Do sleep aids differ in cardiac safety? A comparative eudravigilance analysis of melatonin and zolpidem arrhythmia reports
Y Shhab, S Aoun, Z A Stepanov, S Stoleru, A ZugravuAbstract
Background
Melatonin, an endogenous pineal hormone now widely marketed as an over-the-counter sleep aid, is commonly perceived as cardiovascularly benign, even though experimental and clinical data show that exogenous melatonin can modify blood pressure, autonomic tone and cardiac electrophysiology. Zolpidem, a non-benzodiazepine GABA-ergic hypnotic, is a prescription standard for insomnia with a better characterised safety profile and mixed observational data regarding arrhythmia risk. Despite the growing, often chronic, use of both agents, whether they differ in their pattern of rhythm-related adverse event reporting in large pharmacovigilance datasets has not been systematically evaluated.
Objective
To determine whether melatonin is associated with a higher reporting frequency of supraventricular arrhythmias compared with zolpidem in EudraVigilance.
Methods
Individual case safety reports for melatonin and zolpidem submitted to EudraVigilance up to 16 November 2025 were reviewed. Rhythm-related Preferred Terms, including palpitations, tachycardia, sinus tachycardia, atrial fibrillation and other supraventricular events, were grouped as "arrhythmia-related." For each drug, the proportion of arrhythmia reports among all reports was calculated, and relative reporting was estimated using odds ratios with 95 percent confidence intervals.
Results
Melatonin generated 4,256 overall reports, of which 224 involved arrhythmia-related terms (5.3 percent). Zolpidem produced 21,740 reports, including 532 arrhythmia-related events (2.4 percent). Melatonin was associated with a higher relative reporting frequency of arrhythmia-related complaints compared with zolpidem (odds ratio 2.21, 95 percent confidence interval 1.89–2.60). The disproportionality signal was driven predominantly by palpitations and tachycardia. Females accounted for 58 percent of melatonin submissions.
Conclusion
In this large pharmacovigilance analysis, melatonin displayed a higher reported ratio of supraventricular rhythm complaints than zolpidem. Although spontaneous reports cannot establish causality or quantify absolute risk, the observed pattern suggests that the cardiovascular profile of melatonin, often assumed to be neutral, may warrant closer clinical attention and prospective evaluation, particularly in patients presenting with palpitations or tachycardia while using over-the-counter sleep aids.