A major new analysis challenges the ‘safe and natural’ reputation of the world’s most popular sleep hormone.
Long-term use of melatonin supplements, commonly taken to treat insomnia, may be linked to a higher risk of heart failure and death, according to new preliminary research presented at the American Heart Association’s Scientific Sessions 2025 in New Orleans.
Researchers reviewed five years of health records from more than 130,000 adults diagnosed with insomnia. The study data was from TriNetX, established in 2013, a growing global network of real-world, de-identified patient data available for research.
Those who used melatonin for at least a year were found to have about a 90% higher likelihood of developing heart failure over five years compared with matched non-users (4.6% vs. 2.7%, respectively).
There was a similar result (82% higher) when researchers analysed people who had two or more melatonin prescriptions filled at least 90 days apart. Melatonin is only available by prescription in some countries, including Australia and the UK.
A secondary analysis found participants taking melatonin were nearly 3.5 times as likely to be hospitalised for heart failure when compared to those not taking melatonin (19.0% vs. 6.6%, respectively).
Participants in the melatonin group were nearly twice as likely to die from any cause than those in the non-melatonin group (7.8% vs. 4.3%, respectively) over the five-year 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,” said lead author Dr Ekenedilichukwu Nnadi, chief resident in internal medicine at SUNY Downstate/Kings County Primary Care in New York.
Melatonin is a hormone naturally produced in the body by the pineal gland, and it helps regulate the body’s sleep-wake cycle. Levels increase during darkness and decrease during daylight. Chemically identical synthetic versions of the hormone are often used to treat insomnia and jet lag.
These supplements are widely available over the counter (OTC) in many countries, including the US, where OTC supplements do not require government approval to ensure quality and consistency.
As a result, each brand of supplement can vary in strength, purity, etc. Researchers noted that long-term data on its cardiovascular safety was lacking.
The study compared people with chronic insomnia who had used melatonin for a year or more to those who had never had it recorded in their medical histories. Participants who had previously been diagnosed with heart failure or prescribed other sleep medications were excluded.
The findings remained consistent even when the researchers tightened their criteria to include only patients who had filled multiple melatonin prescriptions over time.
Dr Marie-Pierre St-Onge, chair of the American Heart Association’s writing group on sleep health, said the results were “striking” given the widespread perception of melatonin’s safety.
”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 US, is not indicated for the treatment of insomnia,” she said.
“In the US, 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.”
The researchers cautioned that the findings showed only an association, not a cause-and-effect relationship.
Factors such as severe insomnia, anxiety or depression may have contributed to both melatonin use and heart risk. The study’s limitations include potential undercounting of over-the-counter melatonin users and lack of data on insomnia severity or coexisting mental health conditions.
The authors also noted that the database includes countries that require a prescription for melatonin (such as the UK) and countries that don’t (such as the US).
However, they said the results did raise important safety questions and underscored the need for more research into melatonin’s long-term effects on the heart.
Until then, they recommend that people discuss sleep concerns with their doctors before turning to supplements for chronic use.
The presentation comes just weeks after Australia’s medicines watchdog issued a safety advisory regarding imported unregistered melatonin products following testing by TGA Laboratories.
As reported by The Medical Republic, the results revealed significant discrepancies between the labelled and actual melatonin content, with one product containing more than 400% of the stated amount and another containing no detectable melatonin.
The products tested by TGA Laboratories are known unregistered therapeutic goods. These products can often be purchased online or from local retailers. However, they may not meet Australian standards for safety, quality and effectiveness, the regulator said.
In addition to its safety advisory, the TGA issued a statement about the regulation of melatonin products in Australia.
“In Australia, melatonin is only approved for use in children as a prescription-only medicine in limited circumstances,” it said.
Specifically, melatonin is approved for the treatment of insomnia in children and adolescents (2-18 years) with autism spectrum disorder (ASD) and/or Smith-Magenis syndrome.
“The TGA has not evaluated the safety or efficacy for broader use in children,” it said.
“The TGA advises that children suffering from any medical condition, including sleep disorders or irregular sleep patterns, should see a doctor and not be given medicines purchased over the internet.”
The TGA said it would continue to “monitor signals relating to harmful unregistered products and will notify the Australian Border Force to seize and destroy any of these products intercepted at the border”.
This study is a research abstract. Abstracts presented at American Heart Association’s scientific meetings are not peer-reviewed, and the findings are considered preliminary until published as full manuscripts in a peer-reviewed scientific journal.
