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Table 1.  

right brain regions – medial PFC, DLPFC and ventrolateral PFC
Age† Cohort‡ Category Results/outcomes Exposure
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
Neonatal OPPS Neurobehavior Increased tremors, exaggerated startles and diminished responsiveness to light [46]
Neonatal MHPCD Growth Decreased body length ≥1 J/day, first
Neonatal Growth
No effect on birthweight, length or gestational age
No effect

Neonatal VIPS Growth No effect on birthweight, preterm delivery or abruptio placentae [35]
Neonatal Growth
No effect on birthweight, length or gestational age
More irritable, less responsive to calming, increased jitters and startles

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]
8 mo MHPCD Growth No effect [49]
9 mo MHPCD Mental/motor skills Delayed mental development ≥1 J/day, third
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
19 mo MHPCD Mental/motor skills No effect [26]
2 y OPPS Mental/motor skills No effect [55]
3 y MHPCD Intelligence
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
3 y MHPCD Sleep and arousal Lowered sleep efficiency, more nocturnal arousals and more awake time after sleep onset [153]
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
No effect [155]
6 y MHPCD Growth No effect [156]
6 y OPPS Memory
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
Lower overall composite score
Lower verbal reasoning, quantitative reasoning and short-term memory
≥1 J/day,
first/second Trim
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
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
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
10 y MHPCD Depression Increased levels of depressive symptoms >0.89 J/day,
first/third Trim
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
10 y

14 y
MHPCD Behavior and
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
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
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
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



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).


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
  • Valid for credit through: 7/1/2012, 11:59 PM EST
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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.

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


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  • Chia-Shan Wu, PhD

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


    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


    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


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


  • Elisa Manzotti

    Editorial Director, Future Science Group, London, United Kingdom


    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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  • Nafeez Zawahir, MD

    CME Clinical Director, Medscape, LLC


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    CME Program Manager, Medscape, LLC


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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

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.


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 (TCAmGFP) 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 TCAmGFP reporter mice. (C) Using the TCAmGFP 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.


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.