Lead
New, not-yet-peer-reviewed research presented in November at the American Heart Association Scientific Sessions found an association between long-term prescription melatonin use and increased cardiovascular risk. The analysis of more than 130,000 adults from multiple countries reported an 89% higher risk of heart failure over five years and roughly double the risk of death from any cause for people prescribed melatonin for more than a year. Investigators caution the findings are preliminary and do not prove causation, but they raise questions about chronic melatonin use and the need for controlled trials. The study highlights an evidence gap for prolonged melatonin exposure despite the supplement’s widespread use.
Key Takeaways
- The pooled analysis covered more than 130,000 adults across countries including the US and the UK, using electronic health records as the data source.
- Participants prescribed melatonin for over one year had an 89% higher relative risk of developing heart failure over five years compared with those not prescribed melatonin.
- Long-term melatonin prescription was associated with about a twofold increase in all-cause mortality; absolute mortality rose from 4.3% to 7.8% between comparison groups.
- A secondary analysis reported those on melatonin longer than a year were nearly 3.5 times as likely to be hospitalized for heart failure versus non-prescribed individuals.
- The analysis was presented at the AHA Scientific Sessions in November and has not completed peer review, limiting immediate clinical implications.
- Exposure classification relied on prescription records, which may undercount over-the-counter melatonin use—especially in the US where melatonin is widely available without a prescription.
- Short-term melatonin (typically 1–2 months) remains generally viewed as safe for most non-pregnant adults, but evidence on longer durations is limited.
Background
Melatonin is a hormone produced by the brain to regulate circadian rhythms; synthetic melatonin supplements are widely used to alleviate insomnia and jet lag. In the United States melatonin is sold over the counter and is among the most commonly used natural products, while in countries such as the United Kingdom it is available only by prescription. Randomized trials and safety data have largely focused on short-term use—often weeks to a couple of months—leaving a comparative scarcity of long-term safety evidence. As public use of melatonin has grown, clinicians and researchers have flagged the need to understand potential chronic effects beyond sleep outcomes.
The new analysis emerges against this backdrop of limited longitudinal research. Observational studies using electronic health records can detect associations across large populations but are vulnerable to confounding factors and measurement limitations. Prescription records capture clinician-initiated use but may miss self‑administered over-the-counter doses, producing potential misclassification of exposure. Regulators and professional societies have so far not changed guidance based on this single, preliminary analysis, but the results add to a small and inconsistent literature on long-term melatonin safety.
Main Event
The research team, led by Ekenedilichukwu Nnadi of SUNY Downstate/Kings County Primary Care in New York, pooled electronic health records from cohorts in multiple countries to examine cardiovascular outcomes among adults with insomnia. The analysis focused on people prescribed melatonin and tracked heart failure events and mortality over a five-year follow-up window. Compared with those without a melatonin prescription, the long-term prescription group exhibited an adjusted 89% higher relative risk of heart failure over five years and approximately double the risk of death from any cause.
In a planned secondary analysis the investigators reported that individuals prescribed melatonin for over a year had almost a 3.5-fold greater likelihood of hospitalization for heart failure than non-prescribed peers. The team also reported a jump in absolute all-cause mortality from 4.3% in the comparison group to 7.8% among long-term prescription users. These effect sizes, if validated, would represent sizable population-level impacts given melatonin’s broad use.
However, the study has important methodological caveats. Exposure was inferred from prescription records rather than direct patient-reported intake, meaning some people classified as unexposed may have taken OTC melatonin, particularly in the US. The analysis is observational and cannot exclude confounding by indication—patients given prescriptions long term may differ in health status or comorbidities that independently raise cardiovascular risk. The investigators disclosed the work at the AHA meeting in November and emphasized the need for confirmatory prospective trials.
Analysis & Implications
Biologically, melatonin influences circadian regulation, vascular tone, and metabolic pathways, offering plausible mechanisms through which chronic supplementation could affect cardiovascular physiology, but current mechanistic evidence is mixed. Some animal and small human studies suggest melatonin has antioxidant and vasodilatory effects, while others indicate it can modify blood pressure regulation in ways not yet fully understood. Without randomized data, distinguishing a direct drug effect from confounding factors—such as baseline sleep disorders, comorbid illness, or concurrent medications—remains challenging.
From a clinical-practice perspective, the findings do not warrant immediate changes to short-term melatonin recommendations for acute insomnia or jet lag, where benefit and safety profiles are better established. They do suggest clinicians should ask patients about long-term supplement use, document dosing and duration, and consider alternative sleep therapies when appropriate. For policymakers and regulators, the results strengthen the case for post-market surveillance of over-the-counter sleep aids and for clearer labeling on duration of use.
For researchers, the priority is a prospective, controlled trial or well-designed cohort study with patient-reported ingestion data, dose information, and careful control for confounders. If the association replicates in studies that address these methodological gaps, guideline committees may need to revise recommendations for chronic melatonin use and consider targeted safety advisories for high-risk groups. Until then, the evidence should be treated as hypothesis-generating rather than definitive.
Comparison & Data
| Outcome | Reported Effect | Notes |
|---|---|---|
| Heart failure (5 years) | +89% relative risk | Adjusted association from prescription-record analysis |
| All-cause mortality | ≈2× risk; absolute 4.3% → 7.8% | Absolute rates reported for comparison groups |
| Heart-failure hospitalization | ≈3.5× risk (secondary analysis) | Reported in longer-term prescription subgroup |
The table summarizes the headline associations reported by the investigators. The relative increases are sizable, but readers should note the distinction between relative and absolute change: the absolute mortality difference reported was 3.5 percentage points (from 4.3% to 7.8%). Observational hazard ratios can overstate practical risk when baseline incidence is low; conversely, large relative risks can reflect clinically meaningful changes when baseline rates are substantial. The underlying data source—electronic health records—permits large samples but requires cautious interpretation due to potential misclassification and residual confounding.
Reactions & Quotes
Investigators and independent experts reacted with cautious concern, emphasizing the need for confirmatory research and clearer exposure measurement.
“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.”
Ekenedilichukwu Nnadi, SUNY Downstate/Kings County Primary Care (investigator)
This statement accompanied the team’s presentation at the AHA meeting and underscores the study authors’ framing of their results as provisional. Nnadi highlighted that clinical counseling on sleep management might shift if randomized or prospective evidence corroborates these associations.
“These findings challenge the perception of melatonin as a benign chronic therapy and only highlight the need for a prospective trial with a control group to clarify its safety profile.”
Carlos Egea, President, Spanish Federation of Sleep Medicine Societies (independent expert)
Egea noted methodological limits—particularly exposure measurement—but treated the associations seriously and called for a randomized or controlled prospective study. Independent experts stress balance: short-term, supervised use remains acceptable, while chronic unsupervised use merits closer study.
Unconfirmed
- The analysis is preliminary and has not completed peer review; results require independent confirmation before clinical recommendations change.
- Using prescription records to infer actual melatonin ingestion may misclassify exposure, especially where over-the-counter use is common.
- The study shows association, not causation; residual confounding or differences in baseline health between groups could explain part or all of the observed risks.
Bottom Line
This large observational analysis reported significantly higher relative risks of heart failure and mortality among adults prescribed melatonin for longer than one year, and a marked rise in heart-failure hospitalizations in a secondary analysis. The findings are concerning enough to prompt closer scrutiny but are not sufficient, on their own, to change short-term melatonin guidance for most adults. Clinicians should ask patients about supplement use, document duration and dose, and consider non-pharmacologic sleep interventions when appropriate.
Priority next steps are well‑designed prospective studies that capture actual supplement intake, dosing, duration, and indications, and that control for comorbidities and concomitant medications. Until such data are available, patients and clinicians should weigh the limited evidence on long-term safety against the known short-term benefits for sleep, and regulators should consider enhanced surveillance and clearer labeling for chronic use.