Nutritional Amino Acid Supplementation Reduces Severity and Enhances Recovery of Radiation‐Induced Oral Mucositis: A Triple‐Blind Randomized Clinical Trial

BACKGROUND: Radiation-induced oral mucositis (RIOM) is a common and debilitating complication of radiotherapy for head and neck cancer (HNC), frequently leading to severe pain, impaired oral intake, and treatment interruption. Nutritional interventions that support mucosal integrity may reduce mucosal injury and improve recovery. OBJECTIVE: To evaluate the effects of oral L-arginine and L-glutamine supplementation on the severity and recovery of radiation-induced oral mucositis and their association with salivary inflammatory and regenerative biomarkers. METHODS: In this triple-blind, parallel-arm randomized clinical trial, 84 patients receiving radiotherapy for HNC were allocated to oral L-arginine, L-glutamine, or maltodextrin control three times daily from Week 2 of radiotherapy until treatment completion. RIOM severity was assessed using the WHO scale at Weeks 2, 5, and 7. Salivary interleukin-6 (IL-6), nitric oxide (NO), and epidermal growth factor (EGF) were measured. Longitudinal changes were analysed using linear mixed-effects models, and associations with mucositis severity were evaluated using correlation and receiver operating characteristic analyses. RESULTS: At Week 5, severe mucositis occurred in 92.9% of controls compared with 17.9% and 3.6% in the arginine and glutamine groups (p < 0.001). Intervention groups showed lower IL-6 and NO levels and higher EGF levels (p < 0.001). Biomarkers were significantly correlated with mucositis severity, and IL-6 demonstrated excellent discrimination of severe mucositis (AUC = 0.988). CONCLUSIONS: Oral arginine and glutamine supplementation was associated with reduced severity and enhanced recovery of RIOM. Nutritional amino acid supplementation may represent a useful adjunct in supportive oral care and oral rehabilitation for patients undergoing radiotherapy. TRIAL REGISTRATION: The study was prospectively registered at ClinicalTrials.gov (Identifier: NCT07020754) on June 6, 2025.