Long-term use of melatonin supplements, often used to improve sleep and treat 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 2025 American Heart Association Scientific Sessions. The meeting, which will take place November 7-10 in New Orleans, is a premier global exchange of the latest scientific advances, research and updates to evidence-based clinical practice in the field of cardiovascular disease. science.
Melatonin is a hormone that is naturally produced in the body by the pineal gland and helps regulate the body's sleep-wake cycle. Melatonin levels increase in the dark and decrease in 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 United States. Over-the-counter supplements are not regulated in the US, so each brand of supplement may vary in strength, purity, etc.
In this study, researchers classified people who used melatonin long-term (with long-term use defined as a year or more recorded in their electronic health records) as part of the “melatonin group.” In contrast, those who never had melatonin recorded in their medical records were classified as the “non-melatonin group.”
Melatonin supplements may not be as harmless as commonly believed. If our study is confirmed, it could influence how doctors counsel patients about sleeping pills.”
Ekenedilichukwu Nnadi, MD, lead study author and chief resident in the Department of Internal Medicine at SUNY Downstate/Kings County Primary Care in Brooklyn, New York
Melatonin supplements are advertised and sold as a safe sleep aid; however, data supporting its long-term cardiovascular safety are lacking, prompting researchers to study whether melatonin use modifies the risk of heart failure, particularly in patients with chronic insomnia. 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 disease affecting 6.7 million adults in the United States, according to the American Heart Association's 2025 Heart Disease and Stroke Statistics.
Using a large international database (the TriNetX Global Research Network), researchers analyzed 5 years of electronic medical records for adults with chronic insomnia who had melatonin recorded in their medical records and used them for more than a year. They were matched with peers in the database who also had insomnia but never had melatonin in their medical records. People who had previously been diagnosed with heart failure or were prescribed other sleeping pills were excluded from the analysis.
The main analysis showed:
- Among adults with insomnia, those whose electronic health records indicated long-term melatonin use (12 months or more) had an approximately 90% higher risk of heart failure over 5 years compared with those who did not use melatonin (4.6% vs. 2.7%, respectively).
- The result was similar (82% higher) when the researchers analyzed people who received at least two melatonin prescriptions at least 90 days apart. (Melatonin is only available by prescription in the UK.)
Secondary analysis showed:
- Participants taking melatonin were nearly 3.5 times more likely to be hospitalized for heart failure than 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 as those in the non-melatonin group (7.8% vs. 4.3%, respectively) over the 5-year period.
“Melatonin supplements are widely considered a safe and 'natural' option for improving sleep, so it was striking to see such a consistent and significant increase in serious health effects, even after balancing out many other risk factors,” Nnadi said.
“I am surprised that doctors prescribe melatonin for insomnia and force 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 unless indicated,” said Marie-Pierre St. Onge, Ph.D., CCSH. FAHA, Chair of 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 nutrition in the department of general medicine and director of the Center of Excellence in Sleep and Circadian Rhythm Research at the School of Medicine at Columbia University Irving Medical Center in New York.
The study has several limitations. First, the database included countries that required a prescription for melatonin (eg, the UK) and countries that did not (eg, the US), and patient locations were not part of the anonymized data available to the researchers. Because melatonin use in the study was based only on those identified from medication records in the electronic health record, everyone who took it as an over-the-counter supplement in the US or other countries where a prescription is not required would have been in the no-melatonin group; therefore, analyzes may not accurately reflect this. Hospitalization rates were also higher than rates for a primary diagnosis of heart failure because a number of associated diagnostic codes may be entered for an admission and these may not always include a code for a new diagnosis of heart failure. The researchers also lacked information about the severity of insomnia and the presence of other mental disorders.
“Worsening insomnia, depression/anxiety, or use of other sleep-promoting medications may be associated with both melatonin use and heart risk,” Nnadi said. “Additionally, although the association we found raises concerns about the safety of a widely used supplement, our study cannot prove a direct cause-and-effect relationship. This means more research is needed to test the safety of melatonin for the heart.”
Study details, background and design:
- The study included 130,828 adults (mean age 55.7 years; 61.4% women) diagnosed with insomnia.
- The study data was drawn from TriNetX, established in 2013, a growing global network of real-life anonymized patient data available for research.
- 65,414 participants were prescribed melatonin at least once and reported taking it for at least a year.
- For comparison, a second group of people (the control group) were examined – those who had never been prescribed melatonin and were compared with the group taking melatonin on 40 factors, including demographics, health status and medications taken.
- Participants were excluded if they had already been diagnosed with heart failure or were prescribed other types of sleeping pills, such as benzodiazepines.
- The melatonin and control groups were matched on age, sex, race/ethnicity, heart condition, and health status. nervous system diseases, medications for heart and nervous system diseases, blood pressure and body mass index. The researchers examined electronic medical records for five years after the relevant date.
- To obtain primary outcomes, records were searched for codes associated with the initial diagnosis of heart failure. Secondary outcomes included hospitalization codes for heart failure or death.
- After the initial analysis, the researchers confirmed the validity of their findings by conducting a sensitivity analysis. This required a slight modification of the criteria: participants in the melatonin group had to have received at least two melatonin prescriptions at least 90 days apart. This adjustment was intended to determine whether increased duration of confirmed melatonin prescriptions affected the results.
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