Prenatal Cannabis Exposure Research Articles

Effects of prenatal alcohol and delta-9-tetrahydrocannabinol exposure via electronic cigarettes on motor development.

BackgroundPrenatal alcohol exposure can lead to a wide range of neurological and behavioral deficits, including alterations in motor domains. However, much less is known about the effects of prenatal cannabis exposure on motor development, despite cannabis being the most consumed illicit drug among women. Cannabis use among pregnant women has become increasingly popular given the widespread perception that consumption is safe during pregnancy. Moreover, alcohol and cannabis are commonly used together, even among pregnant women. Yet few studies have explored the potential consequences of combined prenatal exposure on behavioral domains.MethodsUsing our previously established model, during gestational days 5 to 20, four groups of pregnant Sprague–Dawley rats were exposed to vaporized alcohol, delta‐9‐Tetrahydrocannabinol (THC) via electronic (e‐) cigarettes, the combination of alcohol and THC, or a vehicle. Following birth, offspring were tested on early sensorimotor development, adolescent motor coordination, and adolescent activity levels.ResultsPrenatal THC e‐cigarette exposure delayed sensorimotor development early in life and impaired motor coordination later in early adolescence; combined prenatal alcohol and THC exposure did not have additive effects on sensorimotor development. However, combined prenatal exposure produced hyperactivity among male offspring.ConclusionsPrenatal cannabis exposure may lead to impaired motor skills throughout early development and combined exposure with alcohol during gestation may lead to hyperactivity in early adolescence. These findings have important implications for informing pregnant women of the risks to the fetus associated with prenatal cannabis exposure, with and without alcohol, and could influence public policy.

Epigenetic Reprogramming Within the Nucleus Accumbens Sustains Lasting Detrimental Effects of Prenatal Cannabis Exposure on Motivation

Cannabis is one of the most commonly used drugs during pregnancy. The current prevalence of self-reported cannabis use in pregnant women ranges from 2% to 5% in most studies (1), but the number of pregnant women consuming cannabis could likely increase in the future because of the more permissive legislation regarding its recreational and medical use in many countries. In this context, there is an urgent need for evidence encompassing the implications of prenatal cannabis exposure for child mental health outcomes.

Prenatal Cannabis Exposure and Outcomes During Middle Childhood

Cannabis use during pregnancy has risen steadily over the past 2 decades. However, whether prenatal cannabis exposure is associated with adverse outcomes remains poorly understood.

P17. Prenatal Cannabis Exposure Moderates the Relationship Between Sleep Hours and Internalizing Problems: A Causal Inference Analysis of ABCD Data

A 2019 epidemiological survey reported that 5.4% of women used cannabis during their pregnancy, yet we do not understand if this exposure is causally related to child health. Prior studies suggest prenatal cannabis exposure is associated with poor sleep and higher internalizing problems in children. Therefore, using the potential outcomes framework and statistical causal inference methods applied to the Adolescent Brain and Cognitive Development (ABCD) study, it was hypothesized that prenatal cannabis exposure would moderate the relationship between sleep hours and internalizing problems.

Seeing Through the Smoke: Prenatal Cannabis Exposure Impacts Frontolimbic White Matter Development in Children

Some pregnant people use cannabis to assuage morning sickness or anxiety, and some may have not known they were pregnant. However, approximately ⅓ of cannabis constituents (e.g., THC) cross the placenta, and may therefore disrupt offspring neurodevelopment. Here, we use data from the Adolescent Brain Cognitive Development study to examine the impact of prenatal cannabis exposure on integrity of frontolimbic white matter pathways, which are susceptible to cannabis use in adults.

Prenatal cannabis exposure predicts attention problems, without changes on fMRI in adolescents

ObjectivesWe hypothesized that prenatal cannabis exposure (PCE) would be associated with increased attention problems and altered neurocognition in young adolescents. MethodsData were obtained from the Adolescent Brain Cognitive Development (ABCD study®), a cohort of approximately 12,000 children. Presence or absence of PCE after knowledge of pregnancy was measured by caregiver report. All participants with PCE (N = 224) were included and compared to two control groups; those matched on tobacco and alcohol exposure and those without prenatal tobacco or alcohol exposures. Outcomes were measured with the ABCD baseline assessment when participants were 9–10 years old and included attention, internalizing, externalizing and total problems scales on the Child Behavior Checklist (CBCL). Teacher reports were used when available. Mixed effects modeling assessed the association between PCE and outcomes controlling for parental psychopathology, prematurity and socioeconomic status. For participants with available data, patterns of brain activity during three fMRI tasks (the Stop Signal Task measuring response inhibition, the Monetary Incentive Delay (MID) task measuring reward processing and the EN-Back task measuring working memory) were analyzed using Permutation Analyses of the Linear Model. ResultsCompared to both control groups, participants with PCE had significantly higher attention problems, externalizing, and total problem scores. PCE did not impact cognitive performance or patterns of brain activation during fMRI tasks. ConclusionsThere are long-term associations between PCE and early adolescent attention and behavioral problems. These are not reflected in cognitive performance or task fMRI measures, a finding that is consistent with reports that fewer than half of children with ADHD have any specific cognitive deficit (Nigg et al., 2005; Willcutt et al., 2005). The young age of the sample may also relate to this finding and future investigation of neurodevelopmental trajectories of youth with PCE is warranted.

Long-term effects of prenatal cannabis exposure: Pathways to adolescent and adult outcomes

With the increased prevalence, potency, and acceptability of cannabis use during pregnancy, it is important to understand the developmental effects of prenatal cannabis exposure (PCE). This review discusses methodological considerations for studies of PCE, including the assessment of exposures, covariates, and outcomes, and reviews findings from prospective, longitudinal studies of PCE. There is some evidence for associations between PCE and restricted growth at birth, but not for long-term effects on growth. PCE appears to have subtle yet enduring effects on memory and achievement in children and adolescents. Despite differences in sample demographics and measurement, there are remarkably consistent effects of PCE on externalizing behaviors, such as delinquency and substance use, which persist into adulthood. Longitudinal analyses demonstrate the importance of early cannabis initiation for pathways between PCE and adult functioning, including substance use and abuse, memory deficits, and psychotic symptoms. Animal studies demonstrate direct effects on the development of the brain via activation of endogenous endocannabinoid systems. Cannabis-induced activation of the endocannabinoid system causes alterations in the release of neurotransmitters and the modulation of brain plasticity in neural pathways that underlie cognition, motivation, and behavior regulation. Future research should consider cannabis use before pregnancy, the timing and route of exposure, polysubstance exposures, and inter-generational effects.

Epidemiological association of cannabinoid- and drug- exposures and sociodemographic factors with limb reduction defects across USA 1989–2016: A geotemporospatial study

BackgroundReports of major limb defects after prenatal cannabis exposure (PCE) in animals and of human populations in Hawaii, Europe and Australia raise the question of whether the increasing use of cannabis in USA might be spatiotemporally associated with limb reduction rates (LRR) across USA. MethodsCongenital anomaly data was from the National Birth Defects Prevention Network, drug use data was taken from the National Survey of Drug Use and Health (NSDUH), cannabinoid concentration was estimated from Federal seizure data and ethnicity and income data were from the US Census bureau. Geotemporospatial analysis was conducted in R. Results436 LRR datapoints were obtained. LRR was significantly associated with cannabis use and tetrahydrocannabinol (THC) exposure and demonstrated prominent cannabis-use quintile effects. A sharp increase in LRR occurred from the fourth to fifth quintiles of cannabis exposure (mean ± S.E.M 3.78 ± 0.38 to 6.66 ± 0.56/10,000 live births, P = 5.22 × 10−9). In final lagged geospatial models adjusted for ethnicity and income interactive terms including cannabinoids were highly significant and robust to adjustment. States in which cannabis was not legalized had a lower LRR (4.28 v 5.01/10,000 live births, relative risk reduction = −0.15, (95%C.I. −0.25, −0.02), P = 0.021). Internationally 37–63% of cases are estimated to not be born alive. Their inclusion in these analyzes uniformly intensified the identified effects and the significance of the effect of the cannabis legalization paradigm rose from P = 0.0256 to P = 0.0146 to P = 0.0048 with silent factors of 0%, 36% and 63%, respectively. ConclusionTherefore a spatiotemporal and dose-dependent association between several cannabinoids including THC and cannabigerol and LRR is reported, is robust to adjustment, is consistent with pathophysiological and preclinical studies, accords with findings elsewhere, is markedly exacerbated in higher exposure quintiles, is exacerbated by cannabis legalization and evidences dose-related intergenerational sequaelae.

A Review of Associations between Externalizing Behaviors and Prenatal Cannabis Exposure: Limitations & Future Directions.

In utero cannabis exposure can disrupt fetal development and increase risk for various behavioral disruptions, including hyperactivity, inattention, delinquent behaviors, and later substance abuse, among others. This review summarizes the findings from contemporary investigations linking prenatal cannabis exposure to the development of psychopathology and identifies the limitations within the literature, which constrain our interpretations and generalizability. These limitations include a lack of genetic/familial control for confounding and limited data examining real world products, the full range of cannabinoids, and motives for use specifically in pregnant women. Taken together, our review reveals the need to continue to improve upon study designs in order to allow researchers to accurately draw conclusions about the development of behavioral consequences of prenatal cannabis exposure. Findings from such studies would inform policy and practices regarding cannabis use during pregnancy and move the field toward developing a comprehensive teratogenic profile of cannabis similar to what is characterized in the prenatal alcohol and tobacco literature.

Maternal-fetal transmission of delta-9-tetrahydrocannabinol (THC) and its metabolites following inhalation and injection exposure during pregnancy in rats.

Cannabis use during pregnancy has increased over the past few decades, with recent data indicating that, in youth and young adults especially, up to 22% of people report using cannabis during pregnancy. Animal models provide the ability to study prenatal cannabis exposure (PCE) with control over timing and dosage; however, these studies utilize both injection and inhalation approaches. While it is known that Δ9-tetrahydrocannabinol (THC; primary psychoactive component of cannabis) can cross the placenta, examination of the transmission and concentration of THC and its metabolites from maternal blood into the placenta and fetal brain remains relatively unknown, and the influence of route of administration has never been examined. Pregnant female rats were exposed to either vaporized THC-dominant cannabis extract for pulmonary consumption or subcutaneous injection of THC repeatedly during the gestational period. Maternal blood, placenta, and fetal brains were collected following the final administration of THC for analysis of THC and its metabolites, as well as endocannabinoid concentrations, through mass spectrometry. Both routes of administration resulted in the transmission of THC and its metabolites in placenta and fetal brain. Repeated exposure to inhaled THC vapor resulted in fetal brain THC concentrations that were about 30% of those seen in maternal blood, whereas repeated injections resulted in roughly equivalent concentrations of THC in maternal blood and fetal brain. Neither inhalation nor injection of THC during pregnancy altered fetal brain endocannabinoid concentrations. Our data provide the first characterization of maternal-fetal transmission of THC and its metabolites following both vaporized delivery and injection routes of administration. These data are important to establish the maternal-fetal transmission in preclinical injection and inhalation models of PCE and may provide insight into predicting fetal exposure in human studies.

Double trouble: Prenatal immune activation and adolescent cannabis exposure

Double trouble: Prenatal immune activation and adolescent cannabis exposure

Prenatal drug exposure and executive function in early adolescence

PurposeStudy of the relationship between prenatal cocaine exposure (PCE) and executive function (EF) has yielded inconsistent results. The purpose of the current study is to examine whether PCE, biological sex, environmental risk, and their interaction predicted EF in early adolescence. Methods135 12-year-old adolescents (40.7% with PCE), who were followed prospectively from birth, attempted up to 8 Tower of Hanoi (ToH) puzzle trials of increasing complexity. The number of correctly completed puzzles served as the main outcome measure. Survival analysis was used to examine predictors of the number of successfully completed trials. ResultsAs trial difficulty increased, fewer adolescents were able to solve the TOH puzzle. Adolescents from high risk environments and with either prenatal alcohol or prenatal cannabis exposure completed fewer puzzles (p < .05). In addition, a hypothesized 3-way interaction of PCE x sex x environmental risk was found such that cocaine-exposed males with high environmental risk had the worst performance (p < .01). ConclusionsThe current findings are consistent with prior research indicating that males with PCE may be at particular risk of poorer functioning and highlight the potential importance of examining adolescent's sex and environmental risk as moderators of PCE effects.

Prenatal Δ9-Tetrahydrocannabinol Exposure in Males Leads to Motivational Disturbances Related to Striatal Epigenetic Dysregulation

BackgroundCannabis remains one of the most widely abused drugs during pregnancy. In utero exposure to its principal psychoactive component, Δ9-tetrahydrocannabinol (THC), can result in long-term neuropsychiatric risk for the progeny. This study investigated epigenetic signatures underlying these enduring consequences. MethodsRat dams were exposed daily to THC (0.15 mg/kg) during pregnancy, and adult male offspring were examined for reward and depressive-like behavioral endophenotypes. Using unbiased sequencing approaches, we explored transcriptional and epigenetic profiles in the nucleus accumbens (NAc), a brain area central to reward and emotional processing. An in vitro CRISPR (clustered regularly interspaced short palindromic repeats) activation model coupled with RNA sequencing was also applied to study specific consequences of epigenetic dysregulation, and altered molecular signatures were compared with human major depressive disorder transcriptome datasets. ResultsPrenatal THC exposure induced increased motivation for food, heightened learned helplessness and anhedonia, and altered stress sensitivity. We identified a robust increase specific to males in the expression of Kmt2a (histone-lysine N-methyltransferase 2A) that targets H3K4 (lysine 4 on histone H3) in cellular chromatin. Normalizing Kmt2a in the NAc rescued the motivational phenotype of prenatally THC-exposed animals. Comparison of RNA- and H3K4me3-sequencing datasets from the NAc of rat offspring with the in vitro model of Kmt2a upregulation revealed overlapping, significant disturbances in pathways that mediate synaptic plasticity. Similar transcriptional alterations were detected in human major depressive disorder. ConclusionsThese studies provide direct evidence for the persistent effects of prenatal cannabis exposure on transcriptional and epigenetic deviations in the NAc via Kmt2a dysregulation and associated psychiatric vulnerability.

Prenatal Cannabis Use and Infant Birth Outcomes in the Pregnancy Risk Assessment Monitoring System

To examine the association of prenatal cannabis use and adverse infant outcomes in a nationally representative cohort and consider the impact of concurrent cigarette exposure. We conducted a retrospective cohort study on 32 583 new mothers from the 2017-2019 Pregnancy Risk Assessment Monitoring System. Cannabis use was evaluated as a binary variable (use or no use) as well as ordinal categories (no, light, moderate, heavy use). We used multivariable logistic regression to examine the relationship between prenatal cannabis exposure and low birthweight (LBW), preterm birth, and small for gestational age. Prenatal cannabis use was associated with significantly greater odds of LBW (aOR, 1.27; 95% CI, 1.05-1.54) and small for gestational age (aOR, 1.35; 95% CI, 1.09-1.68) but not preterm birth. Compared with nonusers, heavy users (weekly or more) were twice as likely to deliver a LBW infant (aOR, 2.07; 95% CI, 1.46-2.94) or small for gestational age infant (aOR, 2.14; 95% CI, 1.38-3.30). When examining combined cannabis and cigarette use, prenatal exposure to both substances increased the likelihood of LBW (aOR, 2.27; 95% CI, 1.71-3.01), preterm birth (aOR, 1.61; 95% CI, 1.12-2.31), and small for gestational age (aOR, 3.29; 95% CI, 2.39-4.55) compared with no use, and the increased odds were greater than for either substance alone. Our results suggest that cannabis use during pregnancy may harm fetal development, and recommendations to improve birth outcomes should address co-use of cannabis and tobacco.

Cannabinoid exposure as a major driver of pediatric acute lymphoid Leukaemia rates across the USA: combined geospatial, multiple imputation and causal inference study

BackgroundAcute lymphoid leukaemia (ALL) is the commonest childhood cancer whose incidence is rising in many nations. In the USA, between 1975 and 2016, ALL rates (ALLRs) rose 93.51% from 1.91 to 3.70/100,000 < 20 years. ALL is more common in Caucasian-Americans than amongst minorities. The cause of both the rise and the ethnic differential is unclear, however, prenatal cannabis exposure was previously linked with elevated childhood leukaemia rates. We investigated epidemiologically if cannabis use impacted nationally on ALLRs, its ethnic effects, and if the relationship was causal.MethodsState data on overall, and ethnic ALLR from the Surveillance Epidemiology and End Results databank of the Centre for Disease Control (CDC) and National Cancer Institute (NCI) were combined with drug (cigarettes, alcoholism, cannabis, analgesics, cocaine) use data from the National Survey of Drug Use and Health; 74.1% response rate. Income and ethnicity data was from the US Census bureau. Cannabinoid concentration was from the Drug Enforcement Agency Data. Data was analyzed in R by robust and spatiotemporal regression.ResultsIn bivariate analyses a dose-response relationship was demonstrated between ALLR and Alcohol Use Disorder (AUD), cocaine and cannabis exposure, with the effect of cannabis being strongest (β-estimate = 3.33(95%C.I. 1.97, 4.68), P = 1.92 × 10− 6). A strong effect of cannabis use quintile on ALLR was noted (Chi.Sq. = 613.79, P = 3.04 × 10− 70). In inverse probability weighted robust regression adjusted for other substances, income and ethnicity, cannabis was independently significant (β-estimate = 4.75(0.48, 9.02), P = 0.0389). In a spatiotemporal model adjusted for all drugs, income, and ethnicity, cannabigerol exposure was significant (β-estimate = 0.26(0.01, 0.52), P = 0.0444), an effect increased by spatial lagging (THC: β-estimate = 0.47(0.12, 0.82), P = 0.0083). After missing data imputation ethnic cannabis exposure was significant (β-estimate = 0.64(0.55, 0.72), P = 3.1 × 10− 40). 33/35 minimum e-Values ranged from 1.25 to 3.94 × 1036 indicative of a causal relationship. Relaxation of cannabis legal paradigms had higher ALLR (Chi.Squ.Trend = 775.12, P = 2.14 × 10− 112). Cannabis legal states had higher ALLR (2.395 ± 0.039 v. 2.127 ± 0.008 / 100,000, P = 5.05 × 10− 10).ConclusionsData show that ALLR is associated with cannabis consumption across space-time, is associated with the cannabinoids, THC, cannabigerol, cannabinol, cannabichromene, and cannabidiol, contributes to ethnic differentials, demonstrates prominent quintile effects, satisfies criteria for causality and is exacerbated by cannabis legalization.

The Impact of Early Life Exposure to Cannabis: The Role of the Endocannabinoid System.

Cannabis use during pregnancy has continued to rise, particularly in developed countries, as a result of the trend towards legalization and lack of consistent, evidence-based knowledge on the matter. While there is conflicting data regarding whether cannabis use during pregnancy leads to adverse outcomes such as stillbirth, preterm birth, low birthweight, or increased admission to neonatal intensive care units, investigations into long-term effects on the offspring’s health are limited. Historically, studies have focused on the neurobehavioral effects of prenatal cannabis exposure on the offspring. The effects of cannabis on other physiological aspects of the developing fetus have received less attention. Importantly, our knowledge about cannabinoid signaling in the placenta is also limited. The endocannabinoid system (ECS) is present at early stages of development and represents a potential target for exogenous cannabinoids in utero. The ECS is expressed in a broad range of tissues and influences a spectrum of cellular functions. The aim of this review is to explore the current evidence surrounding the effects of prenatal exposure to cannabinoids and the role of the ECS in the placenta and the developing fetus.

Miswiring the brain: Human prenatal Δ9-tetrahydrocannabinol use associated with altered fetal hippocampal brain network connectivity

Increasing evidence supports a link between maternal prenatal cannabis use and altered neural and physiological development of the child. However, whether cannabis use relates to altered human brain development prior to birth, and specifically, whether maternal prenatal cannabis use relates to connectivity of fetal functional brain systems, remains an open question. The major objective of this study was to identify whether maternal prenatal cannabis exposure (PCE) is associated with variation in human brain hippocampal functional connectivity prior to birth. Prenatal drug toxicology and fetal fMRI data were available in a sample of 115 fetuses [43 % female; mean age 32.2 weeks (SD = 4.3)]. Voxelwise hippocampal connectivity analysis in a subset of age and sex-matched fetuses revealed that PCE was associated with alterations in fetal dorsolateral, medial and superior frontal, insula, anterior temporal, and posterior cingulate connectivity. Classification of group differences by age 5 outcomes suggest that compared to the non-PCE group, the PCE group is more likely to have increased connectivity to regions associated with less favorable outcomes and to have decreased connectivity to regions associated with more favorable outcomes. This is preliminary evidence that altered fetal neural connectome may contribute to neurobehavioral vulnerability observed in children exposed to cannabis in utero.

Response: Commentary: Totality of the Evidence Suggest Prenatal Cannabis Exposure Does Not Lead to Cognitive Impairments: A Systematic and Critical Review.

Response: Commentary: Totality of the Evidence Suggest Prenatal Cannabis Exposure Does Not Lead to Cognitive Impairments: A Systematic and Critical Review.

Commentary: Totality of the Evidence Suggests Prenatal Cannabis Exposure Does Not Lead to Cognitive Impairments: A Systematic and Critical Review.

Commentary: Totality of the Evidence Suggests Prenatal Cannabis Exposure Does Not Lead to Cognitive Impairments: A Systematic and Critical Review.

A geospatiotemporal and causal inference epidemiological exploration of substance and cannabinoid exposure as drivers of rising US pediatric cancer rates

BackgroundAge-adjusted US total pediatric cancer incidence rates (TPCIR) rose 49% 1975–2015 for unknown reasons. Prenatal cannabis exposure has been linked with several pediatric cancers which together comprise the majority of pediatric cancer types. We investigated whether cannabis use was related spatiotemporally and causally to TPCIR.MethodsState-based age-adjusted TPCIR data was taken from the CDC Surveillance, Epidemiology and End Results cancer database 2003–2017. Drug exposure was taken from the nationally-representative National Survey of Drug Use and Health, response rate 74.1%. Drugs included were: tobacco, alcohol, cannabis, opioid analgesics and cocaine. This was supplemented by cannabinoid concentration data from the Drug Enforcement Agency and ethnicity and median household income data from US Census.ResultsTPCIR rose while all drug use nationally fell, except for cannabis which rose. TPCIR in the highest cannabis use quintile was greater than in the lowest (β-estimate = 1.31 (95%C.I. 0.82, 1.80), P = 1.80 × 10− 7) and the time:highest two quintiles interaction was significant (β-estimate = 0.1395 (0.82, 1.80), P = 1.00 × 10− 14). In robust inverse probability weighted additive regression models cannabis was independently associated with TPCIR (β-estimate = 9.55 (3.95, 15.15), P = 0.0016). In interactive geospatiotemporal models including all drug, ethnic and income variables cannabis use was independently significant (β-estimate = 45.67 (18.77, 72.56), P = 0.0009). In geospatial models temporally lagged to 1,2,4 and 6 years interactive terms including cannabis were significant. Cannabis interactive terms at one and two degrees of spatial lagging were significant (from β-estimate = 3954.04 (1565.01, 6343.09), P = 0.0012). The interaction between the cannabinoids THC and cannabigerol was significant at zero, 2 and 6 years lag (from β-estimate = 46.22 (30.06, 62.38), P = 2.10 × 10− 8). Cannabis legalization was associated with higher TPCIR (β-estimate = 1.51 (0.68, 2.35), P = 0.0004) and cannabis-liberal regimes were associated with higher time:TPCIR interaction (β-estimate = 1.87 × 10− 4, (2.9 × 10− 5, 2.45 × 10− 4), P = 0.0208). 33/56 minimum e-Values were > 5 and 6 were infinite.ConclusionData confirm a close relationship across space and lagged time between cannabis and TPCIR which was robust to adjustment, supported by inverse probability weighting procedures and accompanied by high e-Values making confounding unlikely and establishing the causal relationship. Cannabis-liberal jurisdictions were associated with higher rates of TPCIR and a faster rate of TPCIR increase. Data inform the broader general consideration of cannabinoid-induced genotoxicity.