Melatonin and Heart Failure: Current Evidence
Based on the most recent high-quality evidence, melatonin supplementation (10 mg nightly) appears to improve NT-Pro BNP levels, quality of life, and NYHA functional class in patients with heart failure with reduced ejection fraction (HFrEF), though effects on ejection fraction and hard clinical endpoints remain uncertain.
Key Findings from Recent Trials
The strongest evidence comes from the MeHR trial 1, a 2022 randomized, double-blind, placebo-controlled study of 92 HFrEF patients receiving 10 mg melatonin nightly for 24 weeks. This trial demonstrated:
- Significant reduction in NT-Pro BNP (estimated difference: 111.0 pg/mL, p=0.044)
- Improved quality of life (difference: 5.8 points, p=0.037)
- Better NYHA functional class (OR: 12.9, p=0.015)
- No significant change in ejection fraction or other echocardiographic parameters
A 2025 meta-analysis 2 synthesizing four trials found:
- Non-significant trend toward improved ejection fraction (MD: 2.39%, p=0.27)
- Significant improvement in quality of life (MD: -5.95, p=0.001)
- Improved NYHA class (OR: 4.84, p=0.05)
- Reduced fatigue and improved sleep quality
Mechanism and Physiological Effects
Melatonin's potential benefits in heart failure stem from multiple mechanisms 3:
- Antioxidant and anti-inflammatory properties
- Counteraction of renin-angiotensin-aldosterone system overactivity
- Sympathetic nervous system modulation
- Endothelial function improvement (7.84% vs 5.98% FMD, p=0.027) 4
Important caveat: The endothelial benefits were not observed in diabetic patients 4, suggesting differential effects based on comorbidities.
Recent Safety Concerns
Critical new data from a 2025 American Heart Association conference abstract (not yet peer-reviewed) reported an association between long-term melatonin use (≥1 year) and increased risk of:
- New-onset heart failure
- Heart failure hospitalization
- All-cause mortality
This finding is hypothesis-generating only and has not been validated 5, 6. A proposed mechanism involves melatonin-induced hyperprolactinemia potentially leading to cardiotoxic prolactin fragments, similar to peripartum cardiomyopathy 5.
However, a 2026 NHANES analysis 6 found no significant association between melatonin use and prevalent cardiovascular disease or heart failure in a nationally representative sample, though this was cross-sectional and subject to confounding.
Dosing and Administration
Based on the MeHR trial protocol 7:
- Dose: 10 mg orally at bedtime
- Duration: 24 weeks demonstrated in trials
- Formulation: Standard oral tablets
Note: Melatonin is not FDA-regulated as a drug but as a dietary supplement 8, raising concerns about product quality and consistency 9.
Clinical Recommendations
When to Consider Melatonin in HFrEF:
- Stable HFrEF patients on guideline-directed medical therapy seeking symptom improvement
- Primary goals: Quality of life enhancement, symptom reduction, potential NT-Pro BNP reduction
- Avoid if: Diabetes mellitus (endothelial benefits not demonstrated) 4
Monitoring Strategy:
- Baseline NT-Pro BNP, quality of life assessment
- Reassess at 12-24 weeks
- Monitor for adverse effects: sedation, headache, morning sleepiness 10, 11
- Do not expect significant ejection fraction improvement based on current evidence
Important Caveats:
- Not a substitute for standard HF therapy (ACE inhibitors, beta-blockers, diuretics, aldosterone antagonists) 12
- Evidence limited to HFrEF; no data for HFpEF
- Long-term safety (>24 weeks) uncertain given recent safety signals
- Product quality varies; recommend USP-verified formulations 11
Evidence Gaps and Contradictions
The evidence presents a paradox:
- Short-term trials (≤24 weeks) show symptomatic benefits and biomarker improvement 13, 2, 1
- Long-term observational data suggest potential harm 5
- Cross-sectional data show no association 6
This discrepancy likely reflects:
- Confounding by indication (sicker patients use melatonin)
- Reverse causality (insomnia as HF symptom)
- Dose-duration interactions not yet understood
The 2026 meta-analysis 13 showed improved LVEF change (3.95 percentage points, p<0.001), particularly in CABG settings, but this conflicts with the MeHR trial's null finding on ejection fraction, highlighting inconsistency across populations and interventions.
Bottom Line for Clinical Practice
Melatonin 10 mg nightly may be considered as adjunctive therapy in stable HFrEF patients for symptomatic improvement and quality of life enhancement, but should not be expected to improve ejection fraction or replace standard therapies. Given emerging safety signals with long-term use, limit initial trials to 24 weeks with careful monitoring, and counsel patients that cardiovascular safety beyond 6 months remains uncertain. Avoid in diabetic HF patients where endothelial benefits are not demonstrated.