A recent preliminary investigation has cast a spotlight on the long-term safety profile of melatonin, a widely consumed sleep aid, suggesting a significant association with elevated risks of heart failure, related hospitalizations, and all-cause mortality among individuals grappling with chronic insomnia. These findings, presented at the American Heart Association’s Scientific Sessions 2025, initiate a critical reevaluation of a supplement frequently perceived as benign or a "natural" solution for sleep disturbances. While the study meticulously identifies an alarming correlation, it is crucial to underscore that the research establishes an association rather than a definitive causal link between prolonged melatonin intake and these adverse cardiovascular outcomes. Nevertheless, the implications are substantial, prompting health professionals and the public alike to reconsider the casual use of this over-the-counter remedy for extended periods.
Melatonin is a hormone naturally synthesized by the pineal gland, a small endocrine gland situated deep within the brain. Its primary physiological function revolves around regulating the body’s intrinsic sleep-wake cycle, known as the circadian rhythm. Typically, endogenous melatonin levels rise in response to darkness, signaling the body to prepare for sleep, and subsequently diminish with exposure to light. This natural fluctuation is fundamental to maintaining healthy sleep patterns. Synthetic melatonin, manufactured to be chemically identical to its endogenous counterpart, has gained immense popularity as an exogenous supplement. It is commonly utilized to alleviate transient insomnia—difficulties in initiating or maintaining sleep—and to mitigate the disruptive effects of jet lag, helping travelers synchronize their internal clocks with new time zones.
The widespread availability and perception of melatonin as a "natural" substance contribute significantly to its pervasive use. In many nations, including the United States, melatonin supplements are readily available without a prescription, sold over-the-counter in various formulations and dosages. This accessibility, however, comes with a notable regulatory caveat. Unlike pharmaceutical drugs, dietary supplements in the U.S. are not subject to the same stringent pre-market approval processes by the Food and Drug Administration (FDA). This regulatory framework means that the potency, purity, and even the precise content of melatonin can vary considerably from one brand to another, and from batch to batch, without comprehensive governmental oversight. In contrast, countries such as the United Kingdom classify melatonin as a prescription-only medication, mandating medical consultation and supervision for its use, particularly for chronic conditions. This international divergence in regulatory approaches highlights a fundamental aspect of the debate surrounding melatonin’s long-term safety.
The impetus behind this particular study stemmed from a recognized void in scientific literature concerning the prolonged cardiovascular effects of melatonin. Despite its widespread promotion as a safe and gentle sleep aid, comprehensive evidence detailing its cardiovascular safety over extended periods remained notably scarce. This critical knowledge gap motivated the research team to investigate whether sustained melatonin supplementation might be linked to the onset of heart failure in a specific demographic: individuals already diagnosed with chronic insomnia. Heart failure, a serious and progressive medical condition, does not imply that the heart has ceased functioning entirely. Rather, it signifies that the heart muscle is unable to pump an adequate volume of oxygen-rich blood to meet the metabolic demands of the body’s organs and tissues. According to the American Heart Association’s 2025 Heart Disease and Stroke Statistics, this debilitating condition impacts approximately 6.7 million adults within the United States, underscoring its significant public health burden.
To conduct their investigation, researchers leveraged data from the TriNetX Global Research Network, an extensive international database comprising de-identified electronic health records. This robust data source allowed for the analysis of vast amounts of patient information while safeguarding individual privacy. The study design involved examining five years of medical records belonging to adult participants suffering from chronic insomnia. These individuals were stratified into two distinct cohorts: a "melatonin group" comprising those with documented melatonin use spanning at least one year within their electronic medical records, and a "non-melatonin group" consisting of individuals with no recorded history of melatonin supplementation. To ensure a rigorous comparison, participants in the melatonin group were carefully matched with counterparts in the non-melatonin group based on a multitude of demographic and clinical characteristics, thereby minimizing potential confounding factors. Crucially, any individuals with a pre-existing diagnosis of heart failure or those who had been prescribed other sleep-inducing medications were systematically excluded from the analysis to isolate the specific effects associated with melatonin.
The primary analysis of the data revealed a statistically significant disparity between the two cohorts. Among adults suffering from chronic insomnia, those with a documented history of long-term melatonin use—defined as 12 months or more—exhibited an approximate 90% higher probability of developing heart failure over the subsequent five-year period when compared to their matched non-user counterparts. Specifically, heart failure was diagnosed in 4.6% of individuals within the melatonin group, compared to 2.7% in the comparison group. To further strengthen the confidence in these findings and address potential misclassification, researchers conducted a secondary analysis. This refined approach focused exclusively on individuals who had demonstrated consistent melatonin use by filling at least two prescriptions for the supplement, with a minimum interval of 90 days between refills. Even under this more stringent criterion, the elevated risk persisted, with this subgroup demonstrating an 82% higher risk of developing heart failure. This particular analysis primarily reflects data from regions where melatonin is a prescription-only medication, such as the United Kingdom, offering a glimpse into usage patterns under stricter medical supervision.
Beyond the incidence of new heart failure diagnoses, the study also uncovered even more pronounced differences in other critical health outcomes. Individuals in the melatonin group faced nearly a 3.5-fold increased likelihood of requiring hospitalization for heart failure compared to those in the non-melatonin group. The hospitalization rates were strikingly disparate, standing at 19.0% for melatonin users versus 6.6% for non-users. Furthermore, the analysis indicated a heightened risk of all-cause mortality among those with documented melatonin use. Over the five-year observation period, 7.8% of participants in the melatonin group succumbed to death from any cause, almost double the rate observed in the non-melatonin group, which recorded 4.3%. Dr. Ekenedilichukwu Nnadi, the lead author of the study and chief resident in internal medicine at SUNY Downstate/Kings County Primary Care in Brooklyn, New York, articulated the gravity of these findings, stating that it was "striking to see such consistent and significant increases in serious health outcomes, even after balancing for many other risk factors," given the widespread perception of melatonin as a benign and natural sleep aid.
These preliminary results also elicited concern from other prominent sleep researchers, including Dr. Marie-Pierre St-Onge, Ph.D., C.C.S.H., FAHA, who was not directly involved in the study. Dr. St-Onge, who chairs the writing group for the American Heart Association’s 2025 scientific statement on Multidimensional Sleep Health, expressed surprise at the notion of physicians prescribing melatonin for chronic insomnia for periods exceeding a year, particularly in the U.S. where it is not specifically indicated for such long-term treatment. As a professor of nutritional medicine and director of the Center of Excellence for Sleep & Circadian Research at Columbia University Irving Medical Center, Dr. St-Onge emphasized that while melatonin is available as an over-the-counter supplement in the U.S., the public should be acutely aware that chronic, unsupervised use without a proper medical indication is not advisable. Her commentary highlights a significant disconnect between the common practice of self-medication with melatonin and established medical guidelines, especially considering the lack of robust long-term safety data.
Despite the compelling nature of these findings, the study is accompanied by several important limitations that warrant careful consideration in interpreting its results. A primary challenge arises from the de-identified nature of the medical data, which precluded researchers from ascertaining participants’ geographic locations. This factor is critical because the regulatory status of melatonin varies significantly across countries; it is prescription-only in some nations like the United Kingdom, while widely available over-the-counter in others, including the United States. Consequently, melatonin use was only identifiable if it was formally recorded in electronic medical records. This creates a potential for misclassification, particularly for individuals in countries like the U.S. who purchased melatonin over-the-counter without any medical documentation, potentially leading them to be incorrectly categorized as non-users. This inherent limitation suggests that the "melatonin" and "non-melatonin" groups might not perfectly reflect actual supplement usage patterns.
Another complicating factor involved the recording of hospitalizations. The study observed a higher number of hospitalizations coded as related to heart failure than the number of newly diagnosed heart failure cases. This discrepancy can arise because hospitals often utilize a range of related diagnostic codes for admissions, which may not always include a specific code definitively identifying a new heart failure diagnosis. Furthermore, the researchers lacked access to crucial granular data regarding the severity of each participant’s insomnia or the presence of other co-occurring psychiatric disorders, such as depression or anxiety. These missing clinical details are significant because individuals experiencing more severe insomnia or mental health conditions might be independently more inclined to use melatonin, and concurrently, may possess an intrinsically higher baseline cardiovascular risk. As Dr. Nnadi acknowledged, "Worse insomnia, depression/anxiety, or the use of other sleep-enhancing medicines might be linked to both melatonin use and heart risk." He further reiterated that while the observed association raises legitimate safety concerns regarding this widely used supplement, the study’s design precludes the establishment of a direct cause-and-effect relationship, underscoring the imperative for further, more definitive research to thoroughly evaluate melatonin’s cardiovascular safety.
In conclusion, this preliminary research serves as a pivotal call for caution and a catalyst for deeper scientific inquiry into the long-term ramifications of melatonin supplementation. While it does not definitively prove that melatonin causes heart failure, the strong association observed warrants a reevaluation of clinical recommendations and public perception surrounding its chronic use. For individuals currently taking melatonin or considering it for ongoing sleep issues, consulting with a healthcare provider is paramount. This allows for an informed discussion of potential risks and benefits, exploration of alternative evidence-based sleep therapies, and consideration of the individual’s overall health profile. The scientific community eagerly awaits subsequent, more robust studies, potentially including randomized controlled trials, which are essential to fully elucidate the complex interplay between melatonin, sleep health, and long-term cardiovascular well-being.
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