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 treat insomnia, was associated with a higher risk of heart failure diagnosis, hospitalization for heart failure, and death from any cause in chronic insomnia, according to a preliminary study to be presented at the 2025 American Heart Association Scientific Sessions.

Melatonin is a hormone naturally produced in the body by the pineal gland and helps regulate the body’s sleep-wake cycle. Melatonin levels increase in darkness and decrease during the day. Chemically identical synthetic versions of the hormone are often used to treat insomnia (difficulty falling and/or staying asleep) and jet lag. Supplements are widely available over the counter in many countries, including the United States. In the United States, 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 record) into the “melatonin group.” On the other hand, those for whom melatonin was never recorded in their medical record were classified in the “non-melatonin group”.

Melatonin supplements may not be as harmless as commonly thought. If our study is confirmed, it could affect how doctors advise patients about sleeping pills. »

Ekenedilichukwu Nnadi, MD, lead study author 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 its long-term cardiovascular safety are lacking, prompting researchers to examine whether melatonin use modifies the risk of heart failure, particularly in patients with chronic insomnia. According to the American Heart Association’s 2025 Heart Disease and Stroke Statistics, heart failure occurs when the heart cannot pump enough oxygen-rich blood to the body’s organs for them to function properly. It is a common disease that affects 6.7 million adults in the United States.

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

The main analysis revealed:

• Among adults with insomnia, those whose electronic health records indicated long-term melatonin use (12 months or more) had approximately a 90% greater 5-year risk of heart failure than matched nonusers (4.6% versus 2.7%, respectively).
• A similar result was obtained (82% higher) when researchers analyzed people who received two or more melatonin prescriptions filled at least 90 days apart. (Melatonin is only available on prescription in the UK.)

Secondary analysis revealed:

• Participants taking melatonin were nearly 3.5 times more likely to be hospitalized for heart failure than those not taking melatonin (19.0% versus 6.6%, respectively).
• Participants in the melatonin group were nearly twice as likely to die from any cause as those in the non-melatonin group (7.8% versus 4.3%, respectively) over a 5-year period.

“Melatonin supplements are widely considered a safe and “natural” option to promote better sleep. “It was therefore striking to see such a consistent and significant increase in serious health conditions, even after accounting for many other risk factors,” Nnadi said.

“I am surprised that doctors prescribe melatonin for the treatment of insomnia and ask their patients to use it for more than 365 days, since melatonin, at least in the United States, is not indicated for the treatment of insomnia. In the United States, melatonin can be taken as an over-the-counter supplement and people should be aware that it should not be taken chronically without proper indication,” said Marie-Pierre St-Onge, Ph.D., CCSH, FAHA, Chair of the American Heart Association 2025 Scientific Statement Writing Group, 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 and Circadian Rhythm Research in the department of medicine at Columbia University Irving Medical Center in New York.

The study has several limitations. First, the database includes countries that require a melatonin prescription (such as the United Kingdom) and countries that do not require it (such as the United States), and patient locations were not part of the anonymized data available to researchers. Since melatonin use in the study was based only on those identified from medication entries in the electronic health record, anyone taking it as an over-the-counter supplement in the United States or other countries that do not require a prescription would have been in the no-melatonin group; therefore, analyzes may not reflect this accurately. The hospitalization figures were also higher than those for the initial diagnosis of heart failure, because a series of associated diagnosis codes can be entered for hospitalization, and they do 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.

“More severe insomnia, depression/anxiety, or use of other sleep-enhancing medications could be linked to both melatonin use and cardiac risk,” Nnadi said. “Additionally, although the association we found raises safety concerns regarding the widely used supplement, our study cannot prove a direct cause-and-effect relationship. This means that additional research is needed to test the safety of melatonin for the heart.”

Study details, context and design:

• The study included 130,828 adults (mean age 55.7 years; 61.4% women) suffering from insomnia.
• The study data came from TriNetX, established in 2013, a growing global network of anonymized and real-world 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 was examined for comparison (control group): those who had never been prescribed melatonin and who were matched to the group taking melatonin on 40 factors, including demographic information, health conditions, and medications.
• Participants were excluded if they had ever been diagnosed with heart failure or had been prescribed other types of sleeping pills such as benzodiazepines.
• The melatonin and control groups were matched on age, gender, 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 five years after the match date.
• For key findings, records were searched for codes related to an initial diagnosis of heart failure. Secondary outcomes included hospitalization codes related to heart failure or death.
• Following the initial analyses, the researchers validated the credibility of their results by carrying out a sensitivity analysis. This involved changing the criteria slightly: They required participants in the melatonin group to have filled at least two melatonin prescriptions spaced at least 90 days apart. This adjustment aimed to determine whether the prolonged duration of confirmed melatonin prescriptions influenced the results.