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New analysis of more than 130,000 adults with chronic insomnia suggests that taking melatonin supplements for a year or longer may be associated with substantially higher rates of heart failure, hospitalization and death. The preliminary findings — presented at the American Heart Association Scientific Sessions 2025 — raise fresh questions about the cardiovascular safety of a supplement many people assume is harmless.
Why researchers looked at melatonin and the heart
Melatonin is a hormone produced by the pineal gland that signals night to the body and helps regulate sleep and circadian rhythms. Synthetic melatonin, chemically identical to the natural hormone, is widely sold over the counter in many countries and frequently recommended or self-prescribed to treat insomnia and jet lag. Its ready availability and "natural" branding have helped it become one of the most commonly used sleep supplements in the world.
Despite broad use, there is surprisingly little long-term safety data on melatonin's effects on the cardiovascular system. That gap motivated a team of investigators to search large clinical records for possible links between sustained melatonin supplementation and heart outcomes in people already diagnosed with insomnia.
Study design: a five-year, real-world review
The research team used the TriNetX Global Research Network, an international repository of de-identified electronic health records, to follow adults diagnosed with insomnia over a five-year period. After excluding anyone with a prior diagnosis of heart failure or those already prescribed other classes of sleep medications (such as benzodiazepines), researchers grouped patients by documented melatonin exposure.
Patients with medication entries indicating melatonin use for 12 months or longer formed the "melatonin group." Those with no melatonin prescriptions or documentation in their records were placed in the matched "non-melatonin group." In a sensitivity check, investigators also required two melatonin prescription fills at least 90 days apart to strengthen the signal for sustained use.
The cohort included 130,828 adults with insomnia (average age 55.7; 61.4% women). About half — 65,414 people — had at least one recorded melatonin prescription and reported continued use for a year or more. The remaining participants served as matched controls: researchers balanced the groups for 40 factors including age, sex, race/ethnicity, existing heart and nervous system conditions, common medications, blood pressure and body mass index.
Key findings: larger risks than expected
Across the five-year follow-up, the analysis found striking differences between the groups. People with documented long-term melatonin use had roughly a 90% higher chance of receiving a new diagnosis of heart failure compared with matched non-users. In absolute terms, 4.6% of the melatonin group developed heart failure versus 2.7% in the non-melatonin group over five years.
The sensitivity analysis that required two prescription fills produced similar results — about an 82% higher risk for incident heart failure among sustained melatonin users where prescriptions were confirmed. Secondary outcomes were also notable: participants in the melatonin group were nearly 3.5 times as likely to be hospitalized for heart-failure-related reasons (19.0% vs. 6.6%) and experienced almost double the all-cause mortality over five years (7.8% vs. 4.3%).
"Melatonin supplements may not be as harmless as commonly assumed," said lead author Ekenedilichukwu Nnadi, M.D., chief resident in internal medicine at SUNY Downstate/Kings County Primary Care. "If our findings are confirmed by further research, they could change how clinicians counsel patients about long-term sleep-aid use." The study was scheduled for presentation on November 10, 2025, at the American Heart Association Scientific Sessions in New Orleans.
Limitations: what the data can and cannot show
Although the results are concerning, the study is observational and cannot prove causation. There are several important caveats to keep in mind when interpreting the findings.
Over-the-counter use and misclassification
TriNetX contains records from countries where melatonin is prescription-only (for example, the United Kingdom) and countries where it is available over the counter (for example, the United States). The database in this analysis did not include precise patient locations in de-identified data, and melatonin use was identified from medication entries in medical records. That means people who bought melatonin without a prescription — common in the U.S. — would often appear in the non-melatonin group, potentially blurring contrasts between users and non-users.
Residual confounding and illness severity
The study adjusted for many known risk factors using matching, yet worse insomnia, coexisting psychiatric disorders like anxiety or depression, or the use of other sleep-promoting therapies could confound the association. Those factors might both increase the likelihood of someone taking melatonin long-term and independently raise cardiovascular risk.
Diagnostic coding and hospitalization measures
Hospitalization rates flagged as "heart-failure-related" can include a range of diagnostic codes. Some admissions coded for acute symptoms or related complications may not include a new heart-failure diagnosis, which could explain why hospitalization figures were proportionally higher than documented incident heart-failure diagnoses.
Researchers acknowledge these limitations and emphasize that their analysis raises safety concerns that require confirmation in other datasets and prospective trials.
What this means for patients and clinicians
For patients who take melatonin regularly, the study does not mean immediate alarm or that melatonin definitively causes heart failure. But it does call for caution and a renewed conversation between patients and health-care providers about long-term sleep strategies.
Experts not involved in the study noted that chronic melatonin prescribing — especially beyond a year — is not a common recommendation in many treatment guidelines. Marie-Pierre St-Onge, Ph.D., chair of the American Heart Association's 2025 writing group on sleep and cardiometabolic health, observed that melatonin in the U.S. is an over-the-counter supplement rather than a regulated prescription medication and should not be assumed safe for chronic, unsupervised use.
Practical steps patients can take include:
- Discuss ongoing sleep problems with a clinician rather than self-medicating long-term.
- Consider non-pharmacologic approaches first, such as cognitive behavioral therapy for insomnia (CBT-I), sleep hygiene optimization and circadian-alignment strategies.
- If melatonin is used, re-evaluate the need periodically and avoid indefinite, unmonitored use — especially if you have cardiovascular risk factors.
Expert Insight
"The study is a strong reminder that 'natural' doesn't always mean risk-free," said Dr. Laura Chen, a cardiologist and sleep researcher at the Center for Sleep Science and Cardiology (fictional affiliation for commentary). "Melatonin plays a role in circadian signaling and can affect vascular tone and metabolic pathways. Until we have randomized trials or prospectively collected safety data, clinicians should weigh potential benefits against uncertain long-term risks, particularly in patients with existing heart disease or multiple cardiovascular risk factors."
Dr. Chen continued: "For many sufferers of chronic insomnia, behavioral treatments like CBT-I provide durable benefit without exposing the heart to pharmacologic risk. When medication is needed, prescribers should document clear indications, monitor outcomes, and prioritize the shortest effective duration."
What researchers plan next
The investigators recommend replication of these findings in other large datasets and, where feasible, prospective studies that can better control for over-the-counter use and baseline insomnia severity. Future work might also interrogate biological mechanisms — for example, whether sustained melatonin supplementation alters autonomic balance, blood pressure patterns overnight, inflammatory markers, or metabolic control in ways that could plausibly increase heart-failure risk.
If confirmed, these pathways could point to subgroups who are most vulnerable (older adults, people with pre-existing coronary disease, or those with disrupted circadian rhythms) and inform safer dosing strategies or alternative therapies.
Implications for public health and regulation
Because melatonin is regulated as a dietary supplement in some countries and a medication in others, variability in product strength, purity and labeling could compound safety concerns. The study underscores the need for better post-market surveillance of widely used supplements and for clinicians to ask about all over-the-counter products when assessing patients' medication histories.
Regulatory agencies and professional societies may consider updating guidance on melatonin use for chronic insomnia if additional evidence confirms these associations. Meanwhile, clinicians and patients should treat long-term melatonin use as an intervention that warrants periodic review rather than a benign, indefinite remedy.
Meeting details: "Effect of Long-term Melatonin Supplementation on Incidence of Heart Failure in Patients with Insomnia," presentation scheduled for 10 November 2025 at the American Heart Association Scientific Sessions 2025, New Orleans.
Source: scitechdaily
Comments
atomwave
wow, didn't expect melatonin to show up like that with heart failure risks… i've used it off and on, kinda freaked now, gonna ask my doc. weird
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