Melatonin
A hormone regulating circadian rhythm; widely studied for sleep onset.
Melatonin reduces sleep onset latency by approximately 7 minutes in adults with primary sleep disorders
A comprehensive meta-analysis of 19 RCTs (1,683 participants) found melatonin reduces sleep latency by ~7 minutes and increases total sleep time by ~8 minutes. Effects are more pronounced in older adults and those with circadian rhythm disruptions.
Low-dose melatonin (0.5mg) effectively shifts circadian rhythm for jet lag, shift work, and delayed sleep phase syndrome
Melatonin is the most potent chronobiotic available. Administered 5 hours before dim-light melatonin onset (DLMO), even low doses (0.5mg) produce a 1-2 hour phase advance. This makes it effective for jet lag, shift work adaptation, and delayed sleep phase syndrome. Timing is more critical than dose.
Cannabinoids reduce insomnia severity and improve sleep quality in adults with insomnia or poor sleep quality
This meta-analysis of 10 RCTs (2134 participants) found that cannabinoids significantly reduced insomnia severity (MD -3.73, 95% CI -5.04 to -2.42) and improved sleep quality (MD -3.94, 95% CI -5.47 to -2.40). Total sleep time increased by 33.99 minutes and sleep efficiency improved by 4.31%, with modest reductions in sleep onset latency. Adverse events were more frequent with cannabinoids (RR 3.96) but mostly mild and no serious harms were observed.
Melatonin provides modest pain relief in chronic musculoskeletal pain but effects are comparable to conventional analgesics and often below minimal clinically important difference thresholds
In a systematic review of 23 RCTs (2028 participants), melatonin was not superior to placebo for chronic MSK pain (MD: -6.76/100, 95% CI: -15.89 to 2.36) but was superior to active controls (MD: -11.21/100, 95% CI: -14.29 to -8.13). Sensitivity analysis limited to low-risk studies showed superiority over placebo (MD: -10.04, 95% CI: -17.68 to -2.39). Sleep quality improved in chronic MSK pain but not postoperative pain, and adverse events were mild and transient.
Melatonin improves sleep quality in chronic non-cancer pain patients without increasing adverse events
Moderate-certainty evidence from a network meta-analysis of 98 RCTs (28,920 participants) showed that melatonin significantly improved subjective sleep quality compared to placebo (SMD = -0.60, 95%CI: -0.98, -0.22). Unlike other pharmacological agents, melatonin was not associated with an increased risk of adverse events (OR = 0.88, 95%CI: 0.19, 3.94).
Melatonin is not superior to placebo for reducing pain in chronic musculoskeletal pain but may provide modest benefits as an adjunct treatment
In a systematic review and meta-analysis of 23 studies (2028 participants), melatonin was not superior to placebo for reducing pain in chronic musculoskeletal pain (MD: -6.76/100, 95% CI: -15.89 to 2.36), but sensitivity analysis excluding high-risk studies showed a significant effect (MD: -10.04/100, 95% CI: -17.68 to -2.39). Melatonin improved sleep quality in chronic MSK pain but not in postoperative pain, and adverse events were mild and transient.
Hypoxia exposure does not produce a statistically significant circadian phase advance in healthy adults
This exploratory crossover study compared the effects of normobaric hypoxia (12% inspired oxygen for 2 hours) with luminotherapy plus melatonin on circadian phase shifting in healthy adults. The hypoxia condition produced an average phase advance of approximately 35 minutes, which was not statistically significant, while the light and melatonin condition produced a significant phase advance of about 78 minutes. The findings do not support hypoxia as an effective intervention for circadian resynchronization.
Melatonin adjunctive to stable pharmacotherapy improves parent-reported sleep disturbances and Stroop Color-Word Test performance in pediatric ADHD over 6 weeks, though causal attribution is limited by the open-label single-arm design.
In 32 children and adolescents with ADHD and comorbid sleep disturbances on stable methylphenidate or atomoxetine, adjunctive melatonin (3-5 mg/day) for 6 weeks reduced Children's Sleep Habits Questionnaire (CSHQ) total scores from 50.25 ± 3.60 to 34.31 ± 2.69 (F=506.238, p < .001, partial η²=0.942). Stroop Color-Word Test scores showed large observed changes (d=1.12-1.19, all p < .001), but practice effects cannot be excluded without a control group.
Melatonin modestly improves sleep latency and duration in children with cerebral palsy compared with placebo
In a systematic review of 12 randomized controlled trials, melatonin was the only intervention showing modest improvement in sleep latency and duration compared with placebo in children with cerebral palsy. Other pharmacological and non-pharmacological interventions showed inconsistent or negligible effects. The overall certainty of evidence was low.
Clonazepam and melatonin remain principal treatments for RBD in synucleinopathies, but evidence is limited and inconsistent, with clonazepam raising safety concerns and melatonin showing inconsistent efficacy.
A systematic review of 18 studies evaluated pharmacological treatments for vPSG-confirmed RBD in synucleinopathies. Clonazepam showed possible benefit but raised safety concerns, while melatonin was better tolerated but had inconsistent efficacy. Evidence for other agents was preliminary, and larger randomized trials are needed.
Melatonin doses ≤5 mg/day for at least four weeks reduce body weight in humans
This review found that sleep deprivation lowers melatonin levels, which impairs insulin sensitivity via IRS/PI3K/AKT and cAMP/PKA/CREB pathways. Intervention studies using melatonin doses of ≤5 mg/day for at least four weeks showed potential for reducing body weight in humans, though findings on appetite-regulating neuropeptides were mixed.
Melatonin impairs glucose tolerance and first-phase insulin secretion in MTNR1B diabetes risk variant carriers
In a randomized, double-blind, placebo-controlled crossover trial, 5 mg oral melatonin worsened glucose tolerance (11.7% increase) and reduced early C-peptide responses (19.2% decrease) in MTNR1B G-allele risk carriers, but not in noncarriers. The impairments were driven by a 40% suppression of glucose-stimulated first-phase β-cell responsivity and dysregulated insulin negative feedback.
Ashwagandha root extract and melatonin combination therapy improves sleep quality in adults with sleep disturbances
In a randomized, double-blind, placebo-controlled trial of 200 adults aged 18-50 years, an 8-week combination of Ashwagandha root extract (600 mg/day) and melatonin (3 mg/day) significantly reduced sleep onset latency (SOL) and improved total sleep time (TST), wake after sleep onset (WASO), and sleep efficiency (SE) compared to placebo (all p < 0.0001). Monotherapy with either Ashwagandha or melatonin produced moderate but comparable benefits.
Melatonin is more effective than olanzapine in improving sleep quality in cancer patients with insomnia, with a superior adverse effect profile.
In a prospective, double-blind, randomized trial of 60 advanced cancer patients with insomnia, both oral melatonin (3 mg/day) and oral olanzapine (5 mg/day) significantly improved sleep parameters over four weeks (p < 0.001). Melatonin showed statistically significant superiority over olanzapine in PSQI scores at week four and overall AIS scores across all time points, and had a more favorable adverse effect profile (olanzapine was associated with somnolence, akathisia, and weight gain).
Adjunctive melatonin or digital cognitive behavioural therapy for insomnia (dCBT-I) may be more effective than pill placebo at reducing depressive symptoms in young adults with mood disorders
The MELODY trial is a phase 3 randomised controlled trial testing whether 12 weeks of adjunctive melatonin or dCBT-I are more effective than pill placebo at reducing depressive symptoms in 660 young people aged 18-30 years with major depressive disorder or bipolar II disorder and significant sleep complaints. The primary outcome is depressive symptoms at week 12, measured by the Quick Inventory of Depressive Symptomatology, Adolescent version. This is a study protocol, so no results are reported yet.
Almond consumption improves subjective sleep quality in adults with poor sleep
In a 5-month randomized controlled trial, adults with poor sleep quality who consumed whole almonds showed significantly greater improvements in subjective sleep efficiency compared to controls (mean change 9.7 vs. 5.4, p=0.021). The almond group also had lower global PSQI scores (3.94 vs. 4.79, p=0.013), higher subjective sleep efficiency (94.45% vs. 91.85%, p=0.012), and shorter subjective sleep latency (18.46 vs. 26.29 min, p=0.016) after adjustment. Endline melatonin concentrations were significantly higher in the almond group (250.63 vs. 206.19 pg/mL, p=0.050).
Ashwagandha root extract combined with melatonin improves sleep quality in adults with sleep disturbances.
In an 8-week RCT, 200 adults aged 18-50 with sleep disturbances received ARE (300 mg twice daily), MLT (3 mg/day), their combination, or placebo. The combination group showed the greatest reduction in sleep onset latency (p < 0.0001) and significant improvements in total sleep time, wake after sleep onset, and sleep efficiency (all p < 0.0001).
Delayed estimated circadian phase is associated with greater restless legs syndrome symptom severity
In an exploratory pilot study of 21 patients with idiopathic RLS and 21 matched insomnia controls, patients with RLS showed a non-significant trend toward delayed estimated dim light melatonin onset (eDLMO) compared to controls (10:01 PM vs 9:33 PM, p=0.069, d=0.58). Within the RLS group, later eDLMO was modestly associated with higher RLS symptom severity scores (β=0.0726, p=0.038) after adjusting for age and depressive symptoms.
Regular kangaroo care improves sleep-wake cycle regulation and physiological stability in premature infants
In a randomized controlled trial of 36 premature infants, regular kangaroo care (KC) for three consecutive days (twice daily, 60 minutes per session) significantly improved Bispectral Index (BIS) values, heart rate, respiratory rate, oxygen saturation, and body temperature compared to control. No significant effects were observed on infant body weight or maternal breast milk cortisol and melatonin levels.
An exercise oncology program improves sleep quality in head and neck cancer patients undergoing chemo-radiation therapy
A randomized controlled trial of 70 head and neck cancer patients found that a 7-week exercise oncology program (15-20 minutes of brisk walking and resistance training) significantly improved Pittsburgh Sleep Quality Index scores from 13.97 to 7.09, while the control group's scores worsened from 13.06 to 14.14 (both p < 0.001). Urinary melatonin levels increased in the exercise group but the between-group difference was not significant after adjusting for baseline values (p = 0.372).
Tart cherry juice may improve sleep quantity and quality in older adults with self-reported insomnia
This protocol describes a randomized, double-blind, placebo-controlled, cross-over pilot study testing 16 oz. of tart cherry juice daily for 4 weeks in 20 older adults with self-reported insomnia. The study aims to evaluate feasibility and collect preliminary data on sleep quantity/quality and biomarkers related to melatonin, cortisol, serotonin, and inflammation.
Short-term intake of Montmorency tart cherry juice improves sleep quality in elite female field hockey players after intermittent exhaustion exercise
A randomized controlled trial with 19 elite female field hockey players found that short-term consumption of tart cherry juice over 48 hours significantly improved sleep quality variables, including total time in bed (TTB, p=0.015), wake after sleep onset (WASO, p=0.044), and movement index (MI, p=0.031), compared to a placebo. However, no significant changes were observed in melatonin or cortisol levels.
Melatonin improves sleep quality in patients with primary breast cancer undergoing adjuvant chemotherapy
In a randomized, double-blind, placebo-controlled trial, 40 patients with stage I-III breast cancer receiving adjuvant chemotherapy were given 6 mg/day melatonin for 6 months. Melatonin significantly improved sleep latency (from 1.50 to 1.00, P=0.001), sleep efficiency (from 1.11 to 0.56, P=0.003), and total PSQI scores (from 8.39 to 6.50, P=0.003) compared to placebo across the three phases of chemotherapy. No significant differences were observed during the Adriamycin phase, but during the Taxol phase, melatonin showed significant improvement in anxiety (P=0.077) and overall PSQI scores (P=0.015).
Dexmedetomidine-flurbiprofen axetil-based opioid-free analgesia improves postoperative sleep quality and attenuates melatonin suppression after thyroidectomy
In a randomized controlled trial of 96 patients undergoing thyroidectomy, an opioid-free PCIA regimen (dexmedetomidine, flurbiprofen axetil, ondansetron) significantly improved sleep quality (RCSQ scores, P<0.001) and preserved nocturnal melatonin secretion (urinary 6-SMT, P<0.001) compared to opioid-based PCIA (sufentanil, ondansetron). The opioid-free group also showed shorter sleep latency, fewer nocturnal awakenings, longer total sleep time, lower anxiety, and reduced opioid-related adverse events.
Tart cherry juice may increase sleep quantity in older adults with insomnia
Two small pilot studies reported that 2 weeks of daily tart cherry juice consumption (half dose morning, half at night) may increase sleep quantity in older adults with insomnia, as assessed by sleep diary or one night of polysomnography. The proposed protocol aims to test a longer duration (4 weeks) with doses closer to bedtime and daily objective monitoring via a wearable device.
Tart cherry juice consumption may increase sleep quantity in older adults with insomnia
Two preliminary pilot studies suggest that 2 weeks of daily tart cherry juice consumption (half dose morning, half at night) may increase sleep quantity in older adults with insomnia, as assessed by sleep diary or one night of polysomnography. The proposed protocol aims to evaluate feasibility of a longer 4-week intervention with doses closer to bedtime and daily objective sleep monitoring via wearable devices.
High-dose melatonin (30 mg/day) is safe and feasible but does not accelerate early biochemical or radiographic bone healing after tibial fracture fixation within 49 days
In a prospective controlled study, 25 adults with closed tibial shaft fractures received either 30 mg/day melatonin for 49 days post-surgery or standard care. Both groups showed significant increases in ALP and RUST scores over time, but no significant between-group differences were found for ALP (p=0.324) or RUST (p=0.261). The intervention was well tolerated with high adherence (91.7%) and no serious adverse events.
Sleep medication use during ICU stay is strongly associated with continued prescription at hospital discharge in critically ill patients in Japan
Among 1,595,351 ICU patients, 30.8% received sleep medications during their ICU stay. Sleep medication use during ICU stay was strongly associated with sleep medication prescription at hospital discharge (odds ratio: 6.90; 95% CI: 6.59-7.23), with 47.0% of users versus 11.3% of nonusers receiving prescriptions at discharge.
Initiating novel hypnotics in BZRA users reduces BZRA use, but success declines with longer prior BZRA use
In a retrospective cohort study of 190 patients on BZRA hypnotics who initiated novel hypnotics, 46% achieved BZRA reduction at 1 year. Success rates were significantly higher in patients with less than 1 year of prior BZRA use (69%) compared to those with 1 year or more (36%).
Evening chronotype is associated with greater social jetlag and higher obsessive-compulsive symptom scores in healthy adults.
In a cross-sectional study of 95 healthy adults, evening chronotypes had significantly longer social jetlag than morning or intermediate types (F=16.70, p<.001). Evening chronotype was also linked to higher obsessive-compulsive symptom scores (p=.027), though overall psychiatric distress did not differ across chronotypes.
The COVID-19 pandemic was associated with a marked increase in central precocious puberty (CPP), particularly among girls, with higher odds during pandemic than pre-pandemic periods.
Pooled estimates show higher odds of central precocious puberty (CPP) during the COVID-19 pandemic compared to pre-pandemic periods, especially in girls. The evidence supports a reproducible epidemiological signal but does not establish a single causal mechanism.
Circadian rhythm sleep disorder is associated with an increased risk of open-angle glaucoma, and melatonin use may reduce this risk.
In a retrospective cohort study of 24,730 matched pairs, patients with circadian rhythm sleep disorder had a significantly higher risk of open-angle glaucoma at 5 years (0.27% vs. 0.08%; aHR 2.88, 95% CI 1.78-4.66). Among melatonin users, the risk was not significantly different from controls, suggesting a potential protective effect of melatonin.
Blue-blocking glasses do not provide clinically meaningful improvements in sleep-related outcomes
This narrative review found that blue-filtering lenses show small and inconsistent effects on sleep-related outcomes. Under typical viewing conditions, screen light exposure remains well below levels associated with photochemical retinal damage in experimental models. The review concludes that current evidence does not support the routine preventive or therapeutic use of blue-blocking glasses.
Circadian rhythm sleep disorder increases risk of open-angle glaucoma, but melatonin use may reduce this risk
In a retrospective cohort study of 24,730 matched pairs, patients with circadian rhythm sleep disorder (CRSD) had a significantly higher risk of open-angle glaucoma (OAG) at 1 year (0.14% vs. 0.04%; aHR 2.67), 3 years (0.25% vs. 0.07%; aHR 3.02), and 5 years (0.27% vs. 0.08%; aHR 2.88). Among CRSD patients using melatonin, the risk of OAG was not significantly different from controls, suggesting a potential protective effect of melatonin.
Long-term melatonin therapy (≥1 year) is associated with increased risk of new onset heart failure, heart failure requiring hospitalization, and all-cause mortality in adult insomnia patients
A single unpublished conference abstract reported a statistically significant increased risk of new onset heart failure, heart failure requiring hospitalization, and all-cause mortality associated with long-term melatonin therapy (one year or longer) in adult patients with insomnia. This observation has not undergone peer review or independent validation and is considered hypothesis-generating.
Sleep disorders precede and increase the risk of sepsis-associated delirium, with melatonin dysregulation mediating this relationship
In a prospective cohort of 99 ICU patients with sepsis, sleep disorders preceded SAD onset with a duration-dependent effect and were associated with a 1.45-7.69-fold higher risk of delirium across multiple analyses. Lower melatonin concentrations correlated with worse multidimensional sleep impairment, and mediation analysis showed that melatonin reduction occurring alongside sleep disturbances was associated with SAD development (ACME = -0.110, P = 0.024).
Blue-filtering lenses do not provide clinically meaningful improvements in sleep-related outcomes
The review found that blue-filtering lenses show small and inconsistent effects on sleep-related outcomes. Current evidence does not support the routine use of blue-blocking glasses for sleep improvement.
Pediatric hypnotic prescribing in Japan increased over the past decade, with a significant acceleration after the April 2020 COVID-19 state of emergency.
The proportion of children and adolescents prescribed hypnotics in Japan rose from 0.4% in 2014 to 1.0% in 2023. Interrupted time-series analysis showed a significant post-emergency slope increase of 3.64 prescriptions per 100,000 population per month (95% CI, 2.69 to 4.58; P < 0.001), though pre-existing trends were already evident.
Melatonin amplitude is positively associated with sleep efficiency in Arctic residents
In 15 Arctic residents, melatonin amplitude showed a significant positive association with sleep efficiency (β = 0.317, p < 0.037, η² = 0.10) after adjusting for photoperiod, while melatonin phase parameters (acrophase or DLMO) had no significant relationship. No seasonal variations in sleep efficiency were observed across winter solstice, spring equinox, and summer solstice.
Morning melatonin profiles are highly variable in preschool-aged children, limiting the reliable calculation of dim-light melatonin offset (DLMOff).
In a study of 20 healthy preschoolers (mean age 4.31 years, 45% female), evening melatonin profiles consistently allowed calculation of DLMO in all participants, but morning melatonin levels were highly variable, enabling DLMOff calculation in only 8 participants. Among those 8, later DLMOff was strongly associated with later chronotype (r=0.81), sleep offset (r=0.84), and midsleep (r=0.80).
Outpatient melatonin use is associated with a small reduction in REM sleep percentage in children
In a propensity score-matched cross-sectional study of 684 children, melatonin users had a lower median percentage of REM sleep than nonusers (16.7% vs 19.0%, Hedges g = -0.22, FDR-corrected P = .003). No significant differences were found in total sleep time, non-REM sleep stages, respiratory indices, arousal index, periodic limb movements, or oxygen desaturation index.
Melatonin (1 mg/day) improves sleep quality and reduces overeating and weight gain in an obese school-aged boy with prenatal diabetes exposure
An 11-year-old boy with obesity born to a mother with type 2 diabetes and severe sleep disturbances was treated with 1 mg/day melatonin. After treatment, parental reports indicated marked improvements in sleep posture and nighttime awakenings, along with reduced overeating episodes and gradual weight reduction, without adverse events. The case suggests melatonin may be a useful adjunct in managing pediatric obesity by optimizing sleep behavior.
Melatonin supplementation improves sleep in older adults
Melatonin supplementation has moderate evidence for improving sleep in older adults. The evidence is based on a critical analysis review of sleep research in the context of healthy aging.
Exogenous melatonin enhances GABA activity, promoting non-REM sleep and reducing stress-related hyperarousal.
This scoping review of 58 studies found that exogenous melatonin enhances GABAergic activity through different mechanisms, promoting non-REM sleep and reducing stress-related hyperarousal. The review identified 20 studies on the GABAergic system supporting this effect.
Melatonin supplementation improves sleep quality in individuals with sleep disturbances
The narrative review summarizes evidence that melatonin, a key regulator of circadian rhythms, can act as a subsidiary sleep aid when used alongside good sleep hygiene practices. The paper highlights melatonin's role in promoting restful sleep, though specific effect sizes are not provided in the abstract.
The article 'Melatonin and Cortisol Concentration Before and After CPAP Treatment of Obstructive Sleep Apnea' has been retracted.
This paper is a retraction notice for the original article DOI: 10.2147/NSS.S553499. No new findings are presented; the retraction indicates that the original study's results are no longer considered valid.
Repurposed drugs targeting multiple pathophysiological mechanisms may improve therapeutic outcomes in fibromyalgia.
This review discusses repurposed drugs for fibromyalgia, including NMDA receptor antagonists, neurokinin-1 receptor antagonists, GABA system drugs, antiepileptics, antidepressants, opioids, cannabinoids, dopamine receptor agonists, melatonin receptor agonists, and antidiabetics. It emphasizes a multi-target strategy addressing neurochemical alterations, central sensitization, neuroinflammation, oxidative stress, mitochondrial dysfunction, gut microbiota disturbances, and autoimmunity.
Acute sleep deprivation disrupts the tryptophan-serotonin-melatonin axis, with effects differing by mood response, and these changes may influence cognitive outcomes after sleep loss.
In 80 healthy adults, a single night of sleep deprivation significantly decreased tryptophan and melatonin levels overall. Non-responders (based on mood change) showed increased serotonin and decreased melatonin, while responders showed different patterns; changes in serotonin and melatonin correlated with cognitive test performance.
Community pharmacists in Saudi Arabia frequently recommend OTC melatonin for insomnia but provide brief consultations, incomplete history taking, limited safety counseling, and rare non-pharmacological advice.
In a cross-sectional study using 251 simulated patient visits across Saudi Arabia, community pharmacists recommended OTC melatonin in 64.5% of cases, but consultations lasted only a median of 1.5 minutes. History taking was incomplete (e.g., sleep patterns inquired in 55.4%, triggers in 51%), safety information was provided in only 4.9% of visits, and non-pharmacological advice was given in just 9.6%.
Melatonin affects sleep outcomes in research
Prescription patterns of sleep medications for critically ill patients: A nationwide retrospective observational cohort study in Japan.. Published in Australian critical care : official journal of the Confederation of Australian Critical Care Nurses (2026). PMID: 42492347.
Oral lichen planus is associated with lower salivary melatonin levels and poorer sleep quality
OLP patients had significantly lower salivary melatonin levels (p=0.015) and higher scores in the sleep disturbances component of the PSQI (p=0.021) compared to controls. Salivary cortisol levels did not differ between groups (p=0.402).
Diagnostic labels alone provide limited guidance for assessment or treatment of sleep disorders in children with neurodevelopmental disorders; a diagnosis-informed, phenotype-directed framework is proposed.
The paper reviews evidence that sleep disorders are highly prevalent in children with neurodevelopmental disorders (NDDs) and that diagnostic labels are insufficient for guiding care. It proposes a framework that integrates diagnosis-informed risk recognition with phenotype-directed assessment, focusing on sleep phenotypes such as insomnia, circadian dysregulation, sleep-disordered breathing, movement disorders, hypersomnolence, and parasomnias. Melatonin has the strongest pharmacological evidence, particularly for insomnia in ASD and selected neurogenetic conditions.
Gestational diabetes mellitus is associated with higher urinary 6-sulfatoxymelatonin and serum TNF-α levels despite increased consumption of tryptophan-rich foods
In a cross-sectional study of 34 women with GDM and 18 with normal-risk pregnancies, those with GDM reported higher consumption of tryptophan-rich foods (especially milk/dairy and fruits) yet had significantly higher urinary 6-sulfatoxymelatonin (p=0.002) and serum TNF-α levels (p=0.023). Multivariable models confirmed GDM remained associated with higher melatonin metabolite levels, while TNF-α was linked to maternal characteristics and interactions.
A phenotype-guided pharmacologic management framework may be clinically useful for postoperative sleep disturbance after breast cancer surgery, but it remains conceptual and has not been prospectively validated.
This narrative review proposes a phenotype-guided approach to managing postoperative sleep disturbance (PSD) in breast cancer patients, where treatment selection is based on symptom presentation: short-course hypnotics for acute insomnia with hyperarousal, melatonin receptor agonists for circadian disruption, and gabapentinoids or multimodal analgesia for pain-dominant presentations. The framework is conceptual and lacks prospective validation in postoperative breast cancer populations.
Community pharmacists in Saudi Arabia provide brief consultations and frequently recommend OTC melatonin for insomnia, but often fail to provide safety counseling or non-pharmacological advice.
In a cross-sectional study using simulated patient visits across Saudi Arabia, 251 pharmacy consultations were observed. The median consultation duration was only 1.5 minutes, 64.5% of pharmacists recommended melatonin, but safety information was provided in only 4.9% of visits and non-pharmacological advice in 9.6%.
Sleep disturbance is consistently associated with elevated C-reactive protein and interleukin-6 in insomnia disorder
The abstract reports that sleep disturbance in insomnia disorder is more consistently associated with selected inflammatory markers, particularly C-reactive protein (CRP) and interleukin-6 (IL-6), while findings for tumor necrosis factor-alpha (TNF-α) remain less consistent. This suggests a link between insomnia and low-grade inflammation, which may contribute to the chronicity and multisystem associations of the disorder.
Evening chronotype is more frequent in children and adolescents with OCD and is associated with lower symptom severity
In a case-control study of 29 children/adolescents with OCD and 30 matched controls, evening chronotype was significantly more common in the OCD group (p<0.05). Within the OCD group, those with evening chronotype had significantly lower CY-BOCS scores (p<0.05) and higher morning salivary melatonin levels (p<0.05), while cortisol did not differ.
Sighted non-24-hour sleep-wake disorder is a heterogeneous condition caused by distinct dysfunctions in the circadian photic entrainment pathway
This multimodal phenotyping of two sighted N24SWD patients revealed two distinct pathophysiological mechanisms: one patient had preserved melanopsin function but absent light-induced melatonin suppression and a markedly prolonged intrinsic period (~25 h), while the other had impaired melanopsin response (reduced PIPR) but retained melatonin suppression and a period within the upper physiological range (24.20 h). These findings indicate that N24SWD in sighted individuals is not a unitary disorder but results from dysfunction at different levels of the circadian photic entrainment pathway.
Melatonin is widely used and generally perceived as a safe and effective sleep aid, though notable variations in dosing, reliance, and misuse exist across demographic groups.
In a cross-sectional study of 335 adults in Baghdad, Iraq, 83.8% of participants agreed that melatonin improved their sleep quality, 78.2% considered it safe, and 75.6% recommended it to others. The most common dose was 5 mg (33.6%), and 56.5% used melatonin as needed. Side effects were common, with drowsiness (28.8%) and headache (25.1%) reported, and only 1.5% had no side effects.
Melatonin alleviates polycystic ovary syndrome, premature ovarian insufficiency, ovarian injury, and age-related ovarian function decline
This review establishes an integrated mechanistic model in which oxidative stress, mitochondrial dysfunction, inflammatory responses, and autophagic imbalance contribute to ovarian disorders, while melatonin acts as a pleiotropic regulator counteracting these pathways. The paper reports that melatonin alleviates PCOS, POI, ovarian injury, and age-related ovarian function decline, but no specific effect sizes or sample sizes are provided.
Home-based, self-collected salivary dim light melatonin onset (DLMO) assessment can classify circadian phase profiles into distinct endotypes in a real-world clinical population.
In two studies totaling 553 patients, a pragmatic home-based DLMO protocol identified six profile types: within predicted onset window, delayed, advanced, hypermelatoninemia, hypomelatoninemia, and irregular/multipeak. Among 159 patients with atypical profiles who self-reported symptoms, 94.3% showed concordance between their circadian profile and at least one presenting complaint.
Tart cherry consumption improves sleep quality and increases melatonin levels in adults with sleep disorders
A systematic review of seven interventional studies found that tart cherry consumption significantly improved sleep indicators such as sleep duration, sleep efficiency, or sleep onset time in three studies, and increased melatonin levels in three studies. Two studies also reported decreases in inflammatory markers like CRP and MDA. However, the evidence is limited and heterogeneous due to variations in dose, duration, and population characteristics.
Clinicians managing pediatric HSCT inpatients estimate 58% develop sleep issues, and they most commonly implement patient-level interventions like melatonin despite rating external factors like noise as most impactful.
A survey of 111 pediatric HSCT clinicians (prescribers, nurses, psychosocial staff) across the US found they estimate 58% of inpatients develop sleep issues. Although clinicians rated external factors (e.g., noise) as most impactful, they were most likely to implement patient-level interventions such as melatonin. The study highlights the lack of clinical guidelines and the need for research on treatment efficacy and systems-level changes.
Melatonin administration at around 6 PM (1-2 hours before bedtime) optimizes sleep cycle regulation and reduces bedtime resistance in elderly patients
The paper recommends administering melatonin 1-2 hours before bedtime (around 6 PM) to regulate sleep cycles and improve bedtime compliance in elderly patients. This timing is proposed as the standard of care in hospitals, nursing homes, and at home for managing insomnia and circadian rhythm disruption.
Nightly melatonin supplementation improves sleep quality and selected oxidative or circadian surrogate endpoints in hemodialysis patients, but its effect on slowing CKD progression or preserving renal function remains unproven.
Current clinical studies suggest that nightly melatonin supplementation can improve sleep quality and certain oxidative or circadian surrogate markers in hemodialysis patients. However, whether melatonin slows chronic kidney disease progression or preserves renal function has not been established.
Sleep dysfunction is common and clinically meaningful in patients with chronic spontaneous urticaria (CSU), supporting routine sleep assessment.
Patients with CSU consistently report worse global sleep quality, shorter sleep duration, longer sleep latency, and greater insomnia severity compared to controls. Poor sleep is associated with higher disease activity (UAS7), lower disease control (UCT), and worse quality of life, along with co-occurring anxiety, depression, fatigue, and headache.
Melatonin-rich foods improve sleep quality, duration, and efficiency in individuals with sleep disturbances
A scoping review of 19 articles (14 interventional trials and 5 cross-sectional studies) found that consuming melatonin-rich foods such as Montmorency tart cherries, Jerte Valley cherries, tomatoes, and kiwifruit may improve sleep quality, duration, and efficiency, particularly in individuals with sleep disturbances. Findings were heterogeneous across studies.
The OPN4 I394T variant (C allele) is associated with altered non-image-forming physiology in young adults, including phase-delayed rhythms, reduced rhythm robustness, and lower nocturnal melatonin levels.
In 25 healthy young adults, carriers of the I394T-C allele showed a phase delay in habitual sleep and wrist temperature rhythms, reduced wrist temperature amplitude, greater internal desynchronization, and lower nocturnal melatonin concentrations under dim light compared to the TT group. Circadian phase (DLMO) remained preserved, leading to an increased phase angle of entrainment, and on free days they showed greater melatonin suppression despite similar light exposure.
Exogenous melatonin exhibits both therapeutic benefits and potential toxicological concerns, particularly in specific populations
This review explores melatonin's dual role as a therapeutic agent for conditions like insomnia and gastrointestinal disorders, while highlighting emerging toxicological concerns. The paper emphasizes the need for further studies to balance therapeutic benefits with safety, especially in susceptible groups.
Circadian disruption is closely associated with Alzheimer's disease pathology and therapeutic response, supporting chronotherapeutic strategies.
This narrative review synthesizes evidence that circadian dysfunction contributes to Alzheimer's disease pathogenesis through interactions between core clock genes and neurodegenerative cascades involving oxidative stress, neuroinflammation, glial reactivity, and proteostasis. Emerging evidence suggests distinct circadian patterns in AD-relevant biomarkers, including melatonin, cortisol, orexin, core body temperature, blood-brain barrier permeability, and glial marker oscillations, which may have diagnostic and prognostic relevance.
Phenotype-supported diagnosis and combined immunotherapy improve sleep and neuromuscular symptoms in seronegative Morvan syndrome
A 63-year-old man with seronegative Morvan syndrome presenting with agrypnia excitata (2-3 h/night sleep, ISI 24/28) and peripheral nerve hyperexcitability was treated with combined immunotherapy (intravenous methylprednisolone, prednisone taper, azathioprine) and symptomatic therapy (carbamazepine, melatonin). At 6 months, sleep restored to 7-8 h/night, ISI decreased from 24 to 4, MRC sum score improved from 48 to 58/60, and CK dropped from 928 to 185 U/L.
Heat stress disrupts sleep in older adults by prolonging sleep onset, fragmenting slow-wave and REM sleep, and suppressing melatonin secretion.
This narrative review synthesizes evidence that elevated nighttime temperatures disrupt sleep in older adults through multiple mechanisms, including prolonged sleep onset, fragmentation of slow-wave and REM sleep, and suppression of melatonin secretion. Age-related declines in thermoregulatory capacity, such as reduced sweating and impaired vasodilation, exacerbate these effects. The review notes that sex-related differences, particularly menopause-associated vasomotor instability in women and testosterone-related autonomic changes in men, further modulate individual vulnerability.
Melatonin should be approached as a pharmacological intervention requiring diagnostic rigor, individualized dosing, and longitudinal assessment, particularly when integrated with behavioral and circadian interventions.
The paper argues that melatonin's clinical use is often undermined by diagnostic imprecision, inappropriate dosing, mistimed administration, inconsistent formulations, and inadequate patient counseling. It emphasizes that melatonin acts primarily as a chronobiotic whose effects depend more on timing than dose, and that supraphysiological doses and reflexive bedtime administration have become normalized despite evidence to the contrary.
Perioperative circadian rhythm disruption is associated with adverse outcomes following skull base surgery
This prospective cohort study of 82 patients undergoing skull base tumor resection found significant perioperative disruption of circadian rhythms, marked by suppressed melatonin and elevated cortisol, which was associated with higher complication rates and longer hospital stays. Patients with the highest circadian disruption had significantly more overall complications (73.9% vs. 39.0%, p=0.042) and longer hospital stay (8.0 vs. 7.9 days, p=0.018).
Circadian misalignment and reduced rest-activity amplitude are candidate phenotypes in insomnia disorder, warranting phenotype-stratified trials of circadian interventions.
This narrative review proposes that some insomnia patients have circadian misalignment, reduced rest-activity amplitude, increased sleep-timing variability, or abnormal light exposure, which may require circadian-targeted adjunctive treatments. It suggests a phenotyping framework combining sleep diaries, actigraphy, light exposure, DLMO, and core body temperature to distinguish CRSWD-dominant insomnia, insomnia with circadian modifiers, and comorbid insomnia and CRSWD. CBT-I remains first-line, with fixed wake time, morning light, evening light restriction, timed low-dose melatonin, and scheduled activity as candidate adjunctive modules for future phenotype-stratified trials.
Zolpidem is associated with a high likelihood of neuropsychiatric adverse effects, including hallucinations, complex sleep-related behaviors, and amnesia, particularly in women, the elderly, psychiatric patients, and those on polypharmacy.
This narrative review found that zolpidem is commonly linked to serious neuropsychiatric adverse effects such as hallucinations, perceptual disturbances, and complex sleep behaviors (e.g., sleep-driving, sleep-eating), especially at high doses and in patients with psychiatric comorbidities. These events can lead to severe personal injury and litigation, and are often unnoticed by the patient.
Melatonin supplementation may influence the developing sleep system in pediatric populations.
The paper reviews the role of melatonin in the developing sleep system, focusing on its effects on sleep regulation in children and adolescents. It discusses the potential benefits and risks of melatonin use in this population, though specific quantitative outcomes are not provided in the abstract.
Melatonin and its receptor agonists may help regulate circadian rhythms and improve subjective sleep quality in cardiac surgery patients, but effects on delirium, length of stay, and objective sleep architecture are inconsistent.
The review indicates that melatonin and its receptor agonists can improve subjective sleep quality and help regulate circadian rhythms in patients undergoing cardiac surgery. However, their effects on key clinical outcomes such as postoperative delirium, length of hospital stay, and objective measures of sleep architecture remain inconsistent across studies.
Salivary biomarkers such as cortisol, melatonin, alpha-amylase, chromogranin A, C-reactive protein, and immunoglobulin A offer a non-invasive method for monitoring stress, sleep quality, and disease severity in patients with atopic dermatitis.
This review highlights the potential of salivary biomarkers as non-invasive tools for monitoring stress, sleep quality, and disease severity in atopic dermatitis patients. The biomarkers include cortisol, melatonin, alpha-amylase, chromogranin A, C-reactive protein, and immunoglobulin A. The paper does not provide quantitative effect sizes or specific clinical thresholds.
Tart cherry juice promotes sleep quantity in athletes and healthy adults
The narrative review found that tart cherry juice can promote sleep quantity in athletes and healthy adults. This conclusion is based on studies that measured sleep duration and efficiency, though specific effect sizes were not reported in the abstract.
Melatonin administration at 6 PM (1-2 hours before bedtime) optimizes sleep cycle regulation and reduces bedtime resistance
The paper recommends administering melatonin around 6 PM, which is 1-2 hours before bedtime, to optimize sleep cycle regulation and help with bedtime resistance. This timing is proposed as the standard of care in hospitals, nursing homes, and at home.
Tart cherry juice and kiwifruit improve sleep outcomes in adults with sleep disturbances
The review identifies functional foods such as tart cherry juice and kiwifruit as having potential benefits for improving sleep quality. These foods are highlighted for their natural content of melatonin and anti-inflammatory compounds that support sleep regulation.
Tart cherry consumption improves sleep quality and duration in adults with sleep disorders
This systematic review of seven interventional studies found that tart cherry consumption significantly improved sleep indicators such as sleep duration, efficiency, and onset time in three studies, and increased melatonin levels in three studies. The evidence is limited and heterogeneous due to variations in dose, duration, and population characteristics.
Chronic photoperiod disruption impairs hepatic protein-synthetic function, which is fully restored by exogenous melatonin in rats
Constant light exposure for 21 days reduced albumin levels by 15.7% in male and 15.9% in female rats, and suppressed BMAL1 and CLOCK expression by over 70% while increasing PER2. Melatonin treatment (12 mg/L in drinking water) fully restored all circadian protein expression and normalized protein synthesis parameters to control levels in both sexes.
Chronic photoperiod disruption reduces hepatic protein-synthetic function (albumin) in rats, which is fully restored by exogenous melatonin.
Constant light exposure for 21 days reduced albumin levels by 15.7% in male and 15.9% in female rats, and suppressed BMAL1 and CLOCK expression by over 70% while increasing PER2 expression. Melatonin treatment (12 mg/L in drinking water) fully restored circadian protein expression and normalized protein synthetic parameters to control levels in both sexes.
Co-administration of cannabidiol and L-theanine synergistically improves sleep-related outcomes in a caffeine-induced sleep disturbance mouse model
In a mouse model of caffeine-induced sleep disturbance, combined administration of CBD and L-theanine at ratios of 1:1, 2:1, or 1:2 significantly reduced sleep onset latency and increased total sleep duration compared to single treatments. Combination index analysis indicated a synergistic interaction at lower doses, and combination treatment was associated with over 40% increases in serum serotonin and melatonin levels, as well as elevated cortical GABA levels.
AdipoRon treatment partially reverses chronic sleep restriction-induced alterations in hypothalamic clock-gene expression, oxidative stress, and SIRT1/NRF2/HO-1 signaling in male mice
In male mice subjected to 21 days of chronic sleep restriction (18h/day), AdipoRon (10 μg intranasal daily) partially reversed CSR-associated changes in clock-gene expression (Clock, Bmal1, Per1, Cry1), attenuated oxidative stress, reduced LDL and ALT levels, and increased expression of SIRT1/NRF2/HO-1 pathway proteins. CSR alone increased oxidative stress and reduced SIRT1/NRF2/HO-1 expression, while AdipoRon mitigated these effects.
Exogenous evening melatonin mitigates the disruptive effects of dim light at night on sleep and metabolism in diurnal zebra finches
In a controlled experiment, zebra finches exposed to 5-lux dim light at night (dLAN) received subcutaneous melatonin injections (10 µg/100 µl vehicle) 30 minutes before dark onset for 11 days. Melatonin-treated birds showed significantly reduced nocturnal sleep fragmentation (fewer awakenings, longer sleep bouts), decreased night-time feeding and body fattening, and restored hepatic expression of glucose and lipid metabolism genes compared to vehicle-treated controls.
Taxifolin modulates circadian protein expression comparable to melatonin in cellular models of mood disorders
Taxifolin, identified via virtual screening of ~150,000 natural compounds against the Melatonin 1 receptor (MT1), showed high binding affinity (-9.527 kcal/mol) and stable protein-ligand complexes in molecular dynamics simulations. Immunocytochemistry analysis revealed that taxifolin modulated circadian regulators CLOCK and BMAL1 expression in a manner similar to melatonin, suggesting potential as a natural neuromodulator for mood disorders.
Chloroxylenol (PCMX) impairs visual system development and induces circadian rhythm disorders with sleep/wake behavioral abnormalities in zebrafish larvae, which can be ameliorated by melatonin intervention.
Exposure to PCMX at concentrations ≥0.4 mg/L caused ocular malformations and suppressed photoreceptor development in zebrafish larvae, while higher concentrations (≥1.2 mg/L) disrupted circadian clock gene expression and led to daytime hyperactivity and insomnia-like sleep fragmentation at night. Melatonin intervention effectively alleviated the sleep/wake behavioral deficits.
Lactobacillus reuteri E9 regulates sleep disorders through its metabolite GABA by modulating inhibitory neurotransmitters and sleep-related receptor expression.
Lactobacillus reuteri E9 significantly upregulated inhibitory neurotransmitters including GABA, taurine, glycine, and serine (p < 0.05) in a PTZ-induced zebrafish model of sleep disorder. It reduced seizures and hyperactivity, and upregulated GABA receptor genes and melatonin receptor (Mtnr1aa) genes in zebrafish neural tissue.
Co-administration of cannabidiol and L-theanine improves sleep-related outcomes in a caffeine-induced sleep disturbance mouse model
In a mouse model of caffeine-induced sleep disturbance, combined administration of CBD and L-theanine at ratios of 1:1, 2:1, or 1:2 significantly reduced sleep onset latency and increased total sleep duration compared to single treatments. The combination also elevated serum serotonin and melatonin levels by more than 40% and increased cortical GABA levels relative to caffeine-treated controls.
Taxifolin modulates circadian protein expression in a manner comparable to melatonin
Taxifolin, identified via virtual screening against the melatonin 1 receptor (MT1), showed a binding affinity of -9.527 kcal/mol and formed stable protein-ligand complexes in molecular dynamics simulations. Immunocytochemistry analysis indicated that taxifolin modulated circadian regulators CLOCK and BMAL1 expression similarly to melatonin in cellular models.
Lactobacillus reuteri E9 regulates sleep disorders by upregulating inhibitory neurotransmitters and sleep-related receptor expression via the microbiota-gut-brain axis.
In a PTZ-induced zebrafish model of sleep disorder, Lactobacillus reuteri E9 significantly upregulated inhibitory neurotransmitters including GABA, taurine, glycine, and serine (p < 0.05). It also reduced seizures and hyperactivity, and upregulated GABA receptor genes and melatonin receptor (Mtnr1aa) genes in neural tissue, suggesting a psychobiotic mechanism for sleep regulation.
LMP-melatonin produces greater formulation-dependent effects than conventional melatonin on caffeine-evoked cortical electrical activity and pentobarbital-induced sedative-hypnotic responses in mice
In male BALB/c mice, a lipid-multiparticulate (LMP) melatonin formulation attenuated caffeine-induced increases in cortical spike frequency and altered ECoG amplitude more effectively than conventional melatonin, with strongest effects at 20 mg/kg. LMP-melatonin also reduced latency to and prolonged duration of pentobarbital-induced loss of righting reflex compared to conventional melatonin. However, the study did not assess pharmacokinetic exposure, physiological sleep stages, or neuroprotection.
Chloroxylenol (PCMX) at ≥0.4 mg/L induces ocular malformations and visual impairments, and at ≥1.2 mg/L disrupts circadian rhythms and sleep/wake behaviors in zebrafish larvae, with melatonin intervention alleviating sleep deficits.
Exposure to PCMX at concentrations ≥0.4 mg/L caused ocular malformations and suppressed photoreceptor development via disrupted thyroid hormone signaling in zebrafish larvae. At 2 and 2.8 mg/L, it impaired image-forming vision and visuomotor responses, while at ≥1.2 mg/L it disrupted circadian clock gene expression and induced daytime hyperactivity and insomnia-like sleep fragmentation, which were alleviated by melatonin treatment.
Melatonin treatment during REM sleep deprivation modulates oxidative stress-related parameters by increasing enzymatic antioxidant levels and reducing lipid peroxidation in rats
In a six-day REM sleep deprivation model using the modified multiple platform method, melatonin treatment increased enzymatic antioxidant levels (CAT, SOD, GPx) and reduced lipid peroxidation (MDA) in male Sprague-Dawley rats. Effects on total oxidant status were not significant, and total antioxidant status changes were limited and time-dependent. During recovery, some oxidative stress markers partially normalized, suggesting reactivation of endogenous antioxidant defenses.
Lactobacillus reuteri E9 regulates sleep disorders by modulating inhibitory neurotransmitters and sleep-related receptor expression via the microbiota-gut-brain axis.
In a PTZ-induced zebrafish model of sleep disorder, Lactobacillus reuteri E9 significantly upregulated inhibitory neurotransmitters including GABA, taurine, glycine, and serine (p < 0.05). It also reduced seizures and hyperactivity, and upregulated GABA receptor genes and melatonin receptor (Mtnr1aa) genes in neural tissue.
Higher plasma melatonin levels are associated with slightly greater objective sleep efficiency but not with subjective sleep quality in adults aged 25-65 years.
In a cross-sectional study of 334 adults (mean age 43 years), plasma melatonin levels showed no significant association with Pittsburgh Sleep Quality Index scores, but higher melatonin levels were linked to slightly greater sleep efficiency measured by actigraphy. Mean plasma melatonin concentration was 14.5 ± 15.9 pg/mL, with higher levels in men and a decreasing trend with age.
Melatonin supplementation may be associated with ventricular arrhythmia in some individuals
A 63-year-old man developed ventricular arrhythmia while taking 10 mg of exogenous melatonin daily, with complete resolution of symptoms and improvement in electrocardiographic findings after discontinuation. A systematic review identified similar arrhythmic events associated with melatonin supplementation, with symptom resolution or clinical improvement after stopping the supplement.