The Clinical Problem

Melatonin is one of the most widely used sleep aids despite limited long-term safety data, especially at nightly doses taken chronically by adults with cardiometabolic risk factors (Kunz, 2004).

A new observational study involving ~130,000 adults found that those taking melatonin for at least one year had roughly three times higher rates of heart-failure–related hospitalization compared with non-users. This signal, however, comes from a 300-word summary with key information missing—dose, timing, severity of insomnia, and lifestyle factors—which prevents any interpretation of causation (AHA Abstract, 2025). The clinical takeaway is that the finding raises a caution but does not offer a verdict. 

Why This Matters to Us as Clinicians

Many of our patients—especially those with hypertension, OSA, obesity, aging physiology, or prostate cancer—assume melatonin is harmless and “natural” (Kunz, 2004).

Chronic, unsupervised dosing between 3–10 mg nightly is common, yet melatonin is not an effective hypnotic for typical insomnia and is often used incorrectly (Andersen, 2016).

This creates a gap between patient perception and physiologic reality, making it essential for us to guide its use based on biology rather than marketing.

What Melatonin Actually Is (and Isn’t)

Melatonin is not a sedative and does not meaningfully improve sleep maintenance. It is a circadian hormone that helps coordinate internal timing systems (Andersen, 2016).

It functions as a chronobiotic, shifting or strengthening circadian rhythms when they are misaligned (Dawson & Armstrong, 1996). It has nighttime antioxidant and anti-inflammatory actions that influence vascular and autonomic physiology (Pieri et al., 1994).

It modulates REM sleep, endothelial function, and nitric-oxide signaling, all of which influence cardiometabolic and cancer biology. Correct timing—30–120 minutes before bed—is often more important than dose (Kunz, 2004).

What the Evidence Shows (Plain Language)

Melatonin improves quality of life in heart failure patients, likely due to better sleep quality, reduced fatigue, and circadian stabilization. It reduces NT-proBNP by roughly 10–25%, indicating lower cardiac wall stress. 

NT-proBNP is a  clinical biomarker used to assess cardiac stress and diagnose or monitor heart failure. It is released from ventricular myocardium when the heart wall is stretched, making elevated levels a sensitive indicator of increased ventricular pressure, fluid overload, or worsening cardiac function. Clinically, NT-proBNP helps differentiate cardiac from non-cardiac causes of dyspnea, stratify heart failure severity, guide therapy intensity, and predict hospitalization and mortality risk.  

It improves endothelial function by ~2–4% (FMD), reflecting enhanced nitric-oxide availability and healthier vasculature. It improves sleep quality by about 20–30% and reduces fatigue by ~15–25%. However, melatonin does not improve ejection fraction, heart-failure class, or cardiac structure. It does not reliably lower blood pressure (Daliri et al., 2025).

Mechanisms & Pathways (Why These Effects Occur)

Melatonin reduces oxidative stress by 30–50%, protecting mitochondria and enhancing cardiomyocyte energy production (Pieri et al., 1994). 

It lowers inflammatory cytokines, reducing vascular and myocardial stiffness. It increases nitric oxide bioavailability, supporting vasodilation and microvascular flow (Daliri et al., 2025). 

It strengthens SCN signaling, improving circadian amplitude, autonomic balance, and blood-pressure variability.It supports REM sleep continuity, which helps stabilize metabolic and autonomic systems. It reduces natriuretic peptides, reflecting lower ventricular strain (Daliri et al., 2025).

What Melatonin Does NOT Do

Melatonin does not improve left ventricular ejection fraction (LVEF)—the percentage of blood the left ventricle pumps out with each heartbeat and a primary measure of cardiac pump strength (Daliri et al., 2025).

It does not improve New York Heart Association (NYHA) functional class, the 4-stage system (Class I–IV) used to assess how severely heart failure limits daily physical activity (Daliri et al., 2025).

It does not reverse structural heart disease (Daliri et al., 2025). And it does not function as an effective hypnotic for typical insomnia, meaning it does not improve sleep onset or sleep maintenance in most “insomnia-type” patients (Andersen, 2016).

Safety & Practical Use

Short-term use (0.5–10 mg for up to 12 weeks) shows mild, placebo-like adverse effects (Andersen, 2016). Children using melatonin for years show no impairment in development or mental health (Van Geijlswijk, 2011). Adults on 10 mg nightly for 28 days show no metabolic or cognitive harm (Seabra, 2000).

High doses (≥10 mg) increase minor symptoms such as dizziness and morning fatigue but no major toxicity (Menczel Schrire, 2022).

The AHA signal suggests caution but not panic; no causal mechanism for heart failure has been established (AHA Abstract, 2025).

When Melatonin Clearly Works

It is highly effective for jet lag, with an NNT of about 2 (Herxheimer and Petrie, 2002). 

It is effective for delayed sleep phase and circadian misalignment and improves REM sleep in older adults with reduced REM proportion (Kunz, 2004). 

It improves sleep quality in cancer patients, including those undergoing chemotherapy (Jafari-Koulaee, 2021).

Melatonin, Sleep & Prostate Cancer

Higher melatonin metabolite levels are associated with ~75% lower risk of advanced prostate cancer. Severe insomnia doubles to triples prostate cancer risk, likely due to circadian disruption (Sigurdardottir, 2013).

Melatonin receptors are present on prostate tumors, suggesting biological relevance. Small clinical signals show potential stabilization of PSA in some patients taking melatonin (Shiu, 2003).

These findings suggest melatonin may support circadian-oncologic balance but is not a primary anticancer therapy.

The Real Therapeutic Goal

The goal is not sedation. The goal is circadian repair—strengthening the central pacemaker, improving autonomic stability, reducing inflammation, supporting endothelial health, and optimizing 24-hour physiological timing. Melatonin is a circadian medicine tool, not a sleep drug.

Final Thoughts

Melatonin is neither the benign panacea patients assume nor the cardiotoxic agent suggested by headlines. Its value lies in circadian stabilization, vascular support, REM enhancement, and antioxidant function—when used correctly, at the right time, and under clinical guidance.

Clinical Takeaways

• Use melatonin as a chronobiotic, not a hypnotic.
• Dose: 0.5–5 mg, 30–120 minutes before bed.
• Avoid chronic high-dose nightly use unless supervised.
• Reassess long-term users, especially those with heart failure risk.
• Use melatonin for circadian issues, not structural cardiac disease.
• Support foundational circadian health: morning sunlight, regular sleep timing, reduced evening light exposure.
• Consider melatonin as a low-toxicity adjunct in prostate cancer for circadian support, not as a direct anticancer agent.
   

References 

AHA Abstract (2025). Melatonin use and heart failure outcomes. Circulation, 152(Suppl 1). Abstract presented at the American Heart Association Scientific Sessions.

Andersen, IM, Korfine, L, and Guilleminault, C. (2016). Melatonin for sleep disorders: Safety and short-term effects. Current Treatment Options in Neurology, 18(12), 50. https://doi.org/10.1007/s11940-016-0437-3

Daliri, AS, Goudarzi, N, Harati, A, and Kabir, K. (2025). Melatonin as a novel drug to improve cardiac function and quality of life in heart failure patients: A systematic review and meta-analysis. Clinical Cardiology, 48(3), e70107. https://doi.org/10.1002/clc.70107

Dawson, D, and Armstrong, SM. (1996). Melatonin as a chronobiotic. Journal of Biological Rhythms, 11(1), 57–64. https://doi.org/10.1177/074873049601100107

Herxheimer, A, and Petrie, KJ. (2002). Melatonin for the prevention and treatment of jet lag. Cochrane Database of Systematic Reviews, (2), CD001520. https://doi.org/10.1002/14651858.CD001520

Jafari-Koulaee, A, et al. (2021). Melatonin and cancer-related sleep disturbances: A systematic review. Supportive Care in Cancer, 29(12), 7431–7444. https://doi.org/10.1007/s00520-021-06253-w

Kunz, D. (2004). The role of circadian timing and melatonin physiology in sleep and health. Sleep and Biological Rhythms, 2(1), 1–9. https://doi.org/10.1111/j.1479-8425.2003.00090.x

Menczel Schrire, Z, Phillips, CL, Chapman, JL, and Yee, BJ. (2022). Safety of higher doses of melatonin in adults: A systematic review and meta-analysis. Journal of Pineal Research, 72(1), e12758. https://doi.org/10.1111/jpi.12758

Pieri, C, Moroni, F, Marra, M, Recchioni, R, and Marcheselli, F. (1994). Melatonin as an antioxidant: One more molecule with therapeutic potential? Journal of Pineal Research, 16(1), 1–11. https://doi.org/10.1111/j.1600-079X.1994.tb00085.x

Seabra, ML, Bignotto, M, Pinto, LR, Jr., and Tufik, S. (2000). Randomized, double-blind clinical trial of the long-term efficacy and safety of melatonin in insomnia. Journal of Pineal Research, 29(4), 193–200. https://doi.org/10.1034/j.1600-079x.2000.290401.x

Sigurdardottir, LG, Valdimarsdottir, UA, Fall, K, Rider, JR, Lockley, SW, Schernhammer, E, and Mucci, LA. (2013). Circadian disruption, sleep loss, and prostate cancer risk: A population-based cohort study. Cancer Epidemiology, Biomarkers & Prevention, 22(5), 872–879. https://doi.org/10.1158/1055-9965.EPI-12-1227

Shiu, SYW, et al. (2003). Evidence for melatonin signal transduction via melatonin receptors in human prostate epithelial cells. Journal of Pineal Research, 35(2), 93–101. https://doi.org/10.1034/j.1600-079X.2003.00046.x

Van Geijlswijk, IM, Mol, RH, Egberts, TCG, and Smits, MG. (2011). Evaluation of sleep, puberty, and mental health in children with long-term melatonin treatment for chronic idiopathic childhood sleep onset insomnia. Journal of Pineal Research, 50(4), 345–352. https://doi.org/10.1111/j.1600-079X.2011.00847.x