Long-Term Melatonin Use Linked to Increased Risk of Heart Failure and Mortality in Preliminary Study

The routine, long-term consumption of melatonin—a widely utilized and generally trusted sleep supplement—has been associated with a significantly elevated risk of heart failure, heart failure-related hospitalizations, and all-cause mortality among individuals suffering from chronic insomnia. These findings stem from preliminary research presented at the American Heart Association’s Scientific Sessions 2025, triggering immediate discussion among cardiologists, sleep researchers, and public health officials regarding the safety profile of a substance frequently categorized by the public as entirely benign or purely natural.

While the observational nature of the research prevents it from establishing a direct cause-and-effect relationship, the statistical correlations have introduced a new layer of complexity to the global conversation surrounding sleep aids. Melatonin is consumed by millions of adults worldwide to combat restless nights, shift-work fatigue, and jet lag. However, as this study suggests, the long-term cardiovascular implications of altering the body’s neurochemical landscape over extended periods remain largely unmapped territory.

Background and Mechanisms of Melatonin in the Human Body

To understand the implications of the new findings, medical professionals emphasize the necessity of examining what melatonin is and how it functions within the human body. Melatonin is a naturally occurring neurohormone synthesized primarily by the pineal gland, a small endocrine gland situated near the center of the brain. The primary function of this hormone is the regulation of the human circadian rhythm—the internal biological clock that dictates sleep-wake cycles across a roughly 24-hour period.

Endogenous melatonin production is intricately tied to light exposure. As natural light fades in the evening, the suprachiasmatic nucleus of the hypothalamus signals the pineal gland to ramp up melatonin synthesis, causing blood concentrations of the hormone to rise. This biochemical shift promotes drowsiness and prepares the body for restorative sleep. Conversely, exposure to sunlight or artificial blue light suppresses melatonin production, promoting alertness and daytime wakefulness.

Synthetic melatonin, which is chemically indistinguishable from the hormone produced endogenously, was developed to mimic these natural regulatory pathways. It has since become a cornerstone over-the-counter remedy for individuals experiencing acute sleep disturbances, traveling across multiple time zones, or grappling with chronic sleep initiation and maintenance disorders.

Regulatory Discrepancies and Public Perception

A central challenge highlighted by researchers and health experts is the stark contrast in how melatonin is regulated and perceived globally. In the United Kingdom and several other nations, synthetic melatonin is classified as a prescription-only medication, meaning its acquisition requires direct medical supervision, clinical evaluation, and monitored intervals of use.

Conversely, in the United States and numerous other countries, melatonin is freely accessible as an over-the-counter dietary supplement. Because nutritional supplements and over-the-counter sleep aids in the U.S. do not undergo the rigorous pre-market safety and efficacy evaluations mandated for pharmaceutical drugs by regulatory bodies like the Food and Drug Administration (FDA), product purity, concentration accuracy, and labeling transparency can vary widely from one brand to another.

This lack of strict oversight has contributed to a pervasive cultural perception that melatonin is fundamentally harmless. Consumers frequently view it as a "natural" alternative to prescription sedatives or hypnotics, which carry well-documented risks of dependence, cognitive fog, and withdrawal. This widespread assumption of safety often leads individuals to consume melatonin nightly for months or even years without clinical guidance.

Chronology of the Research and Methodology

The impetus for the new study originated from a glaring gap in the existing scientific literature: while short-term trials involving melatonin are common, there is a distinct scarcity of data concerning its cardiovascular safety profile when ingested continuously over extended durations.

To address this deficiency, an investigative team led by Dr. Ekenedilichukwu Nnadi, chief resident in internal medicine at SUNY Downstate/Kings County Primary Care in Brooklyn, New York, designed a retrospective cohort study utilizing the TriNetX Global Research Network. This expansive, international database aggregates de-identified electronic health records, offering researchers access to millions of patient trajectories across diverse healthcare systems.

The research timeline and methodological framework were structured as follows:

• Cohort Identification: Researchers examined a five-year window of electronic health records for adult patients diagnosed with chronic insomnia.
• Exposure Classification: Participants with a documented history of continuous melatonin use spanning 12 months or longer were designated as the "melatonin group." These individuals were rigorously matched against a control group of chronic insomnia patients with no documented record of melatonin use anywhere in their medical files.
• Exclusion Criteria: To ensure baseline homogeneity and eliminate confounding variables, researchers systematically excluded any participants who had already been diagnosed with heart failure prior to the study period, as well as those who had active prescriptions for other specialized sleep medications.
• Sensitivity Analysis: To further validate the reliability of the exposure data—particularly given that melatonin is available over-the-counter in various jurisdictions—researchers conducted a secondary analysis focusing strictly on individuals who had filled at least two formal melatonin prescriptions spaced a minimum of 90 days apart.

By controlling for numerous baseline health indicators, the research team sought to isolate the potential impact of long-term melatonin exposure on cardiac health.

Quantitative Findings: Heart Failure, Hospitalization, and Mortality

The results of the primary analysis revealed stark statistical disparities between the chronic melatonin users and the matched non-users over the subsequent five-year monitoring period.

According to the data presented at the American Heart Association’s Scientific Sessions 2025, adults with chronic insomnia who utilized melatonin for a year or more exhibited approximately a 90% higher incidence of developing heart failure compared to their non-using counterparts. Specifically, new-onset heart failure was documented in 4.6% of the melatonin group, contrasted with just 2.7% in the comparison group.

Heart failure, as defined by the American Heart Association, does not imply that the heart has abruptly ceased beating; rather, it describes a chronic, progressive condition wherein the myocardium fails to pump blood with sufficient force or efficiency to meet the body’s metabolic demands for oxygen and nutrients. According to recent epidemiological statistics published by the AHA, heart failure currently affects an estimated 6.7 million American adults, representing a significant public health burden.

When researchers restricted their analysis to individuals with verified prescription records—thereby ensuring a higher certainty of consistent, long-term intake—the elevated risk persisted, showing an 82% higher probability of heart failure development in that subgroup.

The secondary analyses yielded even more pronounced differentials regarding acute medical utilization and survival rates:

• Hospitalization for Heart Failure: Participants in the melatonin group were found to be nearly 3.5 times more likely to require hospitalization for heart failure exacerbations. The hospitalization rate reached 19.0% for the melatonin cohort, compared to 6.6% in the non-melatonin control group.
• All-Cause Mortality: Mortality rates from any cause were also significantly elevated among long-term melatonin users. Over the five-year evaluation window, 7.8% of patients in the melatonin group died, versus 4.3% of those in the non-melatonin group, reflecting a nearly twofold increase in mortality risk.

Expert Reactions and Clinical Implications

The unveiling of these statistics has generated substantial debate within the cardiovascular and sleep medicine communities. The unexpected magnitude of the risk ratios has prompted experts to re-evaluate how physicians discuss sleep management with their patients.

"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," noted Dr. Nnadi during the presentation of the findings. He emphasized that while the data points toward a concerning correlation, the observational nature of the research means it cannot definitively prove direct causation.

The findings elicited sharp commentary from prominent independent researchers, including Dr. Marie-Pierre St-Onge, professor of nutritional medicine and director of the Center of Excellence for Sleep & Circadian Research at Columbia University Irving Medical Center. Dr. St-Onge, who chaired the writing group for the AHA’s 2025 scientific statement on multidimensional sleep health, expressed astonishment at the clinical management patterns revealed by the data.

"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. She underscored that consumers must recognize that over-the-counter supplements are not designed for chronic, unmonitored daily consumption without a specific clinical indication validated by a healthcare professional.

Study Limitations and Areas for Future Research

In keeping with rigorous scientific standards, the study’s authors and independent reviewers were careful to outline several critical limitations that complicate the interpretation of the findings. These methodological constraints highlight the necessity for cautious interpretation and further investigation:

1. Geographic and Exposure Misclassification: Because the research relied on de-identified electronic health records drawn from an international database, investigators lacked precise geographical data regarding participants. Furthermore, because melatonin is sold over-the-counter in countries like the United States, individuals who purchased and consumed the supplement without informing their primary care physicians—or without having the purchase logged in their electronic medical records—may have been incorrectly categorized as non-users. This potential misclassification could skew the comparative baselines.
2. Hospitalization Coding Complexities: The observed disparity in heart failure-related hospitalizations was notably higher than the incidence of newly diagnosed heart failure cases. Researchers noted that hospital administrative coding practices often aggregate multiple related diagnostic codes during a single inpatient admission, which may inflate specific event metrics without necessarily reflecting a newly emergent primary diagnosis.
3. Confounding Variables and Unmeasured Clinical Factors: The study lacked granular data regarding the precise severity of each participant’s insomnia, as well as the presence of co-occurring psychiatric conditions such as clinical depression or generalized anxiety disorder. Individuals experiencing severe sleep fragmentation or psychiatric distress are statistically more likely to seek out sleep aids like melatonin and may simultaneously possess independent, underlying physiological vulnerabilities that increase their 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 observed. "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 Outlook for Sleep Medicine

As the medical community digests the preliminary findings from the American Heart Association’s Scientific Sessions 2025, the overarching takeaway centers on the necessity of vigilance regarding long-term supplement use. Chronic insomnia is a complex medical condition frequently intertwined with cardiovascular, metabolic, and psychological health. Experts suggest that rather than relying on indefinite, unmonitored supplementation with over-the-counter sleep aids, patients struggling with persistent sleep disturbances should pursue comprehensive medical evaluations to identify root causes and explore evidence-based behavioral interventions, such as cognitive behavioral therapy for insomnia (CBT-I), under professional supervision.