Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Jan 30:10:2.
doi: 10.1186/s13229-019-0256-6. eCollection 2019.

Lower circulating endocannabinoid levels in children with autism spectrum disorder

Adi Aran  1 , Maya Eylon  2 , Moria Harel  1 , Lola Polianski  1 , Alina Nemirovski  2 , Sigal Tepper  3 , Aviad Schnapp  1 , Hanoch Cassuto  1 , Nadia Wattad  1 , Joseph Tam  2
Affiliations

Lower circulating endocannabinoid levels in children with autism spectrum disorder

Adi Aran et al. Mol Autism. .

Abstract

Background: The endocannabinoid system (ECS) is a major regulator of synaptic plasticity and neuromodulation. Alterations of the ECS have been demonstrated in several animal models of autism spectrum disorder (ASD). In some of these models, activating the ECS rescued the social deficits. Evidence for dysregulations of the ECS in human ASD are emerging, but comprehensive assessments and correlations with disease characteristics have not been reported yet.

Methods: Serum levels of the main endocannabinoids, N-arachidonoylethanolamine (AEA or anandamide) and 2-arachidonoylglycerol (2-AG), and their related endogenous compounds, arachidonic acid (AA), N-palmitoylethanolamine (PEA), and N-oleoylethanolamine (OEA), were analyzed by liquid chromatography/tandem mass spectrometry in 93 children with ASD (age = 13.1 ± 4.1, range 6-21; 79% boys) and 93 age- and gender-matched neurotypical children (age = 11.8 ± 4.3, range 5.5-21; 79% boys). Results were associated with gender and use of medications, and were correlated with age, BMI, and adaptive functioning of ASD participants as reflected by scores of Autism Diagnostic Observation Schedule (ADOS-2), Vineland Adaptive Behavior Scale-II (VABS-II), and Social Responsiveness Scale-II (SRS-2).

Results: Children with ASD had lower levels (pmol/mL, mean ± SEM) of AEA (0.722 ± 0.045 vs. 1.252 ± 0.072, P < 0.0001, effect size 0.91), OEA (17.3 ± 0.80 vs. 27.8 ± 1.44, P < 0.0001, effect size 0.94), and PEA (4.93 ± 0.32 vs. 7.15 ± 0.37, P < 0.0001, effect size 0.65), but not AA and 2-AG. Serum levels of AEA, OEA, and PEA were not significantly associated or correlated with age, gender, BMI, medications, and adaptive functioning of ASD participants. In children with ASD, but not in the control group, younger age and lower BMI tended to correlate with lower AEA levels. However, these correlations were not statistically significant after a correction for multiple comparisons.

Conclusions: We found lower serum levels of AEA, PEA, and OEA in children with ASD. Further studies are needed to determine whether circulating endocannabinoid levels can be used as stratification biomarkers that identify clinically significant subgroups within the autism spectrum and if they reflect lower endocannabinoid "tone" in the brain, as found in animal models of ASD.

Keywords: 2-arachidonoylglycerol; Anandamide; Arachidonic acid; Autism spectrum disorder; Biomarkers; Cannabinoids; Endocannabinoid system; N-arachidonoylethanolamine; N-oleoylethanolamine; N-palmitoylethanolamine.

PubMed Disclaimer

Conflict of interest statement

All research procedures were approved by the Shaare Zedek Medical Center Review Board and Israeli Ministry of Health prior to participant enrollment. Participants’ parents provided written consent prior to initiation of any experimental procedures, and written assent was obtained from participants when appropriate.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Lower serum endocannabinoid levels in children with ASD. Legend: low endocannabinoid “tone” in serum samples of 93 children with ASD compared with 93 age- and gender-matched controls. Results of anandamide (AEA; panel a), oleoylethanolamine (OEA; panel b), and palmitoylethanolamide (PEA; panel c) are presented as mean, standard error, and distribution respectively
Fig. 2
Fig. 2
Serum endocannabinoid levels in children with ASD and matched controls stratified by ADHD symptoms. Legend: 11 out of 93 children in the control group and 34 out of 93 children in the ASD group had ADHD symptoms. In both groups, there were no significant differences between the endocannabinoid levels in children with and without ADHD symptoms. Results of AEA (panel a),  OEA (panel b) and PEA (panel c) are presented as mean, standard error, and distribution
Fig. 3
Fig. 3
Impact of medication use on serum endocannabinoid levels in children with ASD. Legend: endocannabinoid levels in serum samples of 93 children with ASD stratified by medication use. There were no significant differences between the endocannabinoid levels in either of these subgroups. a Benzodiazepines (n = 8). b Antiepileptic drugs (n = 14). c Stimulants (n = 14). d Selective serotonin reuptake inhibitors (n = 20). e Anti-psychotics (n = 41). f Any medication (n = 74). Results are presented as mean, standard error, and distribution
Fig. 4
Fig. 4
Impact of epilepsy status on serum endocannabinoid levels in children with ASD. Legend: endocannabinoid levels in serum samples of 93 children with ASD—with (n = 9) and without (n = 84) epilepsy. There were no significant differences between children with and without epilepsy. Results of AEA (panel a), OEA (panel b) and PEA (panel c)  are presented as mean, standard error, and distribution
Fig. 5
Fig. 5
Schematic diagram of the endocannabinoid system, relevant to this study. Legend: biosynthesis, degradation, and receptors’ binding of AEA, 2-AG, OEA, and PEA are presented. AEA, PEA, and OEA are synthesized from the membrane’s phospholipids by N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD). PEA and OEA do not bind CB1R, but they can enhance AEA activity at transient receptor potential channels of vanilloid type-1 (TRPV1). AEA, PEA, and OEA are all degraded by fatty acid amide hydrolase (FAAH) and hence OEA and PEA can increase AEA levels by competing with AEA for FAAH (mainly OEA) or by downregulating FAAH expression (mainly PEA). Cannabidiol (CBD), a non-psychoactive component of the cannabis plant, activates peroxisome proliferator-activated receptors (PPARs) and TPRV1 and inhibits FAAH and hence might compensate for lower levels of AEA, OEA, and PEA in children with ASD. DAGL, diacylglycerol lipase; MAGL, monoacylglycerol lipase. EMT, endocannabinoid membrane transporter; GPR55, G protein-coupled receptor 55
See this image and copyright information in PMC

References

    1. Tart CT. Marijuana intoxication common experiences. Nature. 1970;226(5247):701–704. doi: 10.1038/226701a0. - DOI - PubMed
    1. Salzman C, Kochansky GE, Van Der Kolk BA, Shader RI. The effect of marijuana on small group process. Am J Drug Alcohol Abuse. 1977;4(2):251–255. doi: 10.3109/00952997709002763. - DOI - PubMed
    1. Salzman CVDKB, Shader RI. Marijuana and hostility in a small-group setting. Am J Psychiatry. 1976;133(9):1029–1033. doi: 10.1176/ajp.133.9.1029. - DOI - PubMed
    1. Glass M, Dragunow M, Faull RL. Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience. 1997;77(2):299–318. doi: 10.1016/S0306-4522(96)00428-9. - DOI - PubMed
    1. Moreira FA, Kaiser N, Monory K, Lutz B. Reduced anxiety-like behaviour induced by genetic and pharmacological inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) is mediated by CB1 receptors. Neuropharmacology. 2008;54(1):141–150. doi: 10.1016/j.neuropharm.2007.07.005. - DOI - PubMed

Publication types