Melatonin and Heart Health: What You Should Know

Most people who reach for melatonin at bedtime think of it as a gentle, harmless supplement - a natural nudge toward sleep with no serious strings attached. That perception changed meaningfully in November 2025, when researchers presented data at the American Heart Association's annual Scientific Sessions suggesting that long-term melatonin use in people with chronic insomnia was associated with a significantly higher risk of heart failure and death from any cause over five years.

The findings made headlines. They also need context.

Because at the same time that this observational signal was raising questions about long-term cardiovascular safety, a growing body of basic science and clinical research was documenting melatonin's antioxidant, anti-inflammatory, and cardioprotective properties - suggesting it may protect the heart against oxidative damage, atherosclerosis, and ischemia-reperfusion injury under certain conditions.

How can the same hormone appear to protect the heart in some studies and raise risk signals in others? The answer lies in understanding what melatonin is, how it acts on the cardiovascular system, what distinguishes the populations and doses studied, and what the current state of evidence actually supports for everyday supplementation decisions.

What Is Melatonin and What Does It Do in the Body?

Melatonin (N-acetyl-5-methoxytryptamine) is a neuroendocrine hormone produced primarily by the pineal gland in response to darkness. Its levels rise after sunset, peak between 2 and 4 AM, and decline before dawn - directly regulating the sleep-wake cycle and coordinating broader circadian rhythms throughout the body.

But melatonin is not exclusively a sleep hormone. It is produced in multiple extrapineal tissues including the heart, blood vessels, gut, skin, and immune cells - and its receptors (MT1 and MT2) are distributed widely across the cardiovascular system. The heart produces and uses melatonin locally, independent of the pineal gland, suggesting it has direct cardiac functions beyond sleep regulation.

Its pharmacological profile is broad: melatonin is a potent antioxidant capable of directly scavenging reactive oxygen species (ROS), an anti-inflammatory agent, a regulator of mitochondrial function, and a modulator of vascular tone. Each of these properties has direct cardiovascular relevance - which is why melatonin has been extensively studied as a potential cardioprotective agent for decades.

The Cardioprotective Evidence: Where Melatonin May Help the Heart

Antioxidant Protection and Atherosclerosis

Oxidative stress - the accumulation of reactive oxygen species that damage cells and tissues - is a central driver of atherosclerosis, the arterial plaque buildup that underlies heart attack and stroke. Melatonin's direct free radical scavenger activity, its indirect antioxidant qualities (stimulating endogenous antioxidant enzymes), and its anti-inflammatory capabilities collectively contribute to what researchers describe as atheroprotective effects on multiple pathogenic signaling pathways.

A 2025 review published in the Journal of Cardiothoracic Surgery examined melatonin's effects on atherosclerosis, specifically its influence on programmed cell death, inflammation, and oxidative stress. The authors concluded that melatonin's pleiotropic antioxidant and anti-inflammatory mechanisms address several of the molecular pathways through which atherosclerotic plaques form and destabilize - including lipid peroxidation, macrophage foam cell formation, and vascular smooth muscle cell apoptosis.

A 2024 review in the American Journal of Cardiovascular Drugs summarized that exogenous melatonin administration has been reported to decrease blood pressure, protect against atherosclerosis, and attenuate molecular and cellular damage from cardiac ischemia-reperfusion, based on its antioxidant and anti-inflammatory properties.

Ischemia-Reperfusion Injury: The Most Studied Cardioprotective Effect

The most extensively researched area of melatonin's cardiac biology is its effect on ischemia-reperfusion injury (IRI) - the paradoxical cardiac damage that occurs when blood supply is restored to the heart after a heart attack. The reperfusion phase generates a surge of reactive oxygen species that can kill cardiac muscle cells that survived the initial ischemic event.

Melatonin has shown consistent cardioprotective effects against IRI in animal studies, operating through multiple mechanisms: it directly neutralizes the reactive oxygen species generated during reperfusion, stabilizes mitochondrial membrane potential, prevents the opening of the mitochondrial permeability transition pore (mPTP) - a critical gateway to cardiac cell death - and reduces cytochrome c release and activation of apoptotic pathways.

At the cellular signaling level, melatonin activates the AMPK/Nrf2 pathway - a master antioxidant defense mechanism that upregulates the body's own protective enzymes - and protects against ischemic arrhythmias by preserving connexin 43 expression, which maintains electrical coupling between cardiac cells. These mechanisms are well characterized in rodent and porcine cardiac models.

Blood Pressure and Vascular Effects

Several clinical studies have examined melatonin's effect on blood pressure, with generally modest but directionally positive results. A meta-analysis reported in the Frontiers in Cardiovascular Medicine review found that controlled-release melatonin at doses of 2 to 5 mg produced statistically significant reductions in both systolic and diastolic blood pressure in hypertensive patients, with effect sizes of approximately 3 to 6 mmHg systolic. The vasodilatory mechanism likely involves melatonin's effects on vascular smooth muscle relaxation via its antioxidant properties and its interaction with MT receptors on vascular endothelium.

These effects are more consistently observed with controlled-release formulations than immediate-release melatonin, and are more pronounced in nighttime blood pressure (nocturnal hypertension) than daytime readings - consistent with melatonin's circadian biology.

The Human Clinical Trial Picture: Promising but Incomplete

Despite the volume of promising preclinical data, the clinical translation of melatonin's cardioprotective effects into measurable human outcomes has been inconsistent. A meta-analysis reviewed in Basic Research in Cardiology (2026) analyzed nine studies of melatonin in cardiac IRI patients across four major clinical contexts: STEMI, ischemic heart disease patients scheduled for CABG, acute coronary syndrome, and coronary heart disease in diabetics. Pooled analysis revealed that melatonin administration did not significantly improve cardiac function or infarct size overall. However, subgroup analyses showed that melatonin conferred cardioprotection when administered in specific dosing windows - highlighting that timing, dose, and route of administration remain critical unsolved questions for clinical application.

The oral bioavailability of melatonin is only 9 to 33% due to extensive first-pass metabolism in the liver, meaning a significant proportion of an oral dose never reaches the target tissues. This pharmacokinetic limitation has led researchers to investigate melatonin analogs with improved bioavailability for clinical cardioprotection applications.

The 2025 AHA Warning Signal: What the Heart Failure Data Shows

The Study That Changed the Conversation

At the November 2025 American Heart Association Scientific Sessions, researchers presented a large observational study that significantly changed how clinicians and public health authorities discuss melatonin's cardiovascular safety.

The study, using data from the TriNetX Global Research Network, reviewed five years of electronic health records for 130,828 adults with diagnosed chronic insomnia (average age 56; 61% women). Of these, 65,414 had been prescribed melatonin at least once and reported taking it for at least one year. They were matched with peers who also had insomnia but never had melatonin recorded in their health records.

The findings were striking: long-term melatonin use was associated with a higher hazard of heart failure, an increase in heart failure hospitalizations, and a doubling of all-cause mortality over five years compared to matched non-users. The researchers concluded that "robust data on its long-term cardiovascular safety are lacking" and called for further investigation.

The American College of Cardiology summarized the findings as emphasizing "the need to clarify the cardiovascular safety profile of melatonin use as benign chronic therapy."

Why This Study Must Be Interpreted Carefully

The findings are significant and warrant serious consideration - but several limitations require careful acknowledgment before they can be applied to everyday supplementation decisions.

This was an observational, not randomized, study. The most important limitation is that the study could not establish causation - only association. People with chronic insomnia who are also prescribed and use melatonin for over a year represent a clinically distinct population from healthy adults who occasionally take melatonin to shift a time zone or ease occasional sleeplessness.

The study population had chronic insomnia - itself a cardiovascular risk factor. As the Council for Responsible Nutrition (CRN) noted in its response, quality sleep is critical for cardiovascular health, and individuals with chronic insomnia tend to have higher resting heart rates, elevated blood pressure, and more cardiovascular events regardless of melatonin use. The association observed may partly or fully reflect the cardiovascular burden of the underlying insomnia rather than the melatonin itself.

Confounding by indication is a major concern. People who use melatonin for a year or longer likely have more severe or treatment-resistant insomnia than those who did not use it at all. More severe insomnia is independently associated with worse cardiovascular outcomes.

The study is preliminary and not yet peer-reviewed as a full manuscript. AHA states that abstracts presented at scientific meetings "are not peer-reviewed, and the findings are considered preliminary until published as full manuscripts in a peer-reviewed scientific journal."

The finding about elevated melatonin in heart failure is biologically complex. The Basic Research in Cardiology 2026 review noted that children with heart failure have been found to have elevated melatonin levels correlating with disease severity - and hypothesized this may represent a compensatory response, not a cause. The directionality of the melatonin-heart failure relationship requires careful mechanistic investigation before clinical conclusions can be drawn.

The National Geographic's independent analysis of the 2025 findings summarized the situation well: the science surrounding melatonin's cardiovascular effects "is far more complex and unsettled than many consumers realize."

Sleep, Circadian Rhythm, and the Heart: The Bigger Picture

One dimension of this discussion that often gets lost is that inadequate sleep and disrupted circadian rhythms are independently established cardiovascular risk factors - and melatonin's primary biological role is to support both.

Chronic sleep deprivation elevates inflammatory markers, impairs endothelial function, raises cortisol and sympathetic nervous system tone, increases blood pressure, and promotes insulin resistance - each of which contributes to atherosclerotic disease progression. The same circadian disruption that drives melatonin supplementation may itself be the cardiac risk factor, rather than the supplement being used to address it.

This creates a genuinely difficult interpretive challenge for the AHA observational data: people who use melatonin chronically for insomnia are, almost by definition, people experiencing chronic sleep disruption. Attributing their elevated cardiovascular risk to the melatonin rather than the underlying sleep disorder requires a level of causal confidence that observational data simply cannot provide.

The cardioprotective mechanisms of endogenous melatonin - its antioxidant, anti-inflammatory, and circadian regulatory roles in cardiac tissue - are well established. Whether exogenous supplementation meaningfully augments these protective effects in humans, and at what doses and in what populations, remains an open clinical question.

What This Means for Different Groups of People

Occasional Users: Low Concern

For the vast majority of melatonin users - those who take it occasionally for jet lag, shift work, or intermittent sleep difficulties - the current evidence does not support significant cardiovascular concern. The CRN's response to the AHA data explicitly stated that the findings "are unlikely to apply to healthy adults who use melatonin dietary supplements occasionally for sleep support."

CRN's voluntary melatonin labeling guidelines, adopted in 2024, recommend that packaging include the statement "For occasional and/or intermittent use only" and "Consult a healthcare professional if you are experiencing long-term sleep difficulties" - guidance that was already in place before the AHA findings and that now has additional rationale.

Long-Term Users With Chronic Insomnia: A Conversation to Have

For individuals who have been using melatonin nightly for a year or more to manage chronic insomnia, the 2025 AHA data is a reasonable trigger for a conversation with a physician. This is particularly true for people with existing cardiovascular risk factors or diagnosed cardiovascular disease.

The appropriate clinical response is not to immediately discontinue melatonin, but to discuss whether the chronic insomnia is being adequately addressed, whether cognitive behavioral therapy for insomnia (CBT-I) - the evidence-backed first-line treatment for chronic insomnia - has been tried, and whether the cardiovascular risk profile warrants closer monitoring.

People With Existing Cardiovascular Disease

For people with established heart disease, heart failure, or significant cardiovascular risk, the principle of caution applies most strongly. Until the AHA findings are further investigated through controlled study designs, and given the mechanistic complexity of melatonin's cardiovascular effects at higher doses and over longer durations, discussing long-term melatonin use with a cardiologist or primary care physician is reasonable.

Notably, the 2026 Basic Research in Cardiology review highlighted that melatonin may paradoxically correlate with disease severity in certain heart failure populations - an observation that reinforces the need for individualized clinical judgment rather than blanket recommendations.

Dosage: What the Science Supports

One underappreciated dimension of the melatonin and heart health discussion is that the doses used in supplements are frequently far higher than those needed to influence sleep - or than the body naturally produces.

Endogenous melatonin levels peak at approximately 100 to 200 picograms per milliliter of blood (0.1 to 0.2 nanograms/mL). Common OTC melatonin supplements range from 1 to 10 mg per dose - meaning many products deliver doses 10 to 100 times higher than typical physiological levels. Most sleep research shows doses as low as 0.1 to 0.5 mg are effective for sleep onset - suggesting the current standard supplement dosing is substantially above what is physiologically necessary.

The implications for cardiovascular safety are not yet fully characterized, but the principle of using the lowest effective dose for the shortest necessary duration applies here as it does for most bioactive hormonal compounds.

A 2025 PMC retrospective analysis on rethinking melatonin dosing in aged patients with comorbidities found that a cytoprotective high-dose melatonin protocol had beneficial effects on some cardiovascular and metabolic markers in an elderly population managed within a sleep medicine clinic - suggesting dose-dependent effects that may be distinct at clinical versus supplemental levels.

Natural Support for Cardiovascular and Sleep Health: A Complementary Approach

For individuals concerned about sleep quality and cardiovascular health simultaneously, the evidence increasingly points to addressing both through the same underlying mechanisms: reducing oxidative stress, supporting circadian rhythm, and protecting vascular function.

Hydroxytyrosol - the primary polyphenol in olive oil - shares several of melatonin's most established cardioprotective mechanisms. Its well-documented ability to scavenge free radicals and protect LDL from oxidative damage directly addresses the oxidative stress pathway central to atherosclerosis. The European Food Safety Authority has formally recognized that olive oil polyphenols including hydroxytyrosol contribute to the protection of blood lipids from oxidative stress. Unlike melatonin, hydroxytyrosol is a dietary compound with no hormonal activity and an extremely well-characterized safety profile.

Similarly, omega-3 fatty acids from algal DHA and EPA provide anti-inflammatory and antioxidant protection to the cardiovascular system through mechanisms that are complementary to melatonin's proposed cardioprotective pathways - reducing triglycerides, improving HDL function, and dampening the systemic inflammation that drives both atherosclerosis and cardiac arrhythmia risk.

For sleep specifically, compounds that address the underlying neurotransmitter balance - such as L-theanine (which increases GABA and reduces cortisol without hormonal activity) and magnesium (which supports GABA receptor activity and melatonin production naturally) - offer sleep-supportive mechanisms that do not involve exogenous hormonal supplementation. These may be preferable alternatives for individuals with cardiovascular concerns who are seeking sleep support beyond melatonin.

For comprehensive cognitive and neurological support, Naturem™ Memory+ combines hydroxytyrosol with neuroprotective botanicals that support brain health through BDNF stimulation, cerebral circulation enhancement, and neuroinflammation reduction - addressing the sleep-cognition-cardiovascular intersection from a brain health angle without hormonal activity.

What to Do With This Information

The evidence on melatonin and heart health, taken as a whole, leads to several practical conclusions:

For most healthy adults using melatonin occasionally: current evidence does not suggest meaningful cardiovascular risk. Occasional use for jet lag, shift work adaptation, or intermittent sleep support falls outside the chronic insomnia population studied at AHA 2025.

Use the lowest effective dose. Most people need far less melatonin than common supplements contain. Starting with 0.5 to 1 mg rather than the 5 or 10 mg doses found in many products is both safer and often equally effective.

Do not use melatonin as a long-term treatment for chronic insomnia. CBT-I is the first-line, evidence-based treatment for chronic insomnia and addresses root causes rather than providing temporary symptomatic relief. If you have been relying on melatonin nightly for months or years for diagnosable insomnia, discuss CBT-I and other evidence-based approaches with your physician.

If you have cardiovascular disease or significant cardiovascular risk factors: discuss long-term melatonin use with your cardiologist or primary care physician. The AHA 2025 findings are preliminary, but they provide a sufficient signal to make this conversation worthwhile.

Support your cardiovascular health through established pillars: adequate sleep (not just melatonin), regular aerobic and resistance exercise, an anti-inflammatory diet rich in olive polyphenols and omega-3 fatty acids, blood pressure management, and stress reduction.

Conclusion: A Complex Hormone in a Complex System

Melatonin is neither a simple, universally safe sleep supplement nor a cardiovascular hazard. It is a biologically active hormone with pleiotropic effects across the cardiovascular system - some of which appear protective in specific contexts, and some of which may carry risk in specific populations with long-term high-dose use.

The 2025 AHA observational data represents an important signal that should not be dismissed - but should not be extrapolated beyond its studied population to all melatonin users either. The preclinical and early clinical evidence for melatonin's antioxidant, anti-atherosclerotic, and ischemia-protective properties is real and mechanistically grounded - even if human clinical trials have not yet consistently translated these effects into measurable cardiovascular outcome improvements.

What the current state of evidence most clearly supports is caution about long-term high-dose melatonin use in people with chronic cardiovascular conditions or untreated chronic insomnia, alongside continued investigation through rigorous randomized controlled trials. The heart of the matter - quite literally - is that melatonin's relationship with the cardiovascular system is far more nuanced than its over-the-counter accessibility implies, and that the conversation about its long-term cardiovascular safety is just beginning.

This article is for informational purposes only and does not constitute medical advice. Always consult your healthcare provider before beginning or discontinuing any supplement, particularly if you have cardiovascular conditions or are taking medications.