Long-term use of melatonin, a widely used sleep supplement, was linked to a higher risk of heart failure, hospitalization for heart failure, and death from any cause among people with chronic insomnia, according to preliminary research presented at the American Heart Association’s Scientific Sessions 2025.
The findings do not prove that melatonin itself caused the increased risks. However, they raise new questions about the long-term safety of a supplement that many people view as a harmless or “natural” way to improve sleep.
Why Melatonin Is So Widely Used
Melatonin is a hormone made naturally by the pineal gland in the brain. It helps control the body’s sleep and wake cycle, also known as the circadian rhythm. Levels of the hormone typically rise when it gets dark and fall during daylight.
Synthetic melatonin is chemically identical to the hormone produced by the body. It is commonly used for insomnia (difficulty falling and/or staying asleep) and jet lag.
Melatonin supplements are 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.
For the new study, researchers divided participants according to their documented melatonin use. People with at least one year of melatonin use recorded in their electronic medical records were placed in the “melatonin group.” Those with no record of melatonin use anywhere in their medical records were assigned to 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.
Researchers Looked for Long-Term Heart Risks
Melatonin is often promoted as a safe sleep aid, but researchers say there is limited evidence about its cardiovascular safety when taken for extended periods.
That uncertainty led the team to investigate whether long-term melatonin use might be associated with heart failure among people who already had chronic insomnia.
Heart failure does not mean that the heart has completely stopped working. It develops when the heart cannot pump enough oxygen-rich blood to meet the body’s needs. According to the American Heart Association’s 2025 Heart Disease and Stroke Statistics, the condition affects about 6.7 million adults in the U.S.
Researchers used data from the TriNetX Global Research Network, a large international database containing de-identified electronic health records.
They examined five years of medical records for adults with chronic insomnia whose records showed melatonin use for more than a year. Those participants were matched with other people who also had insomnia but had no documented melatonin use.
Anyone who had already been diagnosed with heart failure or who had been prescribed other sleep medications was excluded.
Heart Failure Risk Was About 90% Higher
The main analysis found a substantial difference between the two groups.
Among adults with insomnia, people with documented long-term melatonin use (12 months or more) had about a 90% higher chance of developing heart failure during the following five years compared with matched nonusers. Heart failure occurred in 4.6% of the melatonin group compared with 2.7% of the comparison group.
Researchers then performed another analysis designed to strengthen confidence that participants had actually been using melatonin over an extended period.
When they limited the analysis to people who had filled at least two melatonin prescriptions at least 90 days apart, the association remained. That group had an 82% higher risk of heart failure. (Melatonin is only available by prescription in the United Kingdom.)
Hospitalization and Death Were Also Higher
A secondary analysis found even larger differences in some outcomes.
People in the melatonin group were nearly 3.5 times as likely to be hospitalized for heart failure as those in the comparison group. The hospitalization rates were 19.0% and 6.6%, respectively.
Deaths from any cause were also more common among people with documented melatonin use. During the five-year period, 7.8% of participants in the melatonin group died compared with 4.3% of those in the non-melatonin group, making the risk nearly twice as high.
“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.
The results also drew concern from sleep researcher Marie-Pierre St-Onge, Ph.D., C.C.S.H., FAHA, who was not involved in the study.
“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 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.
Important Limitations Complicate the Findings
The study comes with several significant limitations, particularly because melatonin is handled differently from one country to another.
Some countries, such as the United Kingdom, require a prescription for melatonin, while others, including the United States, allow people to buy it over the counter. Researchers did not have access to participants’ locations because the medical data had been de-identified.
Melatonin use was identified only when it appeared in electronic medical records. That means people in the U.S. or other countries who bought melatonin over the counter without having it entered into their medical records could have been incorrectly classified as nonusers.
As a result, the melatonin and nonmelatonin groups may not perfectly reflect who was actually taking the supplement.
There was another complication involving hospitalizations. The number of heart failure-related hospitalizations was higher than the number of newly diagnosed heart failure cases because hospitals may enter a variety of related diagnostic codes. Those records do not always include a code specifically identifying a new heart failure diagnosis.
Researchers also did not have information about how severe each participant’s insomnia was or whether participants had other psychiatric disorders.
Those missing factors are important because people with more severe insomnia, depression, anxiety, or other conditions may be more likely to use melatonin and could independently have a different cardiovascular risk.
“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.”
What the Study Included
- The analysis included 130,828 adults (average age of 55.7 years; 61.4% women) who had been diagnosed with insomnia.
- The data came from TriNetX, established in 2013, a growing global network of real-world, de-identified patient information used for medical research.
- Of the participants, 65,414 had been prescribed melatonin at least once and reported using it for at least one year.
- Researchers also created a comparison group (control group) made up of people who had never been prescribed melatonin. These participants were matched to the melatonin group using 40 factors, including demographic characteristics, existing health conditions, and medications.
- Anyone who had already been diagnosed with heart failure was excluded, as were people who had been prescribed other kinds of sleeping pills such as benzodiazepines.
- The melatonin and comparison 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 then examined electronic medical records covering the five years after the groups were matched.
- For the primary analysis, they searched for medical codes indicating an initial diagnosis of heart failure. Secondary outcomes included codes associated with hospitalization for heart failure or death.
- The researchers also carried out what is known as a sensitivity analysis, a method used to check whether results remain similar when the study criteria are changed slightly.
- For this additional test, participants in the melatonin group had to have filled at least two melatonin prescriptions at least 90 days apart. The association with higher heart failure risk remained, providing an additional check on the original findings.
- Even so, the researchers emphasize that the study was observational. It identified an association between long-term documented melatonin use and serious health outcomes, but it cannot establish that melatonin directly caused those outcomes. Further research will be needed to determine whether long-term melatonin use itself affects cardiovascular health and, if so, why.
