Endocannabinoid System Dysfunction in Autism: Research Review

Abstract

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by challenges in social interaction, communication, and restricted or repetitive behaviors. The quest for biological markers and a deeper understanding of the underlying mechanisms of ASD has led researchers to explore the endocannabinoid system (ECS). This system, known for its role in regulating synaptic plasticity and neuromodulation, has been implicated in the pathophysiology of ASD. This research analysis delves into a seminal study by Aran et al. (2019), which reports lower circulating levels of endocannabinoids in children with ASD, offering novel insights into the ECS's involvement in ASD. By synthesizing findings from this and related studies, this paper aims to provide a comprehensive review of the ECS's role in ASD, its potential as a biomarker, and the implications for treatment strategies.

Methodology

The research analysis employed a comprehensive review method, focusing on the study by Aran et al. (2019) as the primary source, supplemented by related studies and literature on ECS and ASD. This approach thoroughly examined the study's objectives, methods, results, and conclusions. Furthermore, a systematic search in academic databases for studies on the ECS's role in ASD, including PubMed, Google Scholar, and ScienceDirect, found further studies to evaluate for discussion.

The selection criteria included studies published in English from 2010 to 2023 that investigated the ECS and ASD. Both animal models and human studies were considered in this review to provide a holistic view of the current scientific understanding.

Results of Primary Study Analysis

Aran et al. (2019) conducted a controlled study comparing serum levels of primary endocannabinoids (N-arachidonoylethanolamine or AEA and 2-arachidonoylglycerol or 2-AG) and related compounds (arachidonic acid or AA, N-palmitoylethanolamine or PEA, and N-oleoylethanolamine or OEA) in 93 children with ASD against 93 age- and gender-matched neurotypical children.

The findings revealed significantly lower AEA, PEA, and OEA levels in the ASD group, with no significant differences in LEA and 2-AG levels. These results were independent of age, gender, BMI, medications, and adaptive functioning measures in the ASD participants.

Discussion

Behavioral Assessments Used:

ASD encompasses a range of neurodevelopmental conditions characterized by challenges in social interaction, communication, and restrictive and repetitive behaviors. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), and the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2), set the foundation for ASD diagnosis. Subsequently, a suite of assessments, including the Vineland Adaptive Behavior Scale-II (VABS-II), Social Communication Questionnaire (SCQ) Lifetime Form, and others, offer nuanced insights into the functional abilities and behavioral patterns of individuals with ASD.

VABS-II: A semi-structured interview with caregivers assessing functional skills across five domains: communication, daily living skills, socialization, motor skills, and maladaptive behavior.

SCQ Lifetime Form: A 40-item parent-report measure focusing on reciprocal social interaction, communication, and repetitive behaviors.

CARS2-ST: A direct observation tool with 15 scales that evaluate aspects of behavior, including communication, body use, response to stimuli, and activity level.

HSQ-ASD: A 24-item measure of non-compliant behavior, validated in Hebrew for this study.

CBCL (Hebrew version): Utilized for its externalizing score, assessing emotional and behavioral problems in children aged 4 to 18.

APSI: A 13-item parent-rated measure designed to assess the impact of interventions on parenting stress.

SRS-2 (Hebrew version): A caregiver or teacher questionnaire with subscales for social awareness, cognition, communication, motivation, and autistic mannerisms.

CGI-S: A 7-point scale by trained clinicians to measure the severity of illness, ranging from average to severely ill.

Endocannabinoid System and ASD

The ECS is a key regulator of synaptic function, involved in synaptic plasticity, neuromodulation, and social behavior modulation. Alterations in the ECS are implicit in the study of several neurodevelopmental and psychiatric conditions, including ASD.

The research study by Aran et al. (2019) adds to the growing body of evidence suggesting that dysregulation of the ECS may play a role in the pathophysiology of ASD.

The reduced levels of AEA, AA, and OEA in children with ASD could indicate a lower endocannabinoid tone, which is associated with social deficits in animal models of ASD. These findings are consistent with previous studies that reported alterations in the ECS in both animal models and humans with ASD.

These levels of endocannabinoids, specifically AEA (anandamide), OEA (oleoylethanolamide), and PEA (palmitoylethanolamide), were directly related to age, Body Mass Index (BMI), and gender differences among children diagnosed with Autism Spectrum Disorder (ASD). Initial findings suggested that younger and leaner children with ASD exhibited lower serum levels of AEA.

However, these initial correlations lost statistical significance following adjustments for multiple comparisons, indicating that the initial observations might not hold true across a broader dataset or when considering the influence of numerous tests on statistical outcomes.

Furthermore, the study found no other significant correlations or associations of AEA, OEA, and PEA levels with age, BMI, or gender among the participants. This indicates that while there may be variances in endocannabinoid levels among children with ASD, these variances do not strongly correlate with the demographic and physical characteristics examined in this study.

Potential Mechanisms

The precise mechanisms by which ECS dysregulation contributes to ASD are still under investigation; research is ongoing in the discovery of the Endocannabinoid Systems involvement. However, several hypotheses have been proposed, including altered synaptic plasticity, impaired neural development, and disrupted neuromodulation.

The endocannabinoids AEA and 2-AG, through their action on cannabinoid receptors (CB1R and CB2R), play a crucial role in regulating synaptic function. Lower AEA, PEA, and OEA levels could result in decreased activation of CB1R and other receptors, leading to altered synaptic transmission and plasticity. This dysfunction of the ECS Tone, with lower endocannabinoid counts, could contribute to the neural circuitry abnormalities observed in ASD.

Implications for Treatment

The findings from Aran et al. (2019) and other related studies suggest that targeting the ECS could offer new therapeutic avenues for ASD. Cannabidiol (CBD), a non-psychoactive component of cannabis, has shown promise in modulating the ECS and improving symptoms in some ASD models. CBD's ability to increase AEA levels by inhibiting the enzyme fatty acid amide hydrolase (FAAH) positions it as a potential therapeutic agent.

This research study delves into the significant role of the endocannabinoid system (ECS) in Autism Spectrum Disorder (ASD), emphasizing its potential as both a diagnostic biomarker and a therapeutic target. The paper explains how endocannabinoids are produced on demand in the post-synaptic neuron and quickly broken down by enzymes, making their levels constantly fluctuate.

This dynamic regulation suggests that even minor changes in endocannabinoid concentrations could have significant implications for brain health and ASD.

The study narrative explores how circulating endocannabinoids, derived from multiple organs and tissues, mirror brain concentrations, making them practical markers for investigating the pathophysiology of CNS disorders.

Specifically, the researchers highlight recent research findings indicating lower levels of anandamide (AEA) in children with ASD compared to neurotypical counterparts.

This discrepancy suggests an imbalance in the ECS, potentially contributing to the ASD phenotype. Various studies on animals have shown ECS dysregulation in ASD models, mainly focusing on the effects of prenatal exposure to valproic acid, which alters cannabinoid receptor signaling and affects social behavior. This line of evidence underpins the hypothesis that targeting ECS dysregulation could ameliorate some ASD symptoms.

The research study elaborates on the potential therapeutic implications of these findings, particularly pointing toward the use of Cannabidiol (CBD), a non-psychoactive cannabinoid known for its beneficial effects on the CNS without the high associated with THC. CBD has been found to modulate the ECS by inhibiting the breakdown of endocannabinoids, thus raising their levels and counteracting ECS dysregulation. The U.S. Food and Drug Administration's approval of CBD for treating severe forms of epilepsy, which often co-occurs with ASD, underscores the therapeutic relevance of modulating the ECS in neuropsychiatric conditions.

The significance of utilizing circulating endocannabinoids as biomarkers for ASD is the hallmark of the research study's potential mechanism of the Endocannabinoid System in ASD. It was found that due to the heterogeneity and complexity of ASD, identifying reliable biomarkers is crucial for early diagnosis, prognosis, and monitoring of treatment response. The document notes that levels of AEA, OEA (oleoylethanolamide), and PEA (palmitoylethanolamide) are notably lower in individuals with ASD, which could help delineate a biologically distinct subgroup within the autism spectrum.

Conclusion

The study by Aran et al. (2019) significantly contributes to our understanding of the ECS's involvement in ASD, highlighting reduced circulating levels of certain endocannabinoids in children with ASD. These findings, alongside other research, suggest that ECS dysregulation may play a role in the pathophysiology of ASD and offer new targets for therapeutic intervention. Future research should further elucidate the mechanisms underlying ECS alterations in ASD and explore the therapeutic potential of modulating this system.

While the study by Aran et al. (2019) provides valuable insights into the ECS's role in ASD, it has limitations. The cross-sectional design does not allow for causal inferences, and this paper did not fully consider the effects of medications and comorbid conditions on endocannabinoid levels within the study. Future research should focus on longitudinal studies to track endocannabinoid levels over time in individuals with ASD, explore the mechanistic basis of ECS dysregulation in ASD, and evaluate the efficacy of ECS-targeted therapies in clinical trials.

Clinical trials examining the efficacy of CBD and other ECS-modulating Cannabinoids in ASD are warranted.

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 © 2024 Mike Robinson, Founder Global Cannabinoid Researcher Center and Creator of ECS Balance Control, The Researcher OG

References:

The 2019 Study Reviewed:

Aran, A., Eylon, M., Harel, M. et al. Lower circulating endocannabinoid levels in children with autism spectrum disorder. Molecular Autism 10, 2 (2019). https://doi.org/10.1186/s13229-019-0256-6

Other Research used in this review:

Rosenberg EC, Patra PH, Whalley BJ. Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection. Epilepsy Behav. 2017 May;70(Pt B):319-327. doi: 10.1016/j.yebeh.2016.11.006. Epub 2017 Feb 9. PMID: 28190698; PMCID: PMC5651410.

Di Marzo V, Piscitelli F. The Endocannabinoid System and its Modulation by Phytocannabinoids. Neurotherapeutics. 2015 Oct;12(4):692-8. doi: 10.1007/s13311-015-0374-6. PMID: 26271952; PMCID: PMC4604172.

Abbreviations To Learn:

2-AG: 2-Arachidonoylglycerol

AA: Arachidonic Acid

ADHD: Attention Deficit Hyperactivity Disorder

ADOS: Autism Diagnostic Observation Schedule

AEA: N-arachidonoylethanolamine (Anandamide)

APSI: Autism Parenting Stress Index

ASD: Autism Spectrum Disorder

CARS: Childhood Autism Rating Scale

CB1R, CB2R: Cannabinoid Receptor Type-1, Type-2

CBCL: Child Behavior Checklist

CGI-S: Clinical Global Impression-Severity

DAGL: Diacylglycerol Lipase

DSM-5: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition

EMT: Endocannabinoid Membrane Transporter

FAAH: Fatty Acid Amide Hydrolase

GPR55: G Protein-coupled Receptor 55

HSQ-ASD: Home Situations Questionnaire-Autism Spectrum Disorder

LC-MS/MS: Liquid Chromatography with Tandem Mass Spectrometry

MAGL: Monoacylglycerol Lipase

NAPE-PLD: N-acylphosphatidylethanolamine-specific Phospholipase D

OEA: N-oleoylethanolamine

PEA: N-palmitoylethanolamide

PPARs: Peroxisome Proliferator-Activated Receptors

SCQ: Social Communication Questionnaire

SRS-2: Social Responsiveness Scale-II

SSRI: Selective Serotonin Reuptake Inhibitory

TRPV1: Transient Receptor Potential Channels of Vanilloid Type-1

VABS: Vineland Adaptive Behavior Scale