Melatonin may not be as harmless as it seems, researchers warn

A large real-world analysis reports that adults with chronic insomnia who used melatonin for a year or more were more likely to be diagnosed with and hospitalized for heart failure.

Moreover, they were more likely to die from any cause over five years than similar patients who did not use melatonin. The findings are preliminary, but they point to safety questions about a supplement many people consider both “natural” and harmless.

Presented at the American Heart Association’s Scientific Sessions 2025, the study tracked outcomes in more than 130,000 adults with insomnia and compared long-term melatonin users to closely matched non-users.

While the research cannot prove cause and effect, the signal was consistent across multiple analyzes, prompting calls for caution and more rigorous trials.

Common sleep aid under the microscope

Melatonin is a hormone made by the pineal gland that helps regulate the sleep-wake cycle, rising with darkness and falling in daylight. 

Synthetic versions, chemically identical to the natural hormone, are widely sold over the counter in the U.S. for insomnia and jet lag, though supplement strength and purity can vary because they are not regulated like prescription drugs. 

The researchers focused on adults with chronic insomnia and asked a straightforward question: does long-term, documented melatonin use track with higher rates of heart failure and other serious outcomes?

Study lead author Ekenedilichukwu Nnadi is a chief resident in internal medicine at SUNY Downstate/Kings County Primary Care in Brooklyn, New York.

“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,” said Nnadi.

Tracking long-term melatonin use

Using the TriNetX Global Research Network, the team assembled electronic health records for 130,828 adults (average age 55.7 years; 61.4% women) diagnosed with insomnia. 

Long-term melatonin users were defined as those with at least one recorded melatonin prescription and a year or more of documented use. They were matched to insomnia patients who had no melatonin recorded anywhere in their records. 

The cohort were similar across 40 factors, including demographics, comorbidities, cardiovascular and neurologic medications, blood pressure, and body mass index. 

People with prior heart failure or on other sleep medicines (such as benzodiazepines) were excluded. Researchers then followed both groups through records for five years after matching.

Because melatonin is prescription-only in some countries (e.g., the UK) and over-the-counter in others (e.g., the U.S.), the team also ran a sensitivity analysis requiring at least two melatonin prescriptions filled 90 days apart to strengthen the definition of sustained use.

Melatonin use and heart failure

Among adults with insomnia, those with 12 months or more of recorded melatonin use had roughly a 90% higher chance of incident heart failure over five years than matched non-users (4.6% vs. 2.7%). 

When the researchers tightened exposure to at least two prescriptions 90 days apart, the rise was similar (about 82% higher).

In secondary outcomes, participants taking melatonin were nearly 3.5 times as likely to be hospitalized for heart failure (19.0% vs. 6.6%), and nearly twice as likely to die from any cause (7.8% vs. 4.3%) over the same period.

“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,” Nnadi said.

“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,” said Marie-Pierre St-Onge, a professor of nutritional medicine at Columbia University Irving Medical Center.

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, noted Professor St-Onge.

Limitations of the study

Observational analyses can reveal associations but not causation. The authors note several limitations of the study.

Because over-the-counter melatonin use in countries like the U.S. is often not documented in medical records, some true users may have been misclassified as non-users, potentially biasing results. 

Hospitalization codes may capture a spectrum of heart-failure–related care and not always a new diagnosis. The database did not include patient locations, insomnia severity, or the presence of other psychiatric conditions. 

“Worse insomnia, depression/anxiety or the use of other sleep-enhancing medicines might be linked to both melatonin use and heart risk,” Nnadi said. 

“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.”

Preventing heart issues from melatonin

Heart failure affects an estimated 6.7 million U.S. adults and carries substantial risks of hospitalization and death.

If future research confirms that chronic melatonin use raises that risk in people with insomnia, counseling and prescribing habits may need to change. 

These findings argue for careful documentation of supplement use, clear indications and time limits, and consideration of evidence-based insomnia therapies – like cognitive behavioral therapy for insomnia (CBT-I) – before turning to long-term pharmacologic aids.

Future research directions

The team’s next steps include more granular analyses that account for dosing, formulations, and adherence.

Prospective studies are also needed to track sleep severity alongside cardiovascular outcomes.

Finally, experts should design randomized trials where feasible to clarify whether melatonin itself, underlying insomnia severity, or correlated factors drive the observed risks.

Until then, the message is caution, not panic: discuss melatonin use with a clinician, avoid chronic self-medication for insomnia, and weigh safer, proven sleep strategies while the science catches up.

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