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Endocannabinoid system involvement in autism spectrum disorder: An overview with potential therapeutic applications

1 Department of Cellular and Integrative Physiology, School of Medicine, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA
2 Department of Experimental Medicine, University of Campania, 80138 Naples, Italy
3 Italian Group for Study Autism-GISA, 25018 Brescia, Italy
4 Centre for Autism-La Forza del Silenzio, 81036 Caserta, Italy

Special Issues: Molecular Mechanisms and Therapy of Autism Spectrum Disorders

Persistent deficits in social communication, restricted-repetitive patterns of behavior, interests, or activities are the core domains characterizing autism spectrum disorder (ASD). In this spectrum are grouped a heterogeneous and complex set of neurodevelopmental conditions. ASD shows pro-inflammatory events and immune system dysfunction. The endocannabinoid (EC) system is an intricate molecular network of lipid signaling pathways. The building-blocks are the arachidonic acid-derived compounds (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), their G-protein-coupled receptors (cannabinoid receptors CB1 and CB2), and their associated biosynthesizing and degradating enzymes. Recent evidence highlights a strong involvement of the EC system in the pathophysiology of some neuropsychiatric disorders and of ASD. Indeed, the EC system is able to regulate several metabolic and cellular pathways involved in autism, especially regulation of the immune system. ASD-related changes in the immune system involve alterations in monocyte and macrophage responses and pro-inflammatory cytokine up-regulation. It has been demonstrated that these processes are driven by EC system dysfunction, opening the way for targeting this system with novel drugs for ASD. Potentially, pharmacologic treatment with cannabidiol (CBD) is expected to increase endocannabinoid tone by increasing anandamide levels. Additionally, evidence from the literature indicates that CBD may alleviate many conditions co-occurring with ASD, such as seizures, gastro-intestinal problems, anxiety and depression, attention deficit, and sleep problems.
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Keywords autism spectrum disorder; endocannabinoid system; cannabidiol; inflammation; cytokine

Citation: Stephen Schultz, Dario Siniscalco. Endocannabinoid system involvement in autism spectrum disorder: An overview with potential therapeutic applications. AIMS Molecular Science, 2019, 6(1): 27-37. doi: 10.3934/molsci.2019.1.27


  • 1. American Psychiatric Association (2013) Autism spectrum disorder, 299.00 (F84.0), In: Diagnostic and Statistical Manual of Mental Disorders, 5 Eds., American Psychiatric Publishing, 50–59.
  • 2. Hallmayer J, Cleveland S, Torres A, et al. (2011) Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry 68: 1095–1102.    
  • 3. Schultz ST, Klonoff-Cohen HS, Wingard DL, et al. (2008) Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: The results of a parent survey. Autism 12: 293–307.    
  • 4. Becker KG, Schultz ST (2010) Similarities in features of autism and asthma and a possible link to acetaminophen use. Med Hypotheses 74: 7–11.    
  • 5. Orlowski JP, Hanhan UA, Fiallos MR (2002) Is aspirin a cause of Reye's syndrome? A case against. Drug Saf 25: 225–231.
  • 6. Avella-Garcia CB, Julvez J, Fortuny J, et al. (2016) Acetaminophen use in pregnancy and neurodevelopment: Attention function and autism spectrum symptoms. Int J Epidemiol 45: 1987–1996.
  • 7. Liew Z, Ritz B, Virk J, et al. (2016) Maternal use of acetaminophen during pregnancy and risk of autism spectrum disorders in childhood: A Danish national birth cohort study. Autism Res 9: 951–958.    
  • 8. Masarwa R, Levine H, Gorelik E, et al. (2018) Prenatal exposure to acetaminophen and risk for attention deficit hyperactivity disorder and autistic spectrum disorder: A systematic review, meta-analysis, and meta-regression analysis of cohort studies. Am J Epidemiol 187: 1817–1827.    
  • 9. Schultz ST (2010) Can autism be triggered by acetaminophen activation of the endocannabinoid system? Acta Neurobiol Exp 70: 227–231.
  • 10. Schultz ST, Gould GG (2016) Acetaminophen use for fever in children associated with autism spectrum disorder. Autism Open Access 6: 170.
  • 11. Bertolini A, Ferrari A, Ottani A, et al. (206) Paracetamol: New vistas of an old drug. CNS Drug Rev 12: 250–275.
  • 12. Mallet C, Daulhac L, Bonnefont J, et al. (2008) Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia. Pain 139: 190–200.    
  • 13. Gould GG, Seillier A, Weiss G, et al. (2012) Acetaminophen differentially enhances social behavior and cortical cannabinoid levels in inbred mice. Prog Neuropsychopharmacol Biol Psychiatry 38: 260–269.    
  • 14. Chakrabarti B, Persico A, Battista N, et al. (2015) Endocannabinoid signaling in autism. Neurotherapeutics 12: 837–847.    
  • 15. Barchel D, Stolar O, De-Haan T, et al. (2019) Oral cannabidiol use in children with autism spectrum disorder to treat related symptoms and co-morbidities. Front Pharmacol 9: 1521.    
  • 16. Poleg S, Golubchik P, Offen D, et al. (2019) Cannabidiol as a suggested candidate for treatment of autism spectrum disorder. Prog Neuropsychopharmacol Biol Psychiatry 89: 90–96.    
  • 17. Zamberletti E, Gabaglio M, Parolaro D (2017) The endocannabinoid system and autism apectrum disorders: Insights from animal models. Int J Mol Sci 18: pii: E1916.
  • 18. Hosie S, Malone DT, Liu S, et al. (2018) Altered amygdala excitation and CB1 receptor modulation of aggressive behavior in the neuroligin-3R451C mouse model of autism. Front Cell Neurosci 12: 234.
  • 19. Melancia F, Schiavi S, Servadio M, et al. (2018) Sex-specific autistic endophenotypes induced by prenatal exposure to valproic acid involve anandamide signalling. Br J Pharmacol 175: 3699–3712.    
  • 20. Kuo HY, Liu FC (2018) Molecular pathology and pharmacological treatment of autism spectrum disorder-like phenotypes using rodent models. Front Cell Neurosci 12: 422.
  • 21. Kerr DM, Downey L, Conboy M, et al. (2013) Alterations in the endocannabinoid system in the rat valproic acid model of autism. Behav Brain Res 249: 124–132.    
  • 22. Kerr DM, Gilmartin A, Roche M (2016) Pharmacological inhibition of fatty acid amide hydrolase attenuates social behavioural deficits in male rats prenatally exposed to valproic acid. Pharm Res 113: 228–235.    
  • 23. Siniscalco D, Sapone A, Giordano C, et al. (2013) Cannabinoid receptor type 2, but not type 1, is up-regulated in peripheral blood mononuclear cells of children affected by autistic disorders. J Autism Dev Disord 43: 2686–2695.    
  • 24. Brigida AL, Schultz S, Cascone M, et al. (2017) Endocannabinoid signal dysregulation in autism spectrum disorders: A correlation link between inflammatory state and neuro-immune alterations. Int J Mol Sci 18: pii: E1425.
  • 25. Karhson DS, Krasinska KM, Dallaire JA, et al. (2018) Plasma anandamide concentrations are lower in children with autism spectrum disorder. Mol Autism 9: 18.    
  • 26. Aran A, Eylon M, Harel M, et al. (2019) Lower circulating endocannabinoid levels in children with autism spectrum disorder. Mol Autism 10: 2.    
  • 27. Leweke FM, Piomelli D, Pahlisch F, et al. (2012) Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry 2: e94.    
  • 28. Bar-Lev Schleider L, Mechoulam R, Saban N, et al. (2019) Real life experience of medical cannabis treatment in autism: Analysis of safety and efficacy. Sci Rep 9: 200.    
  • 29. Siniscalco D, Schultz S, Brigida AL, et al. (2018) Inflammation and neuro-immune dysregulations in autism spectrum disorders. Pharmaceuticals (Basel) 11: pii: E56.
  • 30. Watson S, Chambers D, Hobbs C, et al. (2008) The endocannabinoid receptor, CB1, is required for normal axonal growth and fasciculation. Mol Cell Neurosci 38: 89–97.    
  • 31. Zikopoulos B, Liu X, Tepe J, et al. (2018) Opposite development of short- and long-range anterior cingulate pathways in autism. Acta Neuropathol 136: 759–778.    
  • 32. Soltys J, Yushak M, Mao-Draayer Y (2010) Regulation of neural progenitor cell fate by anandamide. Biochem Biophys Res Commun 400: 21–26.    
  • 33. Campos AC, Ortega Z, Palazuelos J, et al. (2013) The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: Involvement of the endocannabinoid system. Int J Neuropsychopharmacol 16: 1407–1419.    
  • 34. Khan AA, Shekh-Ahmad T, Khalil A (2018) Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model. Br J Pharmacol 175: 2097–2115.    
  • 35. Couch DG, Tasker C, Theophilidou E, et al. (2017) Cannabidiol and palmitoylethanolamide are anti-inflammatory in the acutely inflamed human colon. Clin Sci (Lond) 131: 2611–2626.    
  • 36. D'Argenio G, Valenti M, Scaglione G, et al. (2006) Up-regulation of anandamide levels as an endogenous mechanism and a pharmacological strategy to limit colon inflammation. FASEB J 20: 568–570.    
  • 37. Sales AJ, Fogaça MV, Sartim AG, et al. (2018) Cannabidiol induces rapid and sustained antidepressant-like effects through increased BDNF signaling and synaptogenesis in the prefrontal cortex. Mol Neurobiol 56: 1070–1081.
  • 38. Lee JLC, Bertoglio LJ, Guimarães FS, et al. (2017) Cannabidiol regulation of emotion and emotional memory processing: Relevance for treating anxiety-related and substance abuse disorders. Br J Pharmacol 174: 3242–3256.    
  • 39. Cooper RE, Williams E, Seegobin S, et al. (2017) Cannabinoids in attention-deficit/hyperactivity disorder: A randomised-controlled trial. Eur Neuropsychopharmacol 27: 795–808.    
  • 40. Babson KA, Sottile J, Morabito D (2017) Cannabis, cannabinoids, and sleep: A review of the literature. Curr Psychiatry Rep 19: 23.    
  • 41. Parker W, Hornik CD, Bilbo S, et al. (2017) The role of oxidative stress, inflammation and acetaminophen exposure from birth to early childhood in the induction of autism. J Int Med Res 45: 407–438.
  • 42. Hill AJ, Williams CM, Whalley BJ, et al. (2012) Phytocannabinoids as novel therapeutic agents in CNS disorders. Pharmacol Ther 133: 79–97.    
  • 43. Solimini R, Rotolo MC, Pichini S, et al. (2017) Neurological disorders in medical use of cannabis: An update. CNS Neurol Disord Drug Targets 16: 527–533.
  • 44. Urdaneta KE, Castillo MA, Montiel N, et al. (2018) Autism spectrum disorders: Potential neuro-psychopharmacotherapeutic plant-based drugs. Assay Drug Dev Technol 16: 433–444.    


This article has been cited by

  • 1. Rumi Agarwal, Shanna L. Burke, Marlaina Maddux, Current state of evidence of cannabis utilization for treatment of autism spectrum disorders, BMC Psychiatry, 2019, 19, 1, 10.1186/s12888-019-2259-4

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