A newly released study linking long-term melatonin use to heart failure has generated significant attention, but the research contains critical limitations that severely compromise its conclusions. The preliminary findings from Dr. Ekenedilichukwu Nnadi’s team, presented at the American Heart Association’s Scientific Sessions on November 3, 2025, reported that chronic insomnia patients using melatonin for over a year had 90% higher odds of developing heart failure compared to non-users. However, this conference abstract has not undergone peer review, relies on flawed exposure measurement that misclassified thousands of participants, and cannot distinguish whether melatonin causes heart problems or whether sicker patients simply use melatonin more often. Most importantly, decades of research actually demonstrate cardiovascular benefits from melatonin, creating a paradox that experts say likely reflects the study’s methodological problems rather than true drug harm.
The findings emerge at a time when melatonin use has increased fivefold over two decades, from 0.4% of US adults in 1999-2000 to 2.1% in 2017-2018, with sales exceeding $821 million in 2020. This growth reflects widespread belief in melatonin as a safe, natural sleep aid. The Nnadi study challenges this perception by examining 130,828 adults with chronic insomnia over five years, finding not just increased heart failure diagnoses but also 3.5 times higher hospitalization rates and nearly double the mortality risk. Yet the study’s acknowledged inability to capture over-the-counter supplement use means many supposed “non-users” were actually taking melatonin, fundamentally undermining the comparison. The research also cannot account for insomnia severity, depression, anxiety, or sleep apnea—all of which independently increase cardiovascular risk and may be the true culprits driving the association.
What the study actually found and how it was conducted
Dr. Nnadi’s research team analyzed electronic health records from the TriNetX Global Research Network, tracking patients diagnosed with chronic insomnia who had been prescribed melatonin for at least one year. The study matched 65,414 melatonin users with 65,414 non-users across 40 demographic and health factors including age, sex, pre-existing heart conditions, blood pressure, and BMI. The average participant was 56 years old, and 61% were women. All participants had chronic insomnia diagnoses but no prior heart failure, and researchers excluded anyone taking other prescription sleep medications.
Over five years of follow-up, the data revealed striking differences. Heart failure developed in 4.6% of melatonin users versus 2.7% of non-users—an absolute difference of just 1.9 percentage points, but a relative increase of 90%. Hospitalization figures were even more dramatic: 19% of melatonin users required heart failure hospitalization compared to 6.6% of controls. Perhaps most concerning, 7.8% of melatonin users died from any cause during the study period, nearly double the 4.3% mortality rate among non-users. A sensitivity analysis requiring at least two melatonin prescriptions filled 90 days apart yielded similar results with 82% higher risk.
The study design carries fundamental flaws that experts immediately flagged. Most critically, the research captured only prescribed melatonin documented in medical records, yet melatonin is available over-the-counter without prescription in the United States, where most study participants resided. As Dr. Nnadi’s team acknowledged, “everyone taking it as an over-the-counter supplement in the U.S. or other countries that don’t require a prescription would have been in the non-melatonin group.” Given that up to 27% of US adults use melatonin and the vast majority purchase it without prescriptions, this misclassification creates massive bias—many supposed controls were actually exposed, diluting any true effect and potentially flipping the direction of findings.
The database itself presents problems. TriNetX relies on electronic health records collected for billing and clinical purposes rather than research, resulting in coding errors, missing data, and inconsistent quality across institutions. Studies document that over 16% of primary diagnoses change upon audit, and critical variables like insomnia severity, psychiatric disorder presence, sleep apnea, lifestyle factors, and actual medication consumption remain unmeasured. The study also mixed data from countries requiring melatonin prescriptions (UK) with those allowing over-the-counter access (US), creating heterogeneous exposure definitions that cannot be disentangled.
Why leading experts question these findings
The most vocal critic was Dr. Carlos Egea, president of the Spanish Federation of Sleep Medicine Societies, who pointed out that recent systematic reviews have actually found positive effects of melatonin in heart failure patients, considering it “a new treatment for these cardiac patients.” He highlighted the study’s preliminary status—it’s a conference abstract that “has not been filtered by two independent reviewers,” unlike peer-reviewed journal publications. Egea emphasized that observational studies “only show association and do not establish causality” and that the control group contamination with OTC users represents “a very significant bias.”
Dr. Marie-Pierre St-Onge, who chairs the AHA’s scientific statement on sleep health, expressed surprise that “physicians would prescribe melatonin for insomnia and have patients use it for more than 365 days, since melatonin, at least in the U.S., is not indicated for the treatment of insomnia.” Her comment underscores a crucial point: the study examined an unusual population receiving long-term prescriptions for a condition where melatonin isn’t the standard treatment, suggesting these patients may have been sicker or had more complex medical situations than typical supplement users.
The concept of “confounding by indication” looms large in expert critiques. This occurs when a treatment marks patients who are already at higher risk, making the drug appear harmful when the underlying condition is actually responsible. In this case, patients prescribed melatonin for chronic insomnia likely had more severe, treatment-resistant sleep problems potentially driven by depression, anxiety, undiagnosed sleep apnea, or early cardiovascular symptoms manifesting as sleep disturbance. The study controlled for some measured factors but couldn’t account for disease severity, psychiatric comorbidities, or the many lifestyle and social determinants that affect both sleep and heart health.
Reverse causality presents another plausible explanation. Early heart failure causes sleep problems through orthopnea, paroxysmal nocturnal dyspnea, and frequent urination, leading patients to seek sleep aids. The Rotterdam Study confirmed that “clinical heart failure increased the risk of sleep problems,” and sleeping difficulties are “a frequent side effect of heart failure.” Rather than melatonin causing heart disease, subclinical cardiac dysfunction may cause insomnia that prompts melatonin use, with heart failure becoming clinically apparent later—creating the appearance of drug harm when the disease timeline actually runs in reverse.
The cardiovascular paradox: extensive evidence shows heart protection
The Nnadi findings clash dramatically with decades of research demonstrating melatonin’s cardioprotective properties, creating a paradox that experts say likely reflects methodological problems rather than true harm. Multiple randomized controlled trials have documented blood pressure reductions: Scheer et al. found that 2.5 mg nightly for three weeks reduced systolic blood pressure by 6 mmHg and diastolic by 4 mmHg in hypertensive men, with effects most pronounced during sleep. Other RCTs showed similar nocturnal blood pressure improvements of 3-6 mmHg, significant given that even modest reductions decrease cardiovascular event risk.
The mechanisms explaining melatonin’s cardiovascular benefits are well-established and diverse. As a potent antioxidant, melatonin directly scavenges free radicals and stimulates antioxidant enzymes, protecting cardiac tissue from oxidative damage. Research demonstrates that “melatonin has shown significant benefits in reducing cardiac pathology, and preventing the death of cardiac muscle in response to ischemia-reperfusion in rodent species.” In animal models of heart attack, melatonin reduces infarct size, prevents cardiac muscle death during reperfusion, and protects mitochondrial function. The molecule also exhibits anti-inflammatory properties by reducing cytokines like IL-6 and TNF-α, and prevents cardiac hypertrophy that can lead to heart failure.
Perhaps most tellingly, epidemiological studies reveal a strong inverse relationship between endogenous melatonin levels and cardiovascular disease—people with low natural melatonin have higher CVD risk, the opposite of what the Nnadi study would predict if exogenous melatonin caused harm. Multiple studies show that nocturnal melatonin synthesis and circulating levels are reduced in patients with coronary heart disease, hypertension, and heart failure, suggesting that melatonin deficiency may contribute to cardiac problems rather than melatonin supplementation causing them.
A 2025 systematic review by Daliri et al., cited by Dr. Egea, found a “positive effect of melatonin on patient outcomes, in this case, in patients with heart failure, where the authors consider melatonin to be a new treatment for these cardiac patients, even in palliative care.” This directly contradicts the Nnadi associations. Meta-analyses examining high-dose melatonin (over 10 mg daily) found no increase in serious adverse events, with a rate ratio of 0.88—if anything, suggesting a protective trend. Studies using doses up to 300 mg daily for two years showed safety, and phase 1 trials with 100 mg doses reported only mild transient drowsiness.
The most compelling evidence comes from Mendelian randomization studies, which use genetic variants to avoid confounding and establish causation—the gold standard short of randomized trials. Multiple MR studies prove that insomnia itself causes heart disease, with genetic liability to insomnia associated with 19-21% higher odds of heart failure, coronary artery disease, and stroke. These associations persist after adjusting for smoking, education, and depression. The mechanism involves chronic hyperarousal with persistent activation of stress responses, increased metabolic rate and heart rate, decreased heart rate variability, elevated cortisol secretion, inflammation, and sympathetic nervous system overactivity. A meta-analysis by Sofi et al. determined that insomnia carries a 45% increased risk of developing or dying from cardiovascular disease independent of any treatments.
This creates a critical interpretive framework: chronic insomnia requiring long-term treatment likely marks the true cardiovascular risk factor, with melatonin serving as a marker for disease severity rather than a cause of harm. The study’s requirement for one-year minimum use before seeing associations supports this interpretation—if melatonin directly damaged hearts, effects should appear earlier or show dose-dependence, yet high-dose studies show safety. The one-year threshold more plausibly reflects the progression of underlying insomnia and cardiac disease rather than melatonin toxicity developing gradually.
Context for the 27% of Americans using melatonin
Understanding the study in context requires knowing how melatonin is actually used. Melatonin consumption has exploded from 0.4% of US adults in 1999-2000 to 2.1% by 2017-2018, a fivefold increase documented in NHANES data tracking 55,021 adults. Usage is similar across sexes and age groups, though prescribing rates in the UK are highest in practices serving children and deprived populations. The US market alone exceeded $821 million in 2020, with projections reaching $3-5 billion by 2030. The pandemic accelerated growth, with 81% of physicians reporting increased patients taking melatonin or sleep aids since COVID-19 began.
Typical doses range from 1-3 mg for most OTC formulations, though products available span 0.5 mg to 10 mg or higher. Physiological doses closer to natural production are 0.3-1 mg, but consumer products often contain supraphysiological amounts. Concerning, a study of 31 melatonin supplements found actual content ranged from 83% below to 478% above labeled amounts, with lot-to-lot variability up to 465%. Additionally, 26% contained serotonin, a neurotransmitter that can cause harmful effects and should not be present. The FDA does not regulate supplements as rigorously as medications, creating quality control problems that may contribute to variable outcomes in real-world use.
Most people use melatonin for insomnia, though approved indications include jet lag, delayed sleep-wake phase disorder, and shift work sleep issues. In the United States, melatonin is classified as a dietary supplement and available without prescription, while the UK and most European countries require prescriptions—typically limiting use to adults 55+ with primary insomnia. The American Academy of Sleep Medicine actually recommends against melatonin for sleep onset or maintenance insomnia in adults, giving only weak recommendations for circadian rhythm disorders. This highlights a disconnect between clinical guidelines and consumer use, with many people taking melatonin for unapproved indications.
Existing safety data from systematic reviews spanning 37 randomized controlled trials involving 2,130 patients found melatonin’s most common adverse effects were daytime sleepiness (1.66%), headache (0.74%), and dizziness (0.74%)—rates only slightly above placebo and of minor clinical significance. Meta-analyses conclude that “commonly reported side effects of long-term use of exogenous melatonin are minor, and data from the available studies regarding its long-term safety are generally reassuring.” However, most trials lasted under 12 weeks, creating an evidence gap for the multi-year use examined in Nnadi’s study.
Pediatric safety has emerged as a concern independent of cardiac issues. Melatonin overdoses in children increased from 8,337 reports in 2012 to 52,563 in 2021, with 11,000 emergency department visits from 2019-2022 for unsupervised ingestion by children under 5. While 82.8% had no symptoms, 15% required hospitalization and some needed intensive care. The long-term effects on hormonal development, puberty timing, and prolactin remain unknown. A 2023 analysis found 74% of melatonin gummy products contained inaccurate amounts, ranging from 74-347% of labeled content, raising significant safety concerns for both children and adults.
What this means for current melatonin users and practical next steps
For the estimated 27% of American adults currently using melatonin, this study does not provide sufficient evidence to warrant immediate discontinuation, but it does raise questions worth discussing with healthcare providers. The research examined a specific population—patients with diagnosed chronic insomnia receiving prescriptions—which differs substantially from occasional users taking OTC supplements for jet lag or periodic sleep difficulties. The findings also remain preliminary and unreviewed, requiring replication in controlled studies before changing practice recommendations.
People using melatonin nightly for months or years, particularly those with risk factors for heart disease, should consult their physicians to evaluate whether continued use is appropriate. This conversation should address the underlying cause of sleep problems, as treating the root issue—whether sleep apnea, depression, anxiety, or poor sleep hygiene—may be more effective than ongoing supplementation. Sleep specialists emphasize that melatonin is not intended for chronic insomnia treatment, and Dr. St-Onge’s surprise that physicians prescribed it for over a year underscores that long-term use represents off-label practice without strong evidence.
Those at potentially higher risk based on the study’s findings would include middle-aged and older adults with chronic insomnia, pre-existing cardiovascular conditions, or multiple cardiac risk factors like hypertension, diabetes, or obesity. However, the paradox remains that people in these categories might also benefit most from melatonin’s documented blood pressure reduction and antioxidant effects. The uncertainty reflects the study’s inability to separate melatonin’s direct effects from the cardiovascular burden of severe insomnia itself.
For individuals who decide to continue melatonin after medical consultation, several precautions may help optimize safety. Use the lowest effective dose (often 0.5-1 mg rather than 5-10 mg products), purchase from reputable manufacturers given quality control concerns, and limit use to occasions when actually needed rather than nightly indefinitely. Address sleep hygiene fundamentals including consistent bedtimes, reduced screen exposure before sleep, comfortable sleep environments, and regular exercise. Consider whether melatonin genuinely improves sleep quality or has become habitual without clear benefit.
Alternative approaches for sleep support include cognitive behavioral therapy for insomnia (CBT-I), which multiple studies show equals or exceeds medication effectiveness with lasting benefits. Treating underlying conditions like sleep apnea through CPAP therapy or positional devices can dramatically improve sleep. For circadian rhythm issues, timed light exposure, light therapy boxes, or adjusting sleep schedules may prove effective. Addressing anxiety and depression through therapy or medication often resolves associated insomnia. Prescription sleep medications remain options for appropriate cases, though they carry their own risks and side effects.
The supplement industry’s response emphasized that melatonin is intended for occasional use in healthy individuals, not chronic disease treatment. The Natural Products Association stated that “dietary supplements sold in the United States are not intended to treat, cure, or prevent disease,” and noted the study “examined whether melatonin use alters the risk of heart failure in chronic insomnia patients, which is not the supplement industry’s target population.” The Council for Responsible Nutrition affirmed that “decades of consumer experience and multiple clinical studies indicate that low-dose, short-term supplementation is safe for healthy adults when used as directed,” while supporting ongoing research into long-term use patterns.
Making sense of contradictory signals in sleep medicine
The melatonin controversy illustrates fundamental challenges in supplement research and observational epidemiology. When a widely-used compound with established biological benefits suddenly appears harmful in database analysis, skepticism is warranted—particularly when the study cannot measure actual exposure, disease severity, or key confounders. The finding that prescription melatonin users had worse outcomes may simply reflect that the sickest insomnia patients with the most cardiovascular risk factors sought medical care and received documented prescriptions, while healthier occasional users purchased supplements without medical records.
What emerges most clearly is that chronic insomnia itself—not necessarily its treatments—poses serious cardiovascular risk through mechanisms including autonomic dysfunction, inflammation, cortisol dysregulation, and metabolic disturbance. The Mendelian randomization evidence proving genetic liability to insomnia causes heart disease provides far stronger causal inference than this observational study. The practical implication is that people with persistent sleep problems need comprehensive evaluation and treatment of underlying causes rather than indefinite symptomatic management with any sleep aid, whether melatonin, prescription hypnotics, or over-the-counter antihistamines.
The study does serve valuable purposes despite its limitations. It highlights knowledge gaps about long-term supplement use, questions assumptions about melatonin’s universal safety for all populations and durations, and emphasizes that even “natural” compounds require rigorous safety evaluation. It reminds clinicians to document supplement use in medical records and consider potential adverse effects when counseling patients. Most importantly, it illustrates how even large observational studies can generate misleading associations when exposure measurement fails, confounding is inadequately controlled, and reverse causality is plausible.
Future research should include prospective trials with verified supplement consumption, dose-response analyses, separation of healthy users from chronic insomnia populations, comprehensive psychiatric and sleep disorder assessment, and mechanistic studies examining how long-term exogenous melatonin affects endogenous rhythms and receptor function. Only randomized controlled trials can definitively answer whether long-term melatonin supplementation causes, prevents, or has no effect on cardiovascular disease. Until such evidence emerges, the preliminary Nnadi findings warrant attention but not alarm, conversation but not cessation, and further investigation but not clinical practice changes based on a single unreviewed abstract contradicted by decades of protective evidence.
