Presented at the American Heart Association Scientific Sessions 2025, this study used data from the TriNetX Global Research Network. Among 65,414 melatonin users and 65,414 matched controls, incident heart failure occurred in 3,021 melatonin users (4.6%) versus 1,797 controls (2.7%) during 5-year follow-up. All-cause mortality was also higher: 5,118 deaths (7.8%) versus 2,820 (4.3%). Heart failure-related hospitalizations increased three-fold. Important limitations include that the study was observational, not peer-reviewed at time of presentation, and cannot establish causation.

Cohen et al. analyzed 25 commercially available melatonin gummy products sold in the US. Only 3 products (12%) contained a quantity of melatonin within 10% of the labeled amount. The wide variation means consumers may unknowingly take doses far higher or lower than intended, creating unpredictable safety risks with long-term use. This unregulated variability is particularly concerning given that melatonin is classified as a dietary supplement in the US and not subject to FDA pharmaceutical-grade quality controls.

Published in the Journal of Clinical Sleep Medicine, researchers at the University of Guelph analyzed 31 commercial melatonin supplements using ultraperformance liquid chromatography. Lot-to-lot variability within a single product varied by as much as 465%. Serotonin, a controlled substance with potential for serious side effects including serotonin syndrome when combined with certain medications, was found in 8 of 30 products tested. The presence of undisclosed serotonin is a significant safety hazard for long-term users, particularly those on antidepressants.

The National Center for Complementary and Integrative Health, part of the U.S. National Institutes of Health, maintains that while melatonin appears relatively safe for short-term use, its long-term safety simply has not been studied adequately. The agency highlights that most clinical trials have lasted less than 3 months, and there are no large-scale, well-designed studies tracking adults who take melatonin nightly for years. This position is echoed by the U.S. Department of Health and Human Services and represents the official U.S. government assessment.

Givler et al. reviewed the physiological and clinical considerations of chronic melatonin use. They identified significant drug interactions: melatonin can increase bleeding risk with warfarin by affecting INR and PT values; it can stimulate immune function and interfere with immunosuppressive therapy; and it may lower blood sugar, risking hypoglycemia when combined with diabetes medications. These interactions become more consequential with long-term daily use, especially in older adults who commonly take multiple medications. Published in Neurology International.

Li et al. analyzed NHANES survey data and found melatonin use increased from 0.4% of adults in 1999-2000 to 2.1% in 2017-2018. Use of doses greater than 5 mg per day more than tripled from 0.08% to 0.28% during 2005-2018. The rapid growth in use, combined with increasing doses, has far outpaced the pace of safety research - particularly long-term safety studies. The authors noted that this trend is concerning given melatonin''s unregulated status as a dietary supplement. Published in JAMA.

Fatemeh et al. reviewed the risks of melatonin in older adults, published in Clinical Interventions in Aging. They noted that higher doses (10 mg or more) often provide no greater sleep benefit than lower doses but frequently cause next-day grogginess and increased fall risk. Melatonin may remain active longer in older adults due to reduced hepatic clearance. The AASM specifically recommends against melatonin and other sleep-promoting medications for elderly patients with dementia due to increased risks of falls, confusion, and other adverse events.

Studies published in Reproductive Biology and Endocrinology and Frontiers in Endocrinology have demonstrated that exogenous melatonin reduces plasma levels of luteinizing hormone (LH) and 17 beta-estradiol, and can alter menstrual cycle length. While a 2000 study in Human Reproduction found that long-term melatonin did not alter pituitary-gonadal hormone secretion in normal men, the effects in women are less clear. The potential for cumulative endocrine disruption with years of daily supplementation remains essentially unstudied in controlled trials.

Mayo Clinic''s drug information resource lists common melatonin side effects including headache, dizziness, nausea, and drowsiness. They specifically warn about interactions with anticoagulants and anti-platelet drugs (increased bleeding risk), anticonvulsants, blood pressure medications, CNS depressants, diabetes drugs (altered glucose metabolism), immunosuppressants, and contraceptive drugs. The clinic advises that people with autoimmune conditions, seizure disorders, or depression should use melatonin with particular caution. These interaction risks are amplified with long-term daily use.

While the Besag review in CNS Drugs found mild adverse effect rates, the authors explicitly concluded that the scarcity of evidence from long-term randomized controlled trials limits conclusions about continuous melatonin therapy safety. Most studies ran for 4 to 8 weeks, with very few extending beyond 12 weeks. The review noted there are insufficient robust data to meaningfully assess safety concerns in potentially at-risk populations such as older adults, pregnant women, and those with comorbidities - precisely the groups most likely to use melatonin long-term.