Melatonin and Heart Failure: Unraveling a Complex Relationship

Sleep-promoting hormone Melatonin is widely used and is often regarded as benign, over-the-counter in many countries. However, recent studies place the long-term use of melatonin in relationship to the risk of heart failure in a nuanced and somewhat troubling light. In this post, we explore current evidence, mechanisms, clinical trials, and practical implications that are especially relevant to people with or at risk of Heart Failure (HF).

What is Melatonin?

Melatonin is a hormone produced in the pineal gland which secretes in response to darkness, promoting the sleep-wake cycle or circadian rhythm. It also has an impact on antioxidant systems, mitochondrial function, and vascular tone. Supplementally, melatonin is used for insomnia, jet lag, shift-work sleep disorder & other conditions.

Heart Failure: A Brief Overview

Heart failure is a syndrome where the heart cannot pump blood in a sufficiently thick manner (or adequately fill) to respond to the body's demands. It is symptomatically characterized by shortness of breath, fatigue, fluid retention, and reduced quality of life. There are many underlying causes of the disease: ischemic heart disease, hypertension, cardiomyopathy, and valvular disease; the condition remains a major public health burden.

Understanding new adjuncts or modifiers of risk, such as melatonin, is important because HF often involves oxidative stress, endothelial dysfunction, inflammation, neuro-hormonal activation, and metabolic derangements.

The Paradox: Protective vs. Risk Signals for Melatonin in Heart Failure

Evidence for Cardioprotective Effects

On one hand, there is compelling experimental and early clinical evidence showing that melatonin may have beneficial effects in heart failure settings:

A review in 2018 by Nduhirabandi et al. discussed how melatonin may protect against ischemic injury, oxidative stress, apoptosis, adverse cardiac remodeling, and fibrosis in heart failure settings.

Animal studies: Many of the biochemical and functional derangements (e.g., improved Na⁺/K⁺-ATPase, SERCA, caveolin-3, decreased markers of oxidative stress) were reversed in rats with experimentally induced ischemic heart failure by the treatment with melatonin.

In a mouse model of high-fat–diet induced heart failure with preserved ejection fraction, melatonin improved diastolic function and reduced myocardial oxidative stress and apoptosis by the adipocyte-derived CTRP3 → Nrf2 pathway.

In a randomized clinical trial (the “MeHR” trial) of patients with HFwithreducedejectionfraction(HFrEF)HF with reduced ejection fraction (HFrEF)HFwithreducedejectionfraction(HFrEF), melatonin 10 mg for 24 weeks significantly improved flow-mediated dilation (FMD) (a marker of endothelial function) compared to placebo.

A recent systematic review and meta-analysis (2025) showed that in patients with heart failure, the use of melatonin improved quality of life and certain cardiac parameters in a few studies; however, ejection fraction and NYHA class change were not strongly statistically significant.

These data suggest a potential role of melatonin in the treatment of heart failure, especially due to mechanisms such as vascular protection, antioxidant/anti-inflammatory effects, mitochondrial stability, and modulation of neuro-hormonal stress responses.

Evidence of Increased Risk

On the other hand, a recent large observational study, presented by the American Heart Association, has raised concerns about long-term use of melatonin and an increased risk of heart failure:

The study evaluated more than 130,000 adults with chronic insomnia using the TriNetX Global Research Network. Among those whose record indicated use of melatonin for ≥12 months, the incidence of new-onset heart failure over approximately 5 years was 4.6% compared with 2.7% in matched nonusers. This is about a 90% higher risk.

In the melatonin group, heart failure hospitalization was much higher, 19.0% versus 6.6%.

All-cause mortality during the follow-up was ~7.8% vs. ~4.3% among users versus non-users, respectively.

As the authors pointed out: “Melatonin supplements may not be as harmless as commonly assumed.”

But importantly, this is an observational study (non-randomized); therefore, it cannot establish causation. It may be confounded by the underlying insomnia severity, sleep-disordered breathing, comorbidities, other medications, or unrecorded melatonin use.

Reconciling the Two Sides: How Could Melatonin Be Both Protective and Possibly Risky?

The data may appear contradictory at first sight: melatonin could be helpful in heart failure (especially in treated conditions) and long-term use in insomnia could be associated with an increased risk of heart failure. Herein, possible interpretations and mechanisms are discussed:

Difference in Populations

These protective data come from controlled experimental / early clinical trials in patients already with heart failure or specific models.

Data on risk come from observational studies of people with chronic insomnia, without established heart failure at baseline.

This would imply that context, baseline risk, comorbidities, and dosing/timing may be very different.

Confounding by Sleep Disorder / Underlying Risk

Chronic insomnia in itself is a risk factor for cardiovascular disease through sympathetic activation, hypertension, arrhythmias, inflammation, etc.

People who take melatonin over a long period may have more serious insomnia or sleep disorders, for example obstructive sleep apnea, which independently increases heart failure risk.

Therefore, the relationship may reflect the severity of the underlying disease rather than a causal effect of melatonin.

Dose, Duration, Timing and Physiology

Experimental benefits for melatonin often refer to specific conditions using controlled dosages, such as 10 mg for 24 weeks.

Over-the-counter use might involve variable dosing, frequent nightly use, possibly in a population at higher risk, and for extended durations (>12 months), which is a context less studied.

Effects of melatonin may be dependent on circadian timing, sleep architecture, cardiometabolic status and co-medications, all of which vary widely.

Mechanistic Hypotheses for Both Benefit & Risk

Benefit mechanisms: antioxidant, anti-inflammatory, mitochondrial protection, improved endothelial function, reduced remodeling.

Potential risk mechanisms (hypothetical):

In patients, melatonin may suppress sympathetic tone or alter autonomic balance in unpredictable ways.

Melatonin may mask the improvement of sleep architecture superficially when there is persisting underlining sleep apnoea, thus allowing cardiovascular stress to progress.

Unforeseen effects are possible through long-term alteration of circadian physiology or hormone balance.

Dosage and product purity, especially in OTC supplements, can vary widely among products; some may have contaminants or interact with other drugs.

Comorbidity-Based Differential Effects

In the MeHR trial, there were positive endothelial effects of melatonin in non-diabetics, whereas diabetic patients did not show this effect.

That suggests that patient subgroups may respond differently: what is beneficial in one may be neutral or harmful in another.

Clinical Implications for Heart Failure Patients & At-Risk Individuals

With mixed evidence, what are the take-home messages for patients, clinicians, and health-conscious people?

For People with Heart Failure

If you already have heart failure:

Don't assume melatonin is safe just because it is "natural." The experimental data are promising but not definitive.

This should be discussed with your cardiologist or heart failure specialist before commencing melatonin: consider your ejection fraction status, other comorbidities (diabetes, renal disease, sleep apnoea), other medications, and current sleep quality or disturbances.

If melatonin is considered, ensure: appropriate dosage, timing-in relation to bedtime-and for a limited period with monitoring.

Monitor for cardiac symptom changes, such as increased breathlessness, swelling, arrhythmias, decreased exercise tolerance, or other adverse signals.

For Those with a Risk of Heart Failure, for example, hypertension, diabetes, previous myocardial infarction

Be cautious with long-term, nightly melatonin use without supervision, as the observational data indicate an association with incident heart failure.

If you have insomnia, explore non-pharmacologic sleep-hygiene strategies: go to bed/wake up on a consistent schedule, reduce screen time, optimize light exposure, avoid caffeine/alcohol close to bedtime, and learn to manage your stress.

Screen for contributory disorders: sleep apnoea (particularly if you snore or have excessive daytime somnolence), restless legs syndrome, circadian rhythm disorders. Untreated sleep apnoea is a potent cardiovascular risk factor.

If using melatonin, think of it more as a short-term tool, not a nightly lifelong habit, until further studies clarify long-term safety.

For General Users of Melatonin

Use the lowest effective dose for the shortest duration possible. Most guidance documents recommend a starting dose of 1–3 mg rather than high doses.

Supplement quality can be variable: Because melatonin supplements are less regulated in many countries, product purity and dosage accuracy and manufacturing consistency can vary.

Be particularly careful if you have underlying cardiovascular disease, take multiple medications, or if you have sleep-disordered breathing.

Areas of Uncertainty & Research Gaps

Causality: The observational study cannot prove that melatonin causes heart failure; RCTs are lacking in long-term use in large populations.

Optimal dose & duration: what is the “safe” upper dose and safe duration of use in people with or without cardiac risk?

Patient subgroups: Which patients benefit most or are at risk from melatonin? For example: diabetics versus nondiabetics; HFrEF versus HFpEF; older versus younger

Mechanisms of risk: Why is long-term use associated with higher heart failure risk? Is it a direct effect or is it indirect, via masked sleep disorders, autonomic imbalance, or other pathways? Quality and regulation of supplements: Variation in formulations, dosages and impurities may contribute to inconsistent effects. Interaction with other medications: This particularly applies to heart failure where polypharmacy is common, and interactions, for example with beta-blockers, ACE inhibitors, and arrhythmia drugs, need clearer data. Practical Take-Home Points Melatonin is not universally benign, particularly in long-term use, and may carry cardiovascular risks if used without oversight. If you have heart failure, or risk factors for it, discuss melatonin with your cardiologist before use. Use melatonin in the context of a broad strategy, not as an isolated habit every night. Emphasize sleep hygiene and the treatment of sleep disorders. Use a conservative dose and minimize duration of use: reassess need on a regular basis. Monitor your cardiac status: If you notice any worsening symptoms, such as increased fatigue, breathlessness, and swelling, consider reviewing sleep aids, including melatonin. Watch for evolving research—this is a dynamic field and recommendations can change as more data become available. Conclusion In essence, the interaction of melatonin with heart failure is multi-factorial. On one side, promising evidence exists to support the fact that melatonin may be beneficial in maintaining cardiovascular health, reducing oxidative stress, improving endothelial function, and offering therapeutic benefits to heart-failure populations. On the other side, observational data signal a considerably higher risk of heart failure in people with chronic insomnia who use long-term melatonin. The takeaway message: Be cautious. Rather than assuming a supplement is "safe," especially when you have cardiovascular risk, engage with your healthcare provider, scrutinize your sleep habits, and consider melatonin as part of a broader strategy rather than the sole solution. As always, this blog is for information only and does not constitute medical advice. If you have heart failure, sleep disorders, or are considering the use of melatonin, please consult your physician or cardiologist.