Long-term use of melatonin supplements linked to higher risk of heart failure and death

Long-term use of melatonin supplements, often used to promote sleep and address insomnia, was associated with a higher risk of heart failure diagnosis, heart failure hospitalization and death from any cause in chronic insomnia, according to a preliminary study to be presented at the American Heart Association's Scientific Sessions 2025. The meeting, Nov. 7-10, in New Orleans, is a premier global exchange of the latest scientific advancements, research and evidence-based clinical practice updates in cardiovascular science.

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, including the U.S. In the U.S., over-the-counter supplements are not regulated, so each brand of supplement can vary in strength, purity, etc.

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 may not be as harmless as commonly assumed. If our study is confirmed, this could affect how doctors counsel patients about sleep aids."

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

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 and is a common condition that affects 6.7 million adults in the U.S.

Using a large international database (the TriNetX Global Research Network), the researchers reviewed 5 years of electronic health records for adults with chronic insomnia who had melatonin recorded in their health records and used it for more than a year. They were matched with peers in the database who also had insomnia but never had melatonin recorded in their health records. People were excluded from the analysis if they had previously been diagnosed with heart failure or had been prescribed other sleep medications.

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.

"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," Nnadi said.

"I'm surprised that physicians would prescribe melatonin for insomnia and have patients use it for more than 365 days, since melatonin, at least in the U.S., is not indicated for the treatment of insomnia. In the U.S., melatonin can be taken as an over-the-counter supplement and people should be aware that it should not be taken chronically without a proper indication," said Marie-Pierre St-Onge, Ph.D., C.C.S.H., FAHA, chair of the writing group for the American Heart Association's 2025 scientific statement, Multidimensional Sleep Health: Definitions and Implications for Cardiometabolic Health. St-Onge, who was not involved in this study, is a professor of nutritional medicine in the division of general medicine and director of the Center of Excellence for Sleep & Circadian Research in the department of medicine at Columbia University Irving Medical Center in New York City.

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.

"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."

Study details, background and design:

• The study included 130,828 adults (average age of 55.7 years; 61.4% women) diagnosed with insomnia.
• The study data was from TriNetX, established in 2013, a growing global network of real-world, de-identified patient data available for research.
• 65,414 participants had been prescribed melatonin at least once and reported taking it for at least a year.
• A second group of people were examined for comparison (control group) - those who had never been prescribed melatonin and were matched to the group taking melatonin on 40 factors including demographic information, health conditions and medications. 
• Participants were excluded if they had already been diagnosed with heart failure or had been prescribed other types of sleeping pills such as benzodiazepines.
• The melatonin and control groups were matched for age, sex, race/ethnicity, heart and nervous system diseases, medications for heart and nervous system diseases, blood pressure and body mass index. Researchers looked at electronic medical records from the five years after the matching date.
• For the main findings, records were searched for codes related to an initial diagnosis of heart failure. Secondary findings included codes for hospitalization related to heart failure or death.
• Following the initial analyses, researchers validated the credibility of their findings by conducting a sensitivity analysis. This involved slightly changing the criteria: they required participants in the melatonin group to have filled at least two melatonin prescriptions that were at least 90 days apart. This adjustment aimed to determine whether the extended duration of confirmed melatonin prescriptions influenced the outcomes.