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Developmental cannabinoid exposure: New perspectives on outcomes and mechanisms
Developmental cannabinoid exposure: New perspectives on outcomes and mechanisms Sonya K. Sobrian Ph.D. PII: DOI: Reference:
S0892-0362(16)30122-2 doi: 10.1016/j.ntt.2016.10.010 NTT 6661
To appear in:
Neurotoxicology and Teratology
Please cite this article as: Sonya K. Sobrian, Developmental cannabinoid exposure: New perspectives on outcomes and mechanisms, Neurotoxicology and Teratology (2016), doi: 10.1016/j.ntt.2016.10.010
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Developmental Cannabinoid Exposure: New Perspectives on Outcomes and Mechanisms
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Cannabis remains the most widely cultivated, produced, trafficked and commonly used illicit drug worldwide, with an estimated 3.8% of the global population, or 182.5 million people, having used the drug in 2014 (United Nations Office on Drugs and Crime, World Drug Report 2016). In the United States, marijuana is now the most commonly used illicit drug, with over 42% of the population aged 12 years and older trying the drug within their lifetime, and current users numbering 22.2 million (8.4%) (Center for Behavioral Health Statistics and Quality, 2013; 2015). Marijuana is also the most commonly used illicit drug among pregnant women and adolescents. The most recently reported national statistics indicate that approximately 115,000 or 5.2% of pregnant use marijuana annually (SAMHSA, 2014), although prevalence rates ranging from 3% to 30% have been noted (Metz and Stickrath, 2015; Warner et al, 2014; Ko et al, 201). Moreover, the use of marijuana as a potential treatment for hyperemesis gravidarum may result in additional exposures during pregnancy (Roberson et al, 2014). Among adolescents, approximately 7.4% or 1.8 million 12-17 year olds are current users, with prevalence now surpassing that for regular tobacco smoking in this age group (SAMHSA, 2015). In addition, the age at onset of regular cannabis use appears to be occurring earlier, with 6.5% of eighth graders reporting marijuana use in the past 12 months (Lipari et al, 2015).
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Despite marijuana’s classification as an illegal Schedule I drug under U.S. federal law, several factors are likely to increase its popularity. The recent increase in the availability of marijuana due to its legalization and/or decimalization for medical and/or recreational purposes in 25 states, the District of Columbia and Guam, has decreased the perceptions of risk or harm with regular use (Miech et al, 2015; Ko et al, 2015; Volkow et al, 2014), especially when compared with other controlled psychoactive substances, tobacco or alcohol (Lachenmeier and Rehn, 2015). Moreover, the average delta-9tetrahydrocannabinol (THC) content, the main psychoactive component of cannabis, has increased, showing a 6-7 fold increase in potency over the last three to four decades (Warner et al, 2014; Volkow et al, 2014). In addition, synthetic cannabinoids, marketed as Spice or K2, which are more psychoactive than cannabis, and currently non-detectable in standard urine toxicological tests, are now available. Their designation as “legal marijuana”, given that their rapid development has outpaced attempts by the Federal government to classify them as Schedule I substances (Hadland et al, 2015), and marketing as “natural” herbs and incense, enhances their attractiveness and contributes to the perception of their safety among users. The wide spread use of recreational marijuana during pregnancy and by youths is potentially problematic, in that the prenatal/neonatal and adolescent periods represent dynamic phases of brain development which are exquisitely sensitive to disruption. In utero, events are programmed to ensure proper patterning of the central nervous system (CNS), and CNS development during adolescence is characterized by neural maturation, synaptic pruning and dendritic plasticity. It is now clear that the endocannabinod (eCB) system plays a crucial role in brain development. In the fetal brain, it is involved in several organizational events, including cell proliferation and migration, axonal elongation, and later, 1
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synaptogenesis and myelinogenesis (Campolongo et al 2011; Fernandez-Ruiz et al, 2000). THC can cross the placenta during gestation, and is secreted in breast milk during lactation, exposing the fetus and the neonate, respectively, to marijuana (Hutchings et al. 1989; Jakubovic and McGeer, 1977). Overstimulation and/or down regulation of the developing cannabinoid system by exogenous agonists, both natural and synthetic, via maternal exposure, or during adolescence by self-administration, can disrupt fine-tuned molecular signaling pathways and neurodevelopmental programs (Calvigioni et al 2014), and has been linked to altered development and long-term functional abnormalities (Campolongo et al, 2007; Calvigioni et al 2014).
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Despite an emerging body of evidence, adverse neonatal and long-term outcomes related to marijuana use during pregnancy remain unclear (Ross et al, 2015). Results are often conflicting and complicated by polysubstance use, reliance on self-reported measures of use, lack of quantifiable exposure by trimester, and variable outcomes measures (Gunn et al, 2016; Metz and Stickrath, 2015; Volkow et al, 2014). Because of the higher quantities of THC in contemporary products, and the resulting alteration in the ratio of THC to cannabidiol, a cannabinoid with properties that may partially counterbalance effects caused by THC, current outcomes may differ from those reported in the older literature (ElSohly et al, 2016).
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This Special Issue of Neurotoxicology and Teratology focuses on early development effects and longterm consequences of prenatal and/or adolescent exposure to natural and synthetic marijuana. It brings together reviews, clinical cohort studies, and experimental research papers that provide evidence of the consequences of exposure to cannabinoid compounds during critical phases of brain development in humans and animal models. The first seven articles focus on prenatal cannabinoid exposure; the eighth article discusses both developmental epochs and serves as a transition to adolescent exposure presented in the last three experimental papers. The extant clinical literature does not present compelling evidence that prenatal exposure to marijuana induces fetal abnormalities. While decreased birth weight, preterm delivery and increase admission to the NICU have been reported (Gunn et al, 2015), other investigators do not report links between these undesirable birth outcomes and gestational marijuana exposure (Metz and Stickrath, 2015; Conner et al, 2015). In the first article of this special issue, Richardson et al. propose the “double-hit” hypothesis as a mechanistic framework in which to reconcile contradictory reports of both immediate and long-term consequences of prenatal marijuana exposure. This review discusses the function and importance of the eCB system during fetal neurodevelopment and the evidence that prenatal THC provides the “first hit” by inducing covert perturbations or aberrant signaling events in fetal eCB microcircuitry. The first hit results in offspring that are more vulnerable to an environmental “second-hit” delivered postnatally, which injures the developing nervous system, and is manifested in neurodevelopmental and behavioral abnormalities. The authors also relate the double-hit hypothesis to teratology principles, fetal programming and epigenetic inheritance.
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The hypothesis that prenatal exposure to synthetic cannabinoids (SCB) delivers a first-hit to the developing brain is supported by the second article in this issue (Gilbert et al.), who showed that exposure to CP-55,940, a synthetic cannabinoid present in Spice, during closure of the neural tube, resulted in major malformation of the craniofacies and/or eye in mouse embryo. This observation stands in contrast to a lack of specific fetal organ toxicity in the clinical literature following prenatal exposure to THC (Gunn et al, 2015; Meta & Stickrath, 2015; Conner et al, 2016). Unlike THC, which is a weak partial agonist of brain CB1 receptors, CP-55,940 is a highly potent, full agonist of CB1 (Greydanus et al, 2013), which could explain this teratogenic effect.
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Confounding factors complicate the study of the consequences of developmental exposure to cannabinoids in humans. Although animal models have been developed to address the question of causation by controlling or eliminating confounding variables and exploring mechanistic considerations (Sobrian and Holson, 2011; Thompson et al, 2009), the next two papers provide evidence of additional confounds inherent in animal modeling. While they do not involve cannabinoid exposure during the prenatal period, they provide insight into genetic and environmental issues that may account for the contradictory and inconclusive findings in the developmental cannabinoid literature.
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In the first of these papers, Rodriguez-Sanchez et al. suggest that discrepant outcomes reported in preclinical studies may in part reside in the structural and functional variants of components of the eCB system present in different organisms. Analysis and comparison between humans and baboons of cloned and characterized cDNA sequences of selected components of the eCB system indicated that CNR1 and CNR2, which encode for the CB1 and CB2 receptors respectively, show the highest homology of amino acid sequences. Consideration of evolutionary-driven species-specific differences in receptor expression and transition pathways in the eCB system is presented as a method of enhancing the evaluation of data from animal models of developmental cannabis exposure. Prenatal drug studies often involve dams that are shipped from a vendor or to a collaborator’s laboratory. In many cases only vehicle-treated dams serve as controls and non-treated dams are not included. Moreover, environmental enrichment is now a standard housing protocol in many animal facilities. In the fourth article, Dow-Edwards et al. report a complex interaction between these unintentional prenatal and early postnatal and pre-pubertal stressors that reduced CB1 receptors in males and increased them in females in limbic brain regions. Identification of these sexually-dimorphic changes may provide a molecular basis for discrepant behavioral effects reported across various laboratory in the literature, and underscore the necessity of testing both sexes. Three prospective longitudinal epidemiological cohort studies have shown long-lasting outcomes in several behavioral domains from prenatal marijuana exposure (for reviews see Higuera-Matas et al, 2015; Jaddoe et al, 2010). The next 3 papers in this issue involve young adult offspring, 18-22 years of age, from two of these cohorts: the Maternal Health Practices and Childhood Development Project (MHPCD), which began in 1982, and focused on the long-term behavioral consequences of prenatal 3
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marijuana and alcohol exposure in a low-income African-American population in Pittsburgh, Pennsylvania (Goldschmidt et al, 2008), and a cohort from the Ottawa Prenatal Prospective Study (OPPS), initiated in 1978, which collected neurobehavioral data from offspring of a low-risk, middle-class population of women who smoked cigarettes and marijuana during pregnancy (Fried et al, 2003).
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Psychiatric symptoms are well-documented adverse health effects of cannabis use in adolescents and adults (Gage et al, 2016; Hall, 2015). Although the associations between cannabinoids and psychosis have gained increasing recognition, the variables that mediate these effects are less well-understood (Radhakrishnan et al, 2014). Both MHPCD papers investigated the roles played by prenatal predictors and early childhood behavior on adult roles, and findings from both studies support the “double-hit” hypothesis.
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In the first study from the MHPCD cohort, Goldschmidt et al. examined the connection between prenatal marijuana exposure and negative adult roles at 22 years of age. They report the existence of two pathways to unsuccessful attainment in young adult roles, both of which involved intervening variables. One is a direct pathway from prenatal marijuana exposure to use of marijuana before the age of 15 (early age onset of marijuana use: EAOM) to negative adult roles. The other is from behavioral problems at 3 years of age, to EAOM to negative adult roles. The second study with this cohort by Sonon et al. investigated the influence of prenatal marijuana exposure on the development of cannabis use disorder (CUD), a condition that has been diagnosed in approximately 1.7 million young adults aged 18 to 25 (4.9%) (United Nations Office on Drugs and Crime, World Drug Report, 2016). These investigators are the first to identify potential pathways from prenatal marijuana exposure to CUD in 22 year old young adults. Two indirect pathways from prenatal marijuana exposure to CUD were found: one through EAOM, and a second which involved depression at age 10 and EAOM. The findings of these two studies identified several time points at which intervention and prevention programs might be most advantageous: pregnancy, at the appearance of childhood behavior problems or depression, and with the early onset of marijuana use. Previous findings from the MHPDC and OPP cohorts indicated that prenatal marijuana exposure was associated with deficits in cognitive abilities, especially those associated with executive functions, i.e., short-term and working memory, verbal reasoning, cognitive flexibility, and sustained attention. Aspects of cognitive impairment were evident as early as 3 years of age and continued through adolescence and young adulthood. Smith et al. present evidence that in the absence of differences in performance on four tasks requiring executive functioning, prenatal marijuana is associated with longterm neurophysiology consequences in the CNS. In a cohort of young adults from the OPP study, these changes are illustrated by the left lateralization of increased activity in distinct, distributed neural networks that underlie the behavioral tasks, suggestive of a vulnerability that requires enhanced brain activity to perform higher cognitive functions.
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Marijuana use and violent aggression have been causally linked in the popular press. Barthelemy et al. provide an extensive exploration of this (mis)perception with a focus on developmental exposure to marijuana and aggressive behavior. For both exposure periods, potential mechanisms by which marijuana could influence aggressive behavior and the confounding factors that limit attributing causality are presented to provide a framework for evaluation. The paucity of animal literature specifically investigating the relationship between prenatal or perinatal marijuana exposure and aggression, and the equivocal findings from epidemiological studies, offer little support for a direct relationship between prenatal marijuana use and childhood aggression. In contrast, in adolescence, there is an association between marijuana use and aggressive behavior, the strength of which differs with acute intoxication or chronic use, and the longitudinal or cross-sectional design of the study. The most convincing association was found between cannabis withdrawal and aggressive behaviors.
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Adolescence is now recognized as a critical period of brain development. It is a time of neural plasticity characterized by myelinization, and changes in synaptic formation, levels of neurotransmitters and their receptors. It is also a period marked by initial exposure and rapidly escalating rates of drug use SAMHSA, 2015). Because exogenous cannabinoids may cause perturbation of the eCB system in the rapidly changing adolescent brain, adolescence is being increasingly recognized as a particularly critical period of heightened vulnerability to the effects of marijuana.
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Recent drug use research with adolescents has focused on two issues: 1] whether there are pre-existing innate structural differences in the CNS of adolescent substance users that increase the likelihood of their drug use and 2] how drug use during adolescence affects normal brain development and cognitive functioning (Squeglia and Gray, 2016). Jacobus et al. used a longitudinal study design to address these two issues by examining neurocognitive performance and cortical thickness in teenagers at 12-14 years of age tested prior to drug use, and again 6-8 years later after their use of alcohol alone or in combination with marijuana, two intoxicants frequently concurrently consumed by adolescents (Medina et al. 2007). There is a normal decline in cortical volume and thickness during late childhood and adolescence that has been related to the refinement and pruning of neural synapses and enhanced information processing (Stiles and Jernigan, 2010). At baseline, prior to drug use, pre-existing differences in cortical thickness were reported between the alcohol only, alcohol + marijuana, and control groups, suggesting that innate differences in structural brain integrity may play a role in the initiation of substance abuse. Moreover, at follow-up, both the control and alcohol only groups showed the expected decline in thickness in frontal and parietal cortices that was greater than that observed in the alcohol + marijuana group, indicating that the addition of marijuana to the drug regime during adolescence slowed the normal trajectory of cortical developmental.
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Silva et al. explore the hypothesis that alterations in CB1 receptors may provide a mechanism by which exposure to marijuana during adolescence may increase the risk for the development of mental illness. In addition to determining the impact of puberty and sex on marijuana- induced anxiety, depression and schizophrenia, the addition of stress history as a variable supports the idea that a “double-hit” can uncover and elaborate the consequences of marijuana exposure in adolescence.
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The efficacy of using cannabis to treat children with epilepsy is controversial. Existing clinical data are insufficient either to support or refute the use of cannabinoids for the treatment of epilepsy and seizures (Reddy and Golub, 2016). Findings in the animal literature indicate that marijuana and its constituents, primarily cannabidiol, exhibit anticonvulsant effects and reduce seizure-related mortality. However, conflicting reports have shown that cannabinoids lower seizure thresholds, and THC withdrawal increases susceptibility for convulsions (Detyniecki and Hirsch, 2015). The question of whether adolescent treatment with the synthetic cannabinoid, CP 55, 940, would alter adult seizure susceptibility was addressed by Spring et al. Their finding of enhanced lethality following severe seizures in the adult is discussed in terms of the role of the eCB system in regulating neuronal excitably and seizure activity, defending against excitotoxicity, and a reduced functionality of this system following adolescent cannabinoid exposure.
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Clinical and experimental evidence support the long-term impact of developmental cannabis exposure. The final paper by Szutorisz et al. demonstrates that adolescent exposure to THC can produce not only long-term alterations in the user but also effect molecular and behavioral changes in a subsequent generation, not directly exposed to marijuana, as a consequence of parental germline exposure to the drug. Parental THC exposure was associated with abnormalities in mRNA expression of genes functionally implicated in the regulation of synaptic plasticity in the striatum in a sex-specific manner in adolescent and adult F1 offspring. These results are discussed in terms of the concept of epigenetically inherited phenotypes and an enhanced risk for the development of neuropsychiatric disorders that may manifest differently in males and females. These papers represent a sampling of the current work being done to narrow the gap between perception and objective scientific evidence regarding the impact of exposure to cannabinoids during critical periods of brain development on a variety of variables, the long-term nature of these changes and the influence of environmental stressors in their manifestation. They are provided in an effort to inform decision-makers about the potential hazards and/or benefits of exposure to cannabinoid compounds during development. My sincere thanks go to the many authors and co-authors for submitting their work to this issue and persevering through the journal's peer-review process, and the many helpful reviewers who provided their time and expertise to improve these papers. I also thank Dr. Jerrold Meyer for his assistance with the many tasks involved in the initiation and completion of this Special Issue, and Dr. Philip Bushnell for his support and editorial expertise throughout the process. 6
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Sonya K. Sobrian, Ph.D. Guest Editor
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S0892-0362(16)30122-2 doi: 10.1016/j.ntt.2016.10.010 NTT 6661
To appear in:
Neurotoxicology and Teratology
Please cite this article as: Sonya K. Sobrian, Developmental cannabinoid exposure: New perspectives on outcomes and mechanisms, Neurotoxicology and Teratology (2016), doi: 10.1016/j.ntt.2016.10.010
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Developmental Cannabinoid Exposure: New Perspectives on Outcomes and Mechanisms
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Cannabis remains the most widely cultivated, produced, trafficked and commonly used illicit drug worldwide, with an estimated 3.8% of the global population, or 182.5 million people, having used the drug in 2014 (United Nations Office on Drugs and Crime, World Drug Report 2016). In the United States, marijuana is now the most commonly used illicit drug, with over 42% of the population aged 12 years and older trying the drug within their lifetime, and current users numbering 22.2 million (8.4%) (Center for Behavioral Health Statistics and Quality, 2013; 2015). Marijuana is also the most commonly used illicit drug among pregnant women and adolescents. The most recently reported national statistics indicate that approximately 115,000 or 5.2% of pregnant use marijuana annually (SAMHSA, 2014), although prevalence rates ranging from 3% to 30% have been noted (Metz and Stickrath, 2015; Warner et al, 2014; Ko et al, 201). Moreover, the use of marijuana as a potential treatment for hyperemesis gravidarum may result in additional exposures during pregnancy (Roberson et al, 2014). Among adolescents, approximately 7.4% or 1.8 million 12-17 year olds are current users, with prevalence now surpassing that for regular tobacco smoking in this age group (SAMHSA, 2015). In addition, the age at onset of regular cannabis use appears to be occurring earlier, with 6.5% of eighth graders reporting marijuana use in the past 12 months (Lipari et al, 2015).
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Despite marijuana’s classification as an illegal Schedule I drug under U.S. federal law, several factors are likely to increase its popularity. The recent increase in the availability of marijuana due to its legalization and/or decimalization for medical and/or recreational purposes in 25 states, the District of Columbia and Guam, has decreased the perceptions of risk or harm with regular use (Miech et al, 2015; Ko et al, 2015; Volkow et al, 2014), especially when compared with other controlled psychoactive substances, tobacco or alcohol (Lachenmeier and Rehn, 2015). Moreover, the average delta-9tetrahydrocannabinol (THC) content, the main psychoactive component of cannabis, has increased, showing a 6-7 fold increase in potency over the last three to four decades (Warner et al, 2014; Volkow et al, 2014). In addition, synthetic cannabinoids, marketed as Spice or K2, which are more psychoactive than cannabis, and currently non-detectable in standard urine toxicological tests, are now available. Their designation as “legal marijuana”, given that their rapid development has outpaced attempts by the Federal government to classify them as Schedule I substances (Hadland et al, 2015), and marketing as “natural” herbs and incense, enhances their attractiveness and contributes to the perception of their safety among users. The wide spread use of recreational marijuana during pregnancy and by youths is potentially problematic, in that the prenatal/neonatal and adolescent periods represent dynamic phases of brain development which are exquisitely sensitive to disruption. In utero, events are programmed to ensure proper patterning of the central nervous system (CNS), and CNS development during adolescence is characterized by neural maturation, synaptic pruning and dendritic plasticity. It is now clear that the endocannabinod (eCB) system plays a crucial role in brain development. In the fetal brain, it is involved in several organizational events, including cell proliferation and migration, axonal elongation, and later, 1
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synaptogenesis and myelinogenesis (Campolongo et al 2011; Fernandez-Ruiz et al, 2000). THC can cross the placenta during gestation, and is secreted in breast milk during lactation, exposing the fetus and the neonate, respectively, to marijuana (Hutchings et al. 1989; Jakubovic and McGeer, 1977). Overstimulation and/or down regulation of the developing cannabinoid system by exogenous agonists, both natural and synthetic, via maternal exposure, or during adolescence by self-administration, can disrupt fine-tuned molecular signaling pathways and neurodevelopmental programs (Calvigioni et al 2014), and has been linked to altered development and long-term functional abnormalities (Campolongo et al, 2007; Calvigioni et al 2014).
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Despite an emerging body of evidence, adverse neonatal and long-term outcomes related to marijuana use during pregnancy remain unclear (Ross et al, 2015). Results are often conflicting and complicated by polysubstance use, reliance on self-reported measures of use, lack of quantifiable exposure by trimester, and variable outcomes measures (Gunn et al, 2016; Metz and Stickrath, 2015; Volkow et al, 2014). Because of the higher quantities of THC in contemporary products, and the resulting alteration in the ratio of THC to cannabidiol, a cannabinoid with properties that may partially counterbalance effects caused by THC, current outcomes may differ from those reported in the older literature (ElSohly et al, 2016).
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This Special Issue of Neurotoxicology and Teratology focuses on early development effects and longterm consequences of prenatal and/or adolescent exposure to natural and synthetic marijuana. It brings together reviews, clinical cohort studies, and experimental research papers that provide evidence of the consequences of exposure to cannabinoid compounds during critical phases of brain development in humans and animal models. The first seven articles focus on prenatal cannabinoid exposure; the eighth article discusses both developmental epochs and serves as a transition to adolescent exposure presented in the last three experimental papers. The extant clinical literature does not present compelling evidence that prenatal exposure to marijuana induces fetal abnormalities. While decreased birth weight, preterm delivery and increase admission to the NICU have been reported (Gunn et al, 2015), other investigators do not report links between these undesirable birth outcomes and gestational marijuana exposure (Metz and Stickrath, 2015; Conner et al, 2015). In the first article of this special issue, Richardson et al. propose the “double-hit” hypothesis as a mechanistic framework in which to reconcile contradictory reports of both immediate and long-term consequences of prenatal marijuana exposure. This review discusses the function and importance of the eCB system during fetal neurodevelopment and the evidence that prenatal THC provides the “first hit” by inducing covert perturbations or aberrant signaling events in fetal eCB microcircuitry. The first hit results in offspring that are more vulnerable to an environmental “second-hit” delivered postnatally, which injures the developing nervous system, and is manifested in neurodevelopmental and behavioral abnormalities. The authors also relate the double-hit hypothesis to teratology principles, fetal programming and epigenetic inheritance.
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The hypothesis that prenatal exposure to synthetic cannabinoids (SCB) delivers a first-hit to the developing brain is supported by the second article in this issue (Gilbert et al.), who showed that exposure to CP-55,940, a synthetic cannabinoid present in Spice, during closure of the neural tube, resulted in major malformation of the craniofacies and/or eye in mouse embryo. This observation stands in contrast to a lack of specific fetal organ toxicity in the clinical literature following prenatal exposure to THC (Gunn et al, 2015; Meta & Stickrath, 2015; Conner et al, 2016). Unlike THC, which is a weak partial agonist of brain CB1 receptors, CP-55,940 is a highly potent, full agonist of CB1 (Greydanus et al, 2013), which could explain this teratogenic effect.
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Confounding factors complicate the study of the consequences of developmental exposure to cannabinoids in humans. Although animal models have been developed to address the question of causation by controlling or eliminating confounding variables and exploring mechanistic considerations (Sobrian and Holson, 2011; Thompson et al, 2009), the next two papers provide evidence of additional confounds inherent in animal modeling. While they do not involve cannabinoid exposure during the prenatal period, they provide insight into genetic and environmental issues that may account for the contradictory and inconclusive findings in the developmental cannabinoid literature.
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In the first of these papers, Rodriguez-Sanchez et al. suggest that discrepant outcomes reported in preclinical studies may in part reside in the structural and functional variants of components of the eCB system present in different organisms. Analysis and comparison between humans and baboons of cloned and characterized cDNA sequences of selected components of the eCB system indicated that CNR1 and CNR2, which encode for the CB1 and CB2 receptors respectively, show the highest homology of amino acid sequences. Consideration of evolutionary-driven species-specific differences in receptor expression and transition pathways in the eCB system is presented as a method of enhancing the evaluation of data from animal models of developmental cannabis exposure. Prenatal drug studies often involve dams that are shipped from a vendor or to a collaborator’s laboratory. In many cases only vehicle-treated dams serve as controls and non-treated dams are not included. Moreover, environmental enrichment is now a standard housing protocol in many animal facilities. In the fourth article, Dow-Edwards et al. report a complex interaction between these unintentional prenatal and early postnatal and pre-pubertal stressors that reduced CB1 receptors in males and increased them in females in limbic brain regions. Identification of these sexually-dimorphic changes may provide a molecular basis for discrepant behavioral effects reported across various laboratory in the literature, and underscore the necessity of testing both sexes. Three prospective longitudinal epidemiological cohort studies have shown long-lasting outcomes in several behavioral domains from prenatal marijuana exposure (for reviews see Higuera-Matas et al, 2015; Jaddoe et al, 2010). The next 3 papers in this issue involve young adult offspring, 18-22 years of age, from two of these cohorts: the Maternal Health Practices and Childhood Development Project (MHPCD), which began in 1982, and focused on the long-term behavioral consequences of prenatal 3
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marijuana and alcohol exposure in a low-income African-American population in Pittsburgh, Pennsylvania (Goldschmidt et al, 2008), and a cohort from the Ottawa Prenatal Prospective Study (OPPS), initiated in 1978, which collected neurobehavioral data from offspring of a low-risk, middle-class population of women who smoked cigarettes and marijuana during pregnancy (Fried et al, 2003).
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Psychiatric symptoms are well-documented adverse health effects of cannabis use in adolescents and adults (Gage et al, 2016; Hall, 2015). Although the associations between cannabinoids and psychosis have gained increasing recognition, the variables that mediate these effects are less well-understood (Radhakrishnan et al, 2014). Both MHPCD papers investigated the roles played by prenatal predictors and early childhood behavior on adult roles, and findings from both studies support the “double-hit” hypothesis.
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In the first study from the MHPCD cohort, Goldschmidt et al. examined the connection between prenatal marijuana exposure and negative adult roles at 22 years of age. They report the existence of two pathways to unsuccessful attainment in young adult roles, both of which involved intervening variables. One is a direct pathway from prenatal marijuana exposure to use of marijuana before the age of 15 (early age onset of marijuana use: EAOM) to negative adult roles. The other is from behavioral problems at 3 years of age, to EAOM to negative adult roles. The second study with this cohort by Sonon et al. investigated the influence of prenatal marijuana exposure on the development of cannabis use disorder (CUD), a condition that has been diagnosed in approximately 1.7 million young adults aged 18 to 25 (4.9%) (United Nations Office on Drugs and Crime, World Drug Report, 2016). These investigators are the first to identify potential pathways from prenatal marijuana exposure to CUD in 22 year old young adults. Two indirect pathways from prenatal marijuana exposure to CUD were found: one through EAOM, and a second which involved depression at age 10 and EAOM. The findings of these two studies identified several time points at which intervention and prevention programs might be most advantageous: pregnancy, at the appearance of childhood behavior problems or depression, and with the early onset of marijuana use. Previous findings from the MHPDC and OPP cohorts indicated that prenatal marijuana exposure was associated with deficits in cognitive abilities, especially those associated with executive functions, i.e., short-term and working memory, verbal reasoning, cognitive flexibility, and sustained attention. Aspects of cognitive impairment were evident as early as 3 years of age and continued through adolescence and young adulthood. Smith et al. present evidence that in the absence of differences in performance on four tasks requiring executive functioning, prenatal marijuana is associated with longterm neurophysiology consequences in the CNS. In a cohort of young adults from the OPP study, these changes are illustrated by the left lateralization of increased activity in distinct, distributed neural networks that underlie the behavioral tasks, suggestive of a vulnerability that requires enhanced brain activity to perform higher cognitive functions.
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Marijuana use and violent aggression have been causally linked in the popular press. Barthelemy et al. provide an extensive exploration of this (mis)perception with a focus on developmental exposure to marijuana and aggressive behavior. For both exposure periods, potential mechanisms by which marijuana could influence aggressive behavior and the confounding factors that limit attributing causality are presented to provide a framework for evaluation. The paucity of animal literature specifically investigating the relationship between prenatal or perinatal marijuana exposure and aggression, and the equivocal findings from epidemiological studies, offer little support for a direct relationship between prenatal marijuana use and childhood aggression. In contrast, in adolescence, there is an association between marijuana use and aggressive behavior, the strength of which differs with acute intoxication or chronic use, and the longitudinal or cross-sectional design of the study. The most convincing association was found between cannabis withdrawal and aggressive behaviors.
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Adolescence is now recognized as a critical period of brain development. It is a time of neural plasticity characterized by myelinization, and changes in synaptic formation, levels of neurotransmitters and their receptors. It is also a period marked by initial exposure and rapidly escalating rates of drug use SAMHSA, 2015). Because exogenous cannabinoids may cause perturbation of the eCB system in the rapidly changing adolescent brain, adolescence is being increasingly recognized as a particularly critical period of heightened vulnerability to the effects of marijuana.
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Recent drug use research with adolescents has focused on two issues: 1] whether there are pre-existing innate structural differences in the CNS of adolescent substance users that increase the likelihood of their drug use and 2] how drug use during adolescence affects normal brain development and cognitive functioning (Squeglia and Gray, 2016). Jacobus et al. used a longitudinal study design to address these two issues by examining neurocognitive performance and cortical thickness in teenagers at 12-14 years of age tested prior to drug use, and again 6-8 years later after their use of alcohol alone or in combination with marijuana, two intoxicants frequently concurrently consumed by adolescents (Medina et al. 2007). There is a normal decline in cortical volume and thickness during late childhood and adolescence that has been related to the refinement and pruning of neural synapses and enhanced information processing (Stiles and Jernigan, 2010). At baseline, prior to drug use, pre-existing differences in cortical thickness were reported between the alcohol only, alcohol + marijuana, and control groups, suggesting that innate differences in structural brain integrity may play a role in the initiation of substance abuse. Moreover, at follow-up, both the control and alcohol only groups showed the expected decline in thickness in frontal and parietal cortices that was greater than that observed in the alcohol + marijuana group, indicating that the addition of marijuana to the drug regime during adolescence slowed the normal trajectory of cortical developmental.
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Silva et al. explore the hypothesis that alterations in CB1 receptors may provide a mechanism by which exposure to marijuana during adolescence may increase the risk for the development of mental illness. In addition to determining the impact of puberty and sex on marijuana- induced anxiety, depression and schizophrenia, the addition of stress history as a variable supports the idea that a “double-hit” can uncover and elaborate the consequences of marijuana exposure in adolescence.
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The efficacy of using cannabis to treat children with epilepsy is controversial. Existing clinical data are insufficient either to support or refute the use of cannabinoids for the treatment of epilepsy and seizures (Reddy and Golub, 2016). Findings in the animal literature indicate that marijuana and its constituents, primarily cannabidiol, exhibit anticonvulsant effects and reduce seizure-related mortality. However, conflicting reports have shown that cannabinoids lower seizure thresholds, and THC withdrawal increases susceptibility for convulsions (Detyniecki and Hirsch, 2015). The question of whether adolescent treatment with the synthetic cannabinoid, CP 55, 940, would alter adult seizure susceptibility was addressed by Spring et al. Their finding of enhanced lethality following severe seizures in the adult is discussed in terms of the role of the eCB system in regulating neuronal excitably and seizure activity, defending against excitotoxicity, and a reduced functionality of this system following adolescent cannabinoid exposure.
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Clinical and experimental evidence support the long-term impact of developmental cannabis exposure. The final paper by Szutorisz et al. demonstrates that adolescent exposure to THC can produce not only long-term alterations in the user but also effect molecular and behavioral changes in a subsequent generation, not directly exposed to marijuana, as a consequence of parental germline exposure to the drug. Parental THC exposure was associated with abnormalities in mRNA expression of genes functionally implicated in the regulation of synaptic plasticity in the striatum in a sex-specific manner in adolescent and adult F1 offspring. These results are discussed in terms of the concept of epigenetically inherited phenotypes and an enhanced risk for the development of neuropsychiatric disorders that may manifest differently in males and females. These papers represent a sampling of the current work being done to narrow the gap between perception and objective scientific evidence regarding the impact of exposure to cannabinoids during critical periods of brain development on a variety of variables, the long-term nature of these changes and the influence of environmental stressors in their manifestation. They are provided in an effort to inform decision-makers about the potential hazards and/or benefits of exposure to cannabinoid compounds during development. My sincere thanks go to the many authors and co-authors for submitting their work to this issue and persevering through the journal's peer-review process, and the many helpful reviewers who provided their time and expertise to improve these papers. I also thank Dr. Jerrold Meyer for his assistance with the many tasks involved in the initiation and completion of this Special Issue, and Dr. Philip Bushnell for his support and editorial expertise throughout the process. 6
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Sonya K. Sobrian, Ph.D. Guest Editor
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