Melatonin Trial Shows Ghrelin Drop But No Appetite Change

Researchers at Tabriz University of Medical Sciences have published a pilot randomized controlled trial investigating whether melatonin supplementation can influence hedonic appetite in women with overweight or obesity. The study, published in Scientific Reports, focuses on the complex interplay between sleep-regulating hormones, endocannabinoid signaling, and the motivation to consume palatable foods. By targeting hedonic appetite, the drive to eat for pleasure rather than physiological necessity, the researchers aimed to explore a novel pathway for managing weight-related disorders that have become a global public health concern. The trial provides preliminary evidence on the biological mechanisms underlying food motivation and the potential role of melatonin in modulating these signals.

The study enrolled forty-one female participants who were identified as having high hedonic appetite, defined by a Power of Food Scale score greater than 2.5. These women, with a mean age of 35.68 years and a mean body mass index of 30.36 kg/m², were randomly assigned to receive either 5 mg of melatonin daily or a placebo for a period of eight weeks. The trial was prospectively registered with the Iranian Registry of Clinical Trials, ensuring adherence to ethical standards and rigorous methodological protocols. The primary objective was to assess the impact of melatonin on plasma levels of 2-arachidonoylglycerol (2-AG) and ghrelin, alongside subjective measures of hedonic appetite intensity, dietary intake, and body weight.

2-Arachidonoylglycerol is an endogenous cannabinoid that plays a significant role in the regulation of appetite and reward pathways in the brain. It is part of the endocannabinoid system, which is increasingly recognized as a key target for obesity research. Ghrelin, often referred to as the hunger hormone, is a peptide hormone produced primarily by the stomach that stimulates appetite and promotes fat storage. By measuring both of these biomarkers, the researchers sought to understand if melatonin could alter the physiological signals that drive overeating. The inclusion of both molecular and behavioral endpoints allowed for a comprehensive assessment of the intervention’s potential efficacy.

At the conclusion of the eight-week intervention, the analysis revealed a statistically significant difference in plasma ghrelin levels between the two groups. The melatonin group exhibited significantly lower ghrelin concentrations compared to the placebo group, with mean values of 4.35 pg/mL versus 4.78 pg/mL, respectively. This reduction in ghrelin suggests that melatonin may influence the hormonal regulation of hunger, potentially leading to a decrease in the physiological drive to eat. However, the study did not find significant between-group differences in plasma 2-AG levels, indicating that the endocannabinoid pathway may not be directly modulated by melatonin in this context. The lack of change in 2-AG levels is a crucial finding, as it suggests that the observed effects on ghrelin are not accompanied by a broader shift in the endocannabinoid system’s appetite-regulating functions.

Despite the significant reduction in ghrelin, the study did not observe significant changes in hedonic appetite intensity, dietary intake, or body weight between the melatonin and placebo groups. This discrepancy highlights the complexity of appetite regulation, where hormonal changes do not always translate into immediate behavioral or weight-related outcomes. The authors note that the effect of melatonin on lowering ghrelin, without significant effects on 2-AG or hedonic appetite, means that any impact on hedonic appetite remains uncertain. This finding underscores the need for further research to clarify the mechanisms by which melatonin might influence food motivation and weight management.

The pilot nature of the trial, with a relatively small sample size, limits the generalizability of the findings and the statistical power to detect subtle changes in behavioral outcomes. However, the significant reduction in ghrelin provides a promising lead for future studies. Larger, longer-term trials are needed to determine whether sustained melatonin supplementation can lead to meaningful changes in eating behavior and body composition. The study also highlights the importance of considering individual differences in hedonic appetite, as the participants were specifically selected for their high scores on the Power of Food Scale. This targeted approach may be crucial for identifying subpopulations that are more responsive to melatonin therapy.

The research contributes to the growing body of evidence linking sleep, circadian rhythms, and metabolic health. Melatonin is known for its role in regulating sleep-wake cycles, but its effects on appetite and metabolism are less well understood. The findings suggest that melatonin may have an independent effect on hunger hormones, separate from its sleep-regulating properties. This opens up new avenues for investigating the role of circadian interventions in the management of obesity and related metabolic disorders. The study also emphasizes the need for a multidisciplinary approach to obesity treatment, integrating pharmacological, behavioral, and lifestyle interventions.

While the results do not support the use of melatonin as a standalone treatment for hedonic appetite or obesity, they provide valuable insights into the biological mechanisms underlying these conditions. The reduction in ghrelin levels indicates a potential mechanism by which melatonin could influence energy balance, but further research is needed to determine the clinical significance of this finding. The study also highlights the importance of measuring multiple endpoints, including molecular, behavioral, and anthropometric outcomes, to fully understand the effects of an intervention. Future studies should explore the long-term effects of melatonin supplementation and its potential interactions with other lifestyle factors, such as diet and physical activity.

In conclusion, this pilot randomized controlled trial demonstrates that melatonin supplementation can significantly reduce plasma ghrelin levels in women with overweight or obesity and high hedonic appetite. However, this hormonal change was not accompanied by significant reductions in 2-AG levels, hedonic appetite intensity, dietary intake, or body weight over the eight-week period. These findings suggest that while melatonin may influence hunger signaling, its impact on the complex behavioral and metabolic aspects of obesity remains uncertain. The study provides a foundation for future research aimed at elucidating the role of melatonin in appetite regulation and weight management, potentially leading to new therapeutic strategies for addressing the global obesity epidemic.

Subject of Research: A pilot randomized controlled trial of melatonin supplementation on plasma 2-arachidonoylglycerol, ghrelin, and hedonic appetite intensity in females with overweight/obesity

Article Title: A pilot randomized controlled trial of melatonin supplementation on plasma 2-arachidonoylglycerol, ghrelin, and hedonic appetite intensity in females with overweight/obesity

Article References: Karamizadeh, M., Parimi, M., Sadeghi, L., Akbarzadeh, M., Mahdavi, R., & Gargari, B. P. (2026). A pilot randomized controlled trial of melatonin supplementation on plasma 2-arachidonoylglycerol, ghrelin, and hedonic appetite intensity in females with overweight/obesity. Scientific Reports. https://doi.org/10.1038/s41598-026-76450-8

Image Credits: AI Generated

DOI: 10.1038/s41598-026-76450-8

Keywords: pilot, randomized, controlled, trial, melatonin, supplementation, plasma, arachidonoylglycerol, ghrelin, hedonic, appetite, intensity