Preliminary findings presented at the American Heart Association’s Scientific Sessions 2025 have illuminated a potential association between prolonged consumption of melatonin, a popular sleep aid, and an increased incidence of heart failure, subsequent hospitalizations for cardiac events, and overall mortality among individuals grappling with chronic insomnia. While these observations do not definitively establish melatonin as the causative agent, they introduce significant questions regarding the long-term cardiovascular safety of a substance frequently perceived as benign or a natural remedy for sleep disturbances.
Melatonin, a neurohormone intrinsically produced by the pineal gland within the brain, plays a pivotal role in regulating the human body’s natural sleep-wake cycles, commonly referred to as circadian rhythms. Its secretion naturally escalates in the absence of light, signaling the body for rest, and diminishes with the onset of daylight. The synthetic version, chemically indistinguishable from its endogenous counterpart, is widely employed to address insomnia, characterized by difficulties initiating or maintaining sleep, and to mitigate the effects of jet lag. Its accessibility as an over-the-counter supplement in numerous jurisdictions, including the United States, contributes to its widespread use. However, the regulatory landscape for dietary supplements in the U.S. lacks the stringent oversight applied to pharmaceuticals, leading to considerable variability in the potency and purity of different melatonin products available on the market.
The investigative team behind this research meticulously categorized study participants based on their documented history of melatonin usage. Individuals whose electronic medical records indicated consistent melatonin intake for a minimum of one year were designated as the "melatonin group." Conversely, those with no recorded instances of melatonin use within their comprehensive medical histories were assigned to the "non-melatonin group." Dr. Ekenedilichukwu Nnadi, the lead author of the study and a chief resident in internal medicine at SUNY Downstate/Kings County Primary Care in Brooklyn, New York, commented on the 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."
The researchers’ impetus for this investigation stemmed from the prevalent perception of melatonin as a safe sleep facilitator, juxtaposed with a discernible scarcity of robust evidence concerning its cardiovascular safety profile when administered over extended durations. This knowledge gap prompted the team to explore a potential correlation between chronic melatonin consumption and the development of heart failure in individuals already contending with persistent insomnia. Heart failure, it is important to clarify, does not signify a complete cessation of cardiac function but rather describes a condition where the heart’s pumping capacity is insufficient to adequately perfuse the body with oxygenated blood. Statistics from the American Heart Association’s 2025 Heart Disease and Stroke Statistics indicate that this condition affects an estimated 6.7 million adults in the United States.
To conduct their analysis, the researchers leveraged the extensive de-identified electronic health records housed within the TriNetX Global Research Network, a substantial international repository. Their examination encompassed a five-year span of medical histories belonging to adults diagnosed with chronic insomnia who had records demonstrating melatonin use exceeding one year. These individuals were then systematically matched with a control cohort, also suffering from insomnia but without any documented history of melatonin supplementation. To ensure the integrity of the comparison, any participant who had a pre-existing diagnosis of heart failure or who had been prescribed alternative sleep medications was deliberately excluded from the study cohort.
The principal analytical phase revealed a statistically significant disparity between the two defined groups. Among adults diagnosed with insomnia, those with a documented history of long-term melatonin use, defined as 12 months or more, exhibited an approximate 90% heightened likelihood of developing heart failure within the subsequent five-year observation period when contrasted with their matched counterparts who did not use melatonin. Specifically, heart failure manifested in 4.6% of individuals in the melatonin group, compared to 2.7% in the non-melatonin group. To further bolster the certainty of prolonged melatonin usage, the researchers conducted a subsequent analysis that focused on participants who had filled at least two melatonin prescriptions with a minimum interval of 90 days between them. This refined analysis maintained the observed association, revealing an 82% elevated risk of heart failure in this more stringently defined group. It is noteworthy that in certain regions, such as the United Kingdom, melatonin is available only by prescription.
Beyond the primary endpoint of heart failure development, secondary analyses uncovered even more pronounced differences in other critical health outcomes. Individuals within the melatonin-consuming cohort demonstrated a nearly 3.5-fold greater propensity for hospitalization due to heart failure when compared to the control group, with hospitalization rates standing at 19.0% and 6.6%, respectively. Furthermore, all-cause mortality was observed to be more prevalent among those with documented long-term melatonin use. Over the five-year study duration, 7.8% of participants in the melatonin group succumbed to various causes, in stark contrast to the 4.3% mortality rate observed in the non-melatonin group, effectively doubling the risk. Dr. Nnadi reiterated his surprise at these findings, emphasizing, "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."
These results also elicited a concerned response from Dr. Marie-Pierre St-Onge, a sleep researcher not involved in the study, who holds a Ph.D. and is a Fellow of the American Heart Association (FAHA). Dr. St-Onge, who chairs the writing group for the American Heart Association’s 2025 scientific statement on "Multidimensional Sleep Health: Definitions and Implications for Cardiometabolic Health," expressed her astonishment, noting, "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." Dr. St-Onge is a professor of nutritional medicine at Columbia University Irving Medical Center and directs its Center of Excellence for Sleep & Circadian Research.
The interpretability of these findings is significantly tempered by several inherent limitations, particularly given the divergent regulatory frameworks governing melatonin across different nations. While countries like the United Kingdom mandate a prescription for melatonin, its over-the-counter availability in the United States and elsewhere presents a unique challenge. Crucially, the de-identified nature of the medical data precluded researchers from ascertaining the geographical location of study participants. This limitation means that individuals in countries where melatonin is readily available without a prescription, and who did not have their use formally documented in their medical records, may have been inaccurately classified as non-users. Consequently, the distinct groups may not perfectly mirror the actual prevalence of melatonin consumption.
Another complicating factor arose from the classification of hospitalizations. The recorded number of heart failure-related hospitalizations exceeded the count of newly diagnosed heart failure cases. This discrepancy can be attributed to hospitals potentially utilizing a range of diagnostic codes that are associated with heart failure, rather than exclusively a specific code identifying a new diagnosis. Furthermore, the study lacked access to crucial information regarding the severity of each participant’s insomnia, as well as the presence of other co-occurring psychiatric disorders. These missing variables are of considerable importance, as individuals experiencing more severe insomnia, depression, anxiety, or other psychological conditions might be more inclined to seek out melatonin and could independently possess a distinct cardiovascular risk profile. Dr. Nnadi acknowledged these potential confounders, stating, "Worse insomnia, depression/anxiety, or the use of other sleep-enhancing medicines might be linked to both melatonin use and heart risk." He concluded by underscoring the study’s limitations, "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."
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