Efficacy of Melatonin as an Adjunct to Non-Surgical Periodontal Therapy: A Systematic Review and Meta-Analysis

Background: Melatonin exhibits anti-inflammatory, antioxidant, and osteogenic properties that may enhance outcomes of non-surgical periodontal therapy (NSPT). Previous reviews were limited by small sample sizes, heterogeneous methodology, and incomplete quantitative synthesis. Purpose: To evaluate the clinical efficacy of melatonin as an adjunct to NSPT compared with NSPT alone in patients with periodontitis. Methods: A systematic search of seven databases (through April 2025) identified randomized controlled trials comparing NSPT with and without adjunctive melatonin. Primary outcomes were clinical attachment level (CAL) gain and probing pocket depth (PPD) reduction at 1, 2, 3, and 6 months. Secondary outcomes included bleeding on probing (BoP) at 1, 3 and 6 months, gingival index (GI) at 1, 2, 3 and 6 months, plaque index (PI) at 1, 3 and 6 months, and glycated hemoglobin (HbA1c) at 2 months only. Random-effects meta-analyses were performed using the Hartung-Knapp-Sidik-Jonkman (HKSJ) method with REML estimation of between-study variance. Prediction intervals were calculated. Sensitivity, subgroup, and influence analyses were conducted. Risk of bias was assessed using RoB 2, and certainty of evidence using GRADE guidelines. Results: Eighteen RCTs (828 patients) were included, with 16 contributing to quantitative synthesis. Adjunctive melatonin significantly improved CAL at 2 months (MD -1.48 mm; 95% CI -2.11 to -0.85), 3 months (MD -0.41 mm; 95% CI -0.69 to -0.13), and 6 months (MD -0.68 mm; 95% CI -1.31 to -0.04), while CAL gain at 1 month was not significant (MD: -0.02 mm; 95% CI: -0.90 to 0.85). PPD reduction at 1 month favored the control group (MD 0.19 mm; 95% CI 0.04 to 0.34), while PPD reduction was significant favoring adjunctive melatonin at 2 months (MD -1.80 mm; 95% CI -2.49 to -1.12) and 3 months (MD -0.29 mm; 95% CI -0.53 to -0.05) but was not statistically significant at 6 months. BoP reduction was not significant across all follow-up timepoints. GI reduction was significant at 2 months (MD: -0.71; 95% CI: - 1.02 to -0.38 ), while PI reduction at 6 months was significant (MD: -0.69; 95% CI: -0.77 to -0.64). HbA1c decreased significantly at 2 months in diabetic patients (MD -1.33%; 95% CI -1.48 to -1.18). Prediction intervals for CAL and PPD crossed the null at all timepoints, suggesting that true effects may vary substantially and could be negligible in some clinical settings. Subgroup analyses did not demonstrate statistically significant effect modification by administration route or disease severity. Conclusions: Melatonin as an adjunct to NSPT may provide short-term improvements in CAL, PPD, and glycemic control. However, substantial heterogeneity and wide prediction intervals limit confidence in consistent clinical benefit across populations. Further high-quality, adequately powered RCTs with standardized protocols and longer follow-up are required to clarify durability and clinical relevance. • Adjunctive melatonin with NSPT improves CAL and PPD at 2 months, with smaller effects at 3-6 months. • Prediction intervals for CAL and PPD crossed the null, indicating uncertainty in reproducibility. • No statistically significant effect modification was observed by administration route. • Adjunctive melatonin improves HbA1c in patients with type 2 diabetes. • Certainty of evidence was moderate for short-term CAL, PPD, and HbA1c outcomes.