Long-term melatonin use may put heart at risk

Long-term supplementation (≥12 months) with melatonin is associated with a higher risk of incident heart failure (HF) diagnosis, hospitalization for HF (HHF), and all-cause mortality in individuals with chronic insomnia in a large retrospective review of electronic health records (EHRs) presented at AHA 2025.

During 5 years of follow-up, the rate of new HF diagnoses was higher among melatonin users vs nonusers (4.6 percent vs 2.7 percent; hazard ratio [HR], 1.89; p<0.001), as were the incidences of HHF (19 percent vs 6.6 percent; HR, 3.44) and all-cause mortality (7.8 percent vs 4.3 percent; HR, 2.09).

The results were consistent on sensitivity analyses evaluating participants who have filled ≥2 melatonin prescriptions ≥90 days apart (HR for HF, 1.82). [AHA 2025, abstract MP2306]

“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,” said lead author Dr Ekenedilichukwu Nnadi from SUNY Downstate Health Sciences University, Brooklyn, New York, US.

A safe sleep aid?

Over-the-counter (OTC) melatonin supplements are widely promoted as a safe sleep aid. However, there is not enough evidence on their long-term cardiovascular (CV) safety. Hence, Nnadi and colleagues sought to evaluate whether melatonin use alters the risk of HF, particularly among individuals with chronic insomnia.

Using a large international database, the investigators reviewed 5 years of EHRs of 130,828 adults with chronic insomnia (mean age 55.7 years, ~61 percent women) who had used melatonin for >1 year. Of these, 65,414 participants had been prescribed melatonin at least once and reported taking it for at least a year. This group was matched with a control group of individuals with no melatonin exposure.

“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,” Nnadi said.

“I am surprised that physicians would prescribe melatonin for insomnia and have patients use it for >365 days, since melatonin, at least in the US, is not indicated for the treatment of insomnia. In the US, melatonin can be taken as an OTC supplement and people should be aware that it should not be taken chronically without a proper indication,” commented Dr Marie-Pierre St-Onge from the Center of Excellence for Sleep & Circadian Research, Columbia University Irving Medical Center, New York City, New York, US, who was not involved in the study.

According to the investigators, the results challenge the perception of melatonin as a benign chronic therapy and underline the need for randomized studies to ascertain its CV safety profile.

Nnadi added that although the associations raise safety concerns about melatonin, the study cannot prove a direct cause-and-effect relationship. “This means more research is needed to test melatonin’s safety for the heart.”

The investigators also pointed out that, despite the large study population, it includes both countries that require a prescription for melatonin (eg, the UK) and countries that don’t (eg, the US). “Since melatonin use in the study was only based on those identified from medication entries in EHRs, everyone taking it as an OTC supplement in the US or other countries that do not require a prescription would have been in the non-melatonin group. Therefore, the analyses may not accurately reflect this.”

Melatonin exposure may have also been possible among control patients, as OTC purchases are not indicated in EHRs, they added.