Lead: An American Heart Association presentation at Scientific Sessions 2025 reported that adults who used melatonin supplements for a year or longer had markedly higher short-term risks of heart failure and death. Researchers analyzed more than 130,000 patient records from the TriNetX Global Research Network over five years and found roughly a 90% higher risk of developing heart failure, nearly double the risk of death, and a 3.5-fold increase in heart-failure hospitalizations among long-term users compared with people with insomnia who did not take melatonin. The results, presented in New Orleans, are observational and do not by themselves prove causation, but they raise questions about chronic over-the-counter melatonin use.
Key takeaways
- Study cohort: analysis included records for over 130,000 adults drawn from the TriNetX Global Research Network covering a five-year window.
- Heart-failure risk: long-term melatonin users (≥1 year) showed about a 90% higher relative risk of being diagnosed with heart failure within five years than insomnia patients who never used melatonin.
- Mortality: long-term users were nearly twice as likely to die from any cause within five years compared with matched insomnia nonusers.
- Hospitalizations: melatonin users had approximately a 3.5-fold higher rate of hospitalization for heart failure over the follow-up period.
- Data source nuance: researchers relied on prescription and medical-record indicators; many OTC purchasers might be misclassified as nonusers.
- Regulatory context: melatonin is widely sold over the counter in the U.S. as a dietary supplement, not a regulated drug, so product potency and purity vary.
- Clinical caution: investigators and sleep-health experts urged clinicians and patients to avoid assuming chronic OTC melatonin use is risk-free without clear indication.
Background
Melatonin is a hormone the body produces to regulate sleep-wake cycles; in the U.S. it is sold widely as an over-the-counter supplement for insomnia and jet lag. Dietary supplements are not regulated like prescription drugs by the Food and Drug Administration, so the amount of active hormone and the presence of contaminants can differ substantially between brands and batches. Chronic insomnia itself is linked to higher cardiovascular risk through pathways such as elevated blood pressure, inflammation and metabolic stress; the interplay between poor sleep and heart disease is well established.
Heart failure affects nearly 7 million Americans and occurs when the heart cannot pump enough blood to meet the body’s needs, producing breathlessness, fluid retention and reduced exercise tolerance. Large observational databases such as TriNetX allow researchers to search for associations across many patients and clinical settings, but they cannot fully account for unmeasured factors such as severity of insomnia, lifestyle, exact supplement dose, or over-the-counter use not recorded in medical charts. Prior research on melatonin and cardiovascular outcomes has been mixed, with small clinical trials and laboratory studies suggesting both potential benefits and harms depending on dose, timing and patient population.
Main event
The analysis presented at the American Heart Association’s Scientific Sessions 2025 compared adults with recorded long-term melatonin use (one year or longer) to patients diagnosed with insomnia who had no recorded melatonin prescriptions or orders. Investigators followed outcomes over five years, tracking new heart-failure diagnoses, hospital admissions for heart failure, and all-cause mortality. The dataset encompassed more than 130,000 patients across the international TriNetX network, which aggregates electronic health records and claims data from multiple health systems.
Key relative estimates reported were a roughly 90% increase in heart-failure diagnosis among long-term users, nearly a twofold increase in five-year all-cause mortality, and a 3.5-times greater likelihood of hospitalization for heart failure. Lead author Dr. Ekenedilichukwu Nnadi emphasized that these findings challenge the common assumption that OTC melatonin is benign when taken chronically and said the results could influence clinician counseling if confirmed by further study. Investigators noted important limitations, including reliance on prescription and chart records that may miss OTC purchases and insufficient detail on dose, formulation and timing of melatonin intake.
The research team used statistical methods to match melatonin users and nonusers on observed characteristics, but residual confounding is possible if melatonin users differ systematically in unmeasured ways (for example, greater insomnia severity, comorbid illness, or medication use). Presenters framed the results as preliminary and called for additional prospective studies and randomized trials to test whether melatonin itself contributes to cardiovascular risk or whether long-term use is a marker for underlying problems that raise heart-failure risk.
Analysis & implications
Interpreting these results requires distinguishing association from causation. The study’s observational design does not prove melatonin causes heart failure; it shows a strong correlation after adjustment for measured covariates. Possible biological mechanisms have been proposed but are not established: melatonin interacts with circadian regulation and autonomic function, and at different doses may exert variable effects on blood pressure, inflammation and glucose metabolism—pathways relevant to heart-failure development.
Clinically, the findings prompt immediate questions for primary-care doctors, cardiologists and sleep specialists. If chronic melatonin use is independently harmful, clinicians may need to reassess long-term prescribing and counsel patients about alternative, nonpharmacologic insomnia treatments such as cognitive-behavioral therapy for insomnia (CBT-I). If melatonin is a marker for severe, untreated sleep disturbance or comorbid conditions, the priority becomes diagnosing and treating those underlying contributors to cardiovascular risk.
From a public-health and regulatory standpoint, the study highlights the challenge of widely used supplements sold without standardization. Regulators and researchers may consider closer scrutiny of supplement labeling, dosing recommendations, and postmarket surveillance. For patients, the practical implication is caution: avoid indefinite, unsupervised melatonin use and discuss sustained sleep problems with a clinician rather than assuming OTC supplements are harmless.
Comparison & data
| Outcome | Relative increase (long-term melatonin users vs insomnia nonusers) |
|---|---|
| New heart-failure diagnosis (5-year) | ≈ +90% (relative risk ≈1.9) |
| All-cause mortality (5-year) | ≈ ×1.9 (nearly double) |
| Hospitalization for heart failure | ≈ ×3.5 |
The table reports relative differences from the study as presented; absolute risks were not provided in the conference summary. Relative measures can appear large even when baseline absolute risk is low, so absolute incidence rates will be critical for patient counseling and risk–benefit decisions. Additional stratified data (by age, sex, baseline cardiovascular disease, and melatonin dose) were not detailed in the press summary but would strongly inform clinical interpretation.
Reactions & quotes
“Melatonin supplements may not be as harmless as commonly assumed.”
Dr. Ekenedilichukwu Nnadi, study lead author
Dr. Nnadi framed the findings as a prompt for clinicians to reconsider assumptions about chronic OTC melatonin use and urged confirmation in further studies.
“People should be aware that it should not be taken chronically without a proper indication.”
Marie‑Pierre St-Onge, Columbia University, chair of AHA writing group on sleep health
St-Onge, representing the AHA sleep-health writing group, stressed that chronic use without clinical oversight is ill-advised and that the results underscore the need to treat sleep disorders rather than rely on indefinite supplements.
Unconfirmed
- Whether melatonin itself biologically increases heart-failure risk remains unproven; the study shows association, not causation.
- Exact doses, formulations and timing of melatonin intake were not available; OTC purchases may have been missed in medical records.
- Potential confounding by insomnia severity, comorbid conditions (for example, sleep apnea, depression, cardiometabolic disease) or concurrent medications could explain part or all of the association.
- Stratified effects by age group, sex, race/ethnicity, and baseline cardiovascular status were not reported in the summary and remain uncertain.
Bottom line
The AHA presentation reporting a near-doubling of mortality and a roughly 90% higher heart-failure diagnosis rate among long-term melatonin users is striking but preliminary. Clinicians should not assume chronic OTC melatonin is without risk; conversely, patients should not abruptly stop indicated short-term use without medical advice. The most actionable message for clinicians is to assess persistent insomnia proactively, prioritize evidence-based nonpharmacologic therapies, and discuss the uncertain risks of long-term melatonin with patients.
Research priorities include prospective cohort studies with better measurement of OTC use, randomized trials where ethical and feasible, and mechanistic studies to test biological effects of sustained melatonin exposure on cardiovascular physiology. Regulators and health systems may also consider improved product oversight and clearer public guidance about long-term supplement use.
Sources
- San Francisco Chronicle — news report summarizing the AHA presentation (media)
- TriNetX — international clinical research network and data provider referenced by the investigators (data provider)
- American Heart Association — Scientific Sessions 2025 — official conference program and abstracts (official conference)