Cardiometabolic Health

Cholesterol and Hypertension

Improvements in LDL cholesterol and blood pressure have been shown in as few as two months of melatonin use (5 mg/day, two hours before bedtime) in thirty patients with documented metabolic syndrome who had not responded to a three-month intervention of therapeutic lifestyle modifications (1). Further, melatonin has been shown to decrease nocturnal hypertension, improve systolic and diastolic blood pressure, reduce the pulsatility index in the internal carotid artery, decrease platelet aggregation, and reduce serum catecholamine levels (2–5). A recent meta-analysis and systematic review by researchers at The Chinese University in Hong Kong concluded that a controlled-release oral melatonin supplement reduced asleep systolic blood pressure by 3.57 mm Hg (2). Another meta-analysis also reported in a decrease in daytime diastolic blood pressure by 1.40 mmHg, without an impact on systolic blood pressure when melatonin was taken in doses under 5 mg per day (6).

Cai et al. (7) correlated low levels of endogenous melatonin to decreased long-term survival in patients with pulmonary hypertension. As illustrated, multiple mechanisms are involved with the pleiotropic abilities of melatonin that not only have been shown to have antioxidant, inhibition of oxidative stress, and anti-inflammatory effects but also in inducing vasodilation, cardio-protective, cancer-protective, and benefits in respiratory diseases. Melatonin levels were attributed to hyper-activation of the sympathetic system and/or the renin-angiotensin system in patients with pulmonary hypertension (7).

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Heart Failure

Other studies have shown that melatonin improves outcomes in patients with heart failure and is considered a preventive and adjunctive curative measure in these patients (5). A randomized double-blinded placebo-controlled clinical trial with two parallel arms using either placebo or oral 10 mg melatonin supplementation per day for twenty-four weeks in patients with heart failure and reduced ejection fraction observed improvements in endothelial function in those who did not also have diabetes (8).

Glycemic Control

There has been some discussion as to whether melatonin may be helpful in conditions involving glycemic control, such as in non-insulin-dependent type 2 diabetes. A recent, relatively small, placebo-controlled study in male diabetics showed reduced insulin sensitivity by 12% after 10 mg of melatonin for three months (9). The difference in effects of melatonin on oral glucose tolerance in the diabetic population may involve polymorphisms in the type 2 diabetes-associated G allele in the melatonin receptor-1B gene (MTNR1B) (10–12). In one clinical trial with Spanish type 2 diabetics (13), the relationship between endogenous melatonin, dietary carbohydrate, and the effects of late-night eating were investigated. It was found that glucose tolerance was impaired in the late versus the early eating condition, especially in MTNR1B G-risk allele carriers, known to have insulin secretion defects. While this type of genotype is not easily assessed through current clinical laboratory assessment, it is best to monitor melatonin supplementation and any changes in blood sugar response in patients with glycemic control issues. A systematic review published in 2024, including 18 animal studies and 15 clinical trials, found that melatonin supplementation reduced insulin and HOMA-IR scores, with mixed findings on the impact melatonin had on fasting glucose levels (14 studies reported a decrease). A dose of 10 mg of melatonin had the most impact on HOMA-IR scores (14).

Obesity

Co-morbidities and complications of obesity can include heart disease, chronic inflammation, metabolic dysfunction-associated steatotic liver disease (MASLD) (formerly referred to as nonalcoholic fatty liver disease NAFD), certain cancers, type 2 diabetes, neurodegeneration, hormonal conditions, and more (15). In animal models, a lack of melatonin (or inadequate production) has been implicated in contributing to leptin resistance (16).

Suriagandhi & Nachiappan (16) explored the mechanism of melatonin on obesity further by assessing target genes of melatonin, which totaled 254 genes. Further, they identified a total of 221 genes that were intersecting targets of leptin resistance and obesity (Image 1). From this data combined with the melatonin target genes, they identified a total of 33 potential targets that were common for melatonin and leptin resistance obesity and highlighted the top ten genes, including TP53, AKT1, MAPK3, PTGS2, TNF, IL6, MAPK1, ERBB2, IL1B, and MTOR (16). Melatonin impacts these genes through its functions as an anti-inflammatory agent, mitochondrial regulator, antioxidant, and potent free radical scavenger.