“Evening home lighting adversely impacts the circadian system and sleep”, (2020-11-05; ; backlinks):
The regular rise and fall of the sun resulted in the development of 24-h rhythms in virtually all organisms. In an evolutionary heartbeat, humans have taken control of their light environment with electric light. Humans are highly sensitive to light, yet most people now use light until bedtime. We evaluated the impact of modern home lighting environments in relation to sleep and individual-level light sensitivity using a new wearable spectrophotometer. We found that nearly half of homes had bright enough light to suppress melatonin by 50%, but with a wide range of individual responses (0–87% suppression for the average home). Greater evening light relative to an individual’s average was associated with increased wakefulness after bedtime. Homes with energy-efficient lights had nearly double the melanopic illuminance of homes with incandescent lighting. These findings demonstrate that home lighting substantially affects sleep and the circadian system, but the impact of lighting for a specific individual in their home is highly unpredictable.
2020-goldin.pdf: “Interplay of chronotype and school timing predicts school performance”, (2020-02-10; ; backlinks):
Most adolescents exhibit very late chronotypes and attend school early in the morning, a misalignment that can affect their health and psychological well-being. Here we examine how the interaction between the chronotype and school timing of an individual influences academic performance, studying a unique sample of 753 Argentinian students who were randomly assigned to start school in the morning (07:45), afternoon (12:40) or evening (17:20). Although chronotypes tend to align partially with class time, this effect is insufficient to fully account for the differences with school start time. We show that (1) for morning-attending students, early chronotypes perform better than late chronotypes in all school subjects, an effect that is largest for maths; (2) this effect vanishes for students who attend school in the afternoon; and (3) late chronotypes benefit from evening classes. Together, these results demonstrate that academic performance is improved when school times are better aligned with the biological rhythms of adolescents.
2014-paulsen.pdf: “Vitamin C and E supplementation hampers cellular adaptation to endurance training in humans: a double-blind, randomised, controlled trial”, (2014-03-03; ; backlinks):
- Recent studies have indicated that antioxidant supplementation may blunt adaptations to exercise, such as mitochondrial biogenesis induced by endurance training. However, studies in humans are sparse and results are conflicting.
- Isolated vitamin C and E supplements are widely used, and unravelling the interference of these vitamins in cellular and physiological adaptations to exercise is of interest to those who exercise for health purposes and to athletes.
- Our results show that vitamin C and E supplements blunted the endurance training-induced increase of mitochondrial proteins (COX4), which is important for improving muscular endurance.
- Training-induced increases in VO2max and running performance were not detectably affected by the supplementation.
- The present study contributes to understanding of how antioxidants may interfere with adaptations to exercise in humans, and the results indicate that high dosages of vitamins C and E should be used with caution.
In this double-blind, randomised, controlled trial, we investigated the effects of vitamin C and E supplementation on endurance training adaptations in humans. Fifty-four young men and women were randomly allocated to receive either 1000 mg of vitamin C and 235 mg of vitamin E or a placebo daily for 11 weeks. During supplementation, the participants completed an endurance training programme consisting of three to four sessions per week (primarily of running), divided into high-intensity interval sessions [4–6 × 4–6 min; >90% of maximal heart rate (HRmax)] and steady state continuous sessions (30–60 min; 70–90% of HRmax). Maximal oxygen uptake (VO2max), submaximal running and a 20 m shuttle run test were assessed and blood samples and muscle biopsies were collected, before and after the intervention. Participants in the vitamin C and E group increased their VO2max (mean ± s.d.: 8 ± 5%) and performance in the 20 m shuttle test (10 ± 11%) to the same degree as those in the placebo group (mean ± s.d.: 8 ± 5% and 14 ± 17%, respectively). However, the mitochondrial marker cytochrome c oxidase subunit IV (COX4) and cytosolic peroxisome proliferator-activated receptor-γ coactivator 1 α (PGC-1α) increased in the m. vastus lateralis in the placebo group by 59 ± 97% and 19 ± 51%, respectively, but not in the vitamin C and E group (COX4: −13 ± 54%; PGC-1α: −13 ± 29%; p ≤ 0.03, between groups). Furthermore, mRNA levels of CDC42 and mitogen-activated protein kinase 1 (MAPK1) in the trained muscle were lower in the vitamin C and E group than in the placebo group (p ≤ 0.05). Daily vitamin C and E supplementation attenuated increases in markers of mitochondrial biogenesis following endurance training. However, no clear interactions were detected for improvements in VO2max and running performance. Consequently, vitamin C and E supplementation hampered cellular adaptations in the exercised muscles, and although this did not translate to the performance tests applied in this study, we advocate caution when considering antioxidant supplementation combined with endurance exercise.
2014-lely.pdf: “Blue Blocker Glasses as a Countermeasure for Alerting Effects of Evening Light-Emitting Diode Screen Exposure in Male Teenagers”, Stéphanie van der Lely M. Sc., Silvia Frey, Corrado Garbazza, Anna Wirz-Justice, Oskar G. Jenni, Rol, Steiner B. Sc., Stefan Wolf, Christian Cajochen, Vivien Bromundt, Christina Schmidt Ph.D. (backlinks)
“Meta-Regression Analyses, Meta-Analyses, and Trial Sequential Analyses of the Effects of Supplementation with Beta-Carotene, Vitamin A, and Vitamin E Singly or in Different Combinations on All-Cause Mortality: Do We Have Evidence for Lack of Harm?”, (2013-08-04; backlinks):
Background and Aims: Evidence shows that antioxidant supplements may increase mortality. Our aims were to assess whether different doses of beta-carotene, vitamin A, and vitamin E affect mortality in primary and secondary prevention randomized clinical trials with low risk of bias.
Methods: The present study is based on our 2012 Cochrane systematic review analyzing beneficial and harmful effects of antioxidant supplements in adults. Using random-effects meta-analyses, meta-regression analyses, and trial sequential analyses, we examined the association between beta-carotene, vitamin A, and vitamin E, and mortality according to their daily doses and doses below and above the recommended daily allowances (RDA).
Results: We included 53 randomized trials with low risk of bias (241,883 participants, aged 18 to 103 years, 44.6% women) assessing beta-carotene, vitamin A, and vitamin E. Meta-regression analysis showed that the dose of vitamin A was statistically-significantly positively associated with all-cause mortality. Beta-carotene in a dose above 9.6 mg statistically-significantly increased mortality (relative risk (RR) 1.06, 95% confidence interval (CI) 1.02 to 1.09, I2 = 13%). Vitamin A in a dose above the RDA (> 800 µg) did not statistically-significantly influence mortality (RR 1.08, 95% CI 0.98 to 1.19, I2 = 53%). Vitamin E in a dose above the RDA (> 15 mg) statistically-significantly increased mortality (RR 1.03, 95% CI 1.00 to 1.05, I2 = 0%). Doses below the RDAs did not affect mortality, but data were sparse.
Conclusions: Beta-carotene and vitamin E in doses higher than the RDA seem to statistically-significantly increase mortality, whereas we lack information on vitamin A. Dose of vitamin A was statistically-significantly associated with increased mortality in meta-regression. We lack information on doses below the RDA.
Background: All essential compounds to stay healthy cannot be synthesized in our body. Therefore, these compounds must be taken through our diet or obtained in other ways. Oxidative stress has been suggested to cause a variety of diseases. Therefore, it is speculated that antioxidant supplements could have a potential role in preventing diseases and death. Despite the fact that a normal diet in high-income countries may provide sufficient amounts of antioxidants, more than one third of adults regularly take antioxidant supplements.
“Meta-Analysis: Melatonin for the Treatment of Primary Sleep Disorders”, (2013-04-05; backlinks):
To investigate the efficacy of melatonin compared to placebo in improving sleep parameters in patients with primary sleep disorders.
PubMed was searched for randomized, placebo-controlled trials examining the effects of melatonin for the treatment of primary sleep disorders. Primary outcomes examined were improvement in sleep latency, sleep quality and total sleep time. Meta-regression was performed to examine the influence of dose and duration of melatonin on reported efficacy.
Adults and children diagnosed with primary sleep disorders.
Melatonin compared to placebo.
Nineteen studies involving 1683 subjects were included in this meta-analysis. Melatonin demonstrated significant efficacy in reducing sleep latency (weighted mean difference (WMD) = 7.06 minutes [95% CI 4.37 to 9.75], Z = 5.15, p < 0.001) and increasing total sleep time (WMD = 8.25 minutes [95% CI 1.74 to 14.75], Z = 2.48, p = 0.013). Trials with longer duration and using higher doses of melatonin demonstrated greater effects on decreasing sleep latency and increasing total sleep time. Overall sleep quality was significantly improved in subjects taking melatonin (standardized mean difference = 0.22 [95% CI: 0.12 to 0.32], Z = 4.52, p < 0.001) compared to placebo. No statistically-significant effects of trial duration and melatonin dose were observed on sleep quality.
This meta-analysis demonstrates that melatonin decreases sleep onset latency, increases total sleep time and improves overall sleep quality. The effects of melatonin on sleep are modest but do not appear to dissipate with continued melatonin use. Although the absolute benefit of melatonin compared to placebo is smaller than other pharmacological treatments for insomnia, melatonin may have a role in the treatment of insomnia given its relatively benign side-effect profile compared to these agents.
2013-preckel.pdf: “Morningness-eveningness and educational outcomes: the lark has an advantage over the owl at high school”, (2012-01-02; ; backlinks):
Background: Chronotype refers to individuals’ preference for morning or evening activities. Its two dimensions (morningness and eveningness) are related to a number of academic outcomes.
Aims: The main goal of the study was to investigate the incremental validity of chronotype as a predictor of academic achievement after controlling for a number of traditional predictors. In so doing, a further aim was ongoing validation of a chronotype questionnaire, the Lark-Owl Chronotype Indicator.
Sample: The sample comprised 272 students attending 9th and 10th grades at five German high schools. Data was also obtained from 132 parents of these students.
Method: Students were assessed in class via self-report questionnaires and a standardized cognitive test. Parents filled out a questionnaire at home. The incremental validity of chronotype was investigated using hierarchical linear regression. Validity of the chronotype questionnaire was assessed by correlating student ratings of their chronotype with behavioural data on sleep, food intake, and drug consumption and with parent ratings of chronotype.
Results: Eveningness was a statistically-significant (negative) predictor of overall grade point average (GPA), math-science GPA, and language GPA, after cognitive ability, conscientiousness, need for cognition, achievement motivation, and gender were held constant. Validity evidence for the chronotype measure was established by statistically-significant correlations with parent-ratings and behavioural data.
Conclusions: Results point to the possible discrimination of adolescents with a proclivity towards eveningness at school. Possible explanations for the relationship between chronotype and academic achievement are presented. Implications for educational practice are also discussed.
“Melatonin in aging and disease -multiple consequences of reduced secretion, options and limits of treatment”, (2012; backlinks):
Melatonin is a pleiotropically acting regulator molecule, which influences numerous physiological functions. Its secretion by the pineal gland progressively declines by age. Strong reductions of circulating melatonin are also observed in numerous disorders and diseases, including Alzheimer’s disease, various other neurological and stressful conditions, pain, cardiovascular diseases, cases of cancer, endocrine and metabolic disorders, in particular diabetes type 2. The significance of melatonergic signaling is also evident from melatonin receptor polymorphisms associated with several of these pathologies. The article outlines the mutual relationship between circadian oscillators and melatonin secretion, the possibilities for readjustment of rhythms by melatonin and its synthetic analogs, the consequences for circadian rhythm-dependent disorders concerning sleep and mood, and limits of treatment. The necessity of distinguishing between short-acting melatonergic effects, which are successful in sleep initiation and phase adjustments, and attempts of replacement strategies is emphasized. Properties of approved and some investigational melatonergic agonists are compared.
“Antioxidants and Skeletal Muscle Performance: "Common Knowledge" vs. Experimental Evidence”, (2012; backlinks):
Antioxidants are assumed to provide numerous benefits, including better health, a reduced rate of aging, and improved exercise performance. Specifically, antioxidants are commonly “prescribed” by the media, supplement industry, and “fitness experts” for individuals prior to training and performance, with assumed benefits of improved fatigue resistance and recovery. This has provoked expansion of the supplement industry which responded by creation of a plethora of products aimed at facilitating the needs of the active individual. However, what does the experimental evidence say about the efficacy of antioxidants on skeletal muscle function? Are antioxidants actually as beneficial as the general populous believes? Or, could they in fact lead to deleterious effects on skeletal muscle function and performance? This Mini Review addresses these questions with an unbiased look at what we know about antioxidant effects on skeletal muscle, and what we still need to know before conclusions can be made.
“Efficacy and safety of prolonged-release melatonin for insomnia in middle-aged and elderly patients with hypertension: a combined analysis of controlled clinical trials”, (2012; backlinks):
Background: Add-on prolonged-release melatonin (PRM) in antihypertensive therapy has been shown to ameliorate nocturnal hypertension. Hypertension is a major comorbidity among insomnia patients. The efficacy and safety of PRM for primary insomnia in patients aged 55 years and older who are treated with antihypertensive drugs were evaluated.
Methods: Post hoc analysis of pooled antihypertensive drug-treated subpopulations from four randomized, double-blind trials of PRM and placebo for 3 weeks (N[PRM] = 195; N[placebo] = 197) or 28 weeks (N[PRM] = 157; N[placebo] = 40). Efficacy measurements included Leeds Sleep Evaluation Questionnaire scores of quality of sleep and alertness and behavioral integrity the following morning after 3 weeks, and sleep latency (daily sleep diary) and Clinical Global Impression of Improvement (CGI-I) after 6 months of treatment. Safety measures included antihypertensive drug-treated subpopulations from these four and three additional single-blind and open-label PRM studies of up to 1 year (N[PRM] = 650; N[placebo] = 632).
Results: Quality of sleep and behavior following wakening improved significantly with PRM compared with placebo (p < 0.0001 and P < 0.0008, respectively). Sleep latency (p = 0.02) and CGI-I (p = 0.0003) also improved significantly. No differences were observed between PRM and placebo groups in vital signs, including daytime blood pressure at baseline and treatment phases. The rate of adverse events normalized per 100 patient-weeks was lower for PRM (3.66) than for placebo (8.53).
Conclusions: The findings demonstrate substantive and sustained efficacy of PRM in primary insomnia patients treated with antihypertensive drugs. PRM appears to be safe for insomnia in patients with cardiovascular comorbidity.
“Reduced phase-advance of plasma melatonin after bright morning light in the luteal, but not follicular, menstrual cycle phase in premenstrual dysphoric disorder: an extended study”, (2011; backlinks):
The authors previously observed blunted phase-shift responses to morning bright light in women with premenstrual dysphoric disorder (PMDD). The aim of this study was to determine if these findings could be replicated using a higher-intensity, shorter-duration light pulse and to compare these results with the effects of an evening bright-light pulse. In 17 PMDD patients and 14 normal control (NC) subjects, the authors measured plasma melatonin at 30-min intervals from 18:00 to 10:00 h in dim (<30 lux) or dark conditions the night before (Night 1) and after (Night 3) a bright-light pulse (administered on Night 2) in both follicular and luteal menstrual cycle phases. The bright light (either 3000 lux for 6 h or 6000 lux for 3 h) was given either in the morning (AM light), 7 h after the dim light melatonin onset (DLMO) measured the previous month, or in the evening (PM light), 3 h after the DLMO. In the luteal, but not in the follicular, phase, AM light advanced melatonin offset between Night 1 and Night 3 statistically-significantly less in PMDD than in NC subjects. The effects of PM light were not significant, nor were there statistically-significant effects of the light pulse on melatonin measures of onset, duration, peak, or area under the curve. These findings replicated the authors’ previous finding of a blunted phase-shift response to morning bright light in the luteal, but not the follicular, menstrual cycle phase in PMDD compared with NC women, using a brighter (6000 vs. 3000 lux) light pulse for a shorter duration (3 vs. 6 h). As the effect of PM bright light on melatonin phase-shift responses did not differ between groups or significantly alter other melatonin measures, these results suggest that in PMDD there is a luteal-phase subsensitivity or an increased resistance to morning bright-light cues that are critical in synchronizing human biological rhythms. The resulting circadian rhythm malsynchonization may contribute to the occurrence of luteal phase depressive symptoms in women with PMDD.
2011-wade.pdf: “Prolonged release melatonin in the treatment of primary insomnia: evaluation of the age cut-off for short-term and long-term response”, (2010-11-24; backlinks):
Objectives: The authors recently reported on efficacy and safety of prolonged-release melatonin formulation (PRM; Circadin 2 mg) in elderly insomnia patients. The age cut-off for response to PRM and the long-term maintenance of efficacy and safety were further evaluated by looking at the total cohort (age 18–80 years) from that study and subsets of patients aged 18–54 and 55–80 years (for whom the drug is currently indicated).
Design: Randomised, double-blind, placebo controlled trial.
Setting: Multicentre, outpatients, primary care setting.
Methods: A total of 930 males and females aged 18–80 years with primary insomnia who reported mean nightly sleep latency (SL) >20 min were enrolled and 791 entered the active phase of the study. The study comprised a 2-week, single-blind placebo run-in period followed by 3 week’s double-blind treatment with PRM or placebo, one tablet per day at 2 hours before bedtime. PRM patients continued whereas placebo completers were re-randomised 1:1 to PRM or placebo for 26 weeks followed by 2-weeks run-out on placebo.
Main Outcome Measures: SL and other sleep variables derived from sleep diary, Pittsburgh Sleep Quality Index (PSQI), Quality of life (WHO-5), Clinical Global Impression of Improvement (CGI-I) and adverse effects, recorded each visit, withdrawal and rebound effects during run-out.
Results: In all, 746 patients completed the 3-week and 555 (421 PRM, 134 placebo) completed the 6-month period. The principal reason for drop-out was patient decision. At 3 weeks, statistically-significant differences in SL (diary, primary variable) in favour of PRM vs. placebo treatment were found for the 55–80-year group (−15.4 vs. −5.5 min, p = 0.014) but not the 18–80-year cut-off which included younger patients. Other variables (SL-PSQI, PSQI, WHO-5, CGI-I scores) improved statistically-significantly with PRM in the 18–80-year population, more so than in the 55–80-year age group. Improvements were maintained or enhanced over the 6–month period with no signs of tolerance. No withdrawal symptoms or rebound insomnia were detected. Most adverse events were mild with no statistically-significant differences between PRM and placebo groups in any safety outcome.
Conclusions: The results demonstrate short-term and long-term efficacy of PRM in insomnia patients aged 18–80 years, particularly those aged 55 and over. PRM was well-tolerated over the entire 6-month period with no rebound or withdrawal symptoms following discontinuation.
Trial Registration: ClinicalTrials.gov identifier: NCT00397189.
[Keywords: melatonin, insomnia, long-term, prolonged-release, sleep latency]
“Experimental ‘Jet Lag’ Inhibits Adult Neurogenesis and Produces Long-Term Cognitive Deficits in Female Hamsters”, (2010-11-03; backlinks):
Circadian disruptions through frequent transmeridian travel, rotating shift work, and poor sleep hygiene are associated with an array of physical and mental health maladies, including marked deficits in human cognitive function. Despite anecdotal and correlational reports suggesting a negative impact of circadian disruptions on brain function, this possibility has not been experimentally examined.
In the present study, we investigated whether experimental ‘jet lag’ (i.e., phase advances of the light∶dark cycle) negatively impacts learning and memory and whether any deficits observed are associated with reductions in hippocampal cell proliferation and neurogenesis. Because insults to circadian timing alter circulating glucocorticoid and sex steroid concentrations, both of which influence neurogenesis and learning/memory, we assessed the contribution of these endocrine factors to any observed alterations. Circadian disruption resulted in pronounced deficits in learning and memory paralleled by marked reductions in hippocampal cell proliferation and neurogenesis. Significantly, deficits in hippocampal-dependent learning and memory were not only seen during the period of the circadian disruption, but also persisted well after the cessation of jet lag, suggesting long-lasting negative consequences on brain function.
Together, these findings support the view that circadian disruptions suppress hippocampal neurogenesis via a glucocorticoid-independent mechanism, imposing pronounced and persistent impairments on learning and memory.
“Vitamin and mineral use and risk of prostate cancer: the case-control surveillance study”, (2009; backlinks):
Background: Many studies have evaluated the association between vitamin and mineral supplement use and the risk of prostate cancer, with inconclusive results.
Methods: The authors examined the relation of use of multivitamins as well as several single vitamin and mineral supplements to the risk of prostate cancer risk among 1,706 prostate cancer cases and 2,404 matched controls using data from the hospital-based case-control surveillance study conducted in the United States. Odds ratios (OR) and 95% confidence intervals (CI) for risk of prostate cancer were estimated using conditional logistic regression model.
Results: For use of multivitamins that did not contain zinc, the multivariable odds ratios of prostate cancer were 0.6 for 1–4 years, 0.8 for 5–9 years, and 1.2 for 10 years or more, respectively (p for trend = 0.70). Men who used zinc for ten years or more, either in a multivitamin or as a supplement, had an approximately two-fold (OR = 1.9, 95% CI: 1.0, 3.6) increased risk of prostate cancer. Vitamin E, beta-carotene, folate, and selenium use were not statistically-significantly associated with increased risk of prostate cancer.
Conclusion: The finding that long-term zinc intake from multivitamins or single supplements was associated with a doubling in risk of prostate cancer adds to the growing evidence for an unfavorable effect of zinc on prostate cancer carcinogenesis.
“Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs”, (2008; backlinks):
Vitamin C is an antioxidant vitamin that has been hypothesized to antagonize the effects of reactive oxygen species-generating antineoplastic drugs. The therapeutic efficacy of the widely used antineoplastic drugs doxorubicin, cisplatin, vincristine, methotrexate, and imatinib were compared in leukemia (K562) and lymphoma (RL) cell lines with and without pretreatment with dehydroascorbic acid, the commonly transported form of vitamin C. The effect of vitamin C on viability, clonogenicity, apoptosis, P-glycoprotein, reactive oxygen species (ROS), and mitochondrial membrane potential was determined. Pretreatment with vitamin C caused a dose-dependent attenuation of cytotoxicity, as measured by trypan blue exclusion and colony formation after treatment with all antineoplastic agents tested. Vitamin C given before doxorubicin treatment led to a substantial reduction of therapeutic efficacy in mice with RL cell-derived xenogeneic tumors. Vitamin C treatment led to a dose-dependent decrease in apoptosis in cells treated with the antineoplastic agents that was not due to up-regulation of P-glycoprotein or vitamin C retention modulated by antineoplastics. Vitamin C had only modest effects on intracellular ROS and a more general cytoprotective profile than N-acetylcysteine, suggesting a mechanism of action that is not mediated by ROS. All antineoplastic agents tested caused mitochondrial membrane depolarization that was inhibited by vitamin C. These findings indicate that vitamin C given before mechanistically dissimilar antineoplastic agents antagonizes therapeutic efficacy in a model of human hematopoietic cancers by preserving mitochondrial membrane potential. These results support the hypothesis that vitamin C supplementation during cancer treatment may detrimentally affect therapeutic response.
“Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis”, (2006; backlinks):
Objective: To conduct a systematic review of the efficacy and safety of exogenous melatonin in managing secondary sleep disorders and sleep disorders accompanying sleep restriction, such as jet lag and shiftwork disorder.
Data Sources: 13 electronic databases and reference lists of relevant reviews and included studies; Associated Professional Sleep Society abstracts (1999 to 2003).
Study Selection: The efficacy review included randomised controlled trials; the safety review included randomised and non-randomised controlled trials.
Quality Assessment: Randomised controlled trials were assessed by using the Jadad Scale and criteria by Schulz et al, and non-randomised controlled trials by the Downs and Black checklist.
Data Extraction and Synthesis: One reviewer extracted data and another reviewer verified the data extracted. The inverse variance method was used to weight studies and the random effects model was used to analyse data.
Main Results: Six randomised controlled trials with 97 participants showed no evidence that melatonin had an effect on sleep onset latency in people with secondary sleep disorders (weighted mean difference -13.2 (95% confidence interval -27.3 to 0.9) min). Nine randomised controlled trials with 427 participants showed no evidence that melatonin had an effect on sleep onset latency in people who had sleep disorders accompanying sleep restriction (-1.0 (-2.3 to 0.3) min). 17 randomised controlled trials with 651 participants showed no evidence of adverse effects of melatonin with short term use (three months or less).
Conclusions: There is no evidence that melatonin is effective in treating secondary sleep disorders or sleep disorders accompanying sleep restriction, such as jet lag and shiftwork disorder. There is evidence that melatonin is safe with short term use.
“Intrinsic period and light intensity determine the phase relationship between melatonin and sleep in humans”, (2005; backlinks):
The internal circadian clock and sleep-wake homeostasis regulate the timing of human brain function, physiology, and behavior so that wakefulness and its associated functions are optimal during the solar day and that sleep and its related functions are optimal at night. The maintenance of a normal phase relationship between the internal circadian clock, sleep-wake homeostasis, and the light-dark cycle is crucial for optimal neurobehavioral and physiological function. Here, the authors show that the phase relationship between these factors-the phase angle of entrainment (psi)-is strongly determined by the intrinsic period (tau) of the master circadian clock and the strength of the circadian synchronizer. Melatonin was used as a marker of internal biological time, and circadian period was estimated during a forced desynchrony protocol. The authors observed relationships between the phase angle of entrainment and intrinsic period after exposure to scheduled habitual wakefulness-sleep light-dark cycle conditions inside and outside of the laboratory. Individuals with shorter circadian periods initiated sleep and awakened at a later biological time than did individuals with longer circadian periods. The authors also observed that light exposure history influenced the phase angle of entrainment such that phase angle was shorter following exposure to a moderate bright light (approximately 450 lux)-dark/wakefulness-sleep schedule for 5 days than exposure to the equivalent of an indoor daytime light (approximately 150 lux)-dark/wakefulness-sleep schedule for 2 days. These findings demonstrate that neurobiological and environmental factors interact to regulate the phase angle of entrainment in humans. This finding has important implications for understanding physiological organization by the brain’s master circadian clock and may have implications for understanding mechanisms underlying circadian sleep disorders.
“The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis”, (2005; backlinks):
Background: Exogenous melatonin has been increasingly used in the management of sleep disorders.
Purpose: To conduct a systematic review of the efficacy and safety of exogenous melatonin in the management of primary sleep disorders.
Data Sources: A number of electronic databases were searched. We reviewed the bibliographies of included studies and relevant reviews and conducted hand-searching.
Study Selection: Randomized controlled trials (RCTs) were eligible for the efficacy review, and controlled trials were eligible for the safety review.
Data Extraction: One reviewer extracted data, while the other verified data extracted. The Random Effects Model was used to analyze data.
Data Synthesis: Melatonin decreased sleep onset latency (weighted mean difference [WMD]: -11.7 minutes; 95% confidence interval [CI]: -18.2, -5.2)); it was decreased to a greater extent in people with delayed sleep phase syndrome (WMD: -38.8 minutes; 95% CI: -50.3, -27.3; n = 2) compared with people with insomnia (WMD: -7.2 minutes; 95% CI: -12.0, -2.4; n = 12). The former result appears to be clinically important. There was no evidence of adverse effects of melatonin.
Conclusions: There is evidence to suggest that melatonin is not effective in treating most primary sleep disorders with short-term use (4 weeks or less); however, additional large-scale RCTs are needed before firm conclusions can be drawn. There is some evidence to suggest that melatonin is effective in treating delayed sleep phase syndrome with short-term use. There is evidence to suggest that melatonin is safe with short-term use (3 months or less).
2002-lewy.pdf: “Low, but not high, doses of melatonin entrained a free-running blind person with a long circadian period”, (2002-02-28):
In a previous report, we were unable to entrain one out of seven totally blind people with free-running endogenous melatonin rhythms to 10 mg of exogenous melatonin. This person had the longest circadian period (24.9 h) of the group. We now find that this person can be entrained to 0.5 mg of melatonin, but not to 20 mg. These results are consistent with the idea that too much melatonin may spill over onto the wrong zone of the melatonin phase-response curve.
[Keywords: circadian rhythms, free-running totally blind people, melatonin, melatonin phase-response curve]
2002-cardinali.pdf: “Melatonin in sleep disorders and jet-lag”, (2002; backlinks):
In elderly insomniacs, melatonin treatment decreased sleep latency and increased sleep efficiency. This is particularly marked in Alzheimer’s disease (AD) patients. Melatonin is effective to reduce substantially benzodiazepine use. In addition, melatonin administration synchronizes the sleep-wake cycle in blind people and in individuals suffering from delayed sleep phase syndrome or jet lag. Urinary levels of 6-sulphatoxymelatonin decrease with age and in chronic diseases like AD or coronary heart disease. The effect of melatonin on sleep is probably the consequence of increasing sleep propensity (by inducing a fall in body temperature) and of a synchronizing effect on the circadian clock (chronobiotic effect).
“Use of slow-release melatonin in treatment-resistant depression”, (2000; backlinks):
Objective: To examine antidepressant augmentation with and hypnotic effects of slow-release melatonin (SR-melatonin) in patients with treatment-resistant depression.
Design: Open-label trial.
Setting: Tertiary care outpatient depression clinic.
Patients: Nine outpatients who had failed to respond to 2 or more 8-week trials of antidepressant medication.
Interventions: Patients received SR-melatonin 5 mg per day for the first 2 weeks and 10 mg per day for the final 2 weeks, in addition to their antidepressant medication.
Outcome Measures: Structured Clinical Interview for DSM-IV, Axis 1 Disorders, Hamilton Rating Scale for Depression (HRSD), Beck Depression Inventory, Response Style Questionnaire, sleep and fatigue measures.
Results: One patient was excluded after 1 week because of the development of a mixed affective state. In the remaining 8 patients there was a 20% mean decrease in HRSD scores after 4 weeks of treatment, with no individual achieving an improvement of 50% or more. There was a 36% decrease on the 3-item HRSD related to insomnia, with 4 of 8 patients showing at least a 50% improvement on this measure. The greatest decrease in insomnia occurred during the last 2 weeks of the study, following the increase in dosage to 10 mg per day of SR-melatonin. Patients also reported significantly lower levels of fatigue post-treatment.
Conclusions: SR-melatonin may be a useful adjunct for sleep, but does not substantially augment existing antidepressant therapies in some patients with treatment-resistant depression.
1996-shafii.pdf: “Nocturnal Serum Melatonin Profile in Major Depression in Children and Adolescents”, (1996-11-01; backlinks):
Background: In major depression, biological rhythm disturbances in sleep, appetite, and mood suggest dysregulation in neuroendocrine functions, possibly in the pineal gland. In this study, pineal gland function was examined by measuring nocturnal serum melatonin levels during both wakefulness and sleep in depressed children and adolescents.
Methods: 22 youths aged 8 to 17 years primarily with major depression were compared with 19 controls. Blood samples were drawn every half hour from 6 PM to 7 AM. Nocturnal serum melatonin levels were measured by radioimmunoassay.
Results: The overall nocturnal serum melatonin profile from 6 PM to 7 AM was statistically-significantly higher (mean±SD, 0.18±0.14nmol/L) in the depressed group than in the controls [mean±SD, 0.15±0.10 nmol/L, F(1,26) = 4.37, p < 0.05]. In dim light, when the subjects were awake, no difference existed between the 2 groups. After lights-out, from 10 PM to 7 AM, the melatonin profile rose in both groups; however, the depressed group had a statistically-significantly higher increase (mean±SD,0.24±0.14nmol/L) than the controls [mean±SD,0.18±0.07nmol/L, F(1,26) = 4.93, mean square error = 0.11, p = 0.04]. Post hoc analysis showed a statistically-significantly higher melatonin profile in depressed subjects without psychosis (n = 15) than in depressed subjects with psychosis (n = 7) or in the controls.
Conclusions: Measuring the overall nocturnal serum melatonin profile during darkness may help to differentiate children and adolescents with major depression without psychosis from those with psychosis and from controls.
1993-ericsson.pdf: “The role of deliberate practice in the acquisition of expert performance”, (1993-07; ; backlinks):
The theoretical framework presented in this article explains expert performance as the end result of individuals’ prolonged efforts to improve performance while negotiating motivational and external constraints. In most domains of expertise, individuals begin in their childhood a regimen of effortful activities (deliberate practice) designed to optimize improvement. Individual differences, even among elite performers, are closely related to assessed amounts of deliberate practice. Many characteristics once believed to reflect innate talent are actually the result of intense practice extended for a minimum of 10 yrs. Analysis of expert performance provides unique evidence on the potential and limits of extreme environmental adaptation and learning.