Melatonin and Heart Failure: Unpacking the Hype and the Evidence
By Dr Andrew Crockett
A recent headline, ‘melatonin linked to heart failure death’, has caused some concern in the media. When news like this comes out, the immediate reaction is often alarm but what it should do is trigger us to pause and think what is really going on. For those of us in health, it's crucial to recognise that the difference between a new statistical signal and a confirmed biological cause is substantial.
The specific finding driving this news is a retrospective analysis by Nnadi et al., titled “Effect of Long-term Melatonin Supplementation on Incidence of Heart Failure in Patients with Insomnia”. The study, which used a large electronic health record (EHR) network, found an association between the use of 'melatonin agonists' and higher mortality in patients with heart failure (HF) and comorbid insomnia compared to patients using benzodiazepines (a class of prescription medications widely used for sedation and anxiety).
This paper serves as a valuable initial screen for the association of melatonin and mortality in those with heart failure, highlighting potential connections that merit further attention. However, it is essential to note that the data does not establish a causal relationship between the two.
This finding should be viewed as a prompt for deeper inquiry and research, not as a definitive conclusion or a reason for immediate concern.
Correlation is Not a Causal Standard
The main limitation of the Nnadi et al. paper is its retrospective, observational design. While large EHR network studies offer scale and long term follow up (up to six years in this case), they are inherently challenged by issues of confounding, especially with over the counter (OTC) supplements like melatonin.
The problems are twofold:
Confounding by Indication (The "Sicker Patient" Problem): Patients who were given melatonin or a melatonin related drug were likely different from those given other sleep aids. Think of it as a form of selection bias: when doctors are faced with a very sick patient (with severe, multi system illness like advanced heart failure), they may avoid potent prescription drugs (like Z drugs or benzodiazepines) because of potential side effects or drug interactions. Instead, they channel the patient toward what is perceived as a gentler option: melatonin. This means the group taking melatonin was sicker, older, or frailer to begin with (a phenomenon known as channeling bias). The statistical link to higher mortality is therefore more likely reflecting the patient's existing, severe frailty, not a harmful effect of the melatonin itself.
Exposure Misclassification (The "Unrecorded Dose" Problem): This is perhaps the most critical flaw when studying melatonin. In the US, the vast majority of melatonin is purchased over the counter (OTC) and is never recorded in the Electronic Health Record (EHR) system used in the study. The study only captures 'melatonin agonists,' which is a clinical category that mixes true prescription drugs (like ramelteon) with whatever little OTC use the system did manage to record. Crucially, the study could not specify the dose, timing, formulation (immediate vs. extended release), or quality of the product taken. Without knowing who took how much or what kind for how long, drawing a causal line from the product to the outcome is highly speculative.
The analysis suggests an association between melatonergic therapy use and higher mortality in this specific patient group. It does not establish that taking melatonin causes heart failure progression or death. For a scientific mind, this study is hypothesis generating, a flag for what to study next, not a definitive conclusion.
The Melatonin Dose Conundrum: Physiologic vs. Supraphysiologic
The limitations of the Nnadi study highlight the challenges of using real-world data to study supplements, but they also shift us toward a more fundamental scientific question: dosing. When we step away from statistical confounding and look purely at the pharmacology, a massive discrepancy emerges between what our body naturally produces and what we commonly consume. Melatonin is a potent hormone produced naturally by the pineal gland and its function is to signal darkness and regulate the timing of our sleep wake cycle the chronobiology of performance [PMID: 30215696].
Endogenous (Self Secreted) Dose: The pineal gland works subtly. The total mass of melatonin an adult secretes across an entire night's sleep cycle is tiny, typically ranging from 20 to 100 micrograms (mcg). To put this into context,100 mcg is just one tenth of a milligram. This is the physiological quantity our systems are designed to process to regulate our clock.
Supplemental (Exogenous) Dose: Common OTC supplements range from 1 mg up to 10 mg. When you ingest a typical1 mg supplement, you are taking a dose that is at least ten times the total mass your body produces over the course of a healthy night. If you take a 5 mg or 10 mg dose, you are multiplying your body's entire nocturnal output by 50 or 100 times. A 5 mg dose is a supraphysiologic hammer, not a subtle nudge [PMID: 33549911]. These massive doses lead to prolonged, elevated plasma levels that can persist for several hours.
This disparity underscores that many users are taking pharmacologic doses levels that are useful for actively shifting the body clock (phase shifting), but are far beyond what is required to simply initiate sleep in an otherwise healthy individual. The lack of dosing clarity in the Ahmed study is therefore also a large problem.
A further note on quality is due: multiple investigations have exposed huge discrepancies between the labeled and actual content in OTC melatonin products, including the detection of various contaminants [PMID: 27855744]. In practice, this variability is unacceptable. We must actively ensure product integrity is factored into any therapeutic strategy by prioritising verified, high-quality manufacturers.
Where Melatonin is useful
Melatonin is a chronobiological tool, not a general sleep aid. Achieving optimal cognitive and physical performance depends on precise timing and physiological adaptation. Melatonin’s true use lies in its ability to shift the clock, not just make you drowsy.
Where do we see clear, evidence based applications?
Jet Lag Protocols & Time Shifting: This is the clearest, most established use case. Timed, low dose melatonin 0.5 - 1 mg is often enough to help achieve a phase advance (for eastward travel) or a phase delay (for westward travel) when combined with strategic light exposure [PMID: 12076414]. The goal is precise chronobiological signalling, not sedation.
Insomnia in Older Adults: Prolonged release melatonin (PRM), which is a licensed medicine in the UK (typically 2 mg nightly), has shown modest but consistent benefit in improving sleep quality and latency in adults over 55 [PMID: 22346363]. The extended release formulation aims to maintain levels throughout the night, mimicking the natural duration of the endogenous signal.
Addressing Secondary Sleep Disturbances: Melatonin can be useful when sleep is disrupted by other medications. For instance, some beta blockers, a class of drug commonly prescribed for cardiac conditions and hypertension, can suppress the body’s natural nocturnal melatonin production, and this reduction has been linked to sleep disturbance [PMID: 3291558, 10335905]. Supplementation has shown promise in restoring sleep architecture in beta‑blocker–treated hypertensive patients [PMID: 23024438].
Scrutiny and Strategy
No single observational study, especially one limited by challenges like unmeasured patient differences (the "Sicker Patient" Problem) and poor tracking of supplement use (the "Unrecorded Dose" Problem), should lead to an immediate change to a patient’s carefully considered, personalised health strategy.
While we lack a long term, randomised controlled trial (RCT) powered to confirm if chronic melatonin use affects major cardiovascular events like heart attack, stroke, or HF progression, the current best level evidence shows that extended release melatonin formulations have been linked to a modest reduction in asleep systolic blood pressure in short‑term hypertension trials, where controlled‑/prolonged‑release melatonin modestly reduced asleep systolic BP, whereas immediate‑release did not [PMID: 21966222, 35388609]. Furthermore, short term data (24 weeks) in HF patients has shown improvements in key biomarkersNT‑proBNP and quality of life [PMID: 35170783], suggesting a positive physiological role in this population, though again, not powered for mortality.
Our takeaway must be one of informed discretion:
Do not infer harm from the Nnadi study; its finding is a yellow flag, not a red light.
Prioritise precision over power. If using melatonin for sleep or circadian indications, the focus must be on the lowest effective dose (often 0.3 - 1 mg) and correct timing, reserving higher doses only for active phase shifting protocols.
Demand quality. When sourcing supplements, ensure you use only products from verified manufacturers that can guarantee label accuracy and purity.
Scientific and clinical decisions must be built on sound principles, not fleeting headlines. The ultimate goal is always to move beyond speculation to a data-driven health strategy.
References
Nnadi, Ekenedilichukwu & Masara, Maureen & Offor, Rita & Unal, Selin & Rebah, Rebhi & Atere, Muhammed & Nigussie, Bisrat & Graham-Hill, Suzette. (2025). Abstract 4371606: Effect of Long-term Melatonin Supplementation on Incidence of Heart Failure in Patients with Insomnia. Circulation. 152. 10.1161/circ.152.suppl_3.4371606.
Hoseini SG, Heshmat-Ghahdarijani K, Khosrawi S, Garakyaraghi M, Shafie D, Mansourian M, Roohafza H, Azizi E, Sadeghi M. Melatonin supplementation improves N-terminal pro-B-type natriuretic peptide levels and quality of life in patients with heart failure with reduced ejection fraction: Results from MeHR trial, a randomized clinical trial. Clin Cardiol. 2022 Apr;45(4):417-426. doi: 10.1002/clc.23796. Epub 2022 Feb 16. PMID: 35170783; PMCID: PMC9019884.
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