A large multinational cohort study presented at AHA 2025 indicates that long-term use of melatonin for insomnia may be associated with a greater risk of heart failure (HF), increased hospitalizations due to HF, and a significant rise in all-cause mortality over five years. These results highlight the need for a clearer understanding of the cardiovascular safety of chronic melatonin therapy.
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Researchers led by Ekenedilichukwu Nnadi, MD, utilized data from the TriNetX Global Research Network, examining the health records of 130,828 adults diagnosed with insomnia. Among these participants, averaging 56 years of age and comprising 61% women, 65,414 had been prescribed melatonin at least once and had taken it for a minimum of one year. The study excluded individuals with a history of heart failure or those using other prescription hypnotics.
To ensure comparability, researchers used propensity score matching to align melatonin users with a control group of 65,414 participants based on demographics and 15 comorbid conditions, with consistent healthcare utilization metrics (all post-match standardized mean differences <0.02). Hazard ratios were derived from stratified Cox models, with outcomes evaluated after five years.
The primary endpoint they measured was the incidence of heart failure (ICD-10 I50), with secondary endpoints including HF hospitalization and overall mortality.
Over the five-year follow-up period, heart failure was observed in 3,021 (5%) of the melatonin group compared to 1,797 (3%) in the control group, yielding a hazard ratio of 1.89 and an absolute risk difference of 1.9% (p<0.001). Furthermore, HF-related hospitalizations occurred in 12,411 (19%) melatonin users versus 4,309 (7%) in the control group, while all-cause mortality rates were also higher among melatonin users (5,118 [8%] compared to 2,820 [4%], with an HR of 2.09). These findings were consistent in sensitivity analyses involving two or more melatonin prescriptions spaced at least 90 days apart (HR for HF 1.82).
The researchers noted, "Melatonin supplements are widely thought of as a safe and 'natural' option to support better sleep, so it was striking to see such consistent and significant increases in serious health outcomes, even after balancing for many risk factors. While the association we found raises safety concerns about the widely used supplement, our study cannot prove a direct cause-and-effect relationship, indicating that further research is necessary to evaluate melatonin's safety for heart health."