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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.

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

  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.

CME Author(s)

  • 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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  • Sarah Fleischman

    CME Program Manager, Medscape, LLC


    Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

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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, PhDFaculty and Disclosures

CME Released: 7/1/2011

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


Abstract and Introduction


Cannabis is the most commonly used illicit substance among pregnant women. Human epidemiological and animal studies have found that prenatal cannabis exposure influences brain development and can have long-lasting impacts on cognitive functions. Exploration of the therapeutic potential of cannabis-based medicines and synthetic cannabinoid compounds has given us much insight into the physiological roles of endogenous ligands (endocannabinoids) and their receptors. In this article, we examine human longitudinal cohort studies that document the long-term influence of prenatal exposure to cannabis, followed by an overview of the molecular composition of the endocannabinoid system and the temporal and spatial changes in their expression during brain development. How endocannabinoid signaling modulates fundamental developmental processes such as cell proliferation, neurogenesis, migration and axonal pathfinding are also summarized.


Cannabis is the world’s third most popular recreational drug, after alcohol and tobacco.[201] The hallmarks of its effects are euphoria and relaxation, perceptual alterations, time distortion, appetite inducement and the intensification of ordinary sensory experiences.[1] Cannabis preparations are largely derived from the female plant of Cannabis sativa, and consist of approximately 60 plant-derived cannabinoid compounds (phytocannabinoids), with Δ9-tetrahydrocannabinol (THC) being the predominant psychoactive constituent.[2] Efforts aimed at understanding how THC produces its psychoactive effects have led to the discovery of the endocannabinoid system.[3]

The endocannabinoid system is comprised of endogenous cannabinoids (endocannabinoids [eCBs]), the metabolic enzymes responsible for the formation and degradation of eCBs, and the cannabinoid receptors and their interacting proteins.[4,5] eCB signaling is involved in a myriad of physiological processes including retrograde signaling and modulation of synaptic function in the CNS, and analgesic and metabolic effects on lipid profile and glucose homeostasis in the periphery.[6–11] Indeed, several therapeutic effects have been ascribed to compounds targeting the endocannabinoid system, including treatment of pain, affective and neurodegenerative disorders, gastrointestinal inflammation, obesity and related metabolic dysfunctions, cardiovascular conditions and liver diseases.[12,13] Synthetic THC (dronabinol) is approved in the USA to alleviate the emesis and nausea associated with cancer and chemotherapy, and weight loss associated with HIV infection. Clinical trials are underway to determine whether cannabis-based compounds are effective in the treatment of multiple sclerosis[14] and neuropathic pain.[15] Sativex, a pharmaceutical preparation containing the psychoactive THC with the nonpsychotropic cannabidiol in approximately a 1:1 weight ratio, was approved in Canada for the treatment of neuropathic pain associated with multiple sclerosis, and in England for the spasticity associated with multiple sclerosis.[16] Furthermore, several forms of pharmacological manipulation of the endocannabinoid system, including synthetic cannabinoid receptor agonists and antagonists and inhibitors of endocannabinoid degradation are undergoing clinical development.[17–20]

The increasing popularity of cannabis consumption among young people between 15 and 30 years of age, the critical period for adolescent brain development, has raised concerns over the health consequences of cannabis use. In addition, cannabis is the most commonly abused illicit drug in pregnant women in Western societies.[202] Given the lipophilic nature of THC, it is estimated that one-third of THC in the plasma crosses the fetoplacental barrier,[21] and is secreted through the breast milk.[22] Given that the THC content of confiscated cannabis samples has increased substantially over the past 20 years,[23] fetuses of cannabis-using mothers could be exposed to significant amounts of THC during the perinatal period. Therefore, cannabis abuse is potentially deleterious to the children of cannabis-using mothers through abnormal brain development owing to exogenous cannabis exposure during the perinatal period. This article will focus on the neurobehavioral consequences of prenatal cannabis exposure in humans.

A central role for eCB signaling in brain development is now emerging.[7,24,25] Perinatal and adolescent cannabis exposure may disrupt the precise temporal and spatial control of eCB signaling at critical stages of neural development, leading to detrimental effects on later nervous system functioning. Indeed, longitudinal studies in humans with prenatal cannabis exposure demonstrated exaggerated startle response and poor habituation to novel stimuli in infants, and hyperactivity, inattention and impaired executive function in adolescents.[26–29] Many of these behavioral effects have also been modeled in animal studies.[30] Furthermore, possible teratogenic effects of endocannabinoid system-based therapies in pregnant women and long-term exposure to eCB signaling-modifying agents such as organophosphate pesticides need to be taken into consideration.

This article aims to summarize the existing literature on the behavioral consequences of prenatal exposure to the phytocannabinoid THC, summarizing key findings from epidemiological studies in humans. Experimental studies in rodents have been reviewed extensively elsewhere and will be only briefly discussed here.[29–32] The molecular composition of the endocannabinoid system and their temporal and spatial distributions in embryonic brain in humans and rodents are also summarized. Finally, experimental evidence demonstrating how eCB signaling in this molecular framework affects specific events in developing neural circuits is discussed.