Summary: A large analysis of over 130,000 adults with chronic insomnia found that long-term melatonin use — defined as one year or more — was associated with substantially higher rates of heart failure, hospital admissions for heart failure, and death from any cause. Using a global electronic health record database, researchers reported that people with documented long-term melatonin use had roughly 90% higher odds of developing heart failure and were nearly twice as likely to die within five years compared with matched insomnia patients who had no melatonin recorded.
These results challenge the common perception of melatonin as an entirely safe, “natural” sleep aid. Although the study is observational and cannot prove cause and effect, the findings highlight the need for careful evaluation of melatonin’s long-term cardiovascular safety and for additional controlled research.
Key Facts
- Heart risk increase: Long-term melatonin users showed up to 90% higher odds of being diagnosed with heart failure and a 3.5-fold greater likelihood of hospitalization for heart failure.
- Higher mortality: Chronic melatonin use was linked with nearly double the risk of death from any cause among people with insomnia over five years.
- Variable regulation: Melatonin is available over the counter in some countries, including the U.S., and product dose and purity can vary, complicating safety assessments.
Source: American Heart Association
Overview: This preliminary study, slated for presentation at the American Heart Association’s Scientific Sessions 2025, examined whether long-term melatonin use among adults with chronic insomnia is associated with increased risk of heart failure, heart failure hospitalization and all-cause mortality.
The Scientific Sessions meeting is a major international forum for sharing cardiovascular research and clinical updates. The study used the TriNetX Global Research Network to review five years of de-identified electronic health records from patients diagnosed with chronic insomnia.
Melatonin is a hormone produced by the pineal gland that helps regulate the sleep–wake cycle. Synthetic, chemically identical melatonin supplements are commonly used to treat insomnia and jet lag. Because regulations differ by country, some populations obtain melatonin by prescription and others as an over-the-counter supplement, which can lead to variability in dose and product quality.
In this analysis, people with at least one year of melatonin use recorded in their electronic health records were assigned to the “melatonin” group. Those with no record of melatonin anywhere in their medical records were assigned to the “non-melatonin” group. Individuals with prior heart failure or who had used other prescription sleep medications were excluded.
Key findings from the matched comparison of insomnia patients included:
- Adults with documented long-term melatonin use (12 months or more) had about a 90% higher probability of an incident heart failure diagnosis over five years than matched non-users (4.6% vs. 2.7%).
- A sensitivity analysis requiring at least two melatonin prescriptions filled 90 days apart produced a similar result (approximately 82% higher risk), supporting the consistency of the association.
Secondary analyses showed:
- Hospitalization for heart failure occurred more frequently in the melatonin group (19.0%) than in the non-melatonin group (6.6%), representing nearly a 3.5-fold difference.
- All-cause mortality over five years was higher among those with long-term melatonin recorded (7.8% vs. 4.3%), roughly a twofold increase.
Lead author Ekenedilichukwu Nnadi, M.D., noted that melatonin supplements “may not be as harmless as commonly assumed,” and that if these findings are confirmed they could change how clinicians advise patients about sleep aids. Experts not involved in the study pointed out that melatonin is often taken as an over-the-counter supplement in the U.S. and is not formally indicated for chronic insomnia treatment there; long-term use without medical supervision may be inappropriate.
The researchers and external reviewers emphasized important limitations. The dataset contains records from countries where melatonin may be prescription-only and from countries where it is available over the counter; patient location was not identifiable in the de-identified dataset. As a result, many over-the-counter melatonin users would be classified in the non-melatonin group if their use was not documented in the medical record, which could bias results.
Other limitations include possible confounding by insomnia severity, psychiatric conditions such as anxiety or depression, and the use of other sleep-promoting treatments that were not fully captured. Hospitalization coding practices may also vary, producing higher hospitalization counts than new-diagnosis counts for heart failure. Importantly, this observational study demonstrates association, not causation; further controlled and mechanistic research is needed to determine whether melatonin itself contributes to increased cardiovascular risk.
Study details and methods:
- The study population included 130,828 adults with insomnia (mean age 55.7 years; 61.4% women).
- Data source: TriNetX Global Research Network, a de-identified clinical dataset for research.
- 65,414 participants had records indicating at least one year of melatonin use.
- A matched control group of patients with insomnia and no melatonin recorded was assembled using 40 matching factors, including demographics, comorbidities and medication use.
- Participants with prior heart failure or prescriptions for other sleep medications (for example benzodiazepines) were excluded.
- Outcomes examined over five years included new heart failure diagnoses, hospitalizations related to heart failure, and all-cause mortality; a sensitivity analysis required at least two melatonin prescription fills at least 90 days apart.
Co-authors, disclosures and funding information are detailed in the study abstract presented to the American Heart Association.
Key Questions Answered:
A: Among adults with chronic insomnia, documented melatonin use lasting a year or longer was associated with higher rates of heart failure, more frequent hospitalizations for heart failure, and increased all-cause mortality compared with matched non-users.
A: Long-term melatonin users were about 90% more likely to receive a heart failure diagnosis, around 3.5 times more likely to be hospitalized for heart failure, and nearly twice as likely to die from any cause over five years in this dataset.
A: No. The study shows an association but cannot establish causation. Further controlled studies are needed to determine whether melatonin itself increases cardiovascular risk or whether other factors account for the observed differences.
About this neurology research news
Author: Karen Astle
Source: American Heart Association
Contact: Karen Astle – American Heart Association
Image: The image is credited to Neuroscience News
Original Research: Findings presented at the American Heart Association’s Scientific Sessions 2025