Long Term Melatonin Linked to Increased Risk of Heart Failure or Death: AHA Study

Long-term use of melatonin, a supplement that is primarily used to manage various sleep disorders by helping to regulate the body's internal clock, may be associated with a significantly higher risk of heart failure, hospitalization, and death, according to a preliminary study to be presented at the American Heart Association’s Scientific Sessions 2025 in New Orleans.

Melatonin is a hormone naturally produced in the body by the pineal gland, and it helps regulate the body’s sleep-wake cycle. Melatonin levels increase during darkness and decrease during daylight. Chemically identical synthetic versions of the hormone are often used to treat insomnia (difficulty falling and/or staying asleep) and jet lag. The supplements are widely available over the counter in many countries.

In this study, researchers classified people who had used melatonin long-term (with long-term use defined as a year or more documented in their electronic health records) as part of the “melatonin group.” In contrast, those who never had melatonin recorded anywhere in their medical records were classified as the “non-melatonin group.”

Melatonin supplements are promoted and marketed as a safe sleep aid; however, data demonstrating their long-term cardiovascular safety are lacking, which prompted the researchers to examine whether melatonin use alters the risk of heart failure, specifically in chronic insomnia patients. According to the American Heart Association’s 2025 Heart Disease and Stroke Statistics, heart failure occurs when the heart can’t pump enough oxygen-rich blood to the body’s organs for them to function properly.

The researchers conducted a retrospective cohort study using the TriNetX Global Research Network, which contains de-identified electronic health records from hospitals worldwide. The study included 130,828 adults diagnosed with chronic insomnia, with an average age of 55.7 years and 61.4% being women. Participants were divided into two groups: those who had documented melatonin use for at least one year and those who had never used melatonin. Individuals previously diagnosed with heart failure or prescribed other sleep medications were excluded.

Both groups were matched on 40 factors, including age, sex, race, medical history, medications, blood pressure, and body mass index, to ensure comparability. Researchers then followed their records for five years to identify new cases of heart failure, related hospitalizations, and deaths from any cause. A sensitivity analysis was also conducted by including only participants who had filled at least two melatonin prescriptions 90 days apart to confirm long-term use. This approach helped strengthen the reliability of the findings, though the study design could not establish a cause-and-effect relationship.

The main analysis found:

• Among adults with insomnia, those whose electronic health records indicated long-term melatonin use (12 months or more) had about a 90% higher chance of incident heart failure over 5 years compared with matched non-users (4.6% vs. 2.7%, respectively).

• There was a similar result (82% higher) when researchers analyzed people who had at least 2 melatonin prescriptions filled at least 90 days apart. (Melatonin is only available by prescription in the United Kingdom.)

A secondary analysis found:

• Participants taking melatonin were nearly 3.5 times as likely to be hospitalized for heart failure when compared to those not taking melatonin (19.0% vs. 6.6%, respectively).

• Participants in the melatonin group were nearly twice as likely to die from any cause than those in the non-melatonin group (7.8% vs. 4.3%, respectively) over the 5-year period.

The study has several limitations. First, the database includes countries that require a prescription for melatonin (such as the United Kingdom) and countries that don’t (such as the United States), and patient locations were not part of the de-identified data available to the researchers. Since melatonin use in the study was based only on those identified from medication entries in the electronic health record, everyone taking it as an over-the-counter supplement in the U.S. or other countries that don’t require a prescription would have been in the non-melatonin group; therefore, the analyses may not accurately reflect this. Hospitalization figures were also higher than those for initial diagnosis of heart failure because a range of related diagnostic codes may be entered for the hospitalization, and they may not always include the code for a new diagnosis of heart failure. The researchers also lacked information on the severity of insomnia and the presence of other psychiatric disorders.

“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,”said Ekenedilichukwu Nnadi, M.D., lead author of the study and chief resident in internal medicine at SUNY Downstate/Kings County Primary Care in Brooklyn, New York.

“Worse insomnia, depression/anxiety or the use of other sleep-enhancing medicines might be linked to both melatonin use and heart risk,” Nnadi said. “Also, 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.”

Reference: Study will be presented at the American Heart Association’s Scientific Sessions 2025 (Nov. 7-10), New Orleans.