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Purpose To determine the dose of melatonin with an optimal pharmacokinetic profile and to test whether this dose reduces the prevalence of delirium in mechanically ventilated ICU patients as compared to placebo. Methods DEMEL, a multicenter adaptive phase 2b/3 randomized, placebo-controlled, double-blind trial included patients at 20 health centers in France from February 1st, 2019 through January 5th, 2021. Patients were randomized (1:1:1) to receive either placebo or low (0.3 mg) or high (3 mg) dose melatonin enterally at 9:00 p.m. for 14 consecutive nights or until death or ICU discharge, whichever came first. The interim primary endpoint (activity stage) was the percentage of patients who achieved an optimal melatonin pharmacokinetic profile 24 h after starting study treatment; the final primary endpoint (efficacy phase) was the percentage of patients who experienced delirium between randomization and day 14 (or until death or ICU discharge, whichever came first). Delirium was assessed twice daily using the Confusion Assessment Method for ICU. Results We randomized 355 patients and included 334 in the primary analysis. At the preplanned analysis of the activity stage performed in 75 patients, the low-dose melatonin group had the highest rate of optimal pharmacokinetic profiles (12/24, 50%) when compared with the high-dose melatonin group (6/25, 24%) and the placebo group (0/26). Therefore, the Steering Committee recommended that the high-dose melatonin group be discontinued and that the low-dose melatonin group be selected to continue in the efficacy phase along with the placebo group. At the end of the efficacy stage, there was no difference in the final primary outcome of delirium incidence between the low-dose melatonin group and the placebo group: 80/147 (54.4%) vs 85/154 (55.2%), risk ratio, 0.986 [95% CI 0.803 to 1.211]; key secondary outcomes were also similar between groups. These included sleep quality, delirium-free, coma-free, and ventilator-free days at day 28; ICU and hospital length of stay; mortality at day 28, in the ICU, and in hospital; as well as long-term outcomes such as quality of life and postintensive care syndrome at day 90. Conclusions This randomized clinical trial found that the low-dose of melatonin (0.3 mg nightly) achieved a better pharmacokinetic profile than the high-dose (3 mg nightly), but did not change the incidence of delirium compared to placebo in mechanically ventilated critically-ill patients. Trial registration ClinicalTrial.gov website (NCT03524937).

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.

Objective: 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. Methods: 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). Results: 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 (p = 0.007); fell asleep 48.6 (10.2) minutes faster (p < 0.001); had 89.1 (25.5) minutes longer uninterrupted sleep episodes (p = 0.001); 0.41 (0.12) less nightly awakenings (>50% decrease; p = 0.001); and better sleep quality (p < 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 (p < 0.001 for both), PSQI global (p < 0.001), and WHO-5 (p = 0.001) improved in statistically significant and clinically relevant manner (n = 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). Conclusion: 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.

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.

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.

ObjectivesA decreased ability to repair oxidative DNA damage, due to melatonin suppression, is a compelling mechanism by which night shift workers are at an increased risk of cancer. We sought to determine if melatonin supplementation would improve oxidative DNA damage repair among night shift workers.MethodsWe conducted a parallel-arm randomised placebo-controlled trial of melatonin supplementation among 40 night shift workers. Supplements were consumed before engaging in day sleep over a 4-week period. All urine excreted during a representative day sleep and night work period before and during the intervention period was collected for measurement of creatinine-adjusted 8-hydroxy-2′-deoxyguanosine (8-OH-dG) as an indicator of oxidative DNA damage repair capacity, with higher concentrations indicating better repair. Linear regression models were used to analyse the association between ln-transformed 8-OH-dG concentration and intervention status during day sleep and night work.ResultsThe melatonin intervention was associated with a borderline statistically significant 1.8-fold increase in urinary 8-OH-dG excretion during day sleep (95% CI 1.0, 3.2, p=0.06). No statistically significant difference in 8-OH-dG excretion was observed during the subsequent night shift (melatonin vs placebo excretion ratio=0.9; 95% CI 0.6, 1.5; p=0.7).ConclusionsOur results suggest that melatonin supplementation improves oxidative DNA damage repair capacity among night shift workers. Future larger-scale trials are needed to evaluate the impact of varying doses of melatonin supplements and examine the impacts of longer-term use of melatonin supplements by night shift workers.

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.

To evaluate the effect of melatonin supplementation on sleep quality and pelvic pain in infertile women with endometriosis and sleep disturbances. A randomized, triple-blind, placebo-controlled trial was conducted among 80 infertile women with endometriosis and sleep disturbances. Participants were randomly assigned to receive either 5 mg melatonin or placebo for 2 months. The primary outcome was change in overall sleep quality as measured by the Pittsburgh Sleep Quality Index (PSQI). Secondary outcomes included changes in specific PSQI domains and chronic pelvic pain. Among 80 infertile women with endometriosis and sleep disturbances, melatonin significantly improved overall sleep quality compared to placebo, with a large effect size (p < 0.001, η² = 0.20, Cohen's d=1). The mean difference in sleep quality was a reduction of -1.7 on the PSQI, although it did not reach the clinically meaningful threshold of 3 points. Melatonin also led to considerable improvements in specific PSQI domains including: a substantial increase in sleep duration and a marked reduction in sleep disturbances. Furthermore, melatonin significantly decreased sleep latency, exhibiting a large effect size, and contributed to a medium reduction in the use of sleep medications. However, no significant improvements were noted in sleep efficiency, daytime dysfunction, or subjective sleep quality. Additionally, melatonin significantly reduced chronic pelvic pain, with a large effect size (p < 0.001, η² = 0.18, Cohen's d = 0.93). While melatonin may improve sleep quality and reduce pelvic pain, further investigation is needed to assess its clinical relevance in this population. ClinicalTrials.gov IRCT20171209037794N4.

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.

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).