Melatonin and Heart Failure: Early Evidence Raises Safety Concerns

Melatonin is widely prescribed as a chronobiotic agent and over-the-counter sleep aid. While its short-term efficacy and safety profile are well established, data on long-term cardiovascular outcomes remain limited. Recent analysis of real-world electronic health records indicates a potential association between chronic melatonin use and elevated risk of heart failure, heart failure-related hospitalization, and all-cause mortality. This article summarizes these findings and discusses clinical and research implications.

Overview

Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone synthesized by the pineal gland and frequently administered as a pharmacologic supplement for sleep disturbances, circadian rhythm disorders, and adjunctive therapy in certain neurologic conditions. Historically regarded as safe, melatonin’s long-term cardiovascular safety profile has not been rigorously evaluated in large populations.

Emerging evidence from the TriNetX Global Research Network, presented at the American Heart Association Scientific Sessions 2025, highlights a potential relationship between prolonged melatonin exposure and adverse cardiac outcomes in adults with chronic insomnia.

Study Design and Methods

• Data Source: The study analyzed de-identified electronic health records from a large international research network.
• Population: 130,828 adults with a documented diagnosis of chronic insomnia were included (mean age 55.7 years; 61% female).
• Exposure Definition: Long-term melatonin use was defined as documented use for at least 12 months. Among the cohort, 65,414 participants met this criterion.
• Exclusions: Patients with a prior diagnosis of heart failure or those on other prescription hypnotics were excluded.
• Matching: Melatonin users were propensity-score matched 1:1 with non-users (also 65,414), balancing over 40 covariates including demographics, comorbidities, lab values, vital signs, cardiometabolic medications, and healthcare utilization.

Outcomes

Primary outcomes assessed over a 5-year follow-up were:

1. Incident heart failure (ICD-10 I50)

2. Hospitalization for heart failure

3. All-cause mortality

Key Findings

1. Incident Heart Failure

• 4.6% of long-term melatonin users developed heart failure compared to 2.7% of matched controls.
• Hazard Ratio (HR) = 1.89, indicating an 89% relative increase in risk.
• Sensitivity analysis restricted to participants with ≥2 prescriptions ≥90 days apart demonstrated HR = 1.82.

2. Heart Failure-Related Hospitalization

• Hospitalization occurred in 19.0% of melatonin users versus 6.6% in controls.
• HR = 3.44, suggesting more than a threefold increased risk.

3. All-Cause Mortality

• Mortality over 5 years was 7.8% in melatonin users versus 4.3% in controls.
• HR = 2.09, indicating a doubling of relative risk.

Interpretation

Chronic melatonin supplementation was associated with nearly double the risk of incident heart failure, a threefold increase in hospitalization, and a twofold increase in all-cause mortality.

Potential mechanisms include melatonin’s pleiotropic effects on oxidative stress, vascular function, and circadian signaling, which may influence myocardial remodeling over prolonged exposure.

Confounding factors such as severity of insomnia, comorbid psychiatric or metabolic disorders, or other lifestyle factors could contribute to the observed associations.

As an observational study, causality cannot be confirmed, and further research is necessary.

Strengths and Limitations

• Strengths:

Large, real-world cohort with robust EHR data

Comprehensive covariate adjustment and propensity matching

Clinically meaningful outcomes

• Limitations:

Observational design precludes causal inference.

Data on dose, formulation, and adherence were unavailable.

Residual confounding (e.g., undiagnosed sleep apnea, lifestyle factors) may persist.

Generalizability limited to adults with chronic insomnia.

Clinical Implications

Caution in Long-Term Use: Clinicians should carefully evaluate the need for prolonged melatonin supplementation, particularly in patients with cardiovascular risk factors.

Behavioral Interventions: Non-pharmacologic strategies such as cognitive behavioral therapy for insomnia (CBT-I) and sleep hygiene optimization should remain first-line.

Monitoring: Patients on extended melatonin therapy may benefit from closer monitoring for heart failure symptoms.

Research Needs: Randomized controlled trials are needed to establish causality and elucidate the mechanisms of cardiovascular risk associated with long-term melatonin use.

Conclusion

While melatonin remains a valuable therapeutic agent for short-term sleep disturbances, these findings highlight a potentially underrecognized cardiovascular risk associated with long-term supplementation. Clinicians should carefully weigh benefits against potential harms, particularly in populations with pre-existing cardiovascular risk factors, and incorporate behavioral sleep interventions when feasible. Further research is needed to validate these associations and guide evidence-based clinical recommendations.

References

• American Heart Association. Long-term use of melatonin supplements to support sleep may have negative health effects. AHA Newsroom, Nov 03, 2025.
• Solomon, L. “AHA: Long-Term Melatonin Use for Insomnia Tied to Higher Risk for Heart Failure.” Drugs.com, Nov 06, 2025.
• Nnadi, E., et al. (presented at AHA Scientific Sessions 2025). “Research Suggests Long-Term Melatonin Use for Insomnia Increases HF Risk.” ACC News Story, Nov 10, 2025.
• Mathur, B. “Long-term melatonin use may raise heart failure risk by 90%: Study.” Business Standard, Nov 10, 2025.
• India Today. “Study flags dangers of long-term melatonin supplement use.” Nov 04, 2025.
• ASRN. “Long-Term Melatonin Use Linked To 90% Greater Heart Failure Risk.” Nursing Journal, 2025.
• Medical News Today. “Long-term melatonin use linked to 90% greater heart failure risk.” 2025.