From scitechdaily.com
A five-year review of over 130,000 adults with insomnia found that long-term melatonin use was linked to a higher risk of heart failure and death, prompting researchers to call for further study into its cardiovascular safety.
People who regularly used melatonin supplements for at least a year were found to have a higher likelihood of being diagnosed with heart failure, being hospitalized for heart failure, or dying from any cause compared with those who did not use the supplement.
The finding comes from a preliminary study that will be presented at the American Heart Association’s Scientific Sessions 2025, held November 7–10 in New Orleans.
Melatonin is a hormone produced naturally by the pineal gland in the brain, where it helps control the body’s internal clock and the cycle of sleep and wakefulness. Levels rise at night and drop during the day. Synthetic melatonin, which is chemically identical to the natural hormone, is commonly taken to help with insomnia (difficulty falling and/or staying asleep) and jet lag. The supplement can be purchased without a prescription in many countries, including the United States. However, because over-the-counter products in the U.S. are not regulated, the amount and purity of melatonin can differ significantly between brands.
For this research, scientists reviewed electronic health records and grouped participants according to their melatonin use. Individuals who had documented use of melatonin for one year or longer were placed in the “melatonin group.” Those who had no record of melatonin use in their medical files were categorized 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,” 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.
Why Researchers Investigated Melatonin’s Heart Effects
Melatonin supplements are widely advertised as a safe and natural way to improve sleep. However, there has been little research on how long-term use might affect heart health. This gap in knowledge led scientists to investigate whether taking melatonin regularly could influence the risk of developing heart failure, particularly among people with chronic insomnia.
According to the American Heart Association, heart failure occurs when the heart is unable to pump enough oxygen-rich blood to meet the body’s needs. The condition is common, affecting about 6.7 million adults in the United States.
To explore a possible connection, researchers analyzed data from the TriNetX Global Research Network, a large international database of electronic health records. They examined five years of records from adults with chronic insomnia who had documentation of melatonin use lasting more than one year. These participants were compared with others who also had insomnia but no record of taking melatonin. Individuals were excluded from the study if they already had a diagnosis of heart failure or had been prescribed other types of sleep medication.
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.
Expert Reactions
”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.
Interpreting the Results
“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.
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