NEW ORLEANS — Prolonged use of melatonin for the treatment of insomnia was associated with an increased risk for heart failure, hospitalization, and/or all-cause mortality, an observational study showed.

Individuals with insomnia taking melatonin for a year or more had an 89% higher chance of incident heart failure over 5 years than those who didn’t take it. They were also 3.5 times more likely to be hospitalized for the condition, the preliminary findings, which are not yet peer reviewed, suggested.

“Long-term nightly use may not be as risk-free as we assumed,” lead author Ekenedilichukwu Nnadi, MD, chief resident in internal medicine at SUNY Downstate/Kings County Primary Care, Brooklyn, New York, told Medscape Medical News.

While the study does not show causation and short-term use doesn’t appear to raise cardiac risks, “if you’re using it indefinitely, especially if you have heart disease or risk factors, it’s something worth discussing with your physician,” Nnadi said.

The findings will be presented on November 10 at the American Heart Association (AHA) Scientific Sessions 2025.

Challenging Previous Findings

Previous research suggested melatonin may be beneficial for cardiometabolic health, in part due to its antioxidant properties. Other studies have indicated taking melatonin supplements before sleep can lower blood pressure.

In the US, melatonin is available over the counter and marketed as a low-cost sleep aid. However, the investigators highlighted that robust data on its long-term cardiovascular effects were lacking.

The investigators reviewed data from the TriNetX Global Research Network database of 130,828 adults (average age, 55.7 years; 61% women) with a diagnosis of insomnia. Half of participants were prescribed melatonin at least once and reported taking it for at least 12 months.

Patients in the control group were not prescribed the sleep aid and were matched to the melatonin group on 40 different factors, including age, sex, race or ethnicity, heart and nervous system diseases, medications for heart and nervous system diseases, blood pressure, and BMI.

Patients with a previous history of heart failure or other prescriptions of sleeping pills were excluded from the study.

The primary endpoint was incident heart failure, based on the International Classification of Diseases, 10th Revision, code I50. The secondary endpoints were hospitalization for heart failure and mortality.

Higher Risk for Heart Failure

During a follow-up period of 5 years, incident heart failure occurred in 4.6% of melatonin users compared with 2.7% of control individuals (hazard ratio [HR], 1.89; 95% CI, 1.78-2.00).

The melatonin users were almost 3.5 times as likely to be hospitalized for heart failure, with 19% hospitalized compared with 6.6% of control individuals (HR, 3.44; 95% CI, 3.32-3.56), for an absolute risk difference of 1.9% (P < .001).

The likelihood of all-cause mortality doubled for the melatonin group during this 5-year period compared with the control group (7.8% vs 4.3%; HR, 2.09; 95% CI, 1.99-2.18).

The investigators observed consistent results in a sensitivity analysis of users that filled at least two melatonin prescriptions at least 90 days apart.

“These findings challenge the perception of melatonin as a benign chronic therapy and underscore the need for randomized trials to clarify its cardiovascular safety profile,” the investigators wrote.

No Clear Mechanism

Although chronic insomnia itself can cause heart failure, Nnadi said that wasn’t an issue in this cohort.

“In our study, everyone had insomnia. So, the baseline risk was really the same. What really stood out was that melatonin just had a higher risk,” Nnadi said.

Asked to comment, Logan Schneider, MD, adjunct clinical associate professor of sleep medicine at Stanford Sleep Medicine Center in Redwood City, California, and member of the American Academy of Neurology, agreed.

“It’s likely, based on the sample sizes, that poor sleep is equally represented in both groups, such that it probably doesn’t represent a confounder,” Schneider, who wasn’t involved in the study, told Medscape Medical News.

The US doesn’t require a prescription for melatonin, so it’s possible that those in the control group may have taken it. Other limitations included a lack of information on insomnia severity and psychiatric disorders.

The lack of peer review and the observational or claims-based analysis were also limitations, Schneider said.

He noted the lack of a clear pathophysiologic mechanism to explain the findings and suggested the authors explore potential mechanisms that link melatonin to increased heart failure risk.

A recent systemic review bolstered evidence of melatonin’s positive effects for patients with heart failure, suggesting it as a new treatment for these cardiac patients, even in palliative care. Carlos Egea, president of the Spanish Federation of Sleep Medicine Societies, coordinator of the Sleep Alliance, and coordinator of SEPAR 2025-2026 for sleep disorders, said in a statement for the UK-based nonprofit Science Media Centre.

“I think any time a study questions the conventional wisdom and creates a finding that we struggle to explain…then we need to avoid being reactionary, while also reconsidering the potential safety/efficacy balance of the armamentarium of treatments we have available for condition management,” Schneider said.

Nnadi said he would like to stratify the data and risk factors further and use another database to see if it yields different results.

The study reported receiving no funding. Nnadi, Egea, and Schneider reported having no disclosures.