Melatonin Shows Little Benefit for Arterial Stiffness, Meta-Analysis Finds

Now one of the most thorough attempts to test its effects on the aging of blood vessels has delivered a sobering verdict: the supplement does not appear to produce clinically meaningful improvements in arterial stiffness, even though it modestly lowers several blood pressure measures. The finding comes from a systematic review and meta-analysis published in Artery Research, which pooled randomized controlled trial data on melatonin and its receptor agonists in adults.

Arterial stiffness is widely regarded as an early warning sign on the road to cardiovascular disease. Structural and functional changes in the vascular wall often appear long before any clinical symptoms, which is why researchers place such weight on measuring them. The two dominant markers are pulse wave velocity, or PWV, generally considered the gold standard because it reflects the elastic properties and diameter of the arterial wall, and the augmentation index, or AIx, an indirect measure influenced by total peripheral resistance and heart rate.

There were reasons for optimism going in. Prior observational studies had suggested an inverse relationship between melatonin levels and arterial stiffness: urinary excretion of melatonin metabolites has been inversely associated with arterial stiffness in elderly and postmenopausal women. Early clinical data also indicated that a single one-milligram dose of exogenous melatonin could acutely reduce carotid-femoral PWV in healthy individuals. Melatonin is a pleiotropic molecule with antioxidant, radical-scavenging and anti-inflammatory properties relevant to cardiovascular health, and supplementation has been shown to improve fasting glucose, cholesterol fractions, C-reactive protein and liver enzymes. Yet despite a growing number of clinical trials, results on stiffness itself had remained inconsistent, and no systematic synthesis of the evidence existed.

To fill that gap, a team led by researchers affiliated with Babol University of Medical Sciences registered a protocol with PROSPERO and searched PubMed, Scopus, EMBASE, Web of Science and the Cochrane CENTRAL register from database inception to January 31, 2026. They followed the PRISMA 2020 reporting guidelines and cast a wide net: adults aged 18 or older, healthy or with underlying conditions, receiving melatonin or receptor agonists such as tasimelteon, ramelteon or agomelatine at any dosage, compared against placebo or standard care. Single-dose studies without longitudinal follow-up were excluded to ensure that only sustained intervention effects were assessed, and conference abstracts were screened, with authors contacted for missing data.

The search initially identified 2,026 records. After removing 332 duplicates and screening 1,699 titles and abstracts, 25 studies underwent full-text evaluation and 16 were excluded. Notable exclusions included trials that tested only single doses without follow-up, one study lacking follow-up PWV data despite attempts to recover it from the authors, and one that used the cardio-ankle vascular index rather than PWV as its stiffness measure. One trial, initially identified only as a conference abstract on night workers during the menopausal transition, was included after the corresponding author supplied the full dataset. Ultimately six trials were eligible, involving participants aged 39 to 85 across Russia, Iran, Denmark, Italy and Brazil. Five administered melatonin for 12 to 52 weeks; one used a melatonin receptor agonist.

The headline result came from pooling five trials with 319 participants. Melatonin supplementation was associated with a borderline reduction in PWV, with a standardized mean difference of -0.22 (95% confidence interval -0.44 to 0.00; p = 0.05) and negligible heterogeneity. But the authors translated that statistic into clinical terms: the observed effect corresponds to a PWV reduction of roughly 0.50 meters per second, well below the proposed minimal clinically important difference of 1 meter per second. In other words, even where a statistical signal existed, it fell short of what would matter for a patient’s arteries. The augmentation index showed no significant effect at all (SMD = -0.07; 95% CI -0.30 to 0.15; p = 0.51).

Blood pressure told a somewhat different story. Compared with controls, the intervention groups showed significant reductions in central systolic blood pressure (a mean difference of -6.14 mmHg; 95% CI -8.94 to -3.34), peripheral systolic blood pressure (-4.67 mmHg; 95% CI -8.05 to -1.29) and peripheral diastolic blood pressure (-3.45 mmHg; 95% CI -6.68 to -0.22). Central diastolic pressure did not change significantly, though central pulse pressure fell by 3.21 mmHg across four studies. The disconnect between meaningful blood pressure lowering and negligible stiffness improvement is intriguing, and the authors suggest mechanisms such as enhanced endothelium-dependent vasodilation, reduced oxidative stress, suppressed sympathetic vasomotor tone and modulation of inflammatory pathways may influence the two outcomes differently.

One subgroup finding is generating discussion but deserves heavy caveats. Prolonged-release melatonin formulations were associated with a significant PWV reduction (SMD = -0.31; 95% CI -0.57 to -0.05), while rapid-release formulations were not (SMD = -0.16; 95% CI -0.62 to 0.31). The authors note this is biologically plausible, since sustained-release melatonin produces a longer elimination half-life and higher later-phase plasma concentrations, potentially offering the more continuous nocturnal exposure that vascular effects may require. However, the prolonged-release subgroup rested on only two studies, both conducted in Russia, both in diseased populations, and not fully comparable because one tested melatonin while the other used an analog. The authors themselves label the result hypothesis-generating rather than conclusive.

The certainty of the evidence presents the biggest obstacle to any confident conclusion. Using the GRADE framework, the authors judged all synthesized outcomes to be of very low certainty, reflecting limitations across risk of bias, imprecision and other domains. The Cochrane Risk of Bias 2 assessment found that every included trial carried either some concerns or a high risk of bias: two trials were rated high risk, and four raised concerns, chiefly around unclear allocation concealment and inappropriate analysis of intervention effects. A leave-one-out sensitivity analysis underscored the fragility of the primary result, since removing a single trial, the low-dose study of night-shift healthcare workers, shifted the PWV finding to statistical significance, though still below the clinical importance threshold. An assessment with the ROB-ME tool did, however, suggest a low risk that the pooled estimate was distorted by unpublished or selectively unreported studies.

The authors’ conclusion is measured: current evidence does not support a clinically meaningful effect of melatonin supplementation on arterial stiffness parameters, and given the very low certainty of the evidence, definitive conclusions cannot be drawn. They call for further high-quality randomized controlled trials with adequate power, consistent PWV measurement techniques and rigorous methodology. For consumers, the takeaway is that the hope of melatonin rejuvenating stiff arteries currently rests on a handful of small, methodologically imperfect trials of very low certainty, with an effect size too small to matter clinically. The modest blood pressure reductions are a genuine observation worth pursuing, but they are not, on present evidence, a reason to treat the supplement as a vascular therapy.

Subject of Research: The effects of melatonin supplementation on arterial stiffness and blood pressure in adults

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

Article References: Keshtegar, S., Lashkarbolouki, A.-H., Keshtehgar, H., Tayebi, P., & Shirafkan, H. (2026). Effect of Melatonin and Melatonin Receptor agonist Supplementation on Vascular Stiffness: A Systematic Review and Meta-analysis. Artery Research, 32(1), Article 27. https://doi.org/10.1007/s44200-026-00124-z

Image Credits: AI Generated

DOI: 10.1007/s44200-026-00124-z

Keywords: melatonin, arterial stiffness, pulse wave velocity, augmentation index, blood pressure, meta-analysis, systematic review, randomized controlled trials, GRADE, cardiovascular health, supplements, Effect