and Galea tested the effect of CBD on cultured mouse embryos. As mentioned above, CBD has been approved to treat rare seizure disorders in children but is available over the counter in various forms. Recently personal skin care products with CBD have become popular. CBD can be absorbed through the skin, ingested or inhaled. While the FDA warns against CBD use during pregnancy or breastfeeding, inadvertent exposure of the embryo at a critical time during pregnancy (during the first 2 months) is very possible because women may not know they are pregnant during that critical period and 45% of pregnancies in the United States are “unintended” (Finer & Zolna, 2016). In this study, mouse embryo exposure was targeted to a stage when the neural tube is closing. The embryo culture method allows analysis of direct effects of CBD on the embryo. Even though exposed embryos showed no gross effects in circulation, growth, cell proliferation, apoptosis, or actin cables and protrusions, CBD exposure clearly impaired neural tube closure at both the anterior and posterior closure points, resulting in an increased risk of exencephaly and spina bifida compared with vehicle treatment. While direct neuroteratogenic effects in a rodent model have been reported, the mechanisms by which CBD impairs the progression of neural tube closure remain to be identified. CBD exposure can be added to the many environmental factors that can increase the incidence of neural tube defects: common birth defects that affect morbidity and mortality.