Valeria Gomez

Background: First identified in 1943, autism is an illness that severely affects an individual’s ability to communicate, disrupting emotional and social relationships, manifesting in childhood.¹ It is estimated that ASD affects 2% of children in the United States with most diagnoses occurring before or at 3 years of age.¹ Social communication, maintaining eye contact, language impairment, difficulty with attention, disinterest in social engagement all contribute to hinderance of social development for patients with ASD.³ Social and behavioral deficits in ASD patients persist for the remainder of their lives, often in areas of adaptation, executive dysfunction, and psychomotor symptoms.¹ There are no current treatments to address ASD core symptoms; However, antipsychotics, stimulants, and sleep aides are common pharmacologic treatments to relieve comorbid diagnoses and symptoms². Unpredictability of ASD symptoms across individuals and variability in comorbid disorders creates a greater challenge in developing pharmacological treatments to address core symptoms of autism spectrum disorder.⁵ Stimulants, antipsychotics, and behavioral therapy target symptoms often of comorbid disorders without alleviating the underlying causation of ASD symptoms.⁵ Administration of cannabis therapy to ASD patients has indicated reduction of aggression, irritability, anger issues, psychomotor symptoms, self-mutilation, and sleep problems as well as improvement of social communication skills (increased eye contact).²  Targeting overall brain mechanisms such as neural signaling, synaptic plasticity, and neural circuitry, via the endocannabinoid system, could be a viable target to broadly address autism spectrum disorder despite the wide range of symptoms across different individuals.^2,4

Objective: In this narrative review, mechanisms were explored regarding mechanisms of the endocannabinoid system in autism spectrum disorder and possible drug targets to alleviate ASD symptoms.

Search Methods: An online search in the PubMed database was conducted from 2019 to 2024 using the following key search phrases “endocannabinoid”, “autism spectrum disorder”, and “anandamide”.

Results:  Several mice models, the administration of cannabis oil with higher CBD content allowed for  the accumulation of AEA in the synaptic cleft which alleviated multiple behavioral and social symptoms of ASD.^6,7,8,9,  Longitudinal CBD treatment on human patients indicated a positive improvement in social abilities as well as other core ASD symptoms both through parent reporting and clinical assessment with greater improvements for patients with greater communication deficits.

Conclusion:  The endocannabinoid system is responsible for the neuromodulation of cognition, emotional processing, social behavior, and synaptic plasticity, impacting the connectivity and response ability of the frontal cortex with the signaling of endogenous anandamide and 2-arachidonoylglycerol contributing to the modulation of homeostasis and cognitive function.⁶ For individuals with ASD, endogenous cannabinoid serum AEA and 2-AG levels are significantly low; Additional experiments should be completed to further examine and correlate behavioral and cognitive function improvements to increased AEA levels cleft after CBD therapy.^6,7,10 Overall results of investigation supports hypothesis of targeting endocannabinoid system as future drug therapy via alteration of 2-AG and AEA levels in the patient, Inhibition of endocannabinoids degrading enzymes, and alteration of the CB1 binding site.^7,8,9

 Works Cited:

1. Genovese A, Butler MG. Clinical Assessment, Genetics, and Treatment Approaches in Autism Spectrum Disorder (ASD). Int J Mol Sci. 2020;21(13):4726. Published 2020 Jul 2. doi:10.3390/ijms21134726
2. de Camargo RW, de Novais Júnior LR, da Silva LM, et al. Implications of the endocannabinoid system and the therapeutic action of cannabinoids in autism spectrum disorder: A literature review. Pharmacol Biochem Behav. 2022;221:173492. doi:10.1016/j.pbb.2022.173492
3. Kodak T, Bergmann S. Autism Spectrum Disorder: Characteristics, Associated Behaviors, and Early Intervention. Pediatr Clin North Am. 2020;67(3):525-535. doi:10.1016/j.pcl.2020.02.007
4. Silva EAD Junior, Medeiros WMB, Torro N, et al. Cannabis and cannabinoid use in autism spectrum disorder: a systematic review. Trends Psychiatry Psychother. 2022;44:e20200149. Published 2022 Jun 13. doi:10.47626/2237-6089-2020-0149
5. Wang L, Wang B, Wu C, Wang J, Sun M. Autism Spectrum Disorder: Neurodevelopmental Risk Factors, Biological Mechanism, and Precision Therapy. Int J Mol Sci. 2023;24(3):1819. Published 2023 Jan 17. doi:10.3390/ijms24031819
6. Schiavi S, Manduca A, Carbone E, et al. Anandamide and 2-arachidonoylglycerol differentially modulate autistic-like traits in a genetic model of autism based on FMR1 deletion in rats. Neuropsychopharmacology. 2023;48(6):897-907. doi:10.1038/s41386-022-01454-7
7. Hacohen M, Stolar OE, Berkovitch M, et al. Children and adolescents with ASD treated with CBD-rich cannabis exhibit significant improvements particularly in social symptoms: an open label study. Transl Psychiatry. 2022;12(1):375. Published 2022 Sep 9. doi:10.1038/s41398-022-02104-8
8. Wu HF, Lu TY, Chu MC, Chen PS, Lee CW, Lin HC. Targeting the inhibition of fatty acid amide hydrolase ameliorate the endocannabinoid-mediated synaptic dysfunction in a valproic acid-induced rat model of Autism. Neuropharmacology. 2020;162:107736. doi:10.1016/j.neuropharm.2019.107736
9. Perdikaris P, Dermon CR. Altered GABAergic, glutamatergic and endocannabinoid signaling is accompanied by neuroinflammatory response in a zebrafish model of social withdrawal behavior. Front Mol Neurosci. 2023;16:1120993. Published 2023 May 22. doi:10.3389/fnmol.2023.1120993
10. Zou M, Liu Y, Xie S, et al. Alterations of the endocannabinoid system and its therapeutic potential in autism spectrum disorder. Open Biol. 2021;11(2):200306. doi:10.1098/rsob.200306