Long-term melatonin use linked to increased risk of heart failure

Summary: A large-scale analysis of more than 130,000 adults with chronic insomnia found that long-term melatonin use (defined as one year or more) was associated with a striking increase in heart failure, hospitalization, and mortality risk. Using global health registries, researchers found that melatonin users were about 90% more likely to develop heart failure and almost twice as likely to die from any cause within five years.

The findings challenge the widespread perception of melatonin as a “natural” and completely safe sleep aid. Experts emphasize that while the study does not prove cause and effect, it highlights the urgent need for more research into the long-term cardiovascular safety of melatonin.

Key facts

Increased heart risk: Long-term melatonin users were up to 90% more likely to develop heart failure and 3.5 times more likely to be hospitalized. Link to mortality: Chronic melatonin use was linked to nearly double the risk of death from any cause in people with insomnia. Unregulated use: In the US, melatonin is sold over the counter and varies in potency and purity, complicating safety assessment.

Source: American Heart Association

Long-term use of melatonin supplements, often used to promote sleep and treat insomnia, was associated with an increased 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 American Heart Association’s 2025 Scientific Sessions.

The meeting, to be held November 7-10 in New Orleans, is a major global exchange of the latest scientific advances, research and evidence-based clinical practice updates in cardiovascular science.

Melatonin is a hormone produced naturally in the body by the pineal gland and helps regulate the body’s sleep-wake cycle. Melatonin levels increase during darkness and decrease during the day. Chemically identical synthetic versions of the hormone are often used to treat insomnia (difficulty falling or staying asleep) and jet lag.

Supplements are widely available without a prescription 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 concentration, 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 medical records) as part of the “melatonin group.” In contrast, those who never had melatonin recorded anywhere in their medical records were classified as the “no melatonin group.”

“Melatonin supplements may not be as harmless as commonly assumed. If our study is confirmed, this could affect how doctors advise patients about sleep aids,” said Ekenedilichukwu Nnadi, MD, lead author of the study and chief resident of 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 alters the risk of heart failure, specifically 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 to function properly and is a common condition affecting 6.7 million adults in the US.

Using a large international database (the TriNetX Global Research Network), researchers reviewed 5 years of electronic medical records of adults with chronic insomnia who had melatonin recorded in their medical 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 medical records indicated long-term melatonin use (12 months or more) were approximately 90% more likely to have heart failure within 5 years compared to non-users (4.6% vs. 2.7%, respectively). There was a similar result (82% higher) when researchers looked at people who had at least 2 melatonin prescriptions filled at least 90 days apart. (Melatonin is only available by prescription in the UK.)

A secondary analysis found:

Participants taking melatonin were almost 3.5 times more likely to be hospitalized for heart failure compared to those not taking melatonin (19.0% vs. 6.6%, respectively). Participants in the melatonin group were almost twice as likely to die from any cause as those in the no-melatonin group (7.8% vs. 4.3%, respectively) over the 5-year period.

“Melatonin supplements are widely considered a safe, ‘natural’ option to support better sleep, so it was surprising to see such consistent and significant increases in serious health outcomes, even after balancing many other risk factors,” Nnadi said.

“I am surprised that doctors prescribe melatonin for insomnia and have patients use it for more than 365 days, since melatonin, at least in the US, is not indicated for the treatment of insomnia. In the US, 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 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 Circadian and Sleep 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 do not (such as the United States), and the location of the patients was not part of the anonymized data available to the researchers.

Since melatonin use in the study was based only on those identified from medication entries in the electronic medical record, everyone who took it as an over-the-counter supplement in the US or other countries that do not require a prescription would have been in the no-melatonin group; therefore, analyzes may not accurately reflect this.

Hospitalization numbers were also higher than those for the initial heart failure diagnosis because a variety of related diagnosis codes can be entered for hospitalization and may not always include the code for a new heart failure diagnosis. 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 medications could be related to both melatonin use and cardiac risk,” Nnadi said.

“Furthermore, while the association we found raises concerns about the safety of the widely used supplement, our study cannot prove a direct cause-and-effect relationship. This means that more research is needed to test the safety of melatonin for the heart.”

Details, background and study design:

The study included 130,828 adults (average age 55.7 years; 61.4% women) diagnosed with insomnia. Data for the study came 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, heart and nervous system disease medications, blood pressure, and body mass index. The researchers examined electronic medical records for the five years following the matching date. For main findings, records were searched for codes related to an initial diagnosis of heart failure. Secondary findings included hospitalization codes related to heart failure or death. After initial analyses, the researchers validated the credibility of their findings by conducting a sensitivity analysis. This involved changing the criteria slightly: They required that participants in the melatonin group had filled at least two melatonin prescriptions at least 90 days apart. This adjustment was intended to determine whether the long duration of confirmed melatonin prescriptions influenced the results.

Co-authors, disclosures, and funding sources are listed in the abstract.

Key questions answered:

About this neurology research news

Author: Karen Astle
Source: American Heart Association
Contact: Karen Astle – American Heart Association
Image: Image is credited to Neuroscience News.

Original research: Findings to be presented at American Heart Association 2025 Scientific Sessions