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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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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.

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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).


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    Editorial Director, Future Science Group, London, United Kingdom


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    Freelance writer and reviewer, Medscape, LLC


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    CME Clinical Director, Medscape, LLC


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


Involvement of Endocannabinoid Signaling in Neural Development

During embryogenesis, the cerebral cortex develops from the rostral part of the neural tube designated the telencephalic pallium. In rodents, pyramidal neurons originate from the cortical ventricular zone (VZ) whereas interneurons are generated in the ganglionic eminence of the basal telencephalon.[115,116] Neurons generated early in the VZ migrate radially towards the surface of the cerebral vesicles to form the primordial plexiform layer or preplate (Figure 3). Neurons generated later migrate to form a layer within the preplate, the so-called cortical plate (CP), thus splitting it into a superficial marginal zone (layer I) and a deep subplate. The neurons of the CP assemble into layers II–VI in an ‘inside-out’ sequence: the deepest cellular layers are assembled first and those closest to the surface last (Figure 3). The nonpyramidal cells originate predominantly in the medial ganglionic eminence and migrate tangentially following parallel migratory streams, in the subventricular zone (SVZ), intermediate zone and marginal zone, and progressively enter the developing CP. Accumulating evidence indicates that eCBs regulate several aspects of neural development, including neurogenesis, neuronal migration, neurite outgrowth and axonal pathfinding. Much of the insights came from studies in genetic ablation of CB1R and FAAH (increasing the endogenous levels of AEA) in mice and from pharmacological manipulations (CB1R blockade and inhibition of FAAH). Recent findings on the involvement of AEA- and 2-AG-mediated signaling through CB1R in various aspects of neural development will be summarized in the following section.

Figure 3.


Generation of Neuronal Diversity in Cortical Formation. The earliest born neurons form the preplate (PP), which is later split into the superficial marginal zone (MZ) and the deeper layer subplate (SP). Neuroprogenitors residing in the VZ and SVZ in mice produce pyramidal projection neurons in an ‘inside-out’ fashion, migrating radially towards the surface to populate the cortical plate (CP). The CP develops inbetween the MZ and SP and gives rise to the multilayered pattern, while the progenitor zones progressively reduce in size. The relationship between different populations of cells is depicted at E16.5. Radial glial cells divide symmetrically in the VZ to produce additional radial glial cells. A fraction of these depart from the VZ and migrate radially towards the pial surface, giving rise to different types of projection neurons. Interneurons migrate tangentially from the ganglionic eminence and enter the neocortex around E17.

Cell Proliferation, Neurogenesis & Oligodendrogliogenesis

During mammalian embryogenesis, the generation of the CNS relies on a finely regulated balance of neuroprogenitor proliferation, differentiation and survival that is controlled by a number of extracellular signaling cues.[117] In the adult brain, identification of neuroprogenitor cells in the subgranular zone supports the existence of hippocampal neurogenesis, which is implicated in several brain functions including learning and memory, depression and brain repair.[118–120]

Several lines of evidence support a role for eCBs in neural progenitor proliferation.[24,121–123] The expression of CB1R, FAAH, DAGL and MAGL in VZ/SVZ neuroprogenitor cells has been reported.[103,109,121,122,124] CB1R activation promotes progenitor cell proliferation, while genetic deletion of CB1R decreases cortical progenitor proliferation in VZ/SVZ in the embryonic brain.[121] By contrast, deletion of FAAH increases neural progenitor proliferation in the embryonic brain[121] and inhibition of FAAH by the inhibitor URB597 increased VZ/SVZ progenitor proliferation in embryonic brain slices.[109] Thus, the reciprocal consequences of blockading CB1R and increasing AEA suggest that local AEA levels acting through CB1R, modulate neural progenitor proliferation in the embryonic brain.

The effect of CB1R activation on neurogenesis has been examined in early postnatal and adult brains and in neurospheres, with conflicting results (reviewed in [24,125]). It should be noted that the net effect of cannabinoids on neurogenesis during postnatal development, in adults and in culture, is probably influenced by the status of nervous system maturation, where inherent characteristics of the neural progenitors may differ. Increased proliferation of neural progenitors is observed in the hippocampus of adult FAAH knockout mice,[121] consistent with the observation of decreased neuroprogenitor proliferation in the hippocampus of both early postnatal and adult CB1R knockout mice.[122] Furthermore, using a kainate-induced excitotoxicity model, excitotoxicity-induced hippocampal neural progenitor proliferation is abrogated in CB1R knockout mice and in wildtype mice treated with the CB1R antagonist, SR141716.[126] HU210, a synthetic CB1R agonist, increases adult hippocampal neurogenesis and exerts anxiolytic and antidepressant effects in rats,[127] while the synthetic CB1R/CB2R agonist, WIN55212-2, partially restores hippocampal neurogenesis in the aged rat brain.[128] By contrast, methanandamide, a non-hydrolyzable AEA analog, significantly decreases neurogenesis in the adult hippocampus of rats.[129] Moreover, AEA decreases the expression of a mature neuronal marker and inhibits neurite outgrowth of cortical neural progenitors in vitro, while the CB1R antagonist SR141716 increases the rates of neuronal differentiation of neural progenitors.[129] The same group later reported that activation of CB1R on neural progenitors promotes the differentiation of the latter into glia cells.[122] Together, these studies suggest an endogenous AEA tone that actively modulates neural progenitor differentiation through the CB1R. Furthermore, a role for 2-AG in adult neurogenesis has been demonstrated.[88,124] A DAGL antagonist inhibits the proliferation of cultured neural stem cells, and the proliferation of progenitor cells in young adult mice, and adult neurogenesis in the SVZ and hippocampus, is impaired in both DAGLα and DAGLβ knockout mice.[88,124] Interestingly, a sex difference in cell proliferation in developing rat amygdala, mediated by 2-AG, has recently been reported.[130] Newborn females had higher rates of cell proliferation than males, which were abrogated by inhibition of MAGL in females.[130] The impact of prenatal THC exposure on neurogenesis remains to be examined.

Cannabinoid signaling has also been suggested to participate in postnatal myelination processes.[131–133] Postnatal myelination involves radial migration of astrocyte-like (type B) precursor cells from the SVZ to the overlying white matter, where these cells are differentiated into astrocytes and oligodendrocytes (reviewed in [134,135]). CB1R is expressed in radial glia-like cells and B-like type cells, while CB2R is expressed in a subpopulation of SVZ cells containing the polysialylated neural cell adhesion molecule.[122,132] The 2-AG synthesizing enzymes, DAGLα and β, and degrading enzyme, MAGL, are also found in oligodendrocytes in various differentiation stages.[136] Agonist stimulation of CB1R and CB2R increases the expression of myelin basic protein in subcortical white matter.[132] Furthermore, cannabinoid signaling has been suggested to participate in adult oligodendrogenesis after toxic or autoimmune demyelinating lesions, when precursor cells are recruited from the SVZ towards the injured area and give rise to oligodendrocytes.[14,131,133]

Neuronal Migration

Following mitosis, newborn pyramidal progenitor cells in the VZ/SVZ migrate radially into the cortical plate and populate distinct cortical layers.[116] Proper regulation of this migration is important for appropriate cortical patterning. Genetic deletion or blockade of CB1R leads to delayed migration of cortical neurons. In cultured brain slices, elevating AEA levels through FAAH gene removal or pharmacological blockade enhances the migration of newly borne postmitotic neurons into the cortical plate.[109] In contrast to pyramidal neurons, cortical inhibitory interneurons migrate tangentially from the ganglionic eminences to the cortical plate. CB1R signaling is also implicated in the regulation of the long-distance migration CCK-positive interneurons.[112,113] Stimulation with AEA and WIN55,212–2, in cooperation with brain-derived neurotrophic factor, a major prodifferentiating neurotrophin for this cell class, induces the long-distance migration of GABA-containing interneurons in the ganglionic eminence.[137] Prenatal THC has been demonstrated to increase the density of CCK-expressing interneurons in the rat hippocampus in vivo.[137] Thus, eCBs modulate both migration of cortical principal neurons and certain classes of interneurons. Increases in local AEA concentration probably affect the proper placement of pyramidal neurons and/or CCK+ basket cells. Furthermore, DAGLα and MAGL have been demonstrated to be expressed in mouse migratory neuroblasts that travel along the rostral migratory stream to populate the olfactory bulb, and DAGL inhibition results in decreased migration in scratch wound assays and in explant cultures, suggesting a role for 2-AG in regulating cell migration following adult neurogenesis.[138]

Axon Pathfinding & Fasciculation

Once pyramidal neurons reach their final destination, they must project their axons to connect to their postsynaptic partners. Axon tracts navigate along stereotyped pathways, and fasciculate and defasciculate in distinctive domains along their path.[139,140] The formation of precise neural circuits requires orchestrated interactions between axon tracts, and between the navigating axonal growth cones and the environmental cues at distinctive locations. Genetic deletion of CB1R or prenatal CB1R pharmacological blockade in mice led to increases in the number of axons with aberrant trajectories in the corpus callosum and to abnormal fasciculation of long-range axons.[109,110] Similarly, knockdown of CB1R in zebrafish leads to abnormal axonal fasciculation.[141]

Thalamic axons projecting into the cortex provide the majority of cortical sensory input, while reciprocal innervations from the cortex to the thalamus send critical feed-back to modulate the thalamic responses required to perform the complex information gathering and integration that underlie sensory processing.[142–144] A ‘handshake hypothesis’, which proposes that thalamocortical axons and corticothalamic axons interact and serve as scaffolds to guide each other to their final destinations, has been postulated.[145–147] Recent data suggest that the endocannabinoid system may be modulating this handshake interaction.[110] When thalamic and cortical axons meet and intermingle in the basal telencephalon during development, CB1R is localized to corticothalamic axons, while the 2-AG synthesizing enzymes, DAGLα/β and degrading enzyme MAGL, are present in both thalamocortical and corticothalamic axons (Figure 1).[103,110] Thus, 2-AG could be produced in both axonal tracts to act in both an autocrine and paracrine fashion, while MAGL may serve to restrict 2-AG availability. Interestingly, genetic deletion of CB1R in cortical neurons leads to aberrant fasciculation in both corticothalamic and thalamocortical axons despite normal target recognition,[110] suggesting that 2-AG-mediated signaling at CB1R may be modulating the fasciculation process during the handshake interaction between cortical and thalamic axons.

More recently, a role for CB1R in axonal guidance has been demonstrated in the retinal system.[148] Eye-specific segregation of retinal projections in the dorsal lateral geniculate nucleus of thalamus is impaired in CB1R knockout mice. Furthermore, CB1R appears to act in concert with the adhesion molecule deleted in colorectal cancer (DCC; a receptor for axonal guidance molecule, netrin-1) to influence axonal growth cone behavior.[148]

At the subcellular level, a recent morphometric study provided evidence for a microgradient of 2-AG in elongating axons.[106] While MAGL is coexpressed with both CB1R and DAGLα in cultured cortical neurons, MAGL is differentially recruited to distinct subcellular domains, particularly in the consolidated axon shaft. In this paradigm, CB1Rs are maintained in a state of inactivity by the absence of 2-AG (owing to presence of MAGL) while undergoing vesicular transport along the consolidated axon. The absence of MAGL at the growth cones lifts the restriction on CB1R signaling and promotes cell-autonomous axonal growth. This scheme may serve to prevent ectopic branching and axon guidance errors, since in vitro study in pyramidal cells found that CB1R activation leads to increased neurite branching.[112]

These findings firmly demonstrate multiple roles for the endocannabinoid system in brain development. A detailed knowledge of eCB signaling is important in understanding the long-term consequences of alterations in CB1R activity during neurodevelopment, a potential etiology for the mental health disorders linked to prenatal or adolescent cannabis use, or following therapeutic manipulations of the endocannabinoid system.