Observational study finds long-term melatonin use associated with increased heart failure risk — Evidence Review

Long-term use of melatonin supplements was linked to increased risk of heart failure, hospitalization, and death among adults with chronic insomnia in a large observational study. Most previous research has suggested melatonin may be beneficial or neutral for cardiovascular health, so these new findings from SUNY Downstate/Kings County Primary Care present a notable contrast.

• Most related studies and reviews in animals and humans have described melatonin as cardioprotective, reducing risk factors and improving cardiac health, though human data on long-term safety are limited 1 2 5 9.
• Experimental and some early clinical studies suggest melatonin may help prevent or treat cardiovascular damage, including heart failure, especially through antioxidant and anti-inflammatory effects 1 3 4 5 7 8 10 12.
• Systematic reviews generally report a favorable safety profile for melatonin, with few cardiovascular adverse effects, but acknowledge that data on chronic, high-dose, or long-term use are sparse 11.

Study Overview and Key Findings

Interest in melatonin as a sleep aid has grown rapidly, with widespread over-the-counter use often extending far beyond the durations studied in clinical trials. Despite its reputation as a "natural" supplement, little attention has been paid to potential long-term cardiovascular risks, especially among individuals with chronic insomnia—a group already at higher risk for heart disease. The new study presented preliminary evidence that long-term melatonin use may not be as harmless as commonly believed, underscoring the need for careful evaluation of supplement use in clinical practice.

Property	Value
Study Year	2025
Organization	SUNY Downstate/Kings County Primary Care
Authors	Ekenedilichukwu Nnadi, Marie-Pierre St-Onge
Population	Adults with chronic insomnia
Sample Size	n=130,828
Methods	Observational Study
Outcome	Heart failure risk, hospitalization for heart failure, death
Results	Long-term melatonin use linked to 90% higher heart failure risk

The study analyzed five years of de-identified electronic health records from over 130,000 adults diagnosed with chronic insomnia. Participants with at least one year of documented melatonin use were compared to matched non-users. Key findings include:

• Adults with long-term melatonin use (12 months or more) had about a 90% higher risk of developing heart failure over five years compared to non-users with similar profiles.
• Hospitalization rates for heart failure and all-cause mortality were also significantly increased in the melatonin group.
• The association persisted even after analyses designed to ensure that only long-term, documented melatonin use was counted.
• The study was observational and cannot prove causality; unmeasured confounders (such as insomnia severity or psychiatric comorbidities) may have influenced the results.
• Limitations include reliance on medical records for supplement use (which may undercount over-the-counter use) and lack of data on dose, formulation, and adherence.

Literature Review: Related Studies

To place these findings in context, we searched the Consensus database of over 200 million papers using targeted queries. The following search queries were used:

1. melatonin heart failure correlation
2. long-term melatonin cardiovascular effects
3. melatonin use safety heart health

Below, we group the most relevant findings from the literature into key themes:

Topic	Key Findings
What is the impact of melatonin on cardiovascular health?	- Most animal and mechanistic studies indicate that melatonin is cardioprotective, reducing risk factors and improving heart function 1 3 4 5 7 8 9 10 12. - Some human studies suggest benefits for blood pressure and metabolic risk, though evidence in heart failure is limited and mixed 2 5 9 13.
What are the known risks and safety profile of melatonin?	- Systematic reviews report that melatonin is generally well-tolerated, with most adverse effects being minor and transient 11. - Rare cardiovascular adverse effects have been noted, but data on long-term, high-dose, or chronic use are lacking 11.
Does melatonin use affect heart failure risk or outcomes?	- Animal studies consistently show melatonin reduces cardiac remodeling and mortality in heart failure models 3 4 5 8 12. - Human data are sparse, with some early trials and reviews suggesting possible benefit or safety, but insufficient evidence on chronic outcomes 5 13.
How does melatonin interact with cardiovascular medications or disease processes?	- Melatonin's antioxidant and anti-inflammatory properties may counteract drug-induced or disease-related heart damage 7 10 12. - Limited studies suggest interactions with blood pressure medications and possible effects on cardiovascular parameters 2 11.

What is the impact of melatonin on cardiovascular health?

The majority of basic science and preclinical studies have found that melatonin exerts protective effects on the heart and vasculature, including reduction in oxidative stress, inflammation, and cardiac remodeling. Several human studies and reviews note potential improvements in hypertension and metabolic health, though robust evidence in large-scale clinical populations is limited. The new observational study's finding of increased heart failure risk with long-term use stands in contrast to the largely positive or neutral cardiovascular profile described in the literature.

• Melatonin reduces cardiac pathology, hypertrophy, and ischemia-induced damage in animal models 1 3 4 5 8.
• Reviews emphasize melatonin's antioxidant, anti-inflammatory, and circadian-regulating roles in cardiovascular health 1 7 9 10.
• Some human studies suggest blood pressure benefits and reduced platelet aggregation, but clinical evidence for heart failure prevention is weak 2 5 9 13.
• The new study raises questions about translation from basic science to real-world, long-term use in humans.

What are the known risks and safety profile of melatonin?

Systematic reviews of clinical trials and observational data suggest that melatonin is generally safe, with adverse effects typically mild (e.g., fatigue, mood changes). Cardiovascular adverse events have rarely been reported, and when present, were often associated with specific populations or drug interactions. However, long-term, high-dose, or unsupervised use—common in real-world settings—has not been well studied, leaving important gaps that the new study begins to address.

• Most adverse events are minor and avoidable by aligning dosing with natural circadian rhythms 11.
• Cardiovascular side effects, when reported, are uncommon and usually transient 11.
• There is a lack of data on chronic or high-dose supplementation, especially in populations at elevated cardiovascular risk 11.
• The new findings suggest the need to reevaluate long-term safety, particularly in at-risk groups.

Does melatonin use affect heart failure risk or outcomes?

In animal models, melatonin supplementation consistently reduces cardiac remodeling, oxidative stress, and improves survival in induced heart failure 3 4 5 8 12. Limited clinical studies suggest possible benefit as an adjunct therapy in heart failure patients, but results are preliminary. No prior human study has reported an association between long-term melatonin use and increased heart failure risk, making the new observation notable and warranting further investigation.

• Melatonin improves outcomes in rodent models of heart failure, including reduced mortality and fibrosis 3 4 5 8.
• Reviews highlight melatonin's potential as a preventive or adjunctive therapy in heart failure, but call for more clinical trials 5 13.
• Early-phase randomized trials in humans are ongoing or inconclusive regarding efficacy and safety 13.
• The new study is the first large-scale human analysis to find a possible association with increased risk, in contrast to preclinical findings.

How does melatonin interact with cardiovascular medications or disease processes?

Melatonin's molecular actions include antioxidant, anti-inflammatory, and metabolic effects, which may synergize with or counteract cardiovascular drugs and disease mechanisms. Some studies warn of interactions with antihypertensive medications or changes in blood pressure and heart rate, but these are generally considered rare and manageable. The new study did not specifically address drug interactions, but its findings highlight the need for caution when using melatonin alongside other therapies in vulnerable populations.

• Melatonin may reduce toxicity of some prescription drugs and protect against drug-induced cardiotoxicity 10 12.
• Some evidence suggests altered cardiovascular responses when melatonin is combined with antihypertensive or other medications 2 11.
• The pleiotropic actions of melatonin complicate prediction of long-term outcomes, especially in polypharmacy or comorbid patients 7 9 10.
• The new study underscores the importance of monitoring for potential interactions in clinical practice.

Future Research Questions

Given the unexpected association between long-term melatonin use and increased heart failure risk in people with chronic insomnia, further research is needed to clarify causality, underlying mechanisms, and implications for clinical practice. Key gaps include the need for randomized controlled trials, better tracking of over-the-counter supplement use, and understanding of dose-response relationships.

Research Question	Relevance
Does long-term melatonin use directly cause increased heart failure risk in humans?	Determining causality is essential, as the current evidence is observational and confounded by other risk factors; randomized controlled trials are needed for definitive answers 5 11 13.
What are the effects of melatonin dose, formulation, and duration on cardiovascular outcomes?	Dose and formulation variability may impact both efficacy and safety, especially given the unregulated nature of over-the-counter supplements and lack of standardized dosing 1 11.
How does melatonin use interact with coexisting psychiatric or sleep disorders to affect heart health?	Psychiatric comorbidities and insomnia severity may confound associations with cardiovascular outcomes; better understanding is needed to inform safe, personalized treatment 11 13.
Are there subpopulations who are at increased risk of adverse cardiovascular effects from melatonin use?	Identifying high-risk groups (e.g., older adults, those with pre-existing heart conditions) could help target recommendations and minimize harm 11 13.
What mechanisms could explain a potential increase in heart failure risk with melatonin use?	Mechanistic studies could clarify whether observed risks are due to melatonin itself, unmeasured confounders, or interactions with other biological or behavioral factors 1 7 10.