Abstract
According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Autism Spectrum Disorder (ASD) is characterized by persistent difficulties in social communication and interaction, together with restricted and repetitive behaviors, interests, or activities. The diagnosis of ASD currently relies on comprehensive assessments of developmental history and behavioral patterns, as there are no validated laboratory tests for a definitive clinical diagnosis. While evidence-based interventions are largely restricted to educational and behavioral programs, many individuals with ASD and their caregivers explore complementary approaches, including dietary interventions. Among these, the gluten-free, casein-free (GFCF) diet is one of the most frequently adopted strategies. A leading hypothesis posits that those increased concentrations of opioid peptides such as gluteomorphin and caseomorphin derived from the incomplete digestion of gluten and casein may contribute to the severity of ASD symptoms. It is further suggested that eliminating these dietary proteins could reduce opioid peptide concentrations in biofluids and improve clinical outcomes. The present systematic review was created by reviewers who searched PubMed, Web of Science, and Scopus databases, covering the period from January 1980 to March 2025. The search strategy combined standardized keywords and Medical Subject Headings terms. The search strategy included a combination of keywords commonly used in the literature to represent ASD, opioid peptides, and GFCF diets. A systematic literature search was carried out on PubMed and Web of Science and a total of 17 articles were included. Although preliminary findings from clinical and laboratory studies are promising, conclusive evidence regarding the efficacy of the GFCF diet remains lacking. This review aims to synthesize current findings on the relationship between opioid peptides and ASD, with a particular focus on the neurological effects of food-derived peptides and their potential role in therapeutic dietary interventions.