Melatonin Shows Promise as Adjunctive Therapy in Heart Failure
Based on current evidence, melatonin supplementation appears to improve quality of life and may enhance cardiac function in heart failure patients, though it is not yet part of standard guideline-directed medical therapy. The available research suggests beneficial effects on ejection fraction, functional class, and patient-reported outcomes, but high-quality randomized controlled trials are still limited 1.
Evidence for Melatonin's Effects in Heart Failure
Cardiac Function Improvements
- A 2025 meta-analysis demonstrated that melatonin significantly improved quality of life (mean difference: -5.95, p = 0.001) and showed trends toward improved ejection fraction (mean difference: 2.39, though not statistically significant, p = 0.27) in heart failure patients 1.
- Melatonin improved NYHA functional class with an odds ratio of 4.84 (p = 0.05), indicating patients were nearly 5 times more likely to experience functional improvement 1.
- Additional benefits included reduced fatigue, decreased NT-Pro BNP levels, improved sleep quality, enhanced appetite, and increased flow-mediated dilation 1.
Mechanistic Rationale
- Melatonin addresses multiple pathological processes central to heart failure progression, including ischemic injury, oxidative stress, apoptosis, and adverse cardiac remodeling 2.
- The hormone counteracts renin-angiotensin-aldosterone system and sympathetic overactivity, both of which are key drivers of heart failure pathophysiology 3.
- Melatonin provides cardioprotection through modulation of Sirtuin (Sirt) signaling pathways, which preserve mitochondrial function, reduce oxidative stress and inflammation, prevent cell death, and regulate autophagy in cardiac cells 4.
Clinical Context and Current Guidelines
Absence from Standard Guidelines
- Major heart failure guidelines from the American Heart Association, American College of Cardiology, and European Society of Cardiology do not currently include melatonin as part of guideline-directed medical therapy 5.
- Standard evidence-based therapies remain ACE inhibitors, beta-blockers (bisoprolol, carvedilol, metoprolol succinate), spironolactone, and digoxin for symptomatic patients 5.
Endogenous Melatonin Alterations in Heart Failure
- Patients with advanced heart failure (NYHA class III) demonstrate lower nocturnal melatonin levels compared to those with less severe disease, and nocturnal melatonin secretion correlates negatively with NT-proBNP levels 6.
- This suggests that heart failure itself may disrupt normal melatonin physiology, providing rationale for supplementation 6.
Practical Implementation Considerations
Dosing and Duration
- The most robust clinical trial protocol uses 10 mg oral melatonin daily for 24 weeks as adjunctive therapy to standard heart failure medications 3.
- This dosing regimen has been evaluated for safety and effectiveness in patients with heart failure with reduced ejection fraction 3.
Patient Selection
- Melatonin may be most appropriate as adjunctive therapy in stable outpatients with heart failure with reduced ejection fraction who are already on guideline-directed medical therapy 3.
- Consider melatonin particularly for patients with poor quality of life, sleep disturbances, or persistent symptoms despite optimal standard therapy 1, 3.
Monitoring Parameters
- When using melatonin, monitor echocardiographic indices, NT-proBNP levels, NYHA functional class, quality of life scores, exercise capacity, and any adverse effects 3.
- Continue standard heart failure monitoring including heart rate, blood pressure, signs of congestion, and body weight 5.
Important Caveats
Evidence Limitations
- Only four studies met criteria for the 2025 meta-analysis, indicating the evidence base remains limited 1.
- Most data comes from experimental studies rather than large-scale clinical trials, and melatonin is rarely used by clinicians in current practice 2, 1.
- The ongoing MeHR trial will provide more definitive evidence on melatonin's safety and efficacy as adjunctive therapy 3.
Clinical Integration
- Melatonin should never replace guideline-directed medical therapy but may be considered as an adjunct after optimizing ACE inhibitors/ARBs, beta-blockers, and mineralocorticoid receptor antagonists 5.
- The primary focus must remain on proven mortality-reducing therapies: ACE inhibitors reduce mortality and hospitalizations, beta-blockers (bisoprolol, carvedilol, metoprolol succinate) reduce mortality by up to 65%, and spironolactone reduces mortality in NYHA class III-IV patients 5, 7.