A large team of researchers from Italy, Hungary and the U.S. has found that administering THC to pregnant rats resulted in damage to the brains of male offspring.
In their paper published in the journal Nature Neuroscience, the group describes their experiments with rats and THC and what they found.
In recent years, marijuana has become more accessible in many parts of the United States—several states have removed legal restrictions for recreational use, with a resulting increase in use.
One area of concern is that doctors have reported pregnant women using marijuana to reduce symptoms of morning sickness and anxiety.
Prior research has suggested that doing so might be bad for the baby, leading doctors warn against smoking marijuana when pregnant.
Now, it appears that marijuana ingestion might be even worse for fetal development than doctors had imagined – the researchers with this new effort report that the use of THC, the active ingredient in marijuana, in pregnant rats harms the brains of their offspring.
To test the possible impact of THC on pregnant rats, the researchers fed multiple test animals doses they believed were equivalent to human consumption during a random pregnancy. They allowed the rats to give birth and then charted the progress of the offspring as they grew into adults.
The researchers report that they found what they describe as an increased susceptibility to THC in male offspring, but not females.
They also found higher than normal amounts of dopamine in the brains of the “teen” male offspring – in the ventral tegmental area, which is known to play a role in reward motivation.
They also found that the young male offspring were more likely to engage in risky behavior, such as crossing a shaky bridge the researchers built for testing such behavior.
The researchers report that they were able to “cure” the risky behavior in the young male rats by giving them pregnenolone – a drug that has been approved by the FDA for treating mental disorders in humans, including bipolar disorder, schizophrenia and autism.
The history of cannabis use and its impact on human health and society is complicated and rapidly changing (National Academies Press, 2017). Throughout the world, this flowering plant remains the most commonly used illicit drug and there is a strong shift towards the legalization of its medical and recreational use (Azofeifa et al., 2016).
According to the 2015 National Survey on Drug Use and Health, 22.2 million Americans currently use cannabis and in the last twelve months, 2.6 million individuals aged 12 or older tried cannabis for the first time (Center for Behavioral Health Statistics and Quality, 2016; Lipari et al., 2015).
This sobering statistic translates into approximately 7,100 new users each day. Attitudes about cannabis use are changing and this is particularly apparent in adolescents and young adults. With significant profits at stake, the legal cannabis market has implemented selective growing methods to boost psychoactive potency.
Over the last two decades, the average THC content of cannabis (potency) has increased from approximately 4% to 12% (ElSohly et al., 2016), but levels as high as 30% have recently been documented in legal cannabis grown for recreational use (American Chemical Society, 2015). The cultivation of cannabis is evolving and dramatic increases in potency make it difficult to understand the health risks that may be associated with contemporary use, particularly for sensitive subgroups within the general population.
The increased availability and quality of cannabis, paired with relaxed attitudes about use in younger populations, will likely result in a rise of cannabis use in women of childbearing age. In fact, data collected from 2002–2014 in the U.S. indicate that 7.5% of pregnant women between 18 and 25 years of age use cannabis, while the rate of use in all pregnant women is approximately 4% (Brown et al., 2016).
This statistic places cannabis firmly in the bull’s-eye of public health concerns and suggests that thousands, if not millions, of infants will be prenatally exposed to this chemically-complex compound over the coming decades. Women who become pregnant may continue to use cannabis for a variety of reasons
For example, a survey of women in Vancouver, Canada found that up to 77% of medicinal cannabis use during pregnancy was related to nausea; over 50% of respondents also reported cannabis use to treat a lack of appetite, general pain, insomnia, anxiety, depression and fatigue (Westfall et al., 2009).
Despite knowledge of potential fetal health risks, cannabis use in pregnant women is becoming more commonplace and the need for clear messaging on the safety of use during pregnancy is urgently needed (Mark et al., 2017).
Given the possibility of increased use in pregnant women and the fact that cannabis is being widely investigated as a novel treatment for a variety of diseases, including epilepsy, multiple sclerosis and cancer, it is imperative that significant efforts be immediately dedicated to evaluating the potential consequences of exposure for the fetus.
For example, the oromucosal spray (Sativex) has been approved in Europe to treat spasticity due to multiple sclerosis.
While cannabis use during pregnancy has been studied in humans and several animal model systems, defining the risk of fetal cannabis exposure has been complicated by independent factors such as concurrent maternal use of drugs with their own toxicity profile and an absence of quantitative markers of cannabis exposure.
Studies in human and preclinical model systems are needed to generate mechanistic data on the maternal-fetal kinetics and toxicity of cannabis that can be interpreted within the context of fetal pharmacology and developmental psychobiology.
The consequences of prenatal cannabis exposure will not be elucidated without the methodological control of confounding factors such as tobacco/alcohol use and the quantitative measurements of exposure to generate critical dose-response information. This review was written to bridge our current understanding of
1) THC pharmacokinetics in adults with a focus on pregnancy
2) the consequences of fetal exposure at the molecular and cellular levels and
3) the effects of prenatal exposure on child neurodevelopmental outcomes from birth through adolescence.
The marriage of pharmacokinetics with neurodevelopmental data provides an interdisciplinary framework to generate data-driven messages about fetal risk and highlight directions for future research objectives.
Impact of Cannabinoids on the Developing Brain
The developing brain undergoes substantial structural remodeling that makes it particularly vulnerable to the harmful effects of bioactive ingredients (Chambers et al., 2003; Crews et al., 2007).
Such remodeling occurs in many brain areas involved in vital neuronal function, including sensory inputs and the control of body temperature, as well as higher-order cognitive processes such as learning, memory and decision making (Wise, 2004). CB1R signaling modulates long-range neuronal connectivity, including corticofugal connectivity (Katona and Freund, 2008; Tortoriello et al., 2014).
Accordingly, THC administration to pregnant mice during a restricted time window interferes with subcerebral projection neuron generation, thereby altering corticospinal connectivity and producing long-lasting alterations in the fine motor performance of the adult offspring (de Salas-Quiroga et al., 2015).
Mechanistically, such impairments are reminiscent of those elicited by the genetic ablation of CB1R and accordingly regimented THC administration to pregnant mice leads to down-regulation of CB1R signaling through desensitization (Berghuis et al., 2007; Castelli et al., 2007; Keimpema et al., 2011; Vitalis et al., 2008).
This impairment of long-range neuronal connectivity occurs for dorsal telencephalic glutamatergic neurons but not for forebrain GABAergic neurons (Mulder et al., 2008). Importantly, repeated CB1R activation during such sensitive developmental period of CNS development affects the expression and functionality of multiple additional receptors, including dopaminergic receptors that are critically involved in higher cognitive functions (Renard et al., 2017b).
In mice, in utero exposure to THC leads to CB1R activation and neuronal rewiring through the degradation of the molecular effector, SCG10/statmin 2, known to regulate microtubule dynamics in axons (Tortoriello et al., 2014). A telling example is provided by results showing that CB1Rs activation on the axonal surface induces repulsive growth cone turning and eventual collapse in in vitro model systems (Harkany et al., 2008a; 2008b; Maccarrone et al., 2014).
The molecular mechanism of CB1R-mediated cytoskeletal instability in growth cones involves select signaling pathways, including RHO-family GTPases, RAS, and PI3K–AKT–β-catenin signaling (Alpár et al., 2014; Díaz-Alonso et al., 2012; Maccarrone et al., 2014). Accordingly, THC exposure leads to ectopic formation of filipodia and alterations in axon morphology, together limiting the computational power of neuronal circuits involved in high cognitive function in affected offspring (Cristino and Di Marzo, 2014; Tortoriello et al., 2014).
An interesting cellular component of the impact of THC on brain development that has not been studied in detail is whether repeated activation of cannabinoid receptors expressed by glial cells will also lead to their down-regulation or desensitization and whether this response might affect normal brain maturation and result in persisting impairments.
In accordance with the tripartite synapse hypothesis, which states an involvement of astrocytes in synaptic transmission, peri-synaptic astrocytes that express MAGL should form a barrier limiting 2-AG spread and action on its targets to 20–100 μm and not beyond its immediate site of action (Maccarrone et al., 2014; Metna-Laurent and Marsicano, 2015; Navarrete and Araque, 2010; Oliveira da Cruz et al., 2016; Stella, 2010)
. This MAGL expression pattern is likely to both limit axonal spread in the prospective internal capsule and help delineate migratory routes for CB1R-expressing neurons, such as exemplified by cortical interneurons (Alpár et al., 2014; Keimpema et al., 2010; Wu et al., 2010). Thus, pharmacological manipulation of eCB signaling and its highjack by phyto-CB during crucial periods of synaptogenesis and/ or postnatal pruning might precipitate or predispose an individual to neuropsychiatric disease-like phenotypes.
Pharmacokinetics of THC in Humans
There is strong evidence that THC pharmacology has considerable impacts on neuronal signaling and development and as such, it is plausible to hypothesize that THC exposures during pregnancy could lead to long-term changes in neuronal development.
However, a critical component in understanding the potential consequences of cannabis consumption during pregnancy is the duration of exposure, the overall magnitude of exposure and the extent to which the fetus and fetal brain are exposed to THC after maternal cannabis consumption.
While the pharmacokinetics (PK) of THC and its metabolites have been studied in adult humans following intravenous (iv), oral and inhalation administration, little is known about the changes in cannabis PK during pregnancy and the maternal-fetal transfer and fetal PK of THC.
In addition, it is possible that the route of cannabis consumption (oral, inhalation, and different ways of smoking) will have an impact on the overall fetal toxicity. The absorption pathways between smoked and edible cannabis products are distinctly different. Following oral administration, THC absorption is typically greater than 90% and not affected by formulation (Parikh et al., 2016), but the bioavailability is limited to <20% (e.g. 10–20% in gelatin capsules) (Wall et al., 1983) and 6 ± 3% when ingested in a chocolate cookie (Ohlsson et al., 1980) due to significant liver first pass metabolism.
In contrast, smoked cannabis is not subject to liver first pass metabolism. Loss of THC in side stream smoke and in the butt of the cigarette, as well as loss via pyrolysis, result in low absorption of THC from smoking (Grotenhermen, 2003) and overall highly variable bioavailability of 2–56% (mean 18 ± 6%) (Huestis, 2007; Ohlsson et al., 1980).
An important difference between oral and smoked cannabis is also the rate of THC absorption. Following smoking, THC is rapidly absorbed and its peak concentrations (Cmax) are reached within minutes (Kauert et al., 2007; Ohlsson et al., 1980). In comparison, absorption from oral capsules is considerably slower and maximum THC concentrations are reached 1–3 hrs after dosing (Ahmed et al., 2015; Ohlsson et al., 1980; Schwilke et al., 2009).
As expected from the faster rate of absorption from smoked cannabis, the average Cmax values for THC following smoking are somewhat higher than those observed after oral consumption if similar THC content is consumed.
The average peak concentrations of THC in serum reached after smoking cannabis cigarettes containing 18.2 mg (0.25 mg/kg body weight) and 36.5 mg (0.5 mg/kg body weight) of THC were 48 μg/L and 79 μg/L (Kauert et al., 2007). In a study in occasional users who smoked a cannabis cigarette with 4% THC (20 mg dose) with tobacco, the average Cmax was 25.8 ± 42.9 μg/L with an average time to maximum concentration of 0.2 hrs. (Marsot et al., 2016).
The range of individual peak concentrations (1.6–160 μg/L) emphasizes the large inter-individual variability in THC exposures. After oral dosing in daily cannabis users, the Cmax of THC was 16.5 μg/L after 20 mg THC orally, (Schwilke et al., 2009). In elderly patients the Cmax was , 0.41 μg/L after 0.75 mg oral dose and 1 μg/L after a 1.5 mg oral dose (Ahmed et al., 2015). These differences in absorption kinetics and first pass metabolism may ultimately contribute to different toxicity profiles for oral and smoked cannabis, especially if toxicity is related to peak concentrations and/or if metabolites formed in the liver contribute to fetal pharmacology.
The site of action of THC’s psychoactive effects is in the CNS and hence distribution to the site of action is critical for effects. Indeed, THC distributes extensively into tissues with a steady state volume of distribution of 523–626 L (7.5–8.9 L/kg) (Hunt and Jones, 1980; Wall et al., 1983).
The distribution of THC into the brain is, however, delayed and the initial distribution volume after iv bolus is estimated between 2.6 L (0.04 L/kg) (Hunt and Jones, 1980) and 22.8 L (0.33 L/kg) (Ohlsson et al., 1980). Following iv administration, the maximum rated psychological “high” is reached at 15 minutes after the dose (Ohlsson et al., 1980). This corresponds to the time required to reach distribution equilibrium (minutes to an hour) (Hunt and Jones, 1980; Ohlsson et al., 1980) at the site of action and results in a hysteresis loop that describes the relationship between THC concentrations in plasma and the observed pharmacological effect with time (see also Grotenhermen, 2003). After peak effects are reached, the effects decline slowly due to the long terminal half-life between 20 and 57 hours (Hunt and Jones, 1980; Lemberger et al., 1971) suggesting prolonged exposures and pharmacological effects even after single use.
In humans, THC is extensively metabolized (Fig. 2) with a systemic clearance of 12–36 L/h (Hunt and Jones, 1980; Wall et al., 1983). The clearance is somewhat restricted by plasma protein binding (THC unbound fraction of 3%). The majority of THC clearance in humans is thought to be hepatic, although metabolism of THC exists in the gut mucosa, lung and heart, at least in preclinical species (Grotenhermen, 2003). After iv dosing in humans, <0.05% of the THC dose is recovered as unchanged Δ9-THC in urine or feces as the vast majority of THC is eliminated as metabolites either in urine (20%) or via biliary secretion of the metabolites in feces (25–40%) (Hunt and Jones, 1980; Lemberger et al., 1971; Wall et al., 1983). Over 80 metabolites of THC have been identified to date, but only some of these metabolites are quantitatively important and pharmacologically active, including 11-OH-THC, 11-nor- Δ9-THC-9-carboxylic acid (11-nor-THC-COOH) and 8-OH- Δ9-THC (see Figure 2) (Dinis-Oliveira, 2016; Grotenhermen, 2003).11-OH-Δ9-THC is even more pharmacologically active than THC (Christensen et al., 1971) but the activity of 8-OH-THC is not known. In vitro and in vivo data suggest that 11-OH-THC is formed predominantly by CYP2C9 while 8-OH-THC is mainly formed by CYP3A4 (Bland et al., 2005; Bornheim et al., 1992; Stott et al., 2013; Watanabe et al., 2007). The 11-nor-THC-COOH is formed from 11-OH-THC by microsomal alcohol dehydrogenase enzymes (Narimatsu et al., 1988). Both 11-OH-THC and 11-nor-THC-COOH undergo glucuronidation by UGT1A9 and UGT1A10 (11-OH-THC) and UGT1A1 and UGT1A3 (11-nor-THC-COOH) (Mazur et al., 2009). As the 11-nor-THC-COOH, together with its acyl glucuronide conjugate, account for the majority (30–65%) of THC elimination (Glaz-Sandberg et al., 2007), altered CYP and UGT activity, as occurs during pregnancy, may significantly alter THC and metabolite exposures and pharmacology. Of note, the route of THC consumption will also alter the exposures to the metabolites. Following iv administration of THC or smoking of cannabis, 11-OH-THC plasma concentrations are much lower than those of THC (Grotenhermen, 2003; Wall et al., 1983) declining with the same half-life as THC (25–33 hr). By contrast following oral THC administration, 11-OH-THC plasma concentrations can exceed those of THC but decline with a shorter half-life (12 hrs) than THC suggesting that most of 11-OH-THC is formed during first pass in the liver (Grotenhermen, 2003; Wall et al., 1983). Because of the low clearance of 11-nor-THC-COOH (5.5 L/h), it is the main circulating compound following any route of THC administration (Glaz-Sandberg et al., 2007). Overall, these data show that the route of consumption of THC may result in distinctly different exposures and pharmacology. Further research is needed to determine the role of peak concentrations, duration of exposures and role of metabolites in THC pharmacology and toxicity.
Impact of Prenatal Cannabis Exposure on Neurodevelopmental Outcomes in Humans
There are numerous publications focused on the reproductive and developmental effects of cannabis. Excellent review articles describing a range of reproductive effects in both males and females have been published recently and will not be reviewed here (Plessis et al., 2015; Brents, 2016).
Early chemical or drug exposure can result in subtle injuries to the developing CNS that are expressed as changes in postnatal development (Bellinger et al., 2016; Grant and Rice, 2008). Over the past four decades, a number of prospective studies have found changes in the developmental trajectory of children prenatally exposed to cannabis. The demographic characteristics of subjects in these studies as well as exposure and outcome measures are summarized in Table 1. Most studies were conducted in urban environments with economically-disadvantaged families. The most common metric to estimate use of cannabis during pregnancy is maternal self-report on frequency of use (e.g. # joints/day), while fewer studies have collected biological samples to more accurately estimate real-world levels of exposure. The wide variation in cannabis potency and individual smoking habits make the interpretation of the developmental literature challenging but a careful review reveals certain common themes surrounding the fetal risks associated with prenatal exposure. Much of what is known about maternal cannabis use and child development is based on data collected from 3 longitudinal birth cohort studies; the Ottawa Prenatal Prospective Study, the Maternal Health Practices and Child Development Project and the Generation R Study (McLemore and Richardson, 2016), but other longitudinal and cross-sectional studies focused on the developmental neurotoxicity of this compound have also made important contributions. In this section of the review, we opted to separate the developmental outcomes of cannabis exposure into four domains: physical growth/maturation, neonatal behaviors, cognition and psychological health/adaptive behavior.
As mentioned above, a frequently used approach to the measurement of cannabis exposure is maternal self-report of use during pregnancy. This approach, while commonly employed, may not provide an accurate evaluation of in utero exposure due to underreporting of drug use by pregnant women (Garg et al., 2016). Reluctance to report cannabis use is commonly linked to feelings of guilt, the fear of being arrested and concern over repercussions in child custody cases.
This makes it difficult, if not impossible, to characterize biologically-based dose-response relationships for cannabis-related developmental effects. Few studies have collected biological samples to augment maternal self-report estimates of use and for those that have, the information has been primarily used to determine incidence of drug exposure, not dose-response relationships.
The laboratory analysis of cannabis exposure from biological mediums most often relies on samples of maternal urine and blood (Musshoff and Madea, 2006), but more recently, maternal hair, placenta and fetal meconium have been utilized (Falcon et al., 2012).
Due to the longer half-life of THC metabolites when compared to THC, modeling of urinary and blood metabolite to parent drug ratios would allow development of quantitative markers of timing and magnitude of THC exposures. Development of such measures is highly recommended to improve the understanding of cannabis exposures during pregnancy.
Physical Growth and Maturation
In utero exposure to cannabis does not typically result in congenital birth defects (Warner et al., 2014, Linn et al, 1983, van Gelder et al. 2009) and there is no phenotypic signature of this compound in newborns. Effects on physical growth at birth and during the neonatal period have been reported in some studies (see below) but not others (Bada et al., 2006; Conner et al., 2015; van Gelder et al., 2010).
In a study of maternal cannabis use and effects on fetal growth, decrements in birthweight and neonatal head circumference were associated with prenatal exposure but only when data were restricted to women with a positive urine assay for cannabis (Zuckerman et al., 1989a). When maternal self-report data were used for analysis, no significant relationship between cannabis exposure and early growth was detected.
In a retrospective records study, maternal use of cannabis, as determined by either self-report or a positive urine assay for THC, was associated with decrements in fetal growth (e.g. small-for-gestational age) and an increase of 54% in neonatal intensive care unit admissions (Warshak et al., 2015). This investigation is particularly noteworthy as women who used tobacco during pregnancy were not included in the study population. Because subjects were classified only as cannabis users or nonusers, it is not possible to glean information about dose-response relationships for these effects. Exposure-related changes in early growth were also detected in a study where fetal meconium, maternal self-report and urine were collected from women undergoing voluntary saline-induced abortions (Hurd et al., 2005).
The anthropometric examination of fetuses of varying gestational ages revealed a significant exposure-related decrement in fetal foot length, a standard marker of physical maturation at birth. This effect was observed as early as mid-gestation (weeks 17–22) and statistical trends in the data showed that offspring of women who were heavy users of cannabis during early pregnancy (~1 or more joints/day) were most likely to be affected. In contrast, a study of over 8,000 women that relied on either self-report or a positive THC urine screen to determine fetal exposure found no relationship between maternal cannabis use during pregnancy and a composite score of neonatal morbidity composed of birthweight, APGAR score (health status of newborn immediately after birth ) and umbilical artery pH data (Conner et al., 2015).
Changes in physical growth and development have also been documented in studies relying solely on measures of maternal self-report to estimate cannabis use. Ultrasound images collected from thousands of pregnant women demonstrated that maternal cannabis use was not related to adverse neonatal outcomes, such as perinatal death, but was associated with small but detectable reductions in birthweight and fetal head circumference (El Marroun et al., 2009).
Changes in weight and growth trajectories were primarily observed in infants whose mothers reported using cannabis on a weekly or daily basis. In separate studies using maternal self-report, the use of cannabis during pregnancy has been linked to an increased risk of having a small-for-gestational age infant (Saurel-Cubizolles et al., 2014) and reductions in birthweight (Fergusson et al., 2002).
Our reading of the literature on prenatal cannabis exposure and early physical development indicates equivocal results. Despite some research supporting a significant relationship between cannabis use during pregnancy and decrements in fetal growth, there is no strong evidence that cannabis has a long-term negative impact on physical maturation (Fried and O’Connell, 1987). Longitudinal tracking of children with a history of prenatal cannabis exposure revealed normal physical growth trajectories at the time of school entrance (age 5–6) and during adolescence (Day et al., 1994; Fried et al., 1999) and key pubertal milestones such as age at menstruation in females and shaving in males were also not affected (Fried et al., 1999, 2001).
Neurobehavioral effects of in utero cannabis exposure have been detected in some studies during the newborn period. Infants born to moderate and heavy users of cannabis during pregnancy (≥2 joints/week, maternal self-report) showed increased tremors/startles and poorer habituation to visual stimuli (Fried, 1980; Fried et al., 1987). The authors note that these behavioral findings are consistent with a mild narcotic withdrawal syndrome and may portend exposure-related changes in CNS functioning. Some women who reduced or quit using cannabis during pregnancy showed a reduced risk of delivering an infant with clinical symptomology.
Gestational cannabis exposure has also been associated with changes in postnatal cortical activity. Specifically, a study of neonatal electroencephalography (EEG) sleep patterns found that in utero exposure to cannabis was associated with increased body movements and decreased time in a quiet sleep state (Sher et al., 1988). This effect was most widely observed in infants born to women who used cannabis on a daily basis. When children in this cohort reached 3 years of age, a similar pattern of EEG sleep disturbances was documented (Dahl et al., 1995).
These results suggest that the neurophysiological mechanisms that control infant/toddler arousal and sleep cycling may be disrupted by cannabis use during pregnancy. This behavioral change in affected infants may reflect subtle chemical injury to the brain stem, particularly in neurons that comprise the raphe nuclei. The long-term significance of these effects, if any, is unknown.
Learning and memory are perhaps the most consequential outcome measures in developmental cannabis research but studies are relatively few and findings are inconsistent. With few exceptions (e.g. Noland et al., 2005), the central limitation of studies investigating neurocognitive endpoints is their methodological reliance on maternal self-report of cannabis use during pregnancy to estimate fetal exposure. Several studies focused on early cognitive outcomes have reported that maternal cannabis use during pregnancy was not related to performance on infant tests of mental development (Astley and Little, 1990; Fried and Watkinson, 1988).
Other studies however, have reported that heavy maternal use is associated with a significant decline in early cognitive performance (Richardson et al., 1995). The reduction in test scores for 9 month-old infants with the highest levels of maternal cannabis use (>1 joint per day) was a disquieting 10 points, providing some evidence for dose-related effects in early mental test performance. When these infants were re-evaluated at 19 months using the same exam, fetal THC exposure was no longer related to language and cognitive scores.
During the preschool period of development (3–4 years), results from child assessment studies found that prenatal cannabis exposure was related to adverse effects on sustained attention, short-term memory and verbal processing, although it is important to note that decrements in performance were frequently subtle and limited in scope (Day et al., 1994; Fried and Watkinson, 1990; Noland et al., 2005).
At school age (5–6 years), one prospective, birth-cohort study found no evidence of an adverse effect of prenatal cannabis exposure on any cognitive outcome, including global intelligence quotient (IQ) scores (Fried et al., 1992a).
Additional testing with these children did, however, reveal small deficits in sustained attention and increased levels of impulsivity and hyperactivity (Fried et al., 1992b). The number of lapses in attention (omission errors) during a vigilance task was greatest in children born to heavy users of cannabis during pregnancy (>6 joints/week). In contrast, a separate longitudinal study found that heavy maternal cannabis use during pregnancy (~1 or more joints/day) was associated with diminished scores on a standardized IQ test at age 6, including deficits in short-term memory processing, and the effects varied by trimester of exposure (Goldschmidt et al., 2008).
By middle childhood and adolescence, a pattern of neurocognitive results highlights the resiliency of global IQ and the possible sensitivity of attention and memory to prenatal cannabis exposure. Between 9 and 12 years of age, the data suggest that fetal cannabis exposure is not associated with composite IQ scores or performance on broad-based reading and language exams (Fried et al., 1997,1998). However, the heavy use of cannabis during pregnancy (~1 or more joints/day) has been linked with decreased scores on tests of academic achievement, impulse control, visual analysis/hypothesis testing and learning/memory in exposed children (Fried et al., 1998; Goldschmidt et al., 2004; Richardson et al., 2002). Longitudinal tracking of a birth cohort through adolescence (13–16 years) demonstrated that global IQ scores remain unaffected by fetal cannabis exposure but certain aspects of cognition, particularly those related to sustained attention and visual working memory, may continue to be negatively impacted (Fried et al., 2003).
Two cannabis research programs have paired behavioral protocols with in vivo visualization of the brain using functional magnetic resonance imaging (fMRI) (Smith et al., 2004, 2006, 2016). Prenatal cannabis exposure in subjects ranging in age from 8–22 was not related to decrements in performance on a visuospatial cognitive task but fMRI scans revealed increased neural activity in the frontal gyri, parahippocampal gyrus, occipital gyrus and cerebellum and decreased activity in the right inferior and middle frontal gyri in exposed subjects. Brain imaging techniques were also utilized in a study of 6 year old children to investigate cannabis-related changes in brain morphology (El Marroun et al., 2015). Using MRI technology to compare prenatally exposed and nonexposed children, no differences in brain volume were detected but there were significant differences in cortical thickness. While the mechanism and functional significance of these findings remains unknown, thicker cortices in the frontal regions of both hemispheres suggest exposure-driven changes in the maturation of the frontal cortex.
A collective examination of the body of knowledge on fetal cannabis exposure and childhood neurocognitive development suggests that heavy maternal use of cannabis during pregnancy does not result in a reduction in global IQ but rather may act to diminish performance on tasks that require the harnessing and implementation of executive function skills; a top-down set of cognitive processes that are used to manage attention, exert inhibitory control and plan goal-directed behavior (Fried and Smith, 2001). Functional losses in executive function skills may place children with in utero cannabis exposure at a disadvantage for long-term success in school, in the community and in the workplace (Diamond and Lee, 2011).
Psychological Health and Adaptive Behavior
On the continuum of cannabis-related developmental neurotoxicity, there is growing evidence that psychological health may be particularly vulnerable to the adverse effects of in utero exposure. A study of infant social behavior demonstrated that maternal cannabis use during pregnancy was related to a significant increase in aggressive behavior and attentional problems in 18 month-old girls (El Marroun et al., 2011). In middle childhood, prenatal exposure was predictive of damaging or maladaptive behaviors such as increases in hyperactivity, impulsivity and delinquent behavior (Goldschmidt et al., 2000). In children born to heavy cannabis users (~1 or more joints/day), the risk of scoring in the borderline clinical range for delinquent behavior was 2.4 times that of children born to nonusers. Increased reporting of depressive symptoms and anxiety has also been documented in children with a history of heavy prenatal cannabis exposure during the first trimester (Gray et al., 2005; Leech et al., 2006).
A similar pattern of results has been observed in adolescence where rates of delinquency varied by prenatal exposure history (41% non-exposed, 50% light to moderate exposure and 61% heavy exposure) (Day et al., 2011). It is useful to note that cannabis-exposed children who expressed depressive symptoms at age 10 were at the highest risk of reporting delinquent behaviors during puberty. In separate studies focused on mental health and adaptive behavior during young adulthood, maternal cannabis use during pregnancy was not predictive of non-clinical psychopathology (Zammit et al., 2009) but was related to an increased risk for diagnosis of Tourette syndrome or chronic tic disorder (Mathews et al., 2014). Recent studies have suggested that prenatal exposure predicts the early onset of cannabis use in young adults (22 years of age), but this effect was primarily observed in subjects born to heavy users (~1 or more joints/day) (Sonon et al., 2015). While intriguing, a positive relationship between prenatal cannabis exposure and the early onset of cannabis use was not found in a study that utilized both maternal self-report and infant meconium to measure levels of gestational exposure (Frank et al., 2014).
More information: Roberto Frau et al. Prenatal THC exposure produces a hyperdopaminergic phenotype rescued by pregnenolone, Nature Neuroscience (2019). DOI: 10.1038/s41593-019-0512-2
Journal information: Nature Neuroscience