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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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).

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

Disclosures

Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

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

Start Activity

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

Disclosures

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

Disclosures

Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

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Abstract and Introduction

Abstract

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.

Introduction

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.

Page 1 of 7

Adverse Effect of Prenatal Exposure to Marijuana

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

References

Disclaimer

The material presented here does not necessarily reflect the views of Medscape, LLC, or companies that support educational programming on www.medscape.org. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity.

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

Abstract and Introduction

Abstract

Introduction

Table of Contents