Effect of Melatonin as an Adjunct to NSPT on Periodontal and Systemic Outcomes in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of RCTs.

Background/Objectives: In recent years, a wide range of adjunctive therapies have been employed in conjunction with non-surgical periodontal therapy (NSPT) to enhance treatment outcomes. Among them, melatonin, a hormone with well-documented antioxidant, anti-inflammatory, and immunomodulatory properties, has emerged as a potential adjunctive therapeutic agent. The purpose of the present systematic review was to investigate whether systemic melatonin supplementation, when combined with NSPT, provides any additional periodontal and systemic benefits in patients diagnosed with type 2 diabetes mellitus (T2DM). Methods: Articles indexed in PubMed, Web of Science, Scopus, and the Cochrane Library were systematically retrieved, with additional screening of gray literature, covering all records available up to February 2026. This systematic review included randomized controlled trials (RCTs) evaluating the effect of adjunctive systemic melatonin administration in conjunction with NSPT on clinical and biochemical periodontal parameters and systemic outcomes related to glycemic control, oxidative stress, and inflammation in patients with T2DM compared with NSPT alone or combined with placebo. Three RCTs were eligible for qualitative synthesis, and two placebo-controlled RCTs were included in the quantitative synthesis. Risk of bias and quality of evidence assessments were performed. Results: With a low level of certainty, systemic melatonin supplementation in conjunction with NSPT demonstrated significantly more pronounced improvements in periodontal and systemic outcomes than those observed following NSPT or NSPT combined with placebo. Meta-analysis demonstrated statistically significant improvements in PPD and CAL, as well as in HbA1c and serum hs-CRP, favoring adjunctive melatonin supplementation. Conclusions: Adjunctive systemic melatonin supplementation in combination with NSPT may have a beneficial impact in patients with T2DM. However, the limited number of available studies, relatively small sample sizes, risk of bias concerns, and low quality of evidence limit the confidence that can be placed in these findings. Future research should focus on conducting more well-designed, sufficiently powered, large-scale RCTs employing standardized treatment protocols and longer observation periods.