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IntroductionMelatonin has been studied in headache disorders. Amitriptyline is efficacious for migraine prevention, but its unfavourable side effect profile limits its use.MethodsA randomised, double-blind, placebo-controlled study was carried out. Men and women, aged 18–65 years, with migraine with or without aura, experiencing 2–8 attacks per month, were enrolled. After a 4-week baseline phase, 196 participants were randomised to placebo, amitriptyline 25 mg or melatonin 3 mg, and 178 took a study medication and were followed for 3 months (12 weeks). The primary outcome was the number of migraine headache days per month at baseline versus last month. Secondary end points were responder rate, migraine intensity, duration and analgesic use. Tolerability was also compared between groups.ResultsMean headache frequency reduction was 2.7 migraine headache days in the melatonin group, 2.2 for amitriptyline and 1.1 for placebo. Melatonin significantly reduced headache frequency compared with placebo (p=0.009), but not to amitriptyline (p=0.19). Melatonin was superior to amitriptyline in the percentage of patients with a greater than 50% reduction in migraine frequency. Melatonin was better tolerated than amitriptyline. Weight loss was found in the melatonin group, a slight weight gain in placebo and significantly for amitriptyline users.ConclusionsMelatonin 3 mg is better than placebo for migraine prevention, more tolerable than amitriptyline and as effective as amitriptyline 25 mg.

A recent double-blind randomized placebo-controlled study demonstrated 3-month efficacy and safety of a novel pediatric-appropriate prolonged-release melatonin (PedPRM) for insomnia in children and adolescents with autism spectrum disorder (ASD) and neurogenetic disorders (NGD) with/without attention-deficit/hyperactivity disorder comorbidity. Long-term efficacy and safety of PedPRM treatment was studied. A prospective, open-label efficacy and safety follow-up of nightly 2, 5, or 10 mg PedPRM in subjects who completed the 13-week double-blind trial (51 PedPRM; 44 placebo). Measures included caregiver-reported Sleep and Nap Diary, Composite Sleep Disturbance Index (CSDI), caregiver's Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale, and quality of life (WHO-5 Well-Being Index). Ninety-five subjects (74.7% males; mean [standard deviation] age, 9 [4.24]; range, 2-17.5 years) received PedPRM (2/5 mg) according to the double-blind phase dose, for 39 weeks with optional dose adjustment (2, 5, or 10 mg/day) after the first 13 weeks. After 52 weeks of continuous treatment (PedPRM-randomized group) subjects slept (mean [SE]) 62.08 (21.5) minutes longer (  = 0.007); fell asleep 48.6 (10.2) minutes faster (  < 0.001); had 89.1 (25.5) minutes longer uninterrupted sleep episodes (  = 0.001); 0.41 (0.12) less nightly awakenings (>50% decrease;  = 0.001); and better sleep quality (  < 0.001) compared with baseline. The placebo-randomized group also improved with PedPRM. Altogether, by the end of 39-week follow-up, regardless of randomization assignment, 55/72 (76%) of completers achieved overall improvement of ≥1 hour in total sleep time (TST), sleep latency or both, over baseline, with no evidence of decreased efficacy. In parallel, CSDI child sleep disturbance and caregivers' satisfaction of their child's sleep patterns (  < 0.001 for both), PSQI global (  < 0.001), and WHO-5 (  = 0.001) improved in statistically significant and clinically relevant manner (  = 72) compared with baseline. PedPRM was generally safe; most frequent treatment-related adverse events were fatigue (5.3%) and mood swings (3.2% of patients). PedPRM, an easily swallowed formulation shown to be efficacious versus placebo, is an efficacious and safe option for long-term treatment (up to 52 weeks reported here) of children with ASD and NGD who suffer from insomnia and subsequently improves caregivers' quality of life.

Supplemental melatonin has shown promise in treating sleep onset insomnia in children with autism spectrum disorders (ASD). Twenty-four children, free of psychotropic medications, completed an open-label dose-escalation study to assess dose–response, tolerability, safety, feasibility of collecting actigraphy data, and ability of outcome measures to detect change during a 14-week intervention. Supplemental melatonin improved sleep latency, as measured by actigraphy, in most children at 1 or 3 mg dosages. It was effective in week 1 of treatment, maintained effects over several months, was well tolerated and safe, and showed improvement in sleep, behavior, and parenting stress. Our findings contribute to the growing literature on supplemental melatonin for insomnia in ASD and inform planning for a large randomized trial in this population.

Hedonic eating, reward-driven eating rather than out of biological needs, has been proposed as one of the important causes of overweight and obesity in recent years. Dopamine, endocannabinoids, opioids, and ghrelin are among the physiological factors associated with hedonic eating. Since the results of some previous animal studies have indicated the effectiveness of melatonin supplementation on the levels of endocannabinoids, and ghrelin, therefore this pilot study will investigate the effect of melatonin supplementation on plasma levels of endocannabinoid 2-arachidonylglycerol, ghrelin, and the intensity of hedonic eating in overweight/obese females. In a randomized, double-blinded, placebo-controlled study, forty-six women with overweight/obesity and high hedonic eating intensity (total score of power of food scale > 2.5) will be recruited. They will receive either a 5 mg/day melatonin supplement (n = 23) or a placebo (n = 23) for 8 weeks. The primary outcomes, including the plasma levels of 2-arachidonylglycerol and ghrelin, and the intensity of hedonic eating will be assessed at the baseline and end of the study. Additionally, the secondary outcomes (dietary intake, and body weight) will be evaluated at the study's onset, after four weeks, and upon completion of the intervention. A one-way analysis of covariance (ANCOVA) will be used to detect the effect of melatonin supplementation on outcome variables. Considering the positive effects of melatonin supplementation in reducing endocannabinoid levels, the expression of the ghrelin hormone gene, the level of ghrelin, and the cannabinoid receptor type 1 gene expression in animal studies, it is possible that in human subjects, it could impact the intensity of hedonic eating by lowering endocannabinoid and ghrelin levels. The trial was registered with the Iranian Registry of Clinical Trials in June 2023 under the ID number IRCT20080904001197N22.

Background Advanced maternal age is associated with decreased oocyte quantity and quality and in vitro fertilization (IVF) success rates. This study aimed to investigate whether melatonin supplementation can improve IVF outcomes in women of advanced maternal age by modulating cuproptosis and ferroptosis. Methods This prospective cohort study included 161 women aged 35–45 years undergoing IVF-frozen embryo transfer cycles. Participants were assigned to either melatonin ( n  = 86, 2 mg daily for ≥ 8 weeks) or control ( n  = 75) groups. Cumulus cells were analyzed for cuproptosis and ferroptosis-related gene expression. Additional experiments were conducted on the HGL5 human granulosa cell line to assess mitochondrial function and metabolic reprogramming. Results Melatonin supplementation significantly improved IVF outcomes in women aged ≥ 38 years, increasing clinical pregnancy rates (46.0% vs. 20.3%, P  < 0.01), ongoing pregnancy rates (36.5% vs. 15.3%, P  < 0.01), and live birth rates (33.3% vs. 15.3%, P  < 0.05). In cumulus cells from patients, gene expression analysis revealed that melatonin modulated cuproptosis and ferroptosis-related genes, including ATP7B and GPX4, with more pronounced effects in the ≥ 38 years group. This suggests melatonin enhances cellular resilience against oxidative stress and metal-induced toxicity in the ovarian microenvironment. In vitro studies using HGL5 cells showed melatonin reduced oxidative stress markers, improved mitochondrial function, restored expression of glycolysis and TCA cycle-related genes and modulated cuproptosis and ferroptosis-related gene expression. These findings provide mechanistic insight into melatonin’s protective effects against regulated cell death in ovarian cells, potentially explaining the improved IVF outcomes observed. Conclusions Melatonin supplementation significantly improved IVF outcomes in women of advanced maternal age, particularly those ≥ 38 years old, likely by modulating cuproptosis and ferroptosis and enhancing mitochondrial function in cumulus and granulosa cells. These results suggest that melatonin could be a promising adjuvant therapy for improving IVF success rates in older women.

PurposeThe trial aimed to investigate the effectiveness of exogenous melatonin as an adjuvant to pregabalin for relief of pain in patients suffering from painful diabetic neuropathy (PDN).Patients and methodsThis randomized, double-blind, placebo-controlled trial was carried out between October 2019 and December 2020 in an outpatient specialty clinic in Iran. One-hundred-three type 2 diabetic patients suffering from PDN were randomized into either the melatonin group (n = 52) or the placebo group (n = 51). Besides pregabalin at a dose of 150 mg per day, patients started with melatonin or an identical placebo, at a dose of 3 mg/day at bedtime for 1 week, which was augmented to 6 mg/day for further 7 weeks. The primary outcomes were changes in mean NRS (numerical rating scale) pain score from baseline to endpoint and responder rate (patients with a reduction of 50% and higher in average pain score compared with baseline). Secondary endpoints were changes in mean NRS pain-related sleep-interference score, overall improvement evaluated by Patient and Clinical Global Impressions of Change (PGIC, CGIC), and impact of the intervention on patient’s Health-related quality of life (QOL). All analyses were conducted on an Intention-to-Treat (ITT) analysis data set.ResultsAt the study endpoint, treatment with melatonin resulted in a considerably higher reduction in the mean NRS pain score in comparison with placebo (4.2 ± 1.83 vs. 2.9 ± 1.56; P-value < 0.001). In terms of treatment responders, a greater proportion of melatonin-treated patients satisfied the responder criterion than placebo-treated patients (63.5% vs. 43.1%). Melatonin also reduced pain-related sleep interference scores more than did placebo (3.38 ± 1.49 vs. 2.25 ± 1.26; P-value < 0.001). Further, at the endpoint, more improvement was also seen in terms of PGIC, CGIC, and Health-related QOL in patients treated with melatonin than placebo. Melatonin was also well tolerated.ConclusionThe present results showed that melatonin as an adjunct therapy to pregabalin might be helpful for use in patients with PDN. However, confirmation of these results requires further studies.

ObjectiveTo determine the efficacy of addition of melatonin or triclofos to sleep deprivation as compared with sleep deprivation with placebo for conduct of successful sleep electroencephalogram (EEG) among children between 6 months and 12 years of age.Design, setting and Patients486 children aged between 6 months and 12 years who were uncooperative or referred for sleep EEG were enrolled for this double-blind, placebo-controlled randomised trial between 30 June 2022 and 31 March 2023.InterventionOn the day of sleep EEG, participants were sleep deprived by 25% of their regular sleep duration and then randomly assigned to receive either triclofos (50 mg/kg), melatonin (weight ≤15 kg=3 mg; weight >15 kg=6 mg) or placebo.OutcomePrimary outcome was the conduct of a successful sleep EEG.Results486 children were randomly assigned to intervention with triclofos (n=165), melatonin (n=161) or placebo (n=160). Sleep EEG success (p<0.001) with different interventions was: triclofos=145/165(88%); melatonin=123/161 (76%) and placebo=65/160 (41%). Sleep EEG’s success rate was better with triclofos than melatonin (OR=2.2; 95% CI 1.2 to 4.1) or placebo (OR=10.6; 95% CI 6.1 to 19.0). Melatonin was better than placebo in the rate of successful sleep EEG (OR=4.7; 95% CI 2.9 to 7.7). Beta artefacts were significantly more with triclofos (51/145) than melatonin (19/123) and placebo (12/65), but the readability of EEG was not impacted. Movement/unwanted arousal artefacts were significantly more with placebo (37/65) than with triclofos (37/145) and melatonin (34/123). Drug-related adverse events were comparable between triclofos and melatonin. Neither of the drugs was associated with any serious adverse events.ConclusionsBoth triclofos and melatonin are individually better than sleep deprivation alone for conducting successful sleep EEGs. Triclofos is significantly better than melatonin for conducting sleep EEGs, with no significant increase in adverse events.Trial registration numberCTRI/2022/05/042479; Clinical Trials Registry of India

Advanced glycation end products, systemic and vascular inflammation, and oxidative stress are risk factors for cardiovascular disease in peritoneal dialysis (PD) patients. No studies have examined the effects of melatonin on these risk factors in PD patients. This study was a randomized clinical trial. Forty-four PD patients were randomly assigned to either the melatonin or the placebo group. Participants in the melatonin group received 5 mg melatonin for 10 weeks, while the placebo group received a corresponding placebo. In this study, serum pentosidine, carboxymethyl lysine (CML), high-sensitivity C-reactive protein (hs-CRP), soluble intercellular adhesion molecule type 1 (sICAM-1), malondialdehyde (MDA), and glucose were measured. Serum MDA showed a significant reduction in the melatonin group ( P  = 0.001), and the reduction was significant compared to the placebo group ( P  = 0.03). Serum hs-CRP decreased in the melatonin group, and this reduction was significant compared to the placebo group ( P  = 0.04). Significant reductions were observed in serum sICAM-1 ( P  = 0.02) and pentosidine ( P  = 0.03) in the melatonin group. Serum CML and glucose did not show significant changes within each group. This study indicates that nightly administration of 5 mg melatonin reduces MDA, hs-CRP, sICAM-1 and pentosidine, which are cardiovascular risk factors in PD patients. ClinicalTrials.gov: NCT06096558 (23/10/2023).

PurposeDysmenorrhea is a common, recurring, painful condition with a global prevalence of 71%. The treatment regime for dysmenorrhea includes hormonal therapies and NSAID, both of which are associated with side effects.A dose of 10 mg melatonin daily has previously been shown to reduce the level of pelvic pain in women with endometriosis. We chose to investigate how this regime, administered during the week of menstruation, would affect women with dysmenorrhea but without any signs of endometriosis, as adjuvant analgesic treatment.MethodsForty participants with severe dysmenorrhea were randomized to either melatonin or placebo, 20 in each group. Our primary outcome was pain measured with numeric rating scale (NRS); a difference of at least 1.3 units between the groups was considered clinically significant. Secondary outcomes were use of analgesics, as well as absenteeism and amount of bleeding. Mixed model was used for statistical analysis.ResultsEighteen participants completed the study in the placebo group and 19 in the melatonin group. Mean NRS in the placebo group was 2.45 and 3.18 in the melatonin group, which proved to be statistically, although not clinically significant.ConclusionThis randomized, double-blinded, placebo-controlled trial could not show that 10 mg of melatonin given orally at bedtime during the menstrual week had better analgesic effect on dysmenorrhea as compared with placebo. However, no adverse effects were observed.Clinical trialsNCT03782740 registered on 17 December 2018.

Introduction. Preterm infants are at risk of free radical-mediated diseases from oxidative stress (OS) injury. Increased free radical generation has been demonstrated in preterm infants during the first seven days of life. Melatonin (MEL) is a powerful antioxidant and scavenger of free radicals. In preterm neonates, melatonin deficiency has been reported. Exogenous melatonin administration appears a promising strategy in the treatment of neonatal morbidities in which OS has a leading role. Objective. The aim was to evaluate plasma MEL concentrations and OS biomarkers in preterm newborns after early administration of melatonin. Methods. A prospective, randomized double-blind placebo-controlled pilot study was conducted from January 2019 to September 2020. Thirty-six preterm newborns were enrolled. Starting from the first day of life, 21 received a single dose of oral melatonin 0.5 mg/kg once a day, in the morning (MEL group); 15 newborns received an equivalent dose of placebo (placebo group). Samples of 0.2 mL of plasma were collected at 24 and 48 hours after MEL administration. Plasma concentrations of melatonin, non-protein-bound iron (NPBI), advanced oxidation protein products (AOPP), and F2-isoprostanes (F2-Isopr) were measured. Babies were clinically followed until discharge. Results. At 24 and 48 hours after MEL administration, the MEL concentrations were significantly higher in the MEL group than in the placebo group (52759.30±63529.09 vs. 28.57±46.24 pg/mL and 279397.6±516344.2 vs. 38.50±44.01 pg/mL, respectively). NPBI and AOPP did not show any statistically significant differences between the groups both at 24 and 48 hours. At 48 hours, the mean blood concentrations of F2-Isopr were significantly lower in the MEL group than in the placebo group (36.48±33.85 pg/mL vs.89.97±52.01 pg/mL). Conclusions. Early melatonin administration in preterm newborns reduces lipid peroxidation in the first days of life showing a potential role to protect high-risk newborns. Trial Registration. This trial is registered with NCT04785183, Early Supplementation of Melatonin in Preterm Newborns: the Effects on Oxidative Stress.