Cannabinoid Legalization Unintentionally Impacts Pediatric Neurodevelopment

Cure America of Anosognosia

Cannabinoid Legalization Unintentionally Impacts Pediatric Neurodevelopment

Contributor: Amelia Howard, M.S.- Azusa Pacific University, Department of Clinical Psychology, Psy.D. Program (Doctoral Student)

Overview:
Cannabinoids or delta-9-tetrahydrocannabinol (Δ9-THC) is commonly referred to as Marijuana [1]. There are over 180 million users worldwide and 22.2 million users in the US [1-2]. A comprehensive review of published studies, case series, and case reports revealed that 3,582 children, age 12 years or less, unintentionally ingested cannabis [2]. Ingestion may occur through prenatal exposure, childhood exposures (i.e., passive smoke, edible products, or unsecured joints), and adolescent use [2-3]. Whether through direct or indirect ingestion, marijuana affects seemingly all facets of childhood neurodevelopment [3].

As of November 2016, 28 states and the District of Columbia have approved legislation legalizing medical marijuana [4-5]. Among these states, nine allow marijuana use for recreational purposes [2, 5]. The legalization of cannabinoid use varies from state to state. For example, in California, cannabis legislation (Proposition 63) has recognized the potency and availability of products; which asserts authority to impose limits on potency levels [6]. New York and Minnesota allow cannabis use with restrictions on smoking Δ9-THC [6].Colorado generated $2.39 billion in 2015 from legal cannabis salesNot to mention in 2002 and 2014, the pervasiveness of cannabinoid use with no risk increased from 5.6% to 15.1% while the perceived concerns of cannabis use decreased from 50.4% to 33.3% [4]. However, marijuana is illegal under federal law and remains classified as a Schedule I drug because of its potential for adverse repercussions such as the high potential for abuse, severe psychological and physical dependence [4-6]. In like manner, synthetic cannabinoids have been available since the early 2000s but were made illegal in 2012 under the Synthetic Drug Abuse Act [7].

Despite the popularity of cannabis and approved state legalization-marijuana has been linked to several short and long-term consequences among the pediatric population [4]. For instance, risk factors include impaired working and episodic memory, decreased motor coordination, diminished executive functioning, difficulty with abstract reasoning, as well as acute paranoia or psychosis, risk of chronic psychotic disorders, altered brain development, poor educational and vocational outcomes, psychomotor impairments, and the development of cannabis addiction [6,8-9]. Children may exhibit chest pain, palpitations, and electrocardiographic changes consistent with myocardial ischemia after exposure to Δ9-THC or smoking K2 (one of the most widely used synthetic cannabinoids) [8]. Moreover, in a documented case, an adolescent user was directly linked to an altered mental state parallel to a psychotic episode [7]. In another example, an infant (indirect exposure) was found to be somnolent, agitated, with an altered mental state, tachypnea (62 breaths/min), and tachycardia (187 beats/min) [7]. Hence, it is essential to understand the impact on this population given their neurobiological and psychosocial vulnerabilities [4, 10].

The primary psychoactive component of cannabis are mediated by the cannabinoid type 1 receptor (CB1) via activation of the mesolimbic dopamine system (i.e., the brain’s reward system) [6]. CB1 receptors are widely distributed in fetal and neonatal brains [1, 11]. A disruption in CB1 receptor signaling can lead to the onset of cognitive deficits and anatomical abnormalities found in the prefrontal cortex (PFC) and hippocampus regions [1]. Long-term use is correlated with a dose-dependent decrease in dopamine synthesis capacity in the striatum and modulation of genes connected with schizophrenia [8-9]. Animal model studies have proved that exposure to Δ9-THS in neonatal rats induces cell death in the cerebral cortex and leads to dysregulation of emotional processes, a decrease in social behavior, and reduced coping strategies [12]. What’s more, clinical trials and literature substantiate the claim that cannabinoids may lead to impaired brain maturation [12]. Brain maturation may alter phenotypes later in life producing similar traits to psychotic or depressive-like behaviors [12].Thus, marijuana use increases the risk of cognitive deficits, structural alterations, and psychosis among individuals exposed in their formative years [3, 8, 10].

Within the pediatric population, the exposure of Δ9-THC may also restrict neurodevelopment. Prenatal cannabis use is linked to aberrant behaviors in newborns, impaired inhibitory control, delinquency, and increased risk of drug abuse later in life [4, 12-13]. Fetal exposure increases the level of the maternal cytokine (IL-8) that is related to significant decreases in left entorhinal cortex volumes (similar to individuals with schizophrenia) [10]. Additionally, cannabis-exposed children are found to have thicker frontal cortices, a thicker superior frontal area of the left hemisphere, and a wider frontal lobe in the right hemisphere [11]. A possible interpretation for the thicker prefrontal cortex is altered neurodevelopmental maturation [11]. The emotional immaturity and underdeveloped cortices of adolescent make them particularly susceptible to deceptive marketing targets (i.e., marijuana posing little risk) [4, 6]. Conversely, in a cross-sectional study, few providers considered themselves entirely knowledgeable about the health risks associated with marijuana [5]. Epidemiological studies provide substantial evidence to warrant a public health message that the unintentional exposure of cannabis among the pediatric population increases the risk of psychotic disorders and neurodevelopmental deficits [3, 8]. In conclusion, the inconsistencies between public perceptions, legislation, and the knowledge (or lack thereof) of medical professionals compared to the substantiated risks are alarming. Accordingly, more research and training is needed to provide clarity of the cannabinoid effects on children’s cognitive and neurodevelopment.

Highlighted Abstract:
Chronic Cannabinoid Exposure During Adolescence Leads to Long-Term Structural and Functional Changes in the Prefrontal Cortex
Abstract (taken directly from ncbi.nlm.nih.gov)
In many species, adolescence is a critical phase in which the endocannabinoid system can regulate the maturation of important neuronal networks that underlie cognitive function. Therefore, adolescents may be more susceptible to the neural consequences of chronic cannabis abuse. We reported previously that chronically exposing adolescent rats to the synthetic cannabinoid agonist CP55,940 leads to impaired performances in adulthood i.e. long-lasting deficits in both visual and spatial short-term working memories. Here, we examined the synaptic structure and function in the prefrontal cortex (PFC) of adult rats that were chronically treated with CP55,940 during adolescence. We found that chronic cannabinoid exposure during adolescence induces long-lasting changes, including (1) significantly altered dendritic arborization of pyramidal neurons in layer II/III in the medial PFC (2) impaired hippocampal input-induced synaptic plasticity in the PFC and (3) significant changes in the expression of PSD95 (but not synaptophysin or VGLUT3) in the medial PFC. These changes in synaptic structure and function in the PFC provide key insight into the structural, functional and molecular underpinnings of long-term cognitive deficits induced by adolescent cannabinoid exposure. They suggest that cannabinoids may impede the structural maturation of neuronal circuits in the PFC, thus leading to impaired cognitive function in adulthood.

Journal of European Neuropsychopharmacology Article Site Link with PDF Download:
Chronic cannabinoid exposure during adolescence leads to long-term structural and functional changes in the prefrontal cortex

PDF Download only:
Chronic cannabinoid exposure during adolescence leads to long-term structural and functional changes in the prefrontal cortex

Citation:
Eur Neuropsychopharmacol. 2016 Jan;26(1):55-64. doi: 10.1016/j.euroneuro.2015.11.005. Epub 2015 Dec 3.

Other Media and Resources

Website: National Institute of Drug Abuse-Medical Marijuana
NIH Website

Website: National Conference of State Legislatures (NCSL) -Marijuana Laws
State Laws

Documentary: How the Brain Works and Responds to Marijuana (THC).
Credit: NIDA
How the Brain Works and Responds to THC

Lecture Abstract (Taken directly from NIDA):
Cannabis contains at least 60 types of cannabinoids, chemical compounds that act on receptors throughout our brain. THC, or Tetrahydrocannabinol, is the chemical responsible for most of marijuana’s effects, including the euphoric high. THC resembles another cannabinoid naturally produced in our brains, anandamide, which regulates our mood, sleep, memory, and appetite.

Podcast: Marijuana’s Health Effects-Top Scientists Weigh In
Marijuana’s Health Effects: Top Scientists Weigh In

Speakers (Titles taken directly from npr.org):

Lecture Abstract (Taken directly from npr.org):
So far, more than half of all U.S. states have legalized marijuana for medical use, and eight (plus the District of Columbia) have legalized the drug for recreational use. Varieties of cannabis available today are more potent than ever and come in many forms, including oils and leaves that can be vaped, and lots of edibles, from brownies and cookies to candies — even cannabis gummy bears.

A report published Thursday by the National Academies of Sciences, Engineering and Medicine analyzed more than 10,000 studies to see what could conclusively be said about the health effects of all this marijuana. And despite the drug’s increasing popularity — a recent survey suggests about 22 million American adults have used the drug in the last month — conclusive evidence about its positive and negative medical effects is hard to come by, the researchers say.

“The adolescent brain is very sensitive to these kinds of substances,” McCormick says. “So they continue to use it — and may use it in increasing amounts — and are at risk for developing problematic cannabis use.”
Newspaper: Pregnant Women Turn to Marijuana-Possibly Harming Infants
NYT: Pregnant Women Turn to Marijuana- Possibly Harming Infants

Speakers (Titles taken directly from nytimes.com):

  • Dr. Torri Metz, an obstetrician at Denver Health Medical Center who specializes in high-risk pregnancies.
  • Dr. Lauren M. Jansson, the director of pediatrics at the Center for Addiction and Pregnancy at the Johns Hopkins University School of Medicine.

Lecture Abstract (Taken directly from nytimes.com):
Often pregnant women presume that cannabis has no consequences for developing infants. But preliminary research suggests otherwise: Marijuana’s main psychoactive ingredient — tetrahydrocannabinol, or THC — can cross the placenta to reach the fetus, experts say, potentially harming brain development, cognition and birth weight. THC can also be present in breast milk.

In the federal survey, published online in December, almost 4 percent of mothers-to-be said they had used marijuana in the past month in 2014, compared with 2.4 percent in 2002. (By comparison, roughly 9 percent of pregnant women ages 18 to 44acknowledge using alcohol in the previous month.)

Several studies have found changes in the brains of fetuses, 18 to 22 weeks old, linked to maternal marijuana use. In male fetuses who were exposed, for instance, researchers have noted abnormal function of the amygdala, the part of the brain that regulates emotion.

In a statement, C.D.C. officials expressed concern about memory and attention problems among children exposed to THC in utero.

Further Reading:

Abnormal White Matter Integrity in Synthetic Cannabinoid Users [Abnormal white matter integrity in synthetic cannabinoid users. European Neuropsychopharmacology, 261818-1825. doi:10.1016/j.euroneuro.2016.08.015].

An Introduction to the Endogenous Cannabinoid System [Lu, H., & Mackie, K. (2016). An introduction to the endogenous cannabinoid system. Biological Psychiatry, 79(7), 516-525. doi:10.1016/j.biopsych.2015.07.028]

Increasing Legalization [Thomas, A. A., Moser, E., Dickerson-Young, T., & Mazor, S. (2017). A review of pediatric marijuana exposure in the setting of increasing legalization. Clinical Pediatric Emergency Medicine, 18(Toxicology), 159-162. doi:10.1016/j.cpem.2017.07.003]

Marijuana and Madness: Associations Between Cannabinoids and Psychosis [Ranganathan, M., Skosnik, P. D., & D’Souza, D. C. (2016). Marijuana and madness: Associations between cannabinoids and psychosis. Biological Psychiatry, 79(7), 511-513. doi:10.1016/j.biopsych.2016.02.007.]

Neurotoxicology of cannabis and THC: A review of chronic exposure studies in animals [Scallet, A. C. (1991). Neurotoxicology of cannabis and THC: A review of chronic exposure studies in animals. Pharmacology, Biochemistry, And Behavior, 40(3), 671-676. ]

A Review of Pediatric Marijuana Exposure in the Setting of The Role of Cannabinoids in Neuroanatomic Alterations in Cannabis Users [Lorenzetti, V., Solowij, N., & Yücel, M. (2016). Review: The role of cannabinoids in neuroanatomic alterations in cannabis users. Biological Psychiatry, 79(Cannabinoids and Psychotic Disorders), e17-e31. doi:10.1016/j.biopsych.2015.11.013]

References:

  1. Mizrahi, R., Watts, J. J., & Tseng, K. Y. (2017). Invited review: Mechanisms contributing to cognitive deficits in cannabis users. Neuropharmacology124(A New Dawn in Cannabinoid Neurobiology), 84-88. doi:10.1016/j.neuropharm.2017.04.018
  2. Richards, J. R., Smith, N. E., & Moulin, A. K. (2017). Original Articles: Unintentional cannabis ingestion in children: A Systematic Review. The Journal Of Pediatrics, doi:10.1016/j.jpeds.2017.07.005
  3. Wang, G. S. (2017). Pediatric concerns due to expanded cannabis use: Unintended consequences of legalization. Journal of Medical Toxicology: Official Journal Of The American College Of Medical Toxicology13(1), 99-105.
  4. Carliner, H., Brown, Q. L., Sarvet, A. L., & Hasin, D. S. (2017). Review Article: Cannabis use, attitudes, and legal status in the U.S.: A review. Preventive Medicine, doi:10.1016/j.ypmed.2017.07.008
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  7. Adair, A., Greene, S. C., Greeley, C. S., Coleman, R. D., & Shekerdemian, L. S. (2016). Synthetic cannabinoid exposure: a new risk for children?. Clinical Pediatrics, (11). 1075.
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