Preliminary research presented at the American Heart Association’s Scientific Sessions 2025 has unveiled a potential association between the 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 diagnosed with chronic insomnia. While these findings do not establish a definitive causal link, they prompt a critical re-evaluation of the perceived safety of melatonin, a supplement often considered benign or "natural" for sleep enhancement.
The Ubiquitous Nature of Melatonin
Melatonin, a hormone naturally synthesized by the pineal gland in the brain, plays a crucial role in regulating the body’s sleep-wake cycle, commonly known as the circadian rhythm. Its production typically increases with darkness and diminishes with daylight. Synthetic melatonin, chemically identical to its endogenous counterpart, is widely employed to address sleep disturbances such as insomnia and the effects of jet lag. Available over-the-counter in numerous countries, including the United States, the regulatory landscape for melatonin supplements varies significantly. In the U.S., for instance, the lack of stringent oversight means that the strength, purity, and composition can differ considerably between brands.
This variability underscores a significant challenge in assessing the safety and efficacy of over-the-counter sleep aids. The recent study aimed to address the knowledge gap regarding the long-term cardiovascular implications of melatonin use, particularly within a vulnerable population already struggling with chronic sleep difficulties.
Investigating Cardiovascular Safety: A Growing Concern
Despite melatonin’s popular reputation as a safe sleep aid, scientific evidence supporting its cardiovascular safety over extended periods of use has been notably limited. This uncertainty propelled a research team to investigate a potential association between chronic melatonin consumption and the development of heart failure in individuals with pre-existing chronic insomnia.
Heart failure, a condition where the heart’s ability to pump oxygenated blood sufficiently to meet the body’s demands is compromised, affects an estimated 6.7 million adults in the U.S., according to the American Heart Association’s 2025 Heart Disease and Stroke Statistics. It is crucial to note that heart failure does not signify a complete cessation of heart function but rather a decline in its pumping efficiency.
The research team leveraged data from the TriNetX Global Research Network, a comprehensive international database comprising de-identified electronic health records. Their methodology involved examining five years of medical histories of adults diagnosed with chronic insomnia who had documented melatonin use exceeding one year. These individuals were then meticulously matched with a control group of individuals with insomnia but no recorded history of melatonin use. Participants with pre-existing heart failure diagnoses or those prescribed other sleep medications were deliberately excluded from the study to isolate the potential effects of melatonin.
Study Design and Key Findings
The study’s design meticulously categorized participants into two distinct groups: the "melatonin group," comprising individuals with at least one year of recorded melatonin use in their electronic medical records, and the "non-melatonin group," consisting of individuals with no documented melatonin use within their medical histories.
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, highlighted the study’s implications: "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 primary analysis revealed a striking disparity between the two groups. Among adults with insomnia, those with documented long-term melatonin use (defined as 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 non-user counterparts. Specifically, heart failure occurred in 4.6% of the melatonin group, contrasting with 2.7% in the comparison group.
To further bolster the reliability of the findings, researchers conducted a secondary analysis specifically designed to enhance confidence in the participants’ extended melatonin usage. This refined analysis focused on individuals who had filled at least two melatonin prescriptions separated by at least 90 days. Even within this more stringent cohort, the association persisted, with the group reporting an 82% higher risk of heart failure. This observation is particularly relevant given that melatonin is available by prescription in some regions, such as the United Kingdom, suggesting a more formalized pattern of use.
Beyond Heart Failure: Increased Hospitalization and Mortality
The study’s secondary analyses uncovered even more pronounced differences in other critical health outcomes. Individuals in the melatonin group were nearly 3.5 times more likely to be hospitalized for heart failure compared to the control group, with hospitalization rates standing at 19.0% and 6.6%, respectively.
Furthermore, deaths from any cause were found to be more prevalent among individuals with documented long-term melatonin use. Over the five-year study period, 7.8% of participants in the melatonin group died, compared to 4.3% in the non-melatonin group, indicating a nearly twofold increase in mortality risk.
Dr. Nnadi reiterated the significance 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 study’s results have elicited concern from the wider scientific community. Dr. Marie-Pierre St-Onge, Ph.D., C.C.S.H., FAHA, a sleep researcher not involved in the study, expressed surprise at the findings. "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," she 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 holds a prominent position as the chair of the writing group for the American Heart Association’s 2025 scientific statement, "Multidimensional Sleep Health: Definitions and Implications for Cardiometabolic Health." She is also a professor of nutritional medicine at Columbia University Irving Medical Center.
Navigating the Complexities and Limitations
Despite the compelling nature of the findings, the study is subject to several significant limitations that warrant careful consideration, particularly given the diverse regulatory approaches to melatonin worldwide. The fact that melatonin is available by prescription in some countries, like the UK, while being an over-the-counter product in others, such as the U.S., complicates direct comparisons and interpretations. The researchers did not have access to participants’ geographical locations due to the de-identified nature of the medical data, which prevented them from accounting for these regulatory differences.
A crucial limitation stems from how melatonin use was identified. Reliance on its appearance in electronic medical records means that individuals in the U.S. or other regions who purchased melatonin over-the-counter without it being documented in their medical files may have been misclassified as non-users. This potential misclassification could have skewed the study’s findings, leading to an inaccurate representation of the true melatonin and non-melatonin user groups.
Further complexities arose in the analysis of hospitalizations. The number of heart failure-related hospitalizations was higher than the number of newly diagnosed heart failure cases. This discrepancy can be attributed to hospitals potentially using a variety of related diagnostic codes, some of which may not specifically identify a new heart failure diagnosis.
Moreover, the study lacked data on the severity of each participant’s insomnia or the presence of other psychiatric disorders. These omitted factors are critical because individuals with more severe insomnia, depression, anxiety, or other mental health conditions might be more inclined to use melatonin and could possess an independent predisposition to cardiovascular risk.
"Worse insomnia, depression/anxiety, or the use of other sleep-enhancing medicines might be linked to both melatonin use and heart risk," Dr. Nnadi acknowledged. "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."
Future Directions and Public Health Implications
The preliminary findings from the American Heart Association’s Scientific Sessions 2025 serve as a crucial call for further investigation into the long-term cardiovascular effects of melatonin. While the supplement is widely perceived as a safe and natural sleep aid, this research suggests that this perception may need to be tempered with caution, especially for individuals with chronic insomnia who may be using it consistently over extended periods.
The implications for public health are substantial. Healthcare providers may need to adjust their counseling strategies regarding sleep aids, emphasizing the importance of discussing long-term supplement use with patients. Furthermore, regulatory bodies and manufacturers might face increased pressure to provide clearer guidance on the appropriate duration of melatonin use and to conduct more robust studies on its chronic safety profile.
As the scientific community delves deeper into these findings, the overarching message remains one of informed caution. The perceived harmlessness of melatonin should not preclude a thorough understanding of its potential long-term health impacts, particularly for populations with pre-existing health conditions. Future research, employing more rigorous methodologies and diverse populations, will be essential in definitively clarifying the relationship between melatonin use and cardiovascular health.
