Long-term melatonin use in adults with insomnia was associated with an 89% higher hazard of incident heart failure (HF), a roughly three-fold increase in HF-related hospitalizations, and a doubling of all-cause mortality over five years, according to a preliminary observational study of 130,828 adults presented at the American Heart Association (AHA) Scientific Sessions 2025. The findings, from a retrospective analysis of the TriNetX Global Research Network by researchers at SUNY Downstate/Kings County Primary Care, challenge the common perception of melatonin as a benign chronic therapy, though the study cannot establish cause and effect and awaits peer review.
Why the study was done
Melatonin is one of the most widely used sleep aids in the United States, where it is sold as an over-the-counter dietary supplement rather than a prescription medicine. This regulatory status means that manufacturers do not have to demonstrate long-term safety before marketing, and the amount of melatonin actually in a given tablet can vary substantially from the label. Randomized trials of melatonin in insomnia have generally been small and short. Data on cardiovascular safety of chronic melatonin use, particularly in the doses (5 to 10 mg or higher) commonly sold in the U.S., are limited. The AHA study set out to test whether long-term melatonin use was associated with new-onset HF in adults diagnosed with insomnia.
How the study was designed
Researchers queried the TriNetX Global Research Network, a database of de-identified electronic health records from health systems across multiple countries, for adults aged 18 years or older with a diagnosis of insomnia (ICD-10 code F51.0). The exposed cohort had at least one melatonin prescription and at least 365 days of documented melatonin exposure. Controls had no documented melatonin exposure. Patients with pre-existing HF and patients on other prescription hypnotics were excluded. The analysis included 130,828 adults (mean age 55.7 years; 61.4% women), with 65,414 melatonin users propensity-matched to 65,414 non-users across more than 40 clinical and demographic variables. Outcomes were tracked over five years of follow-up.
The primary outcome was incident HF. Secondary outcomes included HF hospitalizations and all-cause mortality. Because the exposure required documented prescription, the analysis captured only prescribed melatonin, not over-the-counter supplements bought without medical guidance, an important consideration in interpreting the results.
What the study found
Long-term melatonin users had substantially higher risks across all three primary outcomes over five years:
- Incident heart failure: 89% higher hazard versus matched non-users (widely reported in coverage as a 90% increase).
- HF-related hospitalization: 19% among melatonin users versus 6.6% among non-users, representing an approximately three-fold increase.
- All-cause mortality: 7.8% among melatonin users versus 4.3% among non-users, an approximate doubling.
The effect was consistent across the matched cohorts. The associations remained after adjustment for more than 40 baseline variables including age, sex, common comorbidities, cardiovascular risk factors, and use of other medications.
What the effect size means
An 89% higher hazard of HF is a large observational effect. To be interpreted usefully, however, it must be placed in context. HF affects about 6.7 million U.S. adults according to the AHA’s 2025 Heart Disease and Stroke Statistics, and background incidence in an insomnia cohort is not negligible. The absolute increase in HF events attributable to melatonin exposure over five years, if the association is causal, would be meaningful. The doubling of all-cause mortality is a strong signal that warrants attention. Whether the entire signal is driven by melatonin itself, by underlying disease that both causes insomnia and independently raises cardiovascular risk, or by unmeasured confounders remains unresolved.
What the evidence cannot yet answer
This was a retrospective observational study, not a randomized controlled trial, so it cannot prove that melatonin causes HF. The lead author has explicitly acknowledged this limitation. Insomnia itself, or another underlying condition that causes both insomnia and cardiovascular disease, could account for part or all of the association. The exposure definition (prescribed melatonin for at least 365 days) captures a subset of long-term users, and the results may not generalize to typical over-the-counter use in the general population. The study also did not measure melatonin dose or timing, both of which vary widely in real-world use.
The findings are also preliminary in another sense. Abstracts presented at AHA scientific meetings are not peer-reviewed at the time of presentation, and the findings should be considered provisional until published as a full manuscript. Confirmatory prospective studies, including randomized trials that measure both cardiovascular outcomes and dose response, will be needed to establish whether the association is causal.
Where melatonin actually helps
The strongest evidence for melatonin is for circadian-rhythm problems: jet lag, delayed sleep phase disorder, and shift work. For these indications, small doses of about 0.5 to 1 mg, taken at the right time relative to the target sleep window, are often enough. The high doses common in U.S. supplements (5 to 10 mg or more) are substantially above the levels the body makes at night, and no evidence suggests that more is better for sleep. Because melatonin is sold as a supplement in the U.S., it is not FDA-approved for treating insomnia, and label accuracy can vary widely from bottle to bottle.
What to consider if you use melatonin
For chronic insomnia, the gold-standard treatment is not a supplement at all. It is cognitive behavioral therapy for insomnia (CBT-I), a structured, short-term program that addresses the thoughts and behaviors that keep sleep problems going. Major medical guidelines place CBT-I ahead of pills, including melatonin, for chronic insomnia. CBT-I is available in person, through several validated apps, and increasingly through primary care. A visit with a clinician is worthwhile in any case, since conditions such as sleep apnea, restless legs syndrome, depression, and thyroid problems can all present as insomnia and require different treatment.
For anyone already using melatonin nightly, there is no need to stop abruptly. The new signal is a reason to review use, not to panic. A sensible plan is to discuss with a clinician why melatonin is being taken, whether a shorter course or a lower dose would suffice, and whether a proper insomnia workup is warranted. Basic sleep hygiene also deserves attention: a steady wake time even on weekends, morning daylight exposure, less screen light late at night, moderate alcohol intake, and a cool, dark bedroom.
The study’s lead author, Ekenedilichukwu Nnadi, MD, said in an American Heart Association press release that “melatonin supplements may not be as harmless as commonly assumed” and that if the findings are confirmed, “this could affect how doctors counsel patients about sleep aids.” The wider implication is not that melatonin is dangerous. It is that dietary supplements do not undergo the same long-term safety testing as prescription medicines, and patterns of harm often emerge only from long-term observational studies like this one.
References
- Nnadi E, Masara M, Offor R, et al. Effect of long-term melatonin supplementation on incidence of heart failure in patients with insomnia. Circulation, 2025; 152 (Suppl 3): Abstract 4371606 (presented at AHA Scientific Sessions 2025). DOI: 10.1161/circ.152.suppl_3.4371606