Melatonin, first discovered serendipitously in 1958 by American dermatologist Aaron Lerner during his investigation of vitiligo patients, was later found to play a crucial role in regulating the circadian rhythm through a series of subsequent studies [1,2]. Dysregulation of melatonin secretion has been documented in various psychiatric disorders [3]. In particular, abnormalities in melatonin synthesis and release have been reported in major depressive disorder, bipolar disorder, and seasonal affective disorder [4]. Moreover, melatonin and melatonergic agonists have been investigated as potential adjunctive treatments in combination with standard antidepressants or mood stabilizers [4,5]. Melatonin, beyond its well-known role in sleep regulation, has gained attention for its effects on functional gastrointestinal (GI) disorders, such as irritable bowel syndrome (IBS), and functional heartburn. In patients with IBS, melatonin supplementation has been associated with significant improvements in abdominal pain and overall symptom severity. A meta-analysis of randomized controlled trials found that exogenous melatonin supplements can ameliorate IBS severity, pain severity, and quality of life [6]. Furthermore, a randomized, double-blind, placebo-controlled study demonstrated that melatonin improved abdominal pain in IBS patients who have sleep disturbances [7]. Regarding functional heartburn, a randomized, placebo-controlled pilot study demonstrated that melatonin significantly improved both heartburn symptoms and health-related quality of life compared to placebo and nortriptyline [8]. These findings suggest that melatonin may serve as a beneficial adjunctive therapy in managing disorders of gut–brain interaction (DGBI), potentially through mechanisms involving analgesia, regulation of GI motility, and modulation of visceral hypersensitivity.

Functional dyspepsia (FD) is characterized by chronic epigastric pain, postprandial fullness, and early satiety in the absence of structural abnormalities. Although the current Rome IV guidelines recommend acid suppressants and prokinetic agents as primary therapeutic options, FD remains difficult to manage in many cases, underscoring the unmet need for alternative or adjunctive treatments. Therefore, we aimed to evaluate the clinical effectiveness of melatonin in patients with FD. A literature search was performed using PubMed, Embase, and Google Scholar up to May 2025, employing keywords “melatonin,” “functional dyspepsia.” Both randomized controlled trials (RCTs) and pilot studies were included. Among 2255 initially identified records, 23 studies were selected after removing duplicates and conducting a first screening based on titles and abstracts. Subsequently, three RCTs evaluating the therapeutic efficacy of melatonin on symptom improvement in FD were included in the final meta-analysis (Table 1) [9-11].

Klupińska et al. [9] analyzed 60 patients aged 19–39 years who met the Rome II criteria for FD and were negative for Helicobacter pylori infection. Participants were randomized to receive either melatonin (n=30) or placebo (n=30) over a 12-week period. In the melatonin group, 17 patients (56.6%) experienced complete resolution of dyspeptic symptoms, while an additional 9 patients (30.0%) reported partial improvement, particularly in nocturnal pain frequency and severity. In contrast, the placebo group demonstrated minimal benefit, with 93.3% of patients reporting no symptomatic improvement.

Zybach et al. [10] conducted a crossover trial in pediatric patients aged 8–17 years who met the Rome III criteria for FD. Twelve patients completed the study, receiving both melatonin and placebo for two weeks each, separated by a washout period. Symptom improvement was assessed using the Global Clinical Score, along with evaluation of sleep disturbances. The rates of symptom improvement were 42% during the melatonin phase and 50% during the placebo phase; however, the difference was not statistically significant. Additionally, no clear improvement in sleep quality was observed.

Chojnacki et al. [11] investigated the effect of melatonin in postmenopausal women with H. pylori-associated chronic dyspepsia. Although H. pylori gastritis and FD are now considered distinct entities, the study was included in the analysis based on prior diagnostic conventions that grouped H. pylori infection as a contributing factor to FD. Among the 64 analyzed participants (32 in each group), melatonin administration over a 6-month period resulted in significant symptom improvement in 84.3% of patients, compared to 43.7% in the placebo group (p<0.001).

To quantitatively evaluate the efficacy of melatonin on symptom improvement, we performed a meta-analysis of these three studies (Fig. 1). A total of 74 patients in the melatonin group and 74 patients in the placebo group were included in the pooled analysis. The primary outcome was the proportion of patients exhibiting symptom improvement following melatonin treatment compared to placebo. There was considerable heterogeneity among the included studies (I²=76%, τ²=1.7671, p=0.01), warranting the use of a random-effects model. The pooled odds ratio (OR) for symptom improvement using a random-effects model was 4.59 (95% confidence interval [CI]: 0.82–25.80), suggesting a trend toward benefit in the melatonin group, although this result did not reach statistical significance. In contrast, the fixed-effect model yielded a statistically significant result, with an OR of 4.96 (95% CI: 2.19–11.27, p<0.001), suggesting a significantly greater likelihood of symptom improvement with melatonin compared to placebo. These findings suggest that melatonin may exert a beneficial effect on symptom improvement in FD. However, the heterogeneity between studies and lack of statistical significance in the random-effects model suggest that further high-quality, homogeneous trials are warranted. Our analysis was also limited by the small number of included RCTs (n=3), which reduces its statistical power. In addition, both pediatric and adult populations were enrolled, and most studies were conducted between 2007 and 2020 using earlier diagnostic frameworks: Klupińska et al. [9] applied Rome II criteria (2007), Zybach et al. [10] used Rome III criteria (2016), and Chojnacki et al. [11] included patients with H. pylori–associated dyspepsia (2020), a condition now classified separately from FD.

Given the observed therapeutic potential of melatonin in patients with DGBI, we conducted a meta-analysis to evaluate its efficacy specifically in FD. The melatonin supplementation was associated with a trend toward improved symptoms in patients with FD, although statistical significance was not reached in the random-effects model. These findings suggest that melatonin may offer therapeutic benefit in FD, particularly in selected subgroups such as adults with non-H. pylori FD; however, further well-powered and methodologically homogeneous randomized controlled trials are warranted to validate its efficacy and to clarify which patient populations may derive the greatest.