Long-term melatonin use for insomnia was associated with a higher hazard of heart failure (HF), an increase in HF hospitalizations and a doubling of all-cause mortality over five years, according to a large, multinational cohort study presented at AHA 2025. These findings emphasize the need to clarify the cardiovascular safety profile of melatonin use as benign chronic therapy.

Ekenedilichukwu Nnadi, MD, et al., used data from the TriNetX Global Research Network to assess melatonin use in 130,828 adults diagnosed with insomnia. Of included participants (average age of 56 years; 61% women), 65,414 had been prescribed melatonin at least once and reported taking it for at least one year. Of note, patients with prior HF or other prescription hypnotics were excluded.

Using propensity score matching, researchers balanced the melatonin users with 65,414 controls based on demographics, 15 comorbidities, concomitant cardiometabolic drugs, laboratories, vitals and health care utilization (all post-match standardized mean differences <0.02). Hazard ratios (HR) were obtained from stratified Cox models and outcomes were assessed after five years.

The primary endpoint was incident HF (International Classification of Diseases-10 I50) and secondary endpoints were HF hospitalization and all-cause mortality.

During five-year follow-up, incident HF occurred in 3,021 (5%) participants in the melatonin group vs. 1,797 (3%) participants in the control group, which corresponds to an HR of 1.89 and an absolute risk difference of 1.9% (p<0.001). Additionally, HF-related hospitalization occurred in 12,411 (19%) melatonin users vs. 4,309 (7%) in the control group, and all-cause mortality was higher in melatonin users (5,118 [8%] vs. 2,820 [4%]; HR, 2.09). Results were consistent in sensitivity analyses requiring two or more melatonin fills ≥90 days apart (HR for HF 1.82).

"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 other risk factors," the researchers explain. "…while the association we found raises safety concerns about the widely used supplement, our study cannot prove a direct cause-and-effect relationship. This means more research is needed to test melatonin's safety for the heart."

Clinical Topics: Heart Failure and Cardiomyopathies, Statins, Acute Heart Failure

Keywords: AHA Annual Scientific Sessions, AHA25, Melatonin, Sleep Initiation and Maintenance Disorders, Heart Failure, Risk