• A large review of health data from more than 130,000 adults with insomnia found that people who took melatonin for a year or longer were more likely to develop heart failure, be hospitalized for the condition, or die from any cause compared to those who didn't take the supplement.
• While the study cannot prove that melatonin directly causes these outcomes, the strong association raises important safety questions about long-term use of this popular sleep aid. Researchers emphasize that more studies are needed to fully understand melatonin's impact on heart health and ensure it can be used safely.

Long-Term Melatonin Use Linked to Higher Heart Failure Risk

People who regularly take melatonin to improve sleep may face serious health risks. A preliminary study presented at the American Heart Association's Scientific Sessions 2025 found that adults with chronic insomnia who used melatonin for a year or longer were more likely to develop heart failure, be hospitalized for heart failure, and die from any cause than those who did not take the supplement. The findings will be discussed at the AHA's annual meeting, taking place Nov. 7-10 in New Orleans, a leading international event for cardiovascular science and clinical research updates.

Melatonin is a hormone produced by the pineal gland that regulates the body's sleep-wake cycle. Its levels naturally rise in the dark and drop during daylight hours. Synthetic melatonin, which is chemically identical to the natural hormone, is widely used to treat insomnia (difficulty falling and/or staying asleep) and jet lag. In many countries, including the U.S., melatonin supplements can be purchased over the counter. However, because they are not regulated in the U.S., products can differ widely in purity and dosage.

How the Study Was Conducted

Researchers divided participants into two groups based on their medical records. Those who had taken melatonin for at least one year were classified in the "melatonin group," while individuals with no record of melatonin use were placed in 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.

Investigating Heart Failure and Sleep Aid Safety

Although melatonin is marketed as a safe and natural sleep remedy, little evidence exists on its long-term cardiovascular effects. The research team wanted to know whether long-term use could influence heart failure risk in people 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 sustain the body's organs. The condition affects about 6.7 million U.S. adults.

To explore this question, scientists used data from the TriNetX Global Research Network, an international database of de-identified medical records. They reviewed five years of data on adults diagnosed with chronic insomnia who had documented melatonin use for more than a year. Each was matched with another person who also had insomnia but had never used melatonin. Individuals with a previous diagnosis of heart failure or who had been prescribed other sleep medications were excluded.

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 and Caution From Sleep Researchers

"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.

"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.

Note: The study featured in this article is a research abstract. Abstracts presented at American Heart Association's scientific meetings are not peer-reviewed, and the findings are considered preliminary until published as full manuscripts in a peer-reviewed scientific journal.

Published in Science Advances on October 24, 2025, the study suggests that simple retinal scans could eventually serve as a non-invasive tool to evaluate both cardiovascular health and biological aging. Such scans may one day help doctors detect problems early and guide preventive care before symptoms appear.

Linking the Eyes, Genes, and Blood

"By connecting retinal scans, genetics, and blood biomarkers, we have uncovered molecular pathways that help explain how aging affects the vascular system," says Marie Pigeyre, senior author of the study and an associate professor in McMaster's Department of Medicine.

According to Pigeyre, the eye provides an accessible and unique view into the body's circulatory system. "Changes in the retinal blood vessels often mirror changes occurring throughout the body's small vessels," she explains.

To explore these relationships, the researchers analyzed retinal images, genetic profiles, and blood samples from more than 74,000 participants drawn from four large-scale studies: the Canadian Longitudinal Study on Aging (CLSA), the Genetics of Diabetes Audit and Research Tayside Study (GoDARTS), the UK Biobank (UKBB), and the PHRI Prospective Urban Rural Epidemiological (PURE) study.

Their analysis revealed that individuals with simpler and less branched retinal vessels tended to have a higher likelihood of cardiovascular disease. These same individuals also showed biological signs of accelerated aging, including increased inflammation and a reduced lifespan.

Today, evaluating conditions related to aging such as heart disease, stroke, and dementia usually requires multiple, complex tests. Researchers hope that retinal imaging could one day simplify this process, providing a fast and accessible measure of both aging and cardiovascular risk. However, they note that for now, such scans are just one part of a broader clinical picture that still requires comprehensive testing.

Discovering Molecular Clues Behind Aging

A deeper look at blood biomarkers and genetic data revealed more than simple associations -- it pointed to biological mechanisms that may drive these changes. Researchers identified several key proteins linked to inflammation and vascular aging, suggesting new avenues for drug development.

Among the most notable proteins were MMP12 and IgG-Fc receptor IIb, both associated with age-related damage in blood vessels. According to Pigeyre, these molecules could represent promising therapeutic targets.

"Our findings point to potential drug targets for slowing vascular aging, reducing the burden of cardiovascular diseases, and ultimately improving lifespan," Pigeyre says.

The study drew on blood protein biomarker data from the PHRI-led Prospective Urban and Rural Epidemiological study, an international research initiative.

Funding for the project came from the Canadian Institutes of Health Research, the E.J. Moran Campbell Internal Career Research Award from McMaster University, and the Early Career Research Award from Hamilton Health Sciences (HHS). Retinal image analyses conducted through the CLSA were additionally supported by an HHS New Investigator Fund.

Scientists at the University of California San Diego School of Medicine have created a new method that combines artificial intelligence (AI) with cutting-edge molecular biology tools to uncover what determines whether a macrophage becomes inflammatory or restorative.

Their research also sheds light on a mystery that has puzzled scientists for decades: how a gene known as NOD2 influences this process. Discovered in 2001, NOD2 was the first gene linked to an increased risk of Crohn's disease.

Mapping the Gut's Genetic Blueprint

Using advanced machine learning, the team examined thousands of macrophage gene expression profiles taken from both healthy colon tissue and tissue affected by IBD. This analysis revealed a genetic signature made up of 53 genes that consistently distinguished between aggressive, inflammatory macrophages and those responsible for repairing tissue.

Among these 53 genes, one encodes a protein called girdin. The researchers discovered that in non-inflammatory macrophages, a particular part of the NOD2 protein attaches to girdin. This interaction helps keep inflammation under control, removes harmful bacteria, and allows tissue to heal. However, the most common Crohn's disease mutation in the NOD2 gene deletes the section where girdin normally binds. Without that connection, the system becomes unbalanced, tipping toward chronic inflammation.

"NOD2 functions as the body's infection surveillance system," said senior author Pradipta Ghosh, M.D., professor of cellular and molecular medicine at UC San Diego School of Medicine. "When bound to girdin, it detects invading pathogens and maintains gut immune balance by swiftly neutralizing them. Without this partnership, the NOD2 surveillance system collapses."

Testing the Discovery in Animal Models

To confirm their findings, the scientists compared mouse models of Crohn's disease that lacked the girdin protein with those that still had it. The mice missing girdin developed severe gut inflammation and an altered microbiome, and many died from sepsis, a dangerous condition caused by an uncontrolled immune response that inflames the entire body and harms vital organs.

"The gut is a battlefield, and macrophages are the peacekeepers," said co-first author Gajanan D. Katkar, Ph.D., assistant project scientist at UC San Diego School of Medicine. "For the first time, AI has allowed us to clearly define and track the players on two opposing teams."

Toward New Treatments for Crohn's Disease

By merging AI-based analysis, biochemical research, and animal experiments, the study resolves one of the longest-standing questions in Crohn's disease research. The findings explain how a crucial genetic mutation drives inflammation and could guide the development of new therapies aimed at restoring the lost partnership between girdin and NOD2.

The study was published on October 2 in the Journal of Clinical Investigation.