Written by Tabish Mehraj, PhD. Melatonin supplementation enhances cardiovascular and liver health by optimizing lipid profiles, reducing systolic blood pressure, and lowering ALT levels. It also exerts potent anti-inflammatory and antioxidant effects by decreasing markers such as CRP and MDA, while boosting total antioxidant capacity. These findings underscore its potential in managing metabolic risks and systemic inflammation.

Cardio-metabolic risk (CMR) is a broad term encompassing a range of metabolic and cardiovascular conditions, as well as the risk factors associated with them. The strategy of antioxidant supplements has emerged as a potential for reducing inflammatory and oxidative damage. Melatonin, a hormone produced by the pineal gland, is a key circadian regulator that has been extensively studied for its scavenging and broad physiological activities. This study by Shooka Mohammadi and team investigated the effects of melatonin supplementation on cardio-metabolic risk factors (CMRFs). Melatonin reduces the activation of nuclear factor-kappa B (NF-κB), a major transcription factor involved in inflammatory responses. The scientists aimed to determine whether melatonin supplements could improve significant parameters, including glycemic, anthropometric, lipid, oxidative stress, inflammatory, blood pressure, and liver function markers associated with cardio-metabolic health.

This study is registered in PROSPERO and follows PRISMA 2020 guidelines. This systematic review and meta-analysis synthesized 63 randomized controlled trials involving 3,157 participants from diverse clinical and healthy populations. The study assessed melatonin supplementation (0.3–100 mg/day) over 2 to 56 weeks using rigorous statistical models and GRADE evaluation. It covered a wide range of metabolic conditions, including metabolic syndrome, cardiovascular disease, and COVID-19, ensuring a comprehensive and reliable assessment of melatonin’s efficacy.

The meta-analysis demonstrated that melatonin supplementation significantly improved several important cardiometabolic parameters. One of the most clinically relevant findings was the reduction in fasting blood glucose (FBG), with a weighted mean difference (WMD) of −11.63 mg/dL. This suggests that melatonin may positively influence glucose metabolism and glycemic control. However, no statistically significant effects were observed for fasting insulin, HOMA-IR, or HbA1c overall. Subgroup analyses indicated that benefits related to glycemic parameters were more evident in participants receiving lower melatonin doses (≤6 mg/day), in trials of varying durations, and among individuals with normal BMI or baseline normoglycemia.

Key Findings/ Results

Lipid Profile: Significant reductions were observed in total cholesterol (− 6.97 mg/dL) and LDL cholesterol (−6.28 mg/dL). In comparison, HDL cholesterol increased by 2.04 mg/dL, supporting melatonin’s potential to improve dyslipidemia and reduce cardiovascular risk.

Blood Pressure: Systolic blood pressure decreased significantly by approximately 2.34 mmHg.The reductions were more apparent in obese individuals and in studies using lower doses over shorter durations.

Antioxidant and Inflammatory Effect: Melatonin significantly reduced malondialdehyde (MDA), a marker of oxidative stress, while increasing total antioxidant capacity (TAC). Inflammatory markers, including C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), were also significantly reduced.

Liver Function: Melatonin supplementation significantly reduced alanine aminotransferase (ALT) levels, suggesting potential hepatoprotective effects.

Despite the potential outcomes of this study, it had several limitations. One of the main limitations is the heterogeneity across included trials. The inconsistent findings could be attributed to the differences in disease conditions, participant populations, melatonin doses, and supplementation duration. Furthermore, not all included studies had a low risk of bias; 10 trials were considered high risk due to issues related to randomization or deviations in the intervention. The wide variation in melatonin dosing regimens, ranging from physiologic to pharmacologic doses, also complicates identification of an optimal therapeutic dosage.

However, the study has several important strengths, as it represents one of the most comprehensive meta-analyses examining melatonin’s effects across multiple cardiometabolic domains simultaneously. The inclusion of 63 RCTs and over 3,000 participants substantially strengthens the evidence base compared with earlier reviews focusing on isolated outcomes. The use of rigorous methodology, including PRISMA guidelines, PROSPERO registration, subgroup analyses, dose–response modeling, sensitivity analyses, and GRADE assessment, enhances the reliability and clinical relevance of the findings.

Overall, this meta-analysis suggests that melatonin supplementation may benefit several cardiometabolic risk factors, particularly fasting blood glucose, lipid profile, systolic blood pressure, oxidative stress, inflammation, and ALT levels. While the evidence is promising, further large-scale, high-quality RCTs with standardized dosages and longer follow-up periods are needed to establish optimal supplementation strategies and confirm long-term clinical benefits.

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Posted June 4, 2026.

Dr. Tabish Mehraj is a pharmaceutical scientist with expertise in pharmaceutics, drug delivery, and formulation development. She earned her PhD in Pharmaceutical Sciences from the University of Mississippi, where her research focused on the formulation, optimization, and characterization of lipid-based nanocarriers for targeted liver delivery of antimalarial therapeutics. Dr. Mehraj has also served as an ORISE Fellow at the U.S. Food and Drug Administration (FDA), where she evaluated the effects of formulation and process design on the quality and performance of intravaginal drug delivery systems and developed bio-relevant in vitro drug release testing methods. She has teaching experience in pharmaceutical and life sciences courses and has authored peer-reviewed publications, book chapters, and conference presentations. Dr. Mehraj is an active member of the American Association of Pharmaceutical Scientists and has been recognized by honor societies including Rho Chi and Gamma Beta Phi.

References: 

1. Mohammadi, S., Ashtary-Larky, D., Erfanian-Salim, M., Alaghemand, N., Yousefi, M., Sanjari Pirayvatlou, P., … & Reiter, R. J. (2025). Comprehensive Effects of Melatonin Supplementation on Cardiometabolic Risk Factors: A Systematic Review and Dose–Response Meta-Analysis. Nutrients, 18(1), 134.