Preliminary research presented at the American Heart Association’s Scientific Sessions 2025 has revealed a concerning association between long-term use of melatonin, a widely accessible sleep supplement, and a heightened risk of heart failure, hospitalization for heart failure, and all-cause mortality among individuals struggling with chronic insomnia. While these findings do not establish a definitive causal link, they cast a significant shadow of doubt over the perceived safety of a supplement many consumers consider benign or a natural remedy for sleep disturbances.
The Ubiquitous Appeal of Melatonin
Melatonin, a hormone naturally produced by the pineal gland in the brain, plays a crucial role in regulating the body’s 24-hour sleep-wake cycle, or circadian rhythm. Its secretion typically increases with darkness, signaling the body to prepare for sleep, and decreases with daylight. Synthetic melatonin, chemically identical to its endogenous counterpart, is readily available over-the-counter in numerous countries, including the United States, and is frequently employed to address insomnia and the disruptions of jet lag.
However, the regulatory landscape for over-the-counter supplements in the U.S. presents a significant challenge. Unlike prescription medications, these products are not subject to rigorous oversight, meaning that the strength, purity, and actual content can vary substantially from one brand to another. This inherent variability complicates the interpretation of studies involving such supplements.
The research that generated these preliminary findings categorized participants based on their documented history of melatonin use. Individuals with at least one year of recorded melatonin consumption in their electronic medical records were classified into the "melatonin group." Conversely, those with no mention of melatonin use in their medical histories were assigned to the "non-melatonin group."
Dr. Ekenedilichukwu Nnadi, lead author of the study and chief resident in internal medicine at SUNY Downstate/Kings County Primary Care in Brooklyn, New York, articulated the study’s implications, stating, "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."
Investigating Cardiovascular Safety Over Time
Despite melatonin’s common promotion as a safe sleep aid, a critical gap exists in the scientific understanding of its cardiovascular safety profile when used for extended durations. It was this very uncertainty that propelled the research team to examine whether chronic melatonin use might be correlated with an elevated risk of heart failure in a population already predisposed by chronic insomnia.
Heart failure, a condition where the heart is unable to pump blood effectively to meet the body’s oxygen demands, is a significant public health concern. According to the American Heart Association’s 2025 Heart Disease and Stroke Statistics, approximately 6.7 million adults in the U.S. are affected by this condition.
To conduct their investigation, researchers accessed data from the TriNetX Global Research Network, an extensive international repository of de-identified electronic health records. The study meticulously reviewed five years of medical records for adults diagnosed with chronic insomnia. Participants who had records indicating melatonin use for over a year were carefully matched with individuals who also had insomnia but no documented history of melatonin use. Crucially, individuals with pre-existing heart failure diagnoses or those who had been prescribed other sleep medications were excluded from the study cohort to isolate the potential effects of melatonin.
Stark Findings: A Significant Increase in Heart Failure Risk
The primary analysis of the data revealed a striking disparity between the two groups. Among adults with chronic insomnia, those with a documented history of long-term melatonin use (spanning 12 months or more) exhibited approximately a 90% higher likelihood of developing heart failure within the subsequent five-year period when compared to their matched counterparts who did not use melatonin. Specifically, heart failure occurred in 4.6% of the melatonin group, contrasted with 2.7% in the non-melatonin group.
To bolster the confidence in the findings and ensure that participants genuinely engaged in extended melatonin usage, researchers conducted a secondary analysis. This refined analysis focused on individuals who had filled at least two melatonin prescriptions, with a minimum interval of 90 days between them. Even within this more stringent criterion, the association persisted, revealing an 82% higher risk of heart failure among this subset of long-term users. It is noteworthy that in the United Kingdom, melatonin is exclusively available by prescription, a regulatory difference that may influence usage patterns and record-keeping.
Beyond Heart Failure: Hospitalization and Mortality Rates Escalate
The secondary analyses unveiled even more pronounced differences across other critical health outcomes. Individuals in the melatonin group were nearly 3.5 times more likely to be hospitalized for heart failure than those in the control group. The hospitalization rates were starkly divergent: 19.0% for the melatonin users compared to 6.6% for the non-users.
Furthermore, the study indicated a higher incidence of mortality from any cause among individuals with documented long-term melatonin use. Over the five-year observation period, 7.8% of participants in the melatonin group died, in contrast to 4.3% in the non-melatonin group, signifying a nearly twofold increase in the risk of death.
Dr. Nnadi emphasized the unexpected nature of these findings: "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."
Expert Reactions and Concerns
The preliminary results have also drawn significant attention and concern from sleep research experts not directly involved in the study. Dr. Marie-Pierre St-Onge, Ph.D., C.C.S.H., FAHA, a sleep researcher and chair of the writing group for the American Heart Association’s 2025 scientific statement on "Multidimensional Sleep Health: Definitions and Implications for Cardiometabolic Health," expressed her surprise.
"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," Dr. St-Onge stated. "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." Dr. St-Onge, a professor of nutritional medicine at Columbia University Irving Medical Center, highlighted the importance of appropriate medical guidance when considering sleep aids.
Navigating the Nuances: Critical Limitations of the Study
Despite the alarming associations identified, it is imperative to acknowledge several significant limitations inherent in the study’s design and data collection. The varying regulatory status of melatonin across different countries presents a considerable challenge. In some nations, like the UK, it requires a prescription, while in others, such as the U.S., it is readily available as an over-the-counter product. The de-identified nature of the medical data precluded researchers from determining the geographical location of participants, thereby obscuring these crucial regulatory differences.
A primary limitation stems from how melatonin use was identified. The study relied solely on its appearance in electronic medical records. This means that individuals in countries where melatonin is purchased over-the-counter and not recorded in their medical files might have been inaccurately classified as non-users. Consequently, the "melatonin" and "non-melatonin" groups may not perfectly represent the actual consumption patterns of the supplement.
Another complication arose in the analysis of hospitalizations. The higher number of heart failure-related hospitalizations compared to newly diagnosed heart failure cases could be attributed to the way hospitals record diagnostic codes. It is possible that various related codes were used, and not all may specifically identify a new heart failure diagnosis, potentially inflating hospitalization figures.
Furthermore, the study lacked crucial information regarding the severity of participants’ insomnia and the presence of co-occurring psychiatric disorders. These factors are particularly relevant, as individuals with more severe insomnia, depression, anxiety, or other mental health conditions may be more inclined to use melatonin and could independently possess a different cardiovascular risk profile.
Dr. Nnadi acknowledged these complexities, noting, "Worse insomnia, depression/anxiety, or the use of other sleep-enhancing medicines might be linked to both melatonin use and heart risk. 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."
Broader Implications and Future Directions
The preliminary findings from the American Heart Association’s Scientific Sessions 2025 serve as a critical signal for both healthcare providers and consumers. They underscore the need for a more cautious and evidence-based approach to the widespread use of over-the-counter sleep aids, particularly for chronic conditions. The perception of melatonin as a universally safe and benign substance may require significant re-evaluation.
The study’s implications extend to public health messaging and the potential need for enhanced regulatory oversight or clearer consumer advisories regarding the long-term use of melatonin. As Dr. St-Onge pointed out, the lack of a formal indication for insomnia treatment in the U.S. for melatonin highlights a disconnect between its common usage and its approved therapeutic applications.
Moving forward, further robust, well-controlled research is essential to elucidate the precise mechanisms, if any, by which long-term melatonin use might impact cardiovascular health. Prospective studies with standardized data collection on supplement intake, duration, dosage, and purity, alongside comprehensive assessment of confounding factors, will be crucial. Until then, individuals experiencing chronic insomnia who are considering or currently using melatonin should engage in open dialogue with their healthcare providers to weigh the potential benefits against the emerging safety concerns. The focus remains on ensuring that sleep support strategies are both effective and, most importantly, safe for long-term well-being.
