What clinical trials have tested melatonin for erectile dysfunction in humans and what were their designs and outcomes?
Executive summary
Clinical human research directly testing melatonin as a treatment for erectile dysfunction (ED) is extremely limited: one randomized clinical trial tested melatonin versus zolpidem and placebo in men on methadone maintenance and found no improvement in erectile function scores, though some domains of sexual function (desire and overall satisfaction) improved with melatonin [1] [2]. Several small case–control and observational studies report lower serum melatonin levels in men with ED, and preclinical animal work is consistently positive, but there are no large, well-powered randomized controlled trials (RCTs) that demonstrate melatonin’s efficacy for ED in the general male population [3] [4] [5].
1. The notable randomized trial: design, population and primary findings
The clearest interventional human data come from a single randomized, single-blind, placebo-controlled trial conducted in Iran in 2021 among men receiving outpatient treatment for opioid addiction (methadone maintenance therapy) in Isfahan; 98 participants were randomized into melatonin (n = 34), zolpidem (n = 32), and placebo (n = 32) arms to assess mental health and sexual function outcomes [2] [1]. That trial reported that melatonin statistically improved sexual desire and overall satisfaction subscales but did not change erectile dysfunction scores or orgasmic function—explicitly, the erectile dysfunction dimension did not show a significant change [1]. The trial was single-blinded, focused on a specific clinical population with high baseline sexual dysfunction risk, and therefore its ED findings cannot be generalized to broader male populations without caution [2] [1].
2. Observational evidence: low melatonin levels in men with ED
Multiple case–control studies have documented lower serum melatonin concentrations in men diagnosed with ED compared with controls, suggesting an association that motivated clinical interest but does not establish causality or therapeutic benefit [3] [6]. Authors of these studies explicitly call for larger clinical trials to evaluate whether melatonin replacement might have therapeutic value, but they stop short of recommending clinical use based on association alone [3] [6].
3. Adjunct and small-sample reports: combination therapies and conference data
Small and less rigorous reports hint at potential benefit when melatonin is combined with established ED drugs: a 2020-in-proceedings report described 60 patients with premature ejaculation and ED who received combinations including melatonin plus sildenafil and claimed the combination produced the most clinical benefit, but this work is conference-level, lacks randomized control, and cannot be considered high-quality evidence [7]. Such studies point to hypotheses (chronobiological support, symptomatic improvement) but carry high risk of bias and methodological limitations that preclude firm conclusions [7].
4. Preclinical rationale and why human trials are sparse
Animal experiments show consistent beneficial effects of melatonin on erectile physiology—improving cavernosal relaxation, reducing oxidative damage after spinal cord injury, and restoring erectile responses in diabetic or ischemic models—supporting plausible mechanisms (antioxidant, endothelial/nerve protection) that justify human trials [4] [8] [9] [10] [11]. Nevertheless, multiple reviews and clinical guidance note the absence of large, rigorous RCTs in humans to establish dosing, safety, and efficacy for ED; regulatory guidance continues to recommend PDE5 inhibitors as first-line treatments, reflecting the gap between animal promise and human evidence [4] [5].
5. Bottom line, limitations and research agenda
The human evidence base consists of an RCT in a specific opioid-treated population that failed to show erectile function improvement, several associative serum studies, and small uncontrolled combination reports—collectively insufficient to support melatonin as a treatment for ED in general practice [1] [3] [7]. The literature is transparent about these gaps: investigators call for larger, well-designed RCTs to define optimal dose, timing, and target populations, and to separate sleep-mediated from direct vascular or neuroprotective effects [2] [4] [3]. Until such trials exist, melatonin remains mechanistically promising but clinically unproven for treating erectile dysfunction in humans [5] [4].