Background/Objectives: Melatonin, an antioxidant agent with anti-inflammatory and immunomodulatory properties, has recently been investigated as an adjunct to non-surgical periodontal therapy (NSPT). While most studies have focused on systemic administration, a limited number of recent clinical trials have evaluated the local delivery of melatonin in gel form. This systematic review evaluated the clinical and radiographic outcomes of locally delivered melatonin gel as an adjunct to NSPT in patients with periodontitis. Methods: Four databases (PubMed, Scopus, Web of Science, Cochrane Library), along with the gray literature, were systematically searched until November 2025. Randomized controlled trials (RCTs) investigating the effect of locally delivered melatonin gel as an adjunct to NSPT on clinical and radiographic periodontal parameters in patients with periodontitis compared with NSPT alone or combined with placebo administration were included. Assessment of risk of bias and certainty of evidence was conducted. Results: Five RCTs were eligible for qualitative synthesis. With a low level of certainty, the use of melatonin gel as an adjunct to NSPT was generally associated with significant improvements in clinical periodontal parameters and radiographic outcomes compared with NSPT plus placebo. Meta-analysis was not feasible due to substantial methodological heterogeneity across studies, including differences in study design, reporting, and outcome assessment. Conclusions: Adjunctive use of melatonin gel with NSPT may provide additional clinical and radiographic benefits in patients with periodontitis. However, the certainty of evidence is low; therefore, conclusions should be interpreted with caution. Evidence remains limited regarding the optimal melatonin concentration and dosing regimen. Well-designed, adequately powered RCTs with standardized protocols and longer follow-up periods are required to confirm these findings and define optimal use.
Angelopoulou et al. (Mon,) studied this question.