Melatonin (5mg Extended-Release)

BACKGROUND: Equine emotion and welfare are of increasing concern to the general public, equestrians and researchers. There is growing demand for more objective indicators of specific emotional states, as well as the well-being of horses in a variety of contexts. Such markers may also assist in both the diagnosis and selection of biological therapies within equine behavioral medicine. RESULTS: This scoping review summarizes and appraises the published findings relating to relevant biological measurements from the last two decades. Particular attention is given to methodological, subject-related and context-dependent factors that might affect reference values. The most common biomarkers found were ACTH, cortisol and serotonin. Other biomarkers found, but with fewer reports, were oxytocin, melatonin, dopamine and tryptophan. CONCLUSIONS: We conclude that research on these topics has used diverse methodological approaches which makes their current clinical value hard to determine. This could explain the common recommendation for the need for further research. To create useful, valid and applicable indicators for the study of emotional states in clinical environments, there is a need for both agreed definition of relevant subjective states and greater consensus on the standardized protocols to be used for sample collection, analysis and units of measurement reported. Our findings provide a solid basis for the further development of the assaying of these biomarkers for more routine use in both clinical practice and equine welfare research.

BACKGROUND: Insomnia, a prevalent sleep disorder linked to endocrine dysfunction, severely impairs quality of life. Acupuncture has been widely applied for its management, but evidence on its impact on sleep outcomes and endocrine regulation remains uncertain. METHODS: Randomized controlled trials (RCTs) published until August 13, 2025, were explored in the subsequent databases: PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang. Two reviewers independently screened studies, extracted data, and assessed risk of bias with RoB 2. Eligible trials enrolled insomnia patients receiving acupuncture or combined therapy versus sham acupuncture or medication. Outcomes included sleep-related scales, polysomnographic measures, and endocrine indicators. Meta-analysis was conducted using RevMan 5.4. RESULTS: Twelve RCTs were included. Serum melatonin was higher with acupuncture based interventions than with controls (MD = 5.29, 95% CI: 3.01 to 7.57, I2 = 99%), and the electroacupuncture subgroup showed a consistent increase (MD = 0.66, 95% CI: 0.34 to 0.98, I2 = 0%). Salivary melatonin did not differ between groups, whereas salivary cortisol was lower in the acupuncture group (MD = 0.05, 95% CI: 0.02 to 0.08). Acupuncture reduced PSQI scores (MD = 3.39, 95% CI: 4.20 to 2.59). ISI improved in sham controlled trials (MD = 1.82, 95% CI: 2.95 to 0.68) but not in medication controlled comparisons. Polysomnography indicated improved sleep efficiency (MD = 6.40, 95% CI: 4.93 to 7.86) and overall improvements in total sleep time, sleep onset latency, and wake after sleep onset, with subgroup patterns suggesting contributions from treatment intensity and clinical subtype. CONCLUSION: This study suggests that acupuncture significantly improves subjective sleep quality, while also modulating melatonin and cortisol levels, highlighting its potential role in sleep and endocrine regulation. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number is provided as CRD420251125885.

BACKGROUND: Endometriosis, PCOS, adenomyosis, and dysmenorrhea are major illnesses. Hormonal as well as non-hormonal treatments were evaluated for COCs, progestins, GnRH analogues, LNG-IUS, relugolix, and adjunctive therapies. These treatments resulted in the categorization of the benefits in varying degrees. METHODS: 149 clinical trials have been included. Evaluating the methodological quality was done through the Jadad scale, while the GRADE criteria were used to assess the reliability of the evidence. When these data were available, effect sizes, standardized mean differences (SMD), 95% confidence intervals (CI), and p-values were extracted. RESULTS: It was observed that COCs and progestins considerably lowered pelvic pain and menstrual irregularities (SMD -0.35 to -0.58, 95% CI -0.90 to -0.08, p<0.05), and among various trials, dienogest was reported to be the most effective in alleviating dysmenorrhea (SMD -0.58, 95% CI -0.90 to -0.26, p<0.001). The use of relugolix in combination resulted in considerable pain reduction related to endometriosis (SMD -0.72, 95% CI -0.94 to -0.50, p<0.001), and the study was rated as excellent quality with GRADE and Jadad scores of 5. GnRH analogs led to pain reduction all the time (SMD -0.65, 95% CI -0.88 to -0.42, p<0.001), while the application of LNG-IUS was linked to less menorrhagia and lower recurrence after surgery (RR 0.51, 95% CI 0.33-0.79, p=0.002). Besides the main treatments, usage of the like of antioxidants, NAC, melatonin, and digital therapeutics, too, gave extra pain relief and quality-of-life benefits (SMD -0.40 to -0.62, p<0.05). the studies frequently proved to have a very rigorous quality of methodology (Jadad 3-5) and moderate-to-high grade certainty of evidence (GRADE). CONCLUSIONS: Endometriosis disorder have been treated well with hormonal therapies. Different endocrine therapies based on the patient's specific characteristics and the degree of tolerability should be used to achieve the maximum effect of clinical outcomes.

Update of doi: 10.1002/14651858.CD013754. RATIONALE: Neonatal encephalopathy (NE) affects 1.15 million newborns annually and is associated with a high incidence of mortality and long-term neurodevelopmental disability (NDD). Therapeutic hypothermia (TH) is the only proven therapeutic intervention available. However, it is only partially effective, and evidence suggests it is not safe in low-income countries. Melatonin is a promising neuroprotective treatment in NE as it provides anti-inflammatory properties. Pre-clinical models have demonstrated improved outcomes with melatonin. However, its effect on human newborns is unclear. OBJECTIVES: To evaluate the effects and safety of melatonin treatment compared to standard care, with or without therapeutic hypothermia, on survival and neurological sequelae in newborns with neonatal encephalopathy. SEARCH METHODS: We used CENTRAL, MEDLINE, two other databases, and two trial registers, together with reference checking and citation searching, to identify studies for inclusion in the review. The latest search date was 18 August 2025. ELIGIBILITY CRITERIA: We included all randomised and quasi-randomised controlled trials in newborns with NE comparing the use of melatonin and TH versus standard treatment (including TH), and also melatonin monotherapy versus standard treatment (with no TH). We excluded cross-over randomised trials and non-randomised cohort studies. We excluded studies that included preterm newborns born at less than 34 weeks gestational age (GA) or studies that included newborns with major congenital anomalies. OUTCOMES: The critical outcome for both comparisons was the combined outcome of mortality or NDD at ≥ 18 months of age. Our important outcomes included differences in mortality (up to one month), NDD (at ≥ 18 months), abnormalities on a brain MRI (at one month), multiorgan dysfunction (up to one month), and use of anti-seizure medications (up to one month). RISK OF BIAS: We used the Cochrane risk of bias tool (RoB 1) to assess bias in the included studies. SYNTHESIS METHODS: We synthesised results for each outcome using meta-analysis by calculating odds ratios with 95% confidence intervals. Where thi

BACKGROUND: Migraine and sleep disturbances share a bidirectional relationship, influencing each other's frequency and severity. The aim of this systematic review is to examine the effects of migraine-targeted interventions on both migraine outcomes and sleep parameters (including sleep quality and insomnia symptoms), as well as the effects of sleep-focused interventions on both sleep and migraine outcomes. METHODS: Following PRISMA 2020 guidelines, a systematic search was conducted across six databases (PubMed, Medline, Scopus, Embase, PsycINFO, CINAHL) for studies published until December 5, 2023. Eligible studies included Randomized Clinical Trials, Controlled Clinical Trials, and observational studies assessing migraine and/or sleep-targeted interventions in adults. The risk of bias was evaluated using RoB 2 and ROBINS-E tools. RESULTS: Twenty-three studies (1941 participants) were included. Pharmacological treatments such as erenumab, amitriptyline, propranolol, and onabotulinumtoxinA reduced migraine frequency and pain intensity, with variable effects on sleep quality. Melatonin showed no significant impact. Among non-pharmacological treatments, percutaneous electrical nerve stimulation, greater occipital nerve block, green light therapy, binaural beats, mindfulness, and dietary modifications improved both migraine symptoms and sleep. Digital Cognitive-Behavioral Therapy for Insomnia (CBT-I) significantly reduced headache days and improved sleep parameters, whereas evidence on standard CBT-I was mixed. LIMITATIONS: Study heterogeneity, small sample sizes, and variability in outcome measures limit generalizability. Few studies focused on sleep-targeted interventions and their effects on migraine, highlighting a research gap. CONCLUSIONS: Integrated approaches combining migraine and sleep interventions show promise for symptom management. Further research is needed to refine treatment strategies and assess long-term effects. REGISTRATION: CRD42024617217. © 2026 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.

BACKGROUND: Poor sleep is common in people with multiple sclerosis (PwMS). Previous systematic reviews have evaluated intervention effectiveness to improve sleep in PwMS using questionnaires, but no review has comprehensively examined whether sleep interventions improve activity monitor measured sleep outcomes in PwMS. METHODS: Adhering to the PRISMA guidelines, we searched PubMed, EMBASE, and PsycINFO databases to identify randomized controlled trials, quasi-experimental and cohort studies published from inception to October 2025. A random-effects model was used to estimate the pooled intervention effects of sleep interventions on objective sleep outcomes. RESULTS: Ten studies were included in the review for narrative synthesis, with five eligible for quantitative meta-analysis. Six sleep parameters were assessed via activity monitors: total sleep time, sleep efficiency, total time in bed, sleep onset latency, wake after sleep onset, and frequency of awakenings. Sleep interventions utilised included physical activity, mindfulness, cognitive behavioral therapy (CBT), melatonin, eszopiclone and transcranial direct current stimulation (tDCS). Only sleep efficiency improved following mindfulness interventions. The median length of actigraph wear time was 7 days (range 4 nights to 16 weeks). Study quality appraisal scores ranged from moderate to high, suggesting a low risk of bias. CONCLUSION: Activity monitors have been used to assess sleep intervention effectiveness in PwMS in studies assessing physical activity, mindfulness and CBT. Objective improvements in sleep were reported following mindfulness and only using one measure (sleep efficiency). However, the small number of included studies limits definitive conclusions. Future trials should consider a wider range of outcome measures and longer time horizons.

BACKGROUND: Melatonin, an endogenous neurohormone with both chronobiotic and antioxidant properties, has been proposed as a nutritional aid for recovery and performance optimization. However, its timing-dependent effects on athletic performance remain unclear. This systematic review and meta-analysis aimed to evaluate the timing-dependent effects of melatonin supplementation on exercise performance and exercise-induced muscle damage in athletes and physically active individuals. METHODS: A comprehensive search of PubMed, Web of Science, SPORTDiscus, and Cochrane Library was conducted from inception to September 2025. Only randomized controlled trials (RCTs) published in English examining melatonin versus placebo effects on athletic performance and muscle damage biomarkers were included. RESULTS: In total, 19 RCTs involving 266 participants met the inclusion criteria. Meta-analysis revealed small effects on explosive power (SMD = 0.29, 95% CI: 0.05 to 0.53, p = 0.02, I 2 = 0%) and moderate effects on endurance performance (SMD = 0.58, 95% CI: 0.29 to 0.87, p < 0.001, I 2 = 46%). Melatonin significantly reduced creatine kinase levels (SMD = 0.59, 95% CI: 0.29 to 0.89, p < 0.0001, I 2 = 0%), with non-significant effects on lactate dehydrogenase (SMD = 0.45, 95% CI: -0.03 to 0.94, p = 0.07, I 2 = 56%). Subgroup analyses revealed timing-dependent effects: evening administration with >6-h exercise intervals produced superior benefits for both endurance performance and explosive power compared to daytime administration or shorter intervals. Higher doses (6-10 mg) and athlete populations demonstrated greater improvements, while adolescents (≤18 years) showed enhanced explosive power responses. CONCLUSION: These findings suggest that melatonin supplementation, particularly when administered in the evening with adequate timing intervals, enhances endurance performance and reduces exercise-induced muscle damage in athletes during intensive training periods. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251178430, Identifier (CRD420251178430).

BACKGROUND: Melatonin is used as a chronobiotic in the treatment of sleeping disorders to correct disturbances in the circadian rhythm, including in children and adolescents. dim light melatonin onset (DLMO) and the peak in plasma concentration of melatonin contribute to this circadian rhythm. International research shows that the number of prescriptions for melatonin among children and adolescents is increasing significantly. However, there appears to be little empirical research on the best way to taper and/or discontinue melatonin in this population. AIM: To assess the available literature regarding the best way to taper and/or discontinue melatonin in minors with sleep problems, with or without autism spectrum disorder (ASD) or attention-deficit/hyperactivity disorder (ADHD). METHOD: A systematic review of the literature in the PubMed (Medline) and Embase databases. RESULTS: Several effects of the melatonin therapy on sleep onset, sleep latency, sleep duration, sleep efficiency, and nocturnal activity disappear after discontinuation of the treatment. However, we cannot formulate evidence-based guidelines regarding treatment duration, timing of administration, dosage, or the method of discontinuation. DLMO prior to treatment does, however, have predictive value for the effect of discontinuing melatonin therapy. CONCLUSION: A DLMO-measurement prior to starting melatonin treatment provides clinicians with insight into the expected effects of melatonin during therapy. This allows for an estimation of whether melatonin will have not only a soporific but also a chronobiotic effect during treatment. Based on this information, clinicians can consider whether initiating or discontinuing melatonin therapy is appropriate. Consequently, our literature review provides a strong argument for reimbursement of DLMO-measurements by health insurance funds.

BACKGROUND: Melatonin (MLT) might benefit heart and metabolic health, as well as sleep quality, in individuals with chronic kidney disease (CKD), but the research findings are mixed. To better understand this, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess how MLT affects people with CKD. METHODS: Scopus, the Cochrane Library, PubMed, Web of Science, and Embase were searched up to May 30, 2025, for RCTs reporting lipid profiles, oxidative stress markers, or sleep quality. Random-effects meta-analyses were performed, and results are presented as weighted mean differences (WMDs) with 95% confidence intervals (CIs). RESULTS: Ten RCTs (12 trials) were included. MLT supplementation significantly increased high-density lipoprotein cholesterol (HDL-C: WMD = 1.87 mg/dL, 95% CI: 0.24, 3.50, p = 0.025; I 2 = 38.9, p = 0.179), and reduced malondialdehyde (MDA: -1.28 μmol/L, 95% CI: -2.50, -0.06, p = 0.039; I 2 = 93.4, p < 0.001), and improved sleep quality (PSQI: WMD = -3.75, 95% CI: -6.92, -0.57, p = 0.021; I 2 = 94.2, p < 0.001). Also, MLT supplementation had no significant effect on triglycerides, total cholesterol, low-density lipoprotein cholesterol, or C-reactive protein. CONCLUSION: Supplementing with MLT in CKD can gently raise HDL-C levels, decrease oxidative stress, and improve sleep quality. While these effects are encouraging, more extensive and carefully planned clinical trials are necessary to verify the actual benefits.

BACKGROUND: Delirium is a common neuropsychiatric syndrome associated with high morbidity. Circadian disruption is increasingly recognized as a core feature of delirium. However, the circadian-delirium connection remains underexplored. OBJECTIVE: This systematic review examined the relationship between circadian dysfunction and delirium to identify specific metrics of circadian disturbances in delirium and evaluate the influence of specific interventions or environmental variables on the course of delirium. METHODS: This review is reported per Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. PubMed, Embase, PsycINFO, and Web of Science were searched from the start of literature databases through October 2024. Original articles regarding human studies in English were included. Qualitative data for observational and interventional studies were extracted and synthesized. RESULTS: A total of 1908 articles were retrieved, of which 58 met inclusion criteria. Thirty-four studies examined dysrhythmic circadian functioning in relation to delirium using a variety of methods, and 22 studied the effects of nonpharmacologic and/or pharmacologic interventions or exposures with circadian-modifying potential on the course of delirium. Two studies utilized both interventional and observational methods. Among physiologic biomarkers, salivary, serum, and cerebrospinal fluid melatonin were the most frequently studied. However, changes in their levels or rhythms were not reliably linked with delirium. Fluctuations in serum cortisol and urinary 6-sulfatoxymelatonin were more often connected with the onset or course of delirium, though these hormones were infrequently studied. Actigraphy, polysomnography, and electroencephalography frequently detected differences in sleep and circadian parameters in the setting of delirium. Among interventions, bright light therapy shows promise for delirium prevention and potential for larger studies given its relative efficacy, replicability, and low cost. Oral melatonergic agents were inconsistent in efforts to prevent or treat delirium. CONCLUSIONS: Delirium's association with circadian dysfunction remains complex and

The aim of this study is to investigate the effects of melatonin on the left ventricular (LV) function in persistent pulmonary hypertension of the newborn (PPHN) and to assess its potential role in enhancing cardiac performance and reducing oxidative stress. This randomized controlled trial was conducted on 80 neonates (≥ 36 weeks' gestational age) with PPHN confirmed by echocardiography (Echo). Participants were assigned to receive standard therapy alone or in combination with oral melatonin. LV function was evaluated using echocardiographic parameters, and levels of serum biomarkers of oxidative stress and inflammation were also measured. Unlike the placebo group, the melatonin group exhibited significantly better LV function, regarding the conventional and advanced echocardiographic parameters. Additionally, melatonin administration was associated with earlier weaning from mechanical ventilation (MV) and respiratory support, shorter hospital stays, lower levels of serum high-mobility group box-1 (HMGB1) protein, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). CONCLUSION: Melatonin can enhance LV function in PPHN, likely through its cardioprotective and antioxidative mechanisms. These findings support melatonin as a promising adjunctive therapy in neonatal pulmonary hypertension, warranting further investigation in larger clinical trials. TRIAL REGISTRATION: registered on ClinicalTrials.gov (ID: NCT07090720), URL: https://clinicaltrials.gov/study/NCT07090720?cond=NCT07090720&rank=1 , Date: (29/7/2025). WHAT IS KNOWN: • PPHN induces hypoxic respiratory failure, jeopardizing multiorgan function, including LV performance. • Oxidative stress is crucial in pulmonary arterial hypertension development. WHAT IS NEW: • Melatonin's antioxidant and vasodilatory properties may serve as an adjunctive therapy in PPHN and enhance myocardial protection from the hypoxic effect of PPHN. © 2026. The Author(s).

Feeding intolerance (FI) in preterm infants may signal necrotizing enterocolitis (NEC), in which oxidative stress (OS) plays a central role. Melatonin has demonstrated promise in mitigating neonatal OS-related diseases. The study is aimed to assess the effect of enteral melatonin on the progression of FI symptoms, NEC incidence, and tumor necrosis factor-alpha (TNF-α) levels in preterm neonates with FI, compared with conventional therapy (CT). Ninety preterm neonates with FI were randomly assigned to either the melatonin group (MT, n = 45), who received melatonin plus conventional therapy, or the conventional group (CT, n = 45), who received conventional treatment. Melatonin was administered enterally in two doses of 10 mg each, 1 h apart. TNF-α levels were measured in all patients 72 h posttreatment. CT group experienced extended hospital stay, longer feeding discontinuation, delayed full enteral intake, higher NEC incidence, increased mortality, and higher TNF-α compared with the MT group (P = .032, <.001, <.001, <.001, .03, and <.001, respectively). Enteral melatonin significantly reduced NEC incidence and mortality, accelerated achievement of full enteral feeding, and lowered TNF-α levels in preterm neonates with FI. It demonstrates a practical, affordable, orally administered therapy that is accessible and reproducible in low-resource settings, addressing the burden of NEC in preterm infants where it is critically needed. © The Author(s) [2026]. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact [email protected].

Sleep disturbances and mood changes are common during the climacteric, often linked to hormonal fluctuations caused by reduced ovarian function. Evidence suggests that long-term melatonin administration may improve the quality of life in climacteric women. This study aimed to evaluate the effects of exogenous melatonin on climacteric symptoms, sleep quality, and reproductive hormones in women working fixed shifts. A randomized clinical trial was conducted with 46 nurses working fixed shifts at a hospital in São Paulo: morning (7:00-13:00, n = 16; intervention = 7, placebo = 9), afternoon (13:00-19:00, n = 15; intervention = 8, placebo = 7), and night (19:00-7:00, n = 15; intervention = 7, placebo = 8). Participants were randomly assigned to receive either 0.3 mg of melatonin or placebo. For night shift workers, melatonin was administered only on nights off, when they were sleeping at home; the same procedure was applied to morning and afternoon workers. Data collection included sociodemographic information, self-reported sleep quality, and menopausal symptoms. Blood samples were collected at home to measure luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and progesterone before and after the intervention. A significant main effect of melatonin was observed, with a 15.8% reduction in climacteric symptoms compared with placebo (p = 0.01), independent of age or sleep duration, while no significant interaction with work shift was detected. Sleep quality improved by 35.33% on days off in the intervention group (p < 0.001), with morning shift workers showing a 32.46% improvement (p < 0.05). No significant changes were observed in reproductive hormone levels or total sleep duration. Exogenous melatonin effectively alleviates climacteric symptoms and improves sleep quality on days off, particularly among day-shift workers, without affecting reproductive hormone concentrations or total sleep duration. Trial Registration: RBR-10whktxm (UTN: U1111-1305-6221). Registered on 13 August 2025, retrospectively registered. © 2026 The Author(s). Journal of Pineal Research published by John Wiley & Sons Ltd.

BACKGROUND: Hypoxic ischemic encephalopathy (HIE) is a severe brain injury that can lead to death and long-term disability. HIE can be treated with therapeutic hypothermia, and various adjuvant treatments (such as melatonin) are also utilized. Adjuvant therapies are not recommended outside clinical trials, and therapeutic hypothermia is not universally available. This study aimed to investigate the effects of Edaravone on improving levels of consciousness, hemodynamic stability, and short-term clinical outcomes of adult patients with severe HIE. To the best of our knowledge, this study is the first randomized clinical trial investigating the effects of Edaravone in adult patients with severe HIE. METHODS: A double-blind clinical trial enrolled 72 severe HIE patients (aged > 18) within 24 h of onset who were diagnosed clinically and radiologically. Patients were randomized to Edaravone group (n = 20) and non-Edaravone group (n = 52). Measured parameters included level of consciousness, vital signs, Barthel index, and patient outcome (death or discharge). Statistical analysis was performed using SPSS version 27, with a significance level of P < 0.05. RESULTS: In short-term assessment of the patient's level of consciousness, the Edaravone group showed significant improvement in the Glasgow Coma Scale (GCS) post-intervention (p = 0.001). While the Edaravone group and non-Edaravone group showed no significant difference in outcome (p = 0.863) and Barthel score for discharged patients (P = 0.557). Vital signs showed significant differences between groups in temperature (P = 0.002). In the comparison of comorbidities between the Edaravone and non-Edaravone groups, only coronary artery bypass grafting was significantly different (P = 0.021). CONCLUSION: Edaravone improved the short-term level of consciousness in severe HIE adult patients, but there was no significant effect on outcome and level of independence in performing activities of daily living. Further investigation into Edaravone's effectiveness is warranted, particularly in patients with milder forms of HIE, as well as longer follow-up periods. © 2026. Springer-Verlag GmbH Germany, part of Springer Nature.

Background/Objectives: This study examined the acute effects of different doses of melatonin on performance, physiological, and psychophysiological responses during individualized exhaustive cycling exercise. Methods: Fifteen physically active but cycling-inexperienced men (18-35 years) completed a double-blind, randomized, placebo-controlled, crossover protocol. Following an incremental test to determine the anaerobic threshold (AnT), participants performed four exhaustive exercise sessions at 80% of AnT after ingesting placebo or melatonin (5, 12.5, or 20 mg), administered approximately 30 min before exercise. Time to exhaustion (TLim) was considered the primary performance outcome. Heart rate, peripheral oxygen saturation, blood lactate concentration, blood glucose, and ratings of perceived exertion were assessed before, during, and after exercise. Results: No significant differences were observed between experimental conditions for TLim or for any physiological or psychophysiological variable. Only main effects of time were detected, reflecting expected exercise-induced responses, with small effect sizes and no evidence of a dose-response relationship across melatonin conditions. Baseline values were comparable among sessions. These findings indicate that acute melatonin administration at doses ranging from 5 to 20 mg does not elicit ergogenic effects nor modulate physiological or psychophysiological responses during prolonged individualized cycling exercise in healthy individuals. Conclusions: In male, healthy, physically active individuals inexperienced in cycling, acute melatonin administration at the doses tested did not produce ergogenic effects or alter physiological and psychophysiological responses during prolonged, individualized cycling exercise.

BACKGROUND: Sleep disturbances are highly prevalent among older adults and associated with substantial morbidity. Although bright light therapy has shown efficacy for insomnia, the evidence supporting near-infrared (NIR) light is comparatively limited. AIMS: To examine the effects of NIR (850 nm photobiomodulation to the neck), white light (WL, to the eyes), and their combination on sleep and melatonin secretion in older adults with insomnia symptoms, and explore whether chronotype moderated treatment outcomes. METHODS: A randomized clinical trial was conducted among 59 community-dwelling adults aged ≥ 60 years with early wakening and sleep-maintenance insomnia symptoms. Participants were randomized to NIR, WL, or NIR+WL for 60 min nightly over two weeks. Data gathered included actigraphy-derived sleep parameters, Pittsburgh Sleep Quality Index (PSQI), salivary melatonin concentration, and dim-light melatonin onset (DLMO). Chronotype was assessed with the Munich Chronotype Questionnaire, and its moderating effect was examined. RESULTS: PSQI scores improved significantly across all intervention groups, with increases in subjective sleep duration of 0.43 h (WL), 0.81 h (NIR), and 1.08 h (NIR+WL). No significant changes were observed in actigraphy-derived sleep indicators or melatonin measures. Chronotype significantly moderated treatment effects, with late chronotypes demonstrating greater improvement in sleep duration and efficiency with WL, whereas early chronotypes showed greater improvement with NIR+WL. CONCLUSIONS: Both NIR and WL were associated with improvements in subjective sleep quality and duration. Chronotype-specific patterns of response suggest distinct underlying mechanisms and support the potential for personalized light-based interventions for insomnia in older adults. CLINICAL TRIAL REGISTRATION: This study was registered on ClinicalTrials.gov (https://clinicaltrials.gov/study/NCT06292819).

This study aimed to evaluate the effects of melatonin supplementation on disease severity, sleep quality, and quality of life in adult patients with atopic dermatitis (AD). This study was designed as a randomized, double-blind, placebo-controlled clinical trial involving adult patients with mild to moderate AD. Eligible participants were randomly assigned to receive either a 10 mg melatonin tablet or a matching placebo once daily for 4 weeks. The primary outcome was the severity of AD, assessed by SCORAD index at baseline and after 4 weeks of supplementation. Secondary outcomes included the intensity of pain (NPRS), pruritus severity (Pruritus-NRS), sleep quality (ADSS), and quality of life (DLQI). Eighty patients completed the study. The mean age (Standard deviation) of the patients was 33.26 (12.57) years, and 32 patients (40%) were male. The SCORAD, Pruritus-NRS, 12-PSS, ADSS, and DLQI indices improved significantly (p-values of < 0.001, 0.006, 0.011, < 0.05, and 0.003, respectively) after 4 weeks of supplementation. However, melatonin supplementation did not improve the NPRS (p-value: 0.063). No patient reported an adverse effect throughout the study. Melatonin supplementation in adult patients with mild to moderate AD effectively improved disease severity, sleep quality, and quality of life, without any reported adverse effects. However, due to limitations of our study, further research is required to confirm these findings. © 2026 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

This study aimed to determine the effectiveness of different times of bright light therapy (BLT) in alleviating anhedonia and circadian rhythm disturbances in depression patients. The study also explored whether the positive effects of BLT on anhedonia in depression were associated with changes in melatonin and cortisol indices throughout the treatment period. In this single-blind, placebo-controlled study, 81 patients were randomly assigned to one of four groups: morning BLT group, morning placebo group, evening BLT group, or evening placebo group. Participants in the BLT groups received BLT at 10,000 lx, while those in the placebo groups were exposed at 100 lx for 30 min daily over two weeks. The primary outcome measure was the Revised Physical Anhedonia Scale (RPAS) score. Secondary outcome measures included salivary melatonin and cortisol levels, as well as the Hamilton Depression Rating Scale (HAMD) score. The morning BLT group showed a significant delay in the melatonin peak phase and an improvement in RPAS scores compared to the morning placebo group. A correlation between changes in RPAS scores and melatonin peak phase was observed (P = 0.048) after morning BLT, with multiple linear regression analysis further confirming this relationship (P = 0.026). These findings suggest that morning BLT significantly alleviates anhedonia in depression, an effect associated with delayed melatonin peak phase. Depressive symptoms improved following both morning and evening BLT. These results highlight the potential of bright light therapy as a non-pharmacological treatment option, with morning administration showing particular benefit for anhedonia.

BACKGROUND: Preserving ridge volume after tooth extraction is essential for predictable implant outcomes. Various techniques and biomaterials have been proposed to minimize post-extraction dimensional changes. Melatonin, a pineal hormone, is an important mediator of new bone formation. The effect of melatonin gel incorporated into a porcine xenogeneic collagen sponge in post-extraction sockets has not been evaluated in humans, making this trial novel. PURPOSE: To assess the effect of melatonin gel incorporated into a collagen sponge on intra-socket bone formation and tissue characteristics in post-extraction sockets. MATERIALS AND METHODS: Twenty participants requiring extraction of premolars or molars with adjacent teeth were randomly allocated to test (n = 10) and control (n = 10) groups. After extraction, sockets were filled with xenogenic collagen sponge containing either melatonin gel (1.2 mg; test) or placebo gel (control). Ninety days later, during implant placement, bone samples were harvested using a trephine drill. Samples were processed for histomorphometric analysis of newly formed bone and connective tissue. Secondary outcomes included descriptive microscopic histology, quantitative microcomputed tomography (µCT) analyses and intra-alveolar volumetric analysis. RESULTS: Histomorphometry revealed significantly greater bone density in the test group (44.0%) than in the control group (35.4%; p = 0.0099), with a mean difference of 8.6% ± 3.2%. Microscopic evaluation showed increased osteoblastic activity in the test group. Quantitative µCT analysis confirmed more new bone formation in the test group, although qualitative bone characteristics did not differ between groups. The intra-alveolar bone volume formed was numerically higher in the test group than in the control group. CONCLUSION: Incorporating melatonin gel into a collagen sponge enhanced bone repair in human post-extraction sockets over 90 days. This clinical trial is registered at the Brazilian Clinical Trials Registry (ReBEC; https://ensaiosclinicos.gov.br): RBR-67jkxsj.

BACKGROUND AND OBJECTIVES: Based on melatonin's neuroprotective effects in pre-clinical multiple sclerosis models, the MELATOMS-1 study was designed to evaluate melatonin treatment in patients with primary progressive multiple sclerosis (PP-MS) receiving ocrelizumab treatment. The trial was prematurely halted due to hypertransaminasemia. This study aimed to analyse observed cases of hypertransaminasemia and explore potential underlying mechanisms, focusing on drug-drug interactions . METHODS: This study reports findings from MELATOMS-1 (NCT03540485), a multicentre, phase I/II, randomised, double-blind, placebo-controlled trial conducted in the multiple sclerosis units of Hospital Universitario Virgen Macarena, Hospital Universitario Virgen del Rocío and Hospital Vithas Nisa of Seville. The trial was designed to evaluate the safety and efficacy of high-dose oral melatonin (300 mg/day) as an adjunct therapy for patients with PP-MS (Expanded Disability Status Scale 2-7) on stable ocrelizumab therapy (> 9 months). Participants were assigned 1:1 by stratified randomisation (based on MS severity score) to receive either daily oral melatonin or a matching placebo 30 min before bedtime. Safety was evaluated by monitoring adverse events and scheduled biochemical analyses, including routine liver function tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) and bilirubin, quantified by automated immunoassay], every 3 months for up to 2 years (the trial's endpoint). The trial was temporarily stopped after grade 1-2 hepatotoxicity was identified in three patients, according to the scale of the international DILI expert working group. A subsequent post hoc causality analysis focused on potential drug-drug pharmacokinetic interactions between high-dose melatonin and the patients' polypharmacy involving cytochrome P450 (CYP) enzyme pathways. The analysis focused on concomitant medications including acetaminophen, metamizole, omeprazole, ibuprofen, acetylsalicylic acid, nabiximol and tizanidine. RESULTS: The trial was prematurely stopped and unblinded after eight patients had been recruited. Three

Background/Objectives: Oxidative stress plays an important role in the pathophysiology of endometriosis, contributing to inflammation, immune dysregulation, and lesion progression. This has led to growing interest in antioxidant-based strategies as potential supportive interventions. Methods: A literature search was conducted using PubMed, Scopus, and Web of Science databases, covering studies published from database inception until the end of January 2026. The review focused on clinically relevant endpoints, including pain intensity, markers of inflammation and oxidative stress, reproductive parameters, and quality of life. Results: Among the analyzed interventions, the most consistent clinical effects were observed with melatonin, with randomized controlled trials indicating a moderate reduction in pain. N-acetylcysteine shows potentially beneficial effects; however, the available clinical data remain limited and heterogeneous. For other supplements, the evidence is inconsistent or insufficient to support clear clinical conclusions, and in many cases relies on indirect or mechanistic findings rather than well-established clinical outcomes. Conclusions: Current evidence does not support the use of non-mineral antioxidant supplements as standalone therapy for endometriosis. They may be considered as adjunctive strategies, although their clinical effectiveness remains uncertain and requires confirmation in well-designed randomized clinical trials.

Sleep is tightly regulated by thermoregulatory processes that include core body temperature (CBT) modulation, the distal-proximal temperature gradient (DPG), and melatonin rhythms. In this review, we examine how these factors intersect with sleep physiology and contribute to the pathophysiology of common sleep disorders such as ADHD, insomnia, narcolepsy, Obstructive Sleep Apnea (OSA), depression, and Restless Legs Syndrome (RLS). We discuss evidence showing that delayed or disrupted CBT minima, impaired DPG, and altered melatonin secretion can prolong sleep latency, fragment rest, and lead to daytime symptoms. In addition, we explore temperature-based interventions, including foot baths, passive body heating, whole-body hyperthermia, and adjustments in room temperature, which have demonstrated potential to mitigate symptoms and enhance sleep quality. Collectively, these findings emphasize the need for personalized interventions to address thermoregulatory disruptions, presenting a noninvasive avenue for more effective sleep disorder management.

Introduction: Ethanol consumption is a major global health concern associated with many disorders. Melatonin, a circadian neurohormone, also modulates dopamine signaling and drug-seeking behaviors central to addiction. Objective: To investigate the role of melatonergic receptors in reducing ethanol consumption and explore melatonin's therapeutic potential to overcome ethanol dependence in rats. Method: Male Wistar rats were acclimatized for 5 days, then divided into two groups: ethanol-naive (n = 6) and ethanol-exposed (n = 36). The ethanol group was given 10% ethanol (7 days), followed by limited access (27 days). On day 40, the ethanol group was divided into 6 sub-groups, receiving various treatments, including melatonin and receptor blockers (10 days). Ethanol and water consumption were measured daily. On day 49, the rats were sacrificed, and dopamine levels in the nucleus accumbens were quantified using an ELISA. Results: Both melatonin doses and naltrexone significantly reduced ethanol consumption (p < 0.05) compared to their pretreatment levels. Ethanol reduction was greater in the melatonin-treated groups than the control group (p = 0.004, p = 0.007). However, the melatonin's efficacy was blocked when coadministered with receptor antagonists, showing no significant ethanol reduction vs. control (p = 0.075 and p = 0.08). Conclusions: These findings suggest that melatonin reduces ethanol intake via specific receptor pathways, supporting its potential use in treating alcohol dependence.

Oxidative stress critically affects cellular viability and function under in vitro culture conditions, often compromising physiological integrity of somatic cells used in livestock biotechnology. This study aimed to investigate hydrogen peroxide (H2O2)-induced oxidative stress in buffalo fibroblasts and evaluated the cytoprotective effects of melatonin, focusing on redox homeostasis, mitochondrial function, apoptosis, and antioxidant defence. Fibroblasts were exposed to graded concentrations of H2O2 (100-1000 µM) for 2 h, followed by treatment for 72 h in culture media with and without melatonin (10-9 M). Oxidative stress markers, including GSSG/GSH ratio, ROS generation, mitochondrial membrane potential (MMP), and apoptosis, were assessed using flow cytometry and biochemical assays, while antioxidant (GPx, SOD, CAT) and apoptotic (BAX, Caspase 9) gene expression was analyzed by qPCR. H2O2 exposure induced a dose-dependent increase in oxidative stress, evidenced by elevated ROS, redox imbalance, mitochondrial depolarization, and enhanced apoptosis. Severe oxidative damage was observed at higher H2O2 (500-1000 µM) concentrations. Melatonin (MT) significantly (p ≤ 0.05) alleviated oxidative stress under mild to moderate conditions (100-200 µM H2O2) by restoring redox homeostasis, preserving mitochondrial integrity, suppressing ROS accumulation, enhancing antioxidant defence, and reducing apoptosis. However, its protective efficacy was lost under severe oxidative stress, indicating a defined redox threshold beyond which cellular damage becomes irreversible. These findings suggest that melatonin exerts cytoprotective effect against oxidative stress within a limited oxidative window and provide mechanistic insights for improving fibroblasts culture systems in livestock biotechnology and regenerative applications.

Melatonin, a well-known antioxidant, has been widely used in sperm cryopreservation of various animals, but its regulatory mechanism in fish remains unclear. This first study on teleosts suggests a potential molecular mechanism by which melatonin may improve post-thaw sperm quality of Epinephelus fuscoguttatus via targeting mitochondrial function. Compared with the melatonin group, the MT1 receptor-inhibited group showed slightly higher sperm motility (77.09 ± 3.41% vs. 76.50 ± 1.10%), significantly inhibited mitochondrial permeability transition pore (mPTP) opening (12.64 ± 1.05% vs. 18.29 ± 1.38%), and maintained higher mitochondrial membrane potential (MMP; 85.86 ± 0.18% vs. 81.81 ± 0.69%), with both groups performing better than the control. In contrast, the MT2-inhibited and MT1/2 dual-inhibited groups exhibited reduced sperm quality compared with the MT group, suggesting that MT2 may serve as the core receptor for melatonin to regulate mitochondrial homeostasis in teleosts. Mechanistically, melatonin-activated MT2 potentially inhibits mPTP opening via the PI3K/Akt/GSK-3β pathway, and this protective effect was abrogated by the PI3K and GSK-3β inhibitors. This receptor-mediated process synergized with melatonin's direct antioxidant effect, as ROS levels in all melatonin-treated groups were significantly lower than the control. This study is the first to find pharmacological evidence for the melatonin-MT2/PI3K/GSK-3β axis in maintaining teleost sperm mitochondrial function; it also reveals potential mechanistic differences between teleosts and mammals and fills a critical knowledge gap regarding this signaling cascade in teleost reproductive biology.

The use of colored LED lights is a tool for controlling the development of lymphoid organs and the immune system in general. This study aims to analyze the effects of using simple and combined colored LED lights throughout a 6 week period (1-42 days of age). In this study, 336 one-day-old chicks were used, separated randomly into four groups with different sex and lighting systems, with each group being divided into four separate replicates (4 × 21 birds). The chicks in the WL-Male and WL-Female were exposed to white LED light (WL, 400-760 nm) for 6 weeks, while the chicks in the G-GxB-BL-Male and G-GxB-BL-Female were exposed to a combination of monochromatic lights as follows: green (560 nm) from 1 to 14 days of age, green and blue (480-560 nm) for 15-28 days of age, and blue lights (480 nm) for 29-42 days of age. The use of a mixture of green and blue LED lights (G-GxB-BL) resulted in a significant decrease in the average daily feed intake and feed conversion ratio compared to white light, without causing changes in the body weight of the chicks, average daily gain, mortality rate, and coefficient of variability. G-GxB-BL lights also improved the morphological development of the bursa of Fabricius (BF) compared to white light by significantly increasing the organ index and the lymphoid follicle area. At the same time, G-GxB-BL light compared to white light improved B lymphocytes proliferation in the BF by significantly increasing the lymphocyte density in lymphoid follicles, as well as the number of PCNA-positive cells. This light treatment had these results due to the activation of melatonin receptors, which led to a significant increase in Mel1a-positive cells and a significant decrease in the number of RORα-positive cells. These results demonstrate that G-GxB-BL lights improved the growth performance and immune response in the BF of broiler chickens.

This study evaluated whether oral melatonin supplementation influences glycemic outcomes in humans through a systematic review and meta-analysis of randomized controlled trials (RCTs). A systematic search of major electronic databases was conducted to identify RCTs evaluating the effects of melatonin supplementation on metabolic outcomes in adults. Studies reporting fasting glucose, glycated hemoglobin (HbA1c), fasting insulin, or homeostatic model assessment of insulin resistance (HOMA-IR) were included. Data were pooled using a random-effects model. Heterogeneity was assessed using the I2 statistic, and meta-regression analyses were performed to explore potential moderators. Statistical analyses were conducted using Jamovi software. Thirty-one RCTs were included in this systematic review. Quantitative synthesis comprised 27 studies reporting fasting glucose, nine studies reporting HbA1c, seven studies reporting fasting insulin, and four studies reporting HOMA-IR. Melatonin doses ranged from 1 to 10 mg/day, with intervention durations between 14 and 365 days. The meta-analysis showed no significant reduction in fasting glucose levels. However, improvements were observed in secondary metabolic outcomes related to glycemic control and insulin resistance, including HbA1c, fasting insulin, and HOMA-IR. Melatonin supplementation did not significantly reduce fasting glucose but may improve markers of glycemic control and insulin sensitivity, suggesting a modulatory role in metabolic regulation.

Sleep disorders include a range of common problems that affect the quality of sleep at night and, as a result, impact an individual's daily functioning. Treatment protocols vary from over-the-counter products to regulated pharmaceuticals. Melatonin and Tasimelteon are two compounds utilized for severe to moderate sleeping disorders. This study developed and validated a sensitive, simple bioanalytical LC-MS/MS method for the measurement of Melatonin and Tasimelteon in spiked rat brain tissue. Chromatographic analyses were conducted in isocratic mode, with Citalopram selected as an appropriate internal standard. The Supelco Ascentis® Express Phenyl-Hexyl column was used for the stationary phase, and the mobile phase comprised 0.2% formic acid in a mixture of acetonitrile and water (65:35, v/v). A response surface methodology is applied. The Box-Behnken design was used to optimize the influence of three independent factors (acetonitrile%, formic acid%, and flow rate (mL/min)) on the response. The study focused on finding the most significant factors influencing chromatographic separation, namely the resolution between Tasimelteon and Melatonin, as well as the tailing factors of both. Statistical analysis of variance provided the optimal conditions for separating the substances as well as the most influential factors. Validation of the analytical method was conducted in accordance with the International Council for Harmonization guideline M10 related to bioanalytical method validation. The method validated was precise and linear in 55.00-1650 (ng/mL) and 20-600 (ng/mL) for the Melatonin and Tasimelteon, respectively. The validated method's lower limit of quantification values was 55 and 20 ng/mL for Melatonin and Tasimelteon, respectively. For Melatonin, intraday accuracy (recovery, %) ranged from 96.53% to 102.68%, and precision (expressed as relative standard deviation) ranged from 0.26% to 0.96%. And inter-day accuracy ranged from 96.58% to 103.08%, and inter-day precision ranged from 0.33% to 3.55%. Intraday accuracy results for Tasimelteon 99.61%-103. 75% precision results were in the range 0.23%-0.93%; additionally, inter-day accuracy was 99.37-103.87%, and th

BACKGROUND: Off-site fattening of Tibetan sheep is a key strategy to mitigate the effects of high-altitude grassland degradation and winter forage scarcity, promoting sustainable development in plateau animal husbandry. However, transport stress (TS) presents a significant challenge to realizing its benefits. The mechanism by which TS affects the health of Tibetan sheep by regulating rumen microbial and serum metabolite rhythmic changes remains unclear. METHODS: This study selected six healthy male Tibetan sheep, aged seven months and of comparable body weight, for the transport experiment. Blood and rumen fluid samples were collected at four-hour intervals during 24-hour periods pre-transport (CON) and post-transport (TS) for serum indicators, serum metabolome, and rumen microbiome analyses. RESULT: The results showed that TS significantly increased serum concentrations of cortisol (COR), melatonin (MT), lipopolysaccharide-binding protein (LBP), serum amyloid A (SAA), and non-esterified fatty acid (NEFA), while significantly decreasing glucose (GLU), total antioxidant capacity (T-AOC), and glutathione peroxidase (GPx) (P < 0.05). Furthermore, the circadian rhythms of COR, MT, LBP, SAA, NEFA, and GPx were significantly disrupted (ADJ.P < 0.05). TS reduced the proportion of rumen microbial circadian rhythms from 3.46% to 1.99%, with Prevotella, Butyrivibrio, and Ruminococcus losing their circadian rhythmicity in the TS phase (ADJ.P < 0.05). Additionally, TS decreased the proportion of circadian rhythm-regulated serum metabolites from 51.74% to 29.51%. In the TS phase, rhythmically regulated metabolites, including 3',5'-cyclic AMP, fumarate, dopamine, glutathione, and angiotensin (1-7), were enriched in pathways such as oxidative phosphorylation, retinol metabolism, and tryptophan metabolism. Multi-omics analyses demonstrated significant correlations between Ruminococcus and energy metabolites (malic acid, 3',5'-cyclic AMP, fumarate, NEFA), and between Butyrivibrio, Anaeroplasma, and inflammatory/antioxidant markers (glutathione, SAA, LBP). In conclusion, this study reveals that TS induces a homeostatic imbalance in Tibetan sheep by disrupting the circadian rhythm

BACKGROUND: Seed germination and early seedling establishment in triticale (×Triticosecale Wittmack) are highly vulnerable to salinity stress. Seed priming has emerged as a potent and cost-effective strategy to enhance salt tolerance during these critical developmental stages. However, the physiological mechanisms through which melatonin (N-acetyl-5-methoxytryptamine, MT) priming alleviates salt stress in triticale remain poorly understood. METHODS: In this study, four treatments were applied: CK (control), MT (melatonin priming without salt stress), S (non-primed seeds under salt stress), and MS (melatonin-primed seeds under salt stress). We comprehensively assessed the effects of MT priming on seed germination, seedling growth, photosynthetic performance, and key physiological indicators under saline conditions. RESULT: The results revealed that MT priming significantly increased the germination rate by 26.87% compared to non-primed seeds under salt stress. Moreover, seedling height and fresh weight in the MS treatment were significantly higher by 3.86% and 36.00%, respectively, than those in the S group. These enhancements were attributed to the upregulation of antioxidant enzyme activities, including superoxide dismutase and peroxidase, which effectively reduced reactive oxygen species accumulation and mitigated oxidative damage. Additionally, MT priming improved Na⁺/K⁺ homeostasis and stimulated the biosynthesis of osmoregulatory compounds such as soluble sugars and proteins. Notably, MT application also increased endogenous gibberellin levels while reducing abscisic acid content in both seeds and seedlings under salt stress. CONCLUSION: Melatonin alleviates the detrimental effects of salt stress on seed germination and seedling growth in triticale by modulating antioxidant defense, osmotic adjustment, and hormonal homeostasis. © 2026. The Author(s).