Table 1.

right brain regions – medial PFC, DLPFC and ventrolateral PFC

Age†	Cohort‡	Category	Results/outcomes	Exposure details	Ref.
*Fetus*
17–22 GW	–	Growth	Reduced foot length and bodyweight	≥0.4 J/day	[48]
18–22 GW	–	Dopamine signaling	Decreased D2 mRNA in amygdala of males only	≥0.4 J/day	[152]
18–22 GW	–	Endorphin signaling	Decreased opioid peptide (PENK) and receptor (κ) in caudal putamen and thalamus, respectively; increased opioid receptor (µ) in the amygdala	–	[74]
*Neonatal*
Neonatal	OPPS	Neurobehavior	Increased tremors, exaggerated startles and diminished responsiveness to light	–	[46]
Neonatal	MHPCD	Growth	Decreased body length	≥1 J/day, first Trim	[49]
Neonatal	–	Growth Neurobehavior	No effect on birthweight, length or gestational age No effect	– –	[54]
Neonatal	VIPS	Growth	No effect on birthweight, preterm delivery or abruptio placentae	–	[35]
Neonatal	–	Growth Behavior	No effect on birthweight, length or gestational age More irritable, less responsive to calming, increased jitters and startles	– –	[52]
Neonatal	NBDPS	Growth	No effect on birthweight, gestational age or preterm delivery	–	[40]
1 mo	–	Behavior	Less irritable, more alert, more robust autonomic and motor systems, more autonomically stable and increased orientation	≥2.86 J/day	[54]
*Toddler*
8 mo	MHPCD	Growth	No effect	–	[49]
9 mo	MHPCD	Mental/motor skills	Delayed mental development	≥1 J/day, third Trim	[26]
1 y	OPPS	Mental/motor skills	No effect	–	[55]
1 y	–	Mental/motor skills	Decreased motor scores, no effect on mental development	≥0.5 J/day, first Trim	[149]
19 mo	MHPCD	Mental/motor skills	No effect	–	[26]
2 y	OPPS	Mental/motor skills	No effect	–	[55]
3 y	MHPCD	Intelligence Cognition	No effect on overall IQ for entire cohort For African–Americans: decrease in short-term memory and verbal reasoning	– ≥1 J/day, first/second Trim	[57]
3 y	MHPCD	Sleep and arousal	Lowered sleep efficiency, more nocturnal arousals and more awake time after sleep onset	–	[153]
*Childhood*
4 y	–	Sustained attention	Increased number of omission errors	First Trim	[45]
4 y	MHPCD	Motor skills	No effect on balance and coordination skills	–	[154]
5–6 y	OPPS	Cognition and language	No effect	–	[155]
6 y	MHPCD	Growth	No effect	–	[156]
6 y	OPPS	Memory Attention Behavior	No effect Increased number of omission errors Described as more impulsive and hyperactive	≥0.86 J/day	[58]
6 y	MHPCD	Impulsivity Sustained attention	Decrease in errors of omission Lower overall composite score	Second Trim	[60]
6 y	MHPCD	Intelligence Cognition	Lower overall composite score Lower verbal reasoning, quantitative reasoning and short-term memory	≥1 J/day, first/second Trim	[59]
9–12 y	OPPS	Reading and language	No effect in regards to reading or language	–	[68]
9–12 y	OPPS	Intelligence Executive function	No effect in terms of full scale IQ Impulse control and visual hypothesis aspects are negatively impacted	– > 0.86 J/day	[63]
*Adolescence*
10 y	MHPCD	Behavior and emotion Behavior and emotion	Fewer internalizing problems, although not correlated with teacher’s report Predicted lower scores in design memory and screening index	≥0.4 J/day second Trim ≥0.89 J/day, first Trim	[47]
10 y	MHPCD	Learning and memory Sustained attention	Predicted lower scores in design memory and screening index Increase in errors of commission	≥0.89 J/day, first Trim ≥0.89 J/day, second Trim	[47]
10 y	MHPCD	Depression	Increased levels of depressive symptoms	>0.89 J/day, first/third Trim	[64]
12 y	–	Psychotic symptoms	No effect	–	[66]
10–14 y	–	Volumetric MRI	No effect on cortical gray matter volume, white matter volume, cerebral spinal fluid or parenchymal volume	–	[69]
10 y 14 y	MHPCD	Behavior and cognition Delinquent behaviors	Negatively associated with depressive symptoms, IQ, learning and memory Increased delinquent behaviors	≥0.89 J/day, first/second Trim ≥0.89 J/day	[61]
13–16 y	OPPS	Sustained attention	Decreased stability of attention over time	≥0.86 J/day	[71]
13–16 y	OPPS	Growth	No changes in weight, height or puberty symptoms	–	[157]
13–16 y	OPPS	Visual memory	Lower scores in abstract designs and Peabody spelling	≥0.86 J/day	[27]
16 y	MHPCD	Fine motor coordination Visual–motor coordination	Various light deficits in processing speed and interhemispheric motor coordination Slight increase in visual–motor coordination	≥2 J/mo	[158]
*Young adult*
18–22 y	OPPS	Response inhibition Response inhibition by fMRI Intelligence Working memory by fMRI	Slightly more errors of commission Increased bilateral PFC activity, right premotor cortex activity; decreased activity in left cerebellum No effect Increased activity in left medial PFC, inferior frontal gyrus and left cerebellum; decreased activity in	– – – –	[72] [73]

Prenatal Marijuana Exposure Studies in Humans

†Exposed offspring study age.
‡Specified conditions of prenatal exposure.
DLPFC: Dorsolateral prefrontal cortex; GW: Gestation week(s); J: Joint; MHPCD: Maternal Health Practices and Child Development Project; mo: Month(s); NBDPS: National Birth Defects Prevention Study; OPPS: Ottawa Prenatal Prospective Study; PENK: Proenkephalin; PFC: Prefrontal cortex; Trim: Trimester; VIPS: Vaginal Infections and Prematurity Study; y: Year(s).

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•• Along with [74], it is one of only two human studies to date that describe changes in neurotransmitter signaling by as early as midgestation in response to PME.
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Day NL, Richardson GA, Geva D, Robles N. Alcohol, marijuana, and tobacco: effects of prenatal exposure on offspring growth and morphology at age six. Alcohol Clin. Exp. Res. 18(4), 786-794 (1994).
Fried PA, James DS, Watkinson B. Growth and pubertal milestones during adolescence in offspring prenatally exposed to cigarettes and marihuana. Neurotoxicol. Teratol. 23(5), 431-436 (2001).
Willford JA, Chandler LS, Goldschmidt L, Day NL. Effects of prenatal tobacco, alcohol and marijuana exposure on processing speed, visual-motor coordination, and interhemispheric transfer. Neurotoxicol. Teratol. 32(6), 580-588 (2010).

Websites
201. Substance Abuse and Mental Health Services Administration (2010). Results from the 2009 National Survey on Drug Use and Health Mental Health Findings (Center for Behavioral Health Statistics and Quality, NSDUH Series H-39, HHS Publication No.SMA 10-4609) www.oas.samhsa.gov/NSDUH/2k9NSDUH/MH/2k9MHResults.htm
202. Substance Abuse and Mental Health Services Administration: Substance Use among Women During Pregnancy and Following Childbirth. The NSDUH Report (2009) http://oas.samhsa.gov/2k9/135/PregWoSubUse.htm
203. United Nations Office on Drugs and Crime: United Nations Office on Drugs and Crime (UNODC), World Drug Report 2010 (United Nations Publication, Sales No. E. 10.XI.13) www.unodc.org/documents/wdr/WDR_2010/World_Drug_Report_2010_lo-res.pdf

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Author(s)

Chia-Shan Wu, PhD

The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital

Disclosures

Disclosure: Chia-Shan Wu, PhD, has disclosed no relevant financial relationships.

Christopher P. Jew

The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital; Program in Developmental Biology, Baylor College of Medicine, Houston, Texas

Disclosures

Disclosure: Christopher P. Jew has disclosed no relevant financial relationships.

Hui-Chen Lu, PhD

The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital; Department of Pediatrics; Program in Developmental Biology; Department of Neuroscience, Baylor College of Medicine, Houston, Texas

Disclosures

Disclosure: Hui-Chen Lu, PhD, is supported by NIH grants: NS048884 (NINDS), DA029381 (NIDA) and HD065561 (NICHD).

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Elisa Manzotti

Editorial Director, Future Science Group, London, United Kingdom

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Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

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Laurie Barclay, MD

Freelance writer and reviewer, Medscape, LLC

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CME

Lasting Impacts of Prenatal Cannabis Exposure and the Role of Endogenous Cannabinoids in the Developing Brain

Authors: Chia-Shan Wu, PhD; Christopher P. Jew; Hui-Chen Lu, PhD
CME Released: 7/1/2011
THIS ACTIVITY HAS EXPIRED
Valid for credit through: 7/1/2012

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Target Audience and Goal Statement

This activity is intended for primary care clinicians, obstetricians, neurologists, psychiatrists, pediatricians, and other healthcare providers advising pregnant women regarding the effects of prenatal marijuana exposure and/or caring for their offspring.

The goal of this activity is to review the interaction of prenatal exposure to marijuana with endocannabinoid effects on neural development.

Upon completion of this activity, participants will be able to:

Describe the epidemiology of prenatal exposure to marijuana, based on a review
Describe the neurodevelopmental effects of prenatal exposure to marijuana
Describe the effects of endocannabinoids on neural development and how prenatal exposure to marijuana influences these effects

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Author(s)

Chia-Shan Wu, PhD

The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital

Disclosures

Disclosure: Chia-Shan Wu, PhD, has disclosed no relevant financial relationships.

Christopher P. Jew

The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital; Program in Developmental Biology, Baylor College of Medicine, Houston, Texas

Disclosures

Disclosure: Christopher P. Jew has disclosed no relevant financial relationships.

Hui-Chen Lu, PhD

The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital; Department of Pediatrics; Program in Developmental Biology; Department of Neuroscience, Baylor College of Medicine, Houston, Texas

Disclosures

Disclosure: Hui-Chen Lu, PhD, is supported by NIH grants: NS048884 (NINDS), DA029381 (NIDA) and HD065561 (NICHD).

Editor(s)

Elisa Manzotti

Editorial Director, Future Science Group, London, United Kingdom

Disclosures

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME Author(s)

Laurie Barclay, MD

Freelance writer and reviewer, Medscape, LLC

Disclosures

Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

CME Reviewer(s)

Nafeez Zawahir, MD

CME Clinical Director, Medscape, LLC

Disclosures

Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

Sarah Fleischman

CME Program Manager, Medscape, LLC

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Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

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Endocannabinoid System During Neural Development

Endocannabinoid signaling plays important roles in learning and memory, anxiety, depression, addiction, appetite and feeding behaviors, pain and neuroprotection.^[5,13] In the adult brain, eCBs are synthesized and released ‘on demand’ from postsynaptic neuronal compartments, where they act as retrograde messengers by engaging CB₁ cannabinoid receptors (CB₁R) on presynaptic terminals^[6,8,81] to attenuate neurotransmitter release in many excitatory and inhibitory synapses. Examples of eCB-dependent synaptic plasticity include depolarization-induced suppression of inhibition and excitation, metabotropic suppression of inhibition and excitation, and some forms of long-term depression.^[8] However, recent findings establish a strikingly different molecular organization of eCB signaling networks in the developing mammalian forebrain. The following subsections summarize the temporal and spatial distribution of various components of the endocannabinoid system in developing brains with an emphasis on the developmental profile of CB₁R as it is responsible for mediating most of the effects of THC.^[1,82]

Overview of the Endocannabinoid System

Endocannabinoids are amides, esters and ethers of long-chain polyunsaturated fatty acids. There are two major families of eCBs, acyl amides and acyl esters. Anandamide (arachidonoyl ethanolamide [AEA]) and 2-arachidonoyl glycerol (2-AG), respectively, are the prototypical members of each family. The enzymes that synthesize AEA are still uncertain, with at least four routes of AEA biosynthesis proposed to occur in brain homogenates.^[83] These enzymes include N-acyl-phosphatidyl-ethanolamine-specific phospholipase D, α,β-hydrolase domain-containing 4, glycerophosphodiesterase-1 and phosphatases such as PTPN22.^[5,84,85] These biosynthetic pathways demonstrate substantial overlap and may be able to substitute for one another. AEA is hydrolyzed to arachidonic acid and ethanolamine by fatty acid amide hydrolase (FAAH).^[15,86] 2-AG is synthesized by sn-1-selective diacylglycerol lipases α and β (DAGLα and DAGLβ).^[87] Recent data from genetic ablation of these two isoforms suggest DAGLα is the major CNS form in adult mice and is important for postsynaptic release of 2-AG to transiently suppress GABA-mediated transmission at inhibitory synapses in the hippocampus.^[88] Interestingly, DAGLα mRNA level is found to be decreased in the hippocampus of epileptic human patients, while DAGLβ isoform levels were unchanged, suggesting that under pathophysiological conditions, DAGLα is the affected isoform.^[89] However, it remains to be determined which DAGL isoform is responsible for 2-AG production in humans. 2-AG is hydrolyzed to arachidonic acid and glycerol by monoglyceride lipase (MAGL)^[90] and α/β-hydrolase domain-containing serine hydrolases (ABHD6/12).^[91]

The eCBs elicit diverse central and peripheral effects by activating the cannabinoid receptors: CB₁R and CB₂R,^[92,93] G-protein coupled receptor 55 (GPR55),^[94–97] the transient receptor potential of vanilloid type-1 (TRPV1) channel, the peroxisome proliferators-activated receptor (PPAR)α^[4] and at least two, as yet molecularly uncharacterized, receptors.^[98] The signal transduction mechanisms include Gi-mediated inhibition of adenylyl cyclase and modulation of ion channels. Cannabinoid signaling often inhibits voltage-dependent Ca²⁺ channels (N and P/Q type) or activates inwardly rectifying K⁺ channels.^[99] In addition, cannabinoids stimulate various signaling pathways involved in the regulation of cell fate, such as the MAP kinase family (ERK, JNK and p38), protein kinase B and the sphingolipid pathway.^[100,101]

Ontogeny of the Endocannabinoid System

Owing to their lipophilic nature, endocannabinoids are highly unstable and difficult to quantify, hence the paucity of data on endocannabinoid levels during development. The only available data comes from older studies employing mass spectrometry, where levels of AEA and 2-AG have been shown to vary substantially in rodent brains throughout prenatal development.^[78,102] AEA is present at low concentrations in the brain at midgestation and gradually increases through the perinatal period until adult levels are reached,^[102] whereas fetal 2-AG levels gradually increase through the prenatal period, with a surge occurring at birth.^[102,103] Notably, 2-AG concentrations (2–8 nmol/g tissue) are approximately 1000-fold higher than those of AEA (3–6 pmol/g tissue) throughout brain development.^[102] However, additional studies are required to substantiate these findings.

The ontogeny of the metabolizing enzymes and receptors of the endocannabinoid system has not been extensively characterized. Nevertheless, current data suggest that the endocannabinoid system exists from the earliest stage of pregnancy, in the preimplantation embryo and uterus,^[104] placenta^[105] and in the developing fetal brain,^[78] presenting multiple points of vulnerability to exogenous cannabis or cannabimimetic drug exposure throughout gestation. In the mouse, stimulation of CB₁R arrests the development of two-cell embryos into blastocytsts in culture.^[104] AEA is present in the pregnant uterus at relatively high levels (5–10 nmol/g tissue) that fluctuate with changes in the pregnancy status, with higher levels associated with a nonreceptive uterine environment.^[104] Indeed, low levels of the AEA-degrading enzyme FAAH and high levels of CB₁R expression in human placenta are associated with spontaneous miscarriage.^[106] Studies characterizing the endocannabinoid system in early human pregnancy (weeks 7–12 gestation) demonstrated that CB₂R and FAAH are expressed in relatively constant levels in trophoblasts in early gestation, but their cellular distribution changed from syncytiotrophoblast to the mesenchymal core of the villus.^[105]

In the developing mouse brain, CB₁R are expressed as early as day 11 postgestation (comparable with 5–6-week old human embryos), with gradually increasing levels of both mRNA and receptor density (revealed by radiolabeled agonist binding) throughout the prenatal period in the whole brain.^[78] CB₁R are abundantly expressed in corticolimbic areas of the fetal rodent brain.^[78] Pharmacological studies of the ability of the CB₁R agonist, WIN55212-2, to stimulate [³⁵S]GTPγS binding indicate that CB₁Rs are functionally active from early stages of development.^[107] In human fetal brains, CB₁Rs were detected at week 14 of gestation, with preferential expression in the cerebral cortex, hippocampus, caudate nucleus, putamen and cerebellar cortex. By week 20, intense expression is evident in CA2–CA3 of hippocampus and in the basal nuclear group of the amygdala.^[107,108]

More recently, several specific antibodies against different endocannabinoid system components have become available, making it possible to examine the distribution of specific enzymes at the light- and electron-microscopic level. In particular, immunohistological studies using specific antibodies have mapped the temporal and spatial distribution of CB₁R, DAGLα/β and MAGL during neural development in mice.^{[103,109,110]} Similar to ligand binding and mRNA expression studies, CB₁R immunoreactivity can be detected by embryonic day (E)12.5, and is localized to reelin-expressing Cajal-Retzius cells and newly differentiated postmitotic glutamatergic neurons of the mouse telencephalon,^[111] and to the subpial area of the ganglionic eminence and marginal zone of the neocortex.^[112] From E13.5 to birth, abundant CB₁R immunoreactivity is detected in several long-range axonal tracts including corticofugal tracts such as corticothalamic (Figure 1) and corticospinal tracts.^[109,111] On the subcellular level, CB₁R is localized to somato-dendritic endosomes at E12.5 and then to developing axons of glutamatergic neurons at E13.5 and after this time.^[111] The ‘atypical’ pattern of CB₁R expression in long-range glutamatergic axons disappears after birth.^[110,111] During late gestation (E17–18), CB₁R immunoreactivity becomes detectable in axons and axonal growth cones of cholecystokinin (CCK)-positive GABAergic interneurons.^[113,114] The origin of these CB₁R containing interneurons has been traced to the caudal ganglionic eminence and pallial–subpallial boundary at E11–12. These cells undergo a complex long-distance migration, first radially to the marginal zone, then tangentially in the lateral-to-medial direction within the dorsal telencephalon, eventually reaching their final destination in the cortex, hippocampus and dentate gyrus where they migrate radially and differentiate into CB₁/CCK⁺ or CB₁/reelin/calretinin⁺ GABAergic interneurons.^[112]

Figure 1.

Enlarge

Expression Pattern of CB₁R, DAGLβ and MAGL in Developing Thalamocortical Axonal Tracts. (A) Embryonic brain slice highlighting the path of developing thalamocortical axons (green lines) and corticothalamic axons (blue lines) at E14.5. A thalamocortical axon reporter mice line (TCA^mGFP) was generated by crossing a Cre-reporter line containing a floxed ‘stop transcription’ sequence in front of membrane-anchored green fluorescent protein (mGFP) followed by an IRES-NLS-lacZ gene inserted into exon 2 of the Tau locus with RORα-Cre mice. (B) Thalamocortical axons extending toward the cortex are GFP labeled in TCA^mGFP reporter mice. (C) Using the TCA^mGFP mice, CB₁R is demonstrated to be localized to corticothalamic, but not thalamocortical, axons during brain development. (D–I) DAGLβ is localized mainly to GFP-labeled thalamocortical axons (dashed arrow in F), while MAGL is localized to both CB₁R-containing corticothalamic (arrow in I) and GFP-labeled thalamocortical axons (dashed arrow in I). (F, I) higher magnification of squared areas in (E) and (H). CB₁R: CB₁ cannabinoid receptor; cp: Cortical plate; DAGLβ: Diacylglycerol lipase β; ge: Ganglionic eminence; GFP: Green fluorescent protein; hc: Hippocampus; lv: Lateral ventricle; MAGL: Monoglyceride lipase; RORα: retinoic acid-receptor-related orphan receptor a; st: Striatum; TCA: Thalamocortical axon; th: Thalamus.

The overall protein levels of CB₁Rs are relatively constant throughout forebrain development, while DAGLα protein levels peak at E14.5/E16.5 and then dramatically decrease in neonates, furthermore MAGL transiently decreases around E18.5 (Figure 2).^[103] Similar to CB₁R, the distribution of DAGLα/β and MAGL are localized to long-range glutamatergic axons in the prenatal period (Figure 1).^[103,110] Interestingly, after E16.5, MAGL expression undergoes a dramatic change from cortical plate and long-range axon tracts to a restricted expression in perisomatic segments and proximal dendrites both in the late-gestational brain and at birth.^[103] This coincides with the surge in cortical and hippocampal 2-AG concentrations, suggesting that MAGL plays an essential role in determining 2-AG availability in the developing brain.

Figure 2.

Enlarge

Temporal Changes in the Expression of Endocannabinoid System Components During Development. DAGLα and MAGL are expressed starting at midgestation. Expression levels of DAGLα decrease from E18.5 onwards, while there is a transient decrease in MAGL expression levels around birth. CB₁R is expressed at relatively constant levels throughout brain development and, prenatally, is primarily localized to the corticofugal tract. The expression pattern undergoes a dramatic change after birth, with the adult-like distribution pattern in the cortex is apparent after P1. CB₁R: CB₁ cannabinoid receptor; DAGLα: Diacylglycerol lipase α; MAGL: Monoglyceride lipase; P1: Postnatal day 1.

Together, these expression studies indicate that components of the endocannabinoid system are expressed early in life and are positioned to modulate neuronal generation, differentiation, migration and neural circuit wiring during development.

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Page 3 of 7

Involvement of Endocannabinoid Signaling in Neural Development

CME Information

Abstract and Introduction
Adverse Effect of Prenatal Exposure to Marijuana
Endocannabinoid System During Neural Development
Involvement of Endocannabinoid Signaling in Neural Development
Conclusion
Future Perspective
Executive Summary

References

Table 1.

CME

Lasting Impacts of Prenatal Cannabis Exposure and the Role of Endogenous Cannabinoids in the Developing Brain

Target Audience and Goal Statement

Disclosures

Author(s)

Chia-Shan Wu, PhD

Christopher P. Jew

Hui-Chen Lu, PhD

Editor(s)

Elisa Manzotti

CME Author(s)

Laurie Barclay, MD

CME Reviewer(s)

Nafeez Zawahir, MD

Sarah Fleischman

Accreditation Statements

For Physicians

Instructions for Participation and Credit

Lasting Impacts of Prenatal Cannabis Exposure and the Role of Endogenous Cannabinoids in the Developing Brain: Endocannabinoid System During Neural Development

Endocannabinoid System During Neural Development

Overview of the Endocannabinoid System

Ontogeny of the Endocannabinoid System

Figure 1.

Figure 2.

Table of Contents

Table 1.

References

Faculty and Disclosures

Author(s)

Chia-Shan Wu, PhD

Christopher P. Jew

Hui-Chen Lu, PhD

Editor(s)

Elisa Manzotti

CME Author(s)

Laurie Barclay, MD

CME Reviewer(s)

Nafeez Zawahir, MD

Sarah Fleischman

CME

Lasting Impacts of Prenatal Cannabis Exposure and the Role of Endogenous Cannabinoids in the Developing Brain

Target Audience and Goal Statement

Disclosures

Author(s)

Chia-Shan Wu, PhD

Christopher P. Jew

Hui-Chen Lu, PhD

Editor(s)

Elisa Manzotti

CME Author(s)

Laurie Barclay, MD

CME Reviewer(s)

Nafeez Zawahir, MD

Sarah Fleischman

Accreditation Statements

For Physicians

Instructions for Participation and Credit

Lasting Impacts of Prenatal Cannabis Exposure and the Role of Endogenous Cannabinoids in the Developing Brain: Endocannabinoid System During Neural Development

Endocannabinoid System During Neural Development

Overview of the Endocannabinoid System

Ontogeny of the Endocannabinoid System

Figure 1.

Figure 2.

Table of Contents