Effect of Melatonin and Melatonin Receptor agonist Supplementation on Vascular Stiffness: A Systematic Review and Meta-analysis

Background Arterial stiffness is a critical precursor to clinical cardiovascular disease. This systematic review and meta-analysis aimed to evaluate the impact of melatonin and its receptor agonists on markers of arterial stiffness and hemodynamic parameters in adults. Methods A comprehensive search was performed across PubMed, Scopus, EMBASE, Web of Science, and Cochrane CENTRAL from inception to January 31, 2026. Clinical trials investigating melatonin or its analogues in adult populations were considered eligible regardless of study design. Although both randomized and non-randomized trials were sought, all eligible studies identified through the systematic search were randomized controlled trials (RCTs). The primary outcome was pulse wave velocity (PWV). Secondary outcomes included the augmentation index (AIx) and blood pressure parameters. STATA (version 18.0) was utilized to conduct the meta-analysis via a random effects model. The risk of bias was assessed using the Cochrane Risk of Bias tool (RoB 2), and the certainty of evidence was assessed via the GRADE framework. Results Five RCTs (319 participants) were included in the meta-analysis. Melatonin supplementation was associated with a borderline reduction in the PWV (SMD = -0.22; 95% CI: -0.44, 0.00; p = 0.05; I 2 = 0%); however, the magnitude of the effect corresponds to an estimated change below the minimal clinically important difference. No significant effect was observed for the AIx (SMD = -0.07; 95% CI: -0.30, 0.15; p = 0.51). Melatonin significantly reduced blood pressure parameters, including central systolic blood pressure (SBP) (MD= -6.14 mmHg; 95% CI: -8.94, -3.34; p < 0.001), peripheral SBP (MD = -4.67 mmHg; 95% CI: -8.05, -1.29; p = 0.01), and peripheral DBP (MD = -3.45 mmHg; 95% CI: -6.68, -0.22; p = 0.04). No significant changes were observed for central DBP (MD = 0.47 mmHg; 95% CI: -4.57, 5.50; p = 0.86). Conclusion Current evidence does not support a clinically meaningful effect of melatonin supplementation on arterial stiffness parameters, including PWV and AIx. However, given the very low certainty of the available evidence, definitive conclusions cannot be drawn, and further high-quality randomized controlled trials are warranted .