Lower Circulating Endocannabinoid Levels in Children with Autism Spectrum Disorder

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.

Objectives: To assess circulating levels of various endocannabinoids in children with ASD and delineate the correlations with disease characteristics.

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), OEA (17.3 ± 0.80 vs. 27.8 ± 1.44, P <0.0001) and PEA (4.93 ± 0.32 vs. 7.15 ± 0.37, P <0.0001), but not AA and 2-AG. Serum levels of AEA were correlated with BMI and age in children with ASD, but not in the control group. There were no other correlations or associations of AEA, OEA and PEA with age, gender, BMI, medications and adaptive functioning of ASD participants.

Conclusions: In concordance with previous findings in animal models, we found a lower endocannabinoid ‘tone’ in human ASD. Serum levels of AEA, PEA and OEA are promising novel biomarkers for ASD. These biomarkers can be longitudinally measured, in the exact same way, in human participants and animals, and hence can support the development of novel treatments. Our results also suggest a role for the ECS in ASD pathophysiology, and further support the need for clinical trials to assess the efficacy and safety of phytocannabinoids in ASD.