{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T08:39:15Z","timestamp":1778747955022,"version":"3.51.4"},"reference-count":39,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,4,18]],"date-time":"2021-04-18T00:00:00Z","timestamp":1618704000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Autism spectrum disorder (ASD) pathophysiology is not completely understood; however, altered inflammatory response and glutamate signaling have been reported, leading to the investigation of molecules targeting the immune-glutamatergic system in ASD treatment. Palmitoylethanolamide (PEA) is a naturally occurring saturated N-acylethanolamine that has proven to be effective in controlling inflammation, depression, epilepsy, and pain, possibly through a neuroprotective role against glutamate toxicity. Here, we systematically reviewed all human and animal studies examining PEA and its biobehavioral correlates in ASD. Studies indicate altered serum\/brain levels of PEA and other endocannabinoids (ECBs)\/acylethanolamines (AEs) in ASD. Altered PEA signaling response to social exposure and altered expression\/activity of enzymes responsible for the synthesis and catalysis of ECBs\/AEs, as well as downregulation of the peroxisome proliferator activated receptor-\u03b1 (PPAR-\u03b1) and cannabinoid receptor target GPR55 mRNA brain expression, have been reported. Stress and exposure to exogenous cannabinoids may modulate ECBs\/AEs levels and expression of candidate genes for neuropsychiatric disorders, with implications for ASD. Limited research suggests that PEA supplementation reduces overall autism severity by improving language and social and nonsocial behaviors. Potential neurobiological underpinnings include modulation of immune response, neuroinflammation, neurotrophy, apoptosis, neurogenesis, neuroplasticity, neurodegeneration, mitochondrial function, and microbiota activity, possibly through peroxisome proliferator-activated receptor-\u03b1 (PPAR-\u03b1) activation.<\/jats:p>","DOI":"10.3390\/nu13041346","type":"journal-article","created":{"date-parts":[[2021,4,19]],"date-time":"2021-04-19T06:35:53Z","timestamp":1618814153000},"page":"1346","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Palmitoylethanolamide and Its Biobehavioral Correlates in Autism Spectrum Disorder: A Systematic Review of Human and Animal Evidence"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6139-1920","authenticated-orcid":false,"given":"Marco","family":"Colizzi","sequence":"first","affiliation":[{"name":"Child and Adolescent Neuropsychiatry Unit, Maternal-Child Integrated Care Department, Integrated University Hospital of Verona, 37126 Verona, Italy"},{"name":"Section of Psychiatry, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy"},{"name":"Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0125-4112","authenticated-orcid":false,"given":"Riccardo","family":"Bortoletto","sequence":"additional","affiliation":[{"name":"Child and Adolescent Neuropsychiatry Unit, Maternal-Child Integrated Care Department, Integrated University Hospital of Verona, 37126 Verona, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosalia","family":"Costa","sequence":"additional","affiliation":[{"name":"Community Mental Health Team, Department of Mental Health, ASST Mantova, 46100 Mantua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leonardo","family":"Zoccante","sequence":"additional","affiliation":[{"name":"Child and Adolescent Neuropsychiatry Unit, Maternal-Child Integrated Care Department, Integrated University Hospital of Verona, 37126 Verona, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1515\/revneuro-2017-0015","article-title":"Status of essential elements in autism spectrum disorder: Systematic review and meta-analysis","volume":"28","author":"Saghazadeh","year":"2017","journal-title":"Rev. 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