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The prevention and treatment of jet lag
Abstract
Jet lag commonly affects air travellers who cross several time zones. It results from the body's internal rhythms being out of step with the day-night cycle at the destination. Melatonin is a pineal hormone that plays a central part in regulating bodily rhythms and has been used as a drug to re-align them with the outside world. Melatonin is remarkably effective in preventing or reducing jet lag, and occasional short-term use appears to be safe. It should be recommended to adult travellers flying across five or more time zones, particularly in an easterly direction, and especially if they have experienced jet lag on previous journeys. Travellers crossing 2-4 time zones can also use it if need be.
... Herxheimer et al. [5] revised different studies tied to jet lag concluding that melatonin was effective in forestalling or lessening jet lag, and its occasional short-term use appeared to be safe. Nevertheless, in this systematic review, the effects of melatonin have not yet been proven the in shift workers and its possible side effects in a long-term period. ...
... Nevertheless, a previous Cochrane review [5] affirmed that daily doses of melatonin of 0.5 and 5 mg were equally effective; however, there was less sleep latency and better sleep quality with 5 mg. No greater efficacy was attributed to doses higher than 5 mg. ...
... Nonetheless, like Matheson et al. [48] pointed out, it was considered that further studies to find the optimal minimum effective dose are needed. The pharmacology and toxicology of melatonin requires a thorough systematic study based on well-designed clinical trials with sufficiently large population sizes that can extrapolate the results to the general population [5]. ...
(1) Background: To know the medical documentation related to exogenous melatonin in sleep disorders caused by shift work in health personnel; (2) Methods: Systematic and critical review. Data were obtained by looking up the bibliographic data base: MEDLINE (via Pubmed), Embase, Cochrane Library, Scopus, Web of Science, Latin American and Caribbean literature in Health Sciences (LILACS) and Medicine in Spanish (MEDES). The used terms, as descriptors and text in the title and abstract record fields, were “Health Personnel”, “Melatonin” and “Sleep Disorders”, Circadian Rhythm, by using the following filters: “Humans”, “Adult: 19+ years” and “Clinical Trial”. The search update was in December 2021. The documentary quality of the articles was assessed using the CONSORT questionnaire. (3) Results: Having applied the inclusion and exclusion criteria, 10 clinical essays were selected out of 98 retrieved references. CONSORT scores ranged from a minimum of 6.0 to a maximum of 13. 7 with a median of 10.2. According to the SIGN criteria, this review presented “1-“evidence with a grade of recommendation B. The intervention dose via administration of exogenous melatonin ranged between 1 and 10 mg. It was not mentioned whether the route of administration was by fast or slow absorption. The outcomes showed decreased daytime sleepiness, lessened sleep onset latency, diminished night-time awakenings, increased total sleep period and improved daytime attention in the melatonin-treated group; (4) Conclusions: Exogenously administered melatonin is effective in shift worker health personnel that are suffering from sleep disorders, and given its low adverse effects and tolerability, it might be recommended. A great disparity was evidenced in terms of dose, follow-up periods and type of melatonin, small participant population, same age ranges and young age. Therefore, new trials would be needed to amend these observations in order to have full evidence that is able to ensure the efficacy of exogenous melatonin in the studied population.
... The second objective was to assess the suitability of maternal melatonin treatment as a therapeutic intervention for fetal hypoxia. We have chosen melatonin as our treatment because it is already safely consumed by people to avoid jetlag, 42 it can be transported across the mitochondrial membrane and it is also synthesized in the matrix, 43 so it is considered a mitochondria-targeted antioxidant. [44][45][46] Furthermore, melatonin acts at multiple levels in the mitochondria by upregulating antioxidant enzymes, increasing the activity of respiratory complexes, and directly scavenging free radicals. ...
... The dose of melatonin was chosen as it is comparable with the maximal effective dose recommended for overcoming jet lag in humans. 42 Melatonin was made up fresh every other day and water bottles were covered to prevent light-induced breakdown. Maternal food and water intake were regularly measured throughout pregnancy, and maternal body weight was measured before and at the end of the exposure. ...
... Indeed, there were often trends within our data that melatonin was preventing mitochondrial remodeling, and larger sample size may have resolved these effects. In addition, although we chose a dose of melatonin that was clinically relevant 42 and previously shown to be protective, 11 the concentration may not have been high enough to achieve metabolic protection. With respect to respiration measurements, we provided OXPHOS substrates at a saturating concentration, and therefore our results do not account for potential differences in substrate availability and/or preference in vivo. ...
Insufficient oxygen supply (hypoxia) during fetal development leads to cardiac remodelling and a predisposition to cardiovascular disease in later life. Previous work has shown hypoxia causes oxidative stress in the fetal heart and alters the activity and expression of mitochondrial proteins in a sex‐dependent manner. However, the functional effects of these modifications on mitochondrial respiration remain unknown. Furthermore, while maternal antioxidant treatments are emerging as a promising new strategy to protect the hypoxic fetus, whether these treatments convey similar protection to cardiac mitochondria in the male or female fetus has not been investigated. Therefore, using an established rat model, we measured sex‐dependent effects of gestational hypoxia and maternal melatonin treatment on fetal cardiac mitochondrial respiration, ROS production and lipid peroxidation. Pregnant Wistar rats were subjected to normoxia or hypoxia (13 % oxygen) during gestational days 6‐20 (term ~ 22 days) with or without melatonin treatment (5 µg/ml in maternal drinking water). On gestational day 20, mitochondrial aerobic respiration and H2O2 production were measured in fetal heart tissue, together with lipid peroxidation and citrate synthase activity. Gestational hypoxia reduced maternal body weight gain (p < 0.01) and increased placental weight (p < 0.05) but had no effect on fetal weight or litter size. Cardiac mitochondria from male but not female fetuses of hypoxic pregnancy had reduced respiratory capacity at complex II (p < 0.05), and an increase in H2O2 production/O2 consumption (p < 0.05) without any changes in lipid peroxidation. Citrate synthase activity was also unchanged in both sexes. Despite maternal melatonin treatment increasing maternal and fetal plasma melatonin concentration (p < 0.001), melatonin treatment had no effect on any of the mitochondrial parameters investigated. To conclude, we show that gestational hypoxia leads to ROS generation from the mitochondrial electron transport chain and affects fetal cardiac mitochondrial respiration in a sex‐dependent manner. We also show that maternal melatonin treatment had no effect on these relationships, which has implications for the development of future therapies for hypoxic pregnancies. This article is protected by copyright. All rights reserved.
... Jetlag, the desynchronization of normal circadian rhythm, occurs as a result of rapid travel through multiple time zones [2]. This is characterized by sleep disturbances, daytime fatigue, reduced cognitive and physical performance, and alterations in mood [2,3]. ...
... Jetlag, the desynchronization of normal circadian rhythm, occurs as a result of rapid travel through multiple time zones [2]. This is characterized by sleep disturbances, daytime fatigue, reduced cognitive and physical performance, and alterations in mood [2,3]. The severity of symptoms worsens following eastward travel over multiple time zones [2]. ...
... This is characterized by sleep disturbances, daytime fatigue, reduced cognitive and physical performance, and alterations in mood [2,3]. The severity of symptoms worsens following eastward travel over multiple time zones [2]. ...
Airline passengers experience a range of symptoms when travelling on long flights. This review evaluated the efficacy of functional foods, beverages, and supplements claiming to address the effects of air travel for healthy adults. Products were identified in a scoping review of electronic databases, search engines, and grey literature (March to August 2019). A systematic review of the efficacy of product ingredients was conducted using five electronic databases from inception to February 2021. Articles were screened, data extracted, and assessed for risk of bias by two researchers independently. Meta-analysis was performed. Of the 3842 studies identified, 23 met selection criteria: melatonin (n = 10), Pycnogenol (n = 4), various macronutrients (n = 2), caffeine (n = 2), Centella asiatica (n = 1), elderberry (n = 1), Echinacea (n = 1), fluid (n = 1), and Pinokinase (n = 1). Meta-analysis (random effects model) indicated melatonin reduced self-reported jetlag following eastbound (n = 5) and westbound (n = 4) flights: standard mean difference −0.76 (95% CI = −1.06 to −0.45, I2 0%, p < 0.00001) and −0.66 (95% CI = −1.07 to −0.26, I2 45%, p = 0.001), respectively. Pycnogenol also reduced edema scores (n = 3), standard mean −4.09 (95% CI = −6.44 to −1.74), I2 98%, p = 0.0006). Overall, 12 of 183 ingredients contained in 199 products had evidence to support claims.
... Jet lag is a combination of gastrointestinal and sleep disturbances, fatigue, depressed mood, and a deficit in concentration and other cognitive skills that occurs after travelling across time zones (Eastman et al., 2005). Shifting time zones creates a desynchronization between the circadian rhythms, the rhythmic pattern of all the physiological functions and systems of the human body (Czeisler et al., 1999), and the external clock which ultimately leads to jet lag (Herxheimer & Petrie, 2002;Waterhouse et al., 2004). ...
... These strategies are mostly based on pharmacological interventions (i.e. sleeping tablets) to enhance sleep (Donaldson & Kennaway, 1991;Reilly et al., 2007) or melatonin supplementation (Cardinali et al., 2002;Herxheimer & Petrie, 2002) and light exposure/avoidance (Geerdink et al., 2016;Revell et al., 2006;Sasseville et al., 2006) to hasten the resynchronization rate. Overall, it appears that the majority of the strategies used to reduce the negative effect of travel on athletes focus on a clinical management of the somatic symptoms, for instance, sleep disruption, rather than to a more holistic approach, including management of socio-psychological issues. ...
... The majority of the "Arrival" strategies mentioned by the participants have been extensively investigated (Forbes-Robertson et al., 2012). In particular, supplementation and pharmacological interventions including melatonin (Herxheimer & Petrie, 2002) and sleeping tablet (Sack et al., 2007) have been introduced into the common practice of travel interventions, although with varying degrees of success (Sack et al., 2007). Similarly, the efficacy of light exposure (Youngstedt et al., 2016), sleep education intervention (Nedelec et al., 2015) and a number of "Travel" strategies, including hydration interventions and compression garments (Waterhouse et al., 2004) have been largely documented. ...
Air travel is a key factor in Super Rugby and can have a negative influence on players’ performance and well-being. The aim of this study was to identify the current practice to reduce the effects of air travel and to understand the rationale behind these interventions. “Travel managers” from eight Super Rugby teams were interviewed and answered a questionnaire. A qualitative description was performed to identify common themes and differences between participants’ answers. To protect the privacy and identity of the participants, all data have been de-identified and represented as two fictionalised amalgams (Bob and Peter). The rationale behind each intervention appeared to be based on a mix of anecdotal, practice and, occasionally, literature, confirming that scientific findings are not always easily translatable to applied settings. Two different approaches, clinical (Bob) and holistic (Peter), were identified. Even if both characters acknowledge that travel variables are too many to control, it appears that team culture and practices are perceived as important as biological interventions in controlling the negative effects of travel on players’ performance and well-being.
... The more time zones are crossed, the symptoms are more severe. Jet lag also tends to be more severe when traveling eastward compared with westward, due to less time to adjust to the change of time zone [1]. ...
... None of the mentioned above trials men didn't report any serious side effects caused by this medication therefore occasional short-term use of melatonin seems to be safe. However it is difficult to distinguish side effects from symptoms, therefore they could be inadequately assessed [1]. The trial of Suhner (1998a) showed that there is no significant difference in effectiveness between doses of 0,5 mg and 5 mg of melatonin, except faster falling asleep and better sleep quality after 5 mg. ...
... Suhner et al. (1998a) study suggested that immediate-release formulation of melatonin is far more effective than its controlled-release formulation, because of faster action due to giving a higher concentration in the blood [7]. Most people should start treatment of jet lag with taking 2-3 mg melatonin, and if necessary increase the dose to 5 mg [1]. The effectiveness of melatonin was similar on westward and eastward flights. ...
Jet lag is a circadian rhythm disorder, that occurs as a result of air travel across multiple time zones. Jet lag symptoms include: anxiety, constipation, diarrhea, confusion, dehydration, headache, irritability, nausea, indigestion, difficulty concentrating, sweating, coordination problems, dizziness, daytime sleepiness, malaise, and memory loss.Melatonin, is a hormone that regulates the circadian rhythm by acting on MT1 and MT2 melatonin receptors. It is produced by pinealocytes in the pineal gland and released directly into the blood. Main therapeutical application of this medication is re-entraining disturbed circadian rhythms.All the mentioned studies proved that melatonin is effective in the treatment of jet lag. None of the mentioned above trials didn’t report any serious side effects caused by this medication therefore occasional short-term use of melatonin seems to be safe. Most people should start treatment of jet lag with taking 2-3 mg melatonin, and if necessary increase the dose to 5 mg. Melatonin is the most effective in alleviating symptoms of jet lag when it is given at bedtime on the day of the flight and in the next few days after arrival. Further research is needed to find out the optimal dosage of melatonin fot treatment of jet lag, timing of its administration, time of initiation and duration of the treatment or possible side effects of this medication.
... The most common sleep-related disorders include difficulty falling asleep, early waking, and a feeling of fatigue that disrupts daily activities and consequently leads to difficulties in the individual's work and social life [11,12]. Several studies have shown that the exogenous intake of melatonin for diseases accompanied by sleep disorders increases the body's concentrations of melatonin and favorably affects the quality of sleep; therefore, the systemic application of melatonin for sleep disorders has become generally accepted [13][14][15][16][17][18][19]. Factors that have a negative effect on melatonin production are aging, the presence of certain diseases (e.g., malignant diseases, diabetic neuropathy, and Alzheimer's disease), and the use of certain drugs (e.g., β-blockers, clonidine, naloxone, and anti-inflammatory drugs). ...
... For jet lag, a dose of 0.5-1.0 mg of systemic melatonin can be used [16]. Because of its antioxidant and antiinflammatory properties, melatonin is also used as a natural dietary supplement for athletes for sleep cycle regulation and to protect muscles from oxidative stress [23]. ...
Melatonin is the main hormone that regulates the sleep cycle, and it is mostly produced by the pineal gland from the amino acid tryptophan. It has cytoprotective, immunomodulatory, and anti-apoptotic effects. Melatonin is also one of the most powerful natural antioxidants, directly acting on free radicals and the intracellular antioxidant enzyme system. Furthermore, it participates in antitumor activity, hypopigmentation processes in hyperpigmentary disorders, anti-inflammatory, and immunomodulating activity in inflammatory dermatoses, maintaining the integrity of the epidermal barrier and thermoregulation of the body. Due predominantly to its positive influence on sleep, melatonin can be used in the treatment of sleep disturbances for those with chronic allergic diseases accompanied by intensive itching (such as atopic dermatitis and chronic spontaneous urticaria). According to the literature data, there are also many proven uses for melatonin in photoprotection and skin aging (due to melatonin’s antioxidant effects and role in preventing damage due to DNA repair mechanisms), hyperpigmentary disorders (e.g., melasma) and scalp diseases (such as androgenic alopecia and telogen effluvium).
... Many studies support melatonin's use in reducing the ill effects of jet lag and speeding up the normalization of circadian rhythms [73]. In a Cochrane review, nine out of ten trials found that melatonin effectively reduced jet lag symptoms in travelers, especially if traveling eastward or over five time zones [74]. Specific phaseshifting protocols support the sleep phase during travel across time zones. ...
... Most research on the use of melatonin for jet lag is from 10-20 years ago or longer. Melatonin may not be effective for everyone but could be well-suited for those individuals with a history of jet lag and/or for those flying across ≥ five time zones to the East [74]. Upon arriving in a new time zone, it is advised to follow the new time zone sleep cycle, taking the oral melatonin supplement thirty to sixty minutes before desired sleep on the first night and continuing for the following three to four nights, gradually reducing the dose. ...
Melatonin has become a popular dietary supplement, most known as a chronobiotic, and for establishing healthy sleep. Research over the last decade into cancer, Alzheimer’s disease, multiple sclerosis, fertility, PCOS, and many other conditions, combined with the COVID-19 pandemic, has led to greater awareness of melatonin because of its ability to act as a potent antioxidant, immune-active agent, and mitochondrial regulator. There are distinct similarities between melatonin and vitamin D in the depth and breadth of their impact on health. Both act as hormones, affect multiple systems through their immune-modulating, anti-inflammatory functions, are found in the skin, and are responsive to sunlight and darkness. In fact, there may be similarities between the widespread concern about vitamin D deficiency as a “sunlight deficiency” and reduced melatonin secretion as a result of “darkness deficiency” from overexposure to artificial blue light. The trend toward greater use of melatonin supplements has resulted in concern about its safety, especially higher doses, long-term use, and application in certain populations (e.g., children). This review aims to evaluate the recent data on melatonin’s mechanisms, its clinical uses beyond sleep, safety concerns, and a thorough summary of therapeutic considerations concerning dietary supplementation, including the different formats available (animal, synthetic, and phytomelatonin), dosing, timing, contraindications, and nutrient combinations.
... Furthermore, posttranscriptional and -translational modifications to core circadian clock components should also in immutable modifications, small molecules can be used in reversible, time-and dose-dependent manners (102,103). One common example is the amelioration of jet lag via use of the hormone melatonin (104,105). A double-blind trial showed that melatonin can significantly reduce jet lag and sleep disturbance in an international cabin crew (106). ...
... Reduced retinal light sensitivity, especially during the winter months, as a pathophysiological hypothesis of SAD (101)(102)(103) recently gained first supporting evidence. A study by Roecklein et al. found a reduced post-illumination pupil response (PIPR) in SAD patients, compared with controls, in winter but not in summer (104). ...
Mammalian circadian rhythms are controlled by a master pacemaker located in the suprachiasmatic nuclei (SCN), which is synchronized to the environment by photic and nonphotic stimuli. One of the main functions of the SCN is to regulate peripheral oscillators to set temporal variations in the homeostatic control of physiology and metabolism. In this sense, the SCN coordinate the activity/rest and feeding/fasting rhythms setting the timing of food intake, energy expenditure, thermogenesis, and active and basal metabolism. One of the major time cues to the periphery is the nocturnal melatonin, which is synthesized and secreted by the pineal gland. Under SCN control, arylalkylamine N-acetyltransferase (AA-NAT)—the main enzyme regulating melatonin synthesis in vertebrates—is activated at night by sympathetic innervation that includes the superior cervical ganglia (SCG). Bilateral surgical removal of the superior cervical ganglia (SCGx) is considered a reliable procedure to completely prevent the nocturnal AA-NAT activation, irreversibly suppressing melatonin rhythmicity. In the present work, we studied the effects of SCGx on rat metabolic parameters and diurnal rhythms of feeding and locomotor activity. We found a significant difference between SCGx and sham-operated rats in metabolic variables such as an increased body weight/food intake ratio, increased adipose tissue, and decreased glycemia with a normal glucose tolerance. An analysis of locomotor activity and feeding rhythms showed an increased daytime (lights on) activity (including food consumption) in the SCGx group. These alterations suggest that superior cervical ganglia-related feedback mechanisms play a role in SCN-periphery phase coordination and that SCGx is a valid model without brain-invasive surgery to explore how sympathetic innervation affects daily (24 h) patterns of activity, food consumption and, ultimately, its role in metabolism homeostasis.
... The dose of melatonin was equivalent to the maximal dose recommended for overcoming jet lag in humans. 42 Dams not receiving melatonin in their drinking water were given a vehicle containing three drops of ethanol per 500 ml drinking water. ...
... 26,54,55 The dose of melatonin treatment used in this study was based on previous studies showing protective actions of melatonin on fetal development, 27 and it was less than the maximal dose recommended for overcoming jet lag in humans. 42 The resulting concentration of melatonin in maternal plasma following melatonin treatment was similar than that found in other studies using pregnant rats, 56,57 and within the range or lower than those measured in men and women following melatonin intake to avoid jet lag. 58 The cardiovascular data in the present study show that hypoxic pregnancy induced aortic wall thickening without affecting the cardiac walls in fetal life. ...
Adopting an integrative approach, by combining studies of cardiovascular function with those at cellular and molecular levels, this study investigated whether maternal treatment with melatonin protects against programmed cardiovascular dysfunction in the offspring using an established rodent model of hypoxic pregnancy. Wistar rats were divided into normoxic (N) or hypoxic (H, 10% O2) pregnancy ± melatonin (M) treatment (5 μg·ml‐1.day‐1) in the maternal drinking water. Hypoxia ± melatonin treatment was from day 15‐20 of gestation (term is ca. 22 days). To control for possible effects of maternal hypoxia‐induced reductions in maternal food intake, additional dams underwent pregnancy under normoxic conditions but were pair‐fed (PF) to the daily amount consumed by hypoxic dams from day 15 of gestation. In one cohort of animals from each experimental group (N, NM, H, HM, PF, PFM) measurements were made at the end of gestation. In another, following delivery of the offspring, investigations were made at adulthood. In both fetal and adult offspring, fixed aorta and hearts were studied stereologically and frozen hearts were processed for molecular studies. In adult offspring, mesenteric vessels were isolated and vascular reactivity determined by in vitro wire myography. Melatonin treatment during normoxic, hypoxic or pair‐fed pregnancy elevated circulating plasma melatonin in the pregnant dam and fetus. Relative to normoxic pregnancy, hypoxic pregnancy increased fetal haematocrit, promoted asymmetric fetal growth restriction, and resulted in accelerated post‐natal catch‐up growth. While fetal offspring of hypoxic pregnancy showed aortic wall thickening, adult offspring of hypoxic pregnancy showed dilated cardiomyopathy. Similarly, while cardiac protein expression of eNOS was downregulated in the fetal heart, eNOS protein expression was elevated in the heart of adult offspring of hypoxic pregnancy. Adult offspring of hypoxic pregnancy further showed enhanced mesenteric vasoconstrictor reactivity to phenylephrine and the thromboxane mimetic U46619. The effects of hypoxic pregnancy on cardiovascular remodelling and function in the fetal and adult offspring were independent of hypoxia‐induced reductions in maternal food intake. Conversely, the effects of hypoxic pregnancy on fetal and postanal growth were similar in pair‐fed pregnancies. While maternal treatment of normoxic or pair‐fed pregnancies with melatonin on the offspring cardiovascular system was unremarkable, treatment of hypoxic pregnancies with melatonin in doses lower than those recommended for overcoming jet lag in humans enhanced fetal cardiac eNOS expression and prevented all alterations in cardiovascular structure and function in fetal and adult offspring. Therefore, the data support that melatonin is a potential therapeutic target for clinical intervention against developmental origins of cardiovascular dysfunction in pregnancy complicated by chronic fetal hypoxia.
... Some of the earliest studies of therapeutic melatonin were conducted in subjects with jet-lag [67] for which it is widely taken, despite regulatory approval only recently having been granted in the UK for this indication (see above). A notable recent review by Foley and Steel [68] summarised AE findings from controlled studies of melatonin for all indications. ...
... The possibility that melatonin might increase the effects of other hypnotics has been suggested [108], and a possible pharmacokinetic interaction with the antidepressant citalopram in one patient resulting in severe sedation was reported [137]. Herxheimer and Petrie [67] raised concern over a possible interaction with vitamin K antagonists such as warfarin. As stated earlier, fluvoxamine [131,138] and caffeine [132] have been found to elevate endogenous melatonin levels. ...
Background: Melatonin is widely available either on prescription for the treatment of sleep disorders or as an over-the-counter dietary supplement. Melatonin has also recently been licensed in the UK for the short-term treatment of jetlag. Little is known about the potential for adverse events (AEs), in particular AEs resulting from long-term use. Concern has been raised over the possible risks of exposure in certain populations including pre-adolescent children and patients with epilepsy or asthma. / Objectives: The aim of this systematic review was to assess the evidence for AEs associated with short-term and longer-term melatonin treatment for sleep disorders. / Methods: A literature search of the PubMed/Medline database and Google Scholar was conducted to identify randomised, placebo-controlled trials (RCTs) of exogenous melatonin administered for primary or secondary sleep disorders. Studies were included if they reported on both the types and frequencies of AEs. Studies of pre-term infants, studies of < 1 week in duration or involving single doses of melatonin and studies in languages other than English were excluded. Findings from open-label studies that raised concerns relating to AE reports in patients were also examined. Studies were assessed for quality of reporting against the Consolidated Standards of Reporting Trials (CONSORT) checklist and for risk of bias against the Cochrane Collaboration risk-of-bias criteria. / Results: 37 RCTs met criteria for inclusion. Daily melatonin doses ranged from 0.15 mg to 12 mg. Subjects were monitored for up to 29 weeks, but most studies were of much shorter duration (4 weeks or less). The most frequently reported AEs were daytime sleepiness (1.66%), headache (0.74%), other sleep-related AEs (0.74%), dizziness (0.74%) and hypothermia (0.62%). Very few AEs considered to be serious or of clinical significance were reported. These included agitation, fatigue, mood swings, nightmares, skin irritation and palpitations. Most AEs either resolved spontaneously within a few days with no adjustment in melatonin, or immediately upon withdrawal of treatment. Melatonin was generally regarded as safe and well tolerated. Many studies predated publication of the CONSORT checklist and consequently did not conform closely to the guidelines. Similarly, only eight studies were judged ‘good’ overall with respect to the Cochrane risk-of-bias criteria. Of the remaining papers, 16 were considered ‘fair’ and 13 ‘poor’ but publication of almost half of the papers preceded that of the earliest version of the guidelines. / Conclusion: Few, generally mild to moderate, AEs were associated with exogenous melatonin. No AEs that were life threatening or of major clinical significance were identified. The scarcity of evidence from long-term RCTs, however, limits the conclusions regarding the safety of continuous melatonin therapy over extended periods. There are insufficient robust data to allow a meaningful appraisal of concerns that melatonin may result in more clinically significant adverse effects in potentially at-risk populations. Future studies should be designed to comply with appropriate quality standards for RCTs, which most past studies have not.
... Activation of the MT 1 receptor induces sleep, while stimulation of the MT 2 receptor appears to be related to the light-dark synchronization of the biological clock [41]. Melatonin has been studied for numerous indications, and it is currently mainly administered to prevent jet lag and to improve the onset, duration and quality of sleep (at a dose of 0.5-5 mg before going to sleep, with a maximum dosage of 10-20 mg) [42,43]. Moreover, when administered before anesthesia, it may reduce preoperative anxiety in adults, being as effective as midazolam [44]. ...
Melatonin modulates the circadian rhythm and has been studied as a preventive measure against the development of delirium in hospitalized patients. Such an effect may be more evident in patients admitted to the ICU, but findings from the literature are conflicting. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). We assessed whether melatonin or ramelteon (melatonin agonist) reduce delirium incidence as compared to a placebo in ICU patients. Secondary outcomes were ICU length of stay, duration of mechanical ventilation (MV) and mortality. Estimates are presented as risk ratio (RR) or mean differences (MD) with 95% confidence interval (CI). Nine RCTs were included, six of them reporting delirium incidence. Neither melatonin nor ramelteon reduced delirium incidence (RR 0.76 (0.54, 1.07), p = 0.12; I 2 = 64%), although a sensitivity analysis conducted adding other four studies showed a reduction in the risk of delirium (RR = 0.67 (95%CI 0.48, 0.92), p = 0.01; I 2 = 67). Among the secondary outcomes, we found a trend towards a reduction in the duration of MV (MD −2.80 (−6.06, 0.47), p = 0.09; I 2 = 94%) but no differences in ICU-LOS (MD −0.26 (95%CI −0.89, 0.37), p = 0.42; I 2 = 75%) and mortality (RR = 0.85 (95%CI 0.63, 1.15), p = 0.30; I 2 = 0%). Melatonin and ramelteon do not seem to reduce delirium incidence in ICU patients but evidence is weak. More studies are needed to confirm this finding.
... Due to its chronobiotic properties, exogenous melatonin is used to treat a variety of sleep conditions associated with shifted or abnormal circadian clocks [26,82], such as insomnia [83], jetlag [84], and shift-work syndrome [26], despite inconsistent evidence for sleep improvement [26,85]. In people with or without insomnia, melatonin reduces sleep onset latency and increases total sleep duration, though it is unknown whether these changes are clinically meaningful [73,86]. ...
In this narrative review, we describe what is known about non-pharmacological and pharmacological treatments for insomnia in medical inpatients, with a focus on melatonin. Hospital-acquired insomnia is common, resulting in shortened total sleep time and more nighttime awakenings. Sleep disturbance has been shown to increase systemic inflammation, pain, and the likelihood of developing delirium in hospital. Treatment for insomnia includes both non-pharmacological and pharmacological interventions, the latter of which requires careful consideration of risks and benefits given the known adverse effects. Though benzodiazepines and non-benzodiazepine benzodiazepine receptor agonists are commonly prescribed (i.e., sedative-hypnotics), they are relatively contraindicated for patients over the age of 65 due to the risk of increased falls, cognitive decline, and potential for withdrawal symptoms after long-term use. Exogenous melatonin has a comparatively low likelihood of adverse effects and drug–drug interactions and is at least as effective as other sedative-hypnotics. Though more research is needed on both its effectiveness and relative safety for inpatients, small doses of melatonin before bedtime may be an appropriate choice for inpatients when insomnia persists despite non-pharmacological interventions.
... Appropriately timed bright light exposure prior to travel has been shown to shift circadian rhythms in the desired direction, but requires high motivation and strict compliance with a prescribed light-dark schedule (2,5). Circadian rhythms can also be shifted post-arrival and there is some evidence that melatonin administered at the appropriate time can reduce the symptoms of jet lag and improve sleep after crossing multiple time zones (6,7). While hypnotics can be used to stimulate sleep and stimulants can be used to promote alertness, the potential negative side effects must be weighed against their ultimate usefulness. ...
Jet Lag Disorder is a Circadian Rhythm Sleep-Wake Disorder resulting from a misalignment of the endogenous circadian clock and the sleep and wake pattern required by a change in time zone. Jet lag is most severe following eastward travel. This multicenter, randomized, placebo-controlled clinical trial (JET) assessed the physiological mechanism of jet lag induced by a real-life transmeridian flight and evaluated the efficacy of tasimelteon—a circadian regulator acting as a dual melatonin receptor agonist, in the treatment of Jet Lag Disorder (JLD). Tasimelteon-treated participants slept 76 min longer on Night 3 during their second trip (evaluation phase) as compared to their first (observational phase). Over the three travel nights evaluated, transmeridian jet travelers in the tasimelteon group slept 131 min more (TST2/3) than those in the placebo group. The JET study demonstrated clinically meaningful improvements in nighttime sleep and daytime alertness in both objective and subjective measures as well as global functioning after a real-world flight. These results suggest that tasimelteon can be an effective therapeutic tool to treat JLD in the context of transmeridian travel.
... 15,16 As of 2011, over 40 cases of glucosamine-warfarin interactions had been reported by various drug-monitoring agencies. 17 While there is no higher level evidence available, case reports have associated melatonin, 18 turmeric, 19,20 bilberry, 21 chamomile, 22 fenugreek, 23 milk thistle, 24 and peppermint 25 with increased INR or bleeding in patients on warfarin (Table 3). Another case report described fatal gastrointestinal bleeding in a patient taking dabigatran along with cinnamon and ginger. ...
An estimated one-third of US adults use herbal supplements, often without reporting that use to their physicians. These supplements can potentially alter bleeding and coagulation during surgery and when used concomitantly with anticoagulants. Our objective was to provide a comprehensive review of the evidence of bleeding risks of the most popular herbal and dietary supplements. A PubMed search and review of the literature was performed. We found that garlic and hawthorn supplementation is strongly associated with surgical bleeding independent of anticoagulants. Cordyceps sinensis, echinacea, and aloe vera are loosely associated with surgical bleeding independent of anticoagulants. In patients on anticoagulants, ginkgo biloba, chondroitin-glucosamine, melatonin, turmeric, bilberry, chamomile, fenugreek, milk thistle, and peppermint are associated with bleeding risk. No evidence was found for bleeding with these supplements independent of anticoagulants. Fish oil, ginseng, and saw palmetto are not associated with bleeding. Evidence for overall bleeding risk associated with St. John’s wort, ginger, ginkgo biloba, or cranberry supplementation is conflicting. In conclusion, physicians must be aware of the potential anticoagulant effects of these supplements. It is imperative to report dietary and herbal supplement usage to physicians and is best to discontinue nonessential supplement use 2 weeks prior to surgery.
... Each of these three queries has a different ground-truth answer. According to their corresponding Cochrane reviews 2 : Ginkgo biloba is not effective in treating tinnitus [21]; Melatonin is effective in treating jet-lag [20]; and for omega-3 the answer is inconclusive and further study is required in order to reach a conclusion [15]. The detailed search result entries were manually retrieved by searching the above queries in well-known search engines. ...
Advertisements (ads) are an innate part of search engine business models. Advertisers are willing to pay search engines to promote their content to a prominent position in the search result page (SERP). This raises concerns about the search engine manipulation effect (SEME): the opinions of users can be influenced by the way search results are presented. In this work, we investigate the connection between SEME and sponsored content in the health domain. We conduct a series of user studies in which participants need to evaluate the effectiveness of different non-prescription natural remedies for various medical conditions. We present participants SERPs with different intentionally created biases towards certain viewpoints, with or without sponsored content, and ask them to evaluate the effectiveness of the treatment only based on the information presented to them. We investigate two types of sponsored content: 1. Direct marketing ads that directly market the product without expressing an opinion about its effectiveness, and 2. Indirect marketing ads that explicitly advocate the product's effectiveness on the condition in the query. Our results reveal a significant difference between the influence on users from these two ad types. Though direct marketing ads are mostly skipped by users, they can tilt users decision making towards more positive viewpoints. Indirect marketing ads affect both the users' examination behaviour and their perception of the treatment's effectiveness. We further discover that the contrast between the indirect marketing ads and the viewpoint presented in the organic search results plays an important role in users' decision-making. When the contrast is high, users exhibit a strong preference towards a negative viewpoint, and when the contrast is low or none, users exhibit preference towards a more positive viewpoint.
... reduced sleep onset latency, increased total sleep time, and improved sleep quality [135]. It has also shown beneficial effects in treating jet lag and shift work symptoms and neurological and psychiatric conditions like attention deficit hyperactivity disorder and MDD [134,136]. ...
A complex pathogenesis involving several physiological systems is theorized to underline the development of depressive disorders. Depression is accompanied by circadian regulation disruption and interaction with the functioning of both central and peripheral oscillators. Many aspects of melatonin function unite these systems. The use of drugs for circadian rhythm disorders could inspire a potential treatment strategy for depression. Melatonin plays an essential role in the regulation of circadian rhythms. It exerts effect by activating two types of melatonin receptors, type 1A (MT1) and 1B (MT2). These are G-protein-coupled receptors, predominantly located in the central nervous system. MT1/MT2 agonists could be a useful treatment approach according to all three prevalent theories of the pathogenesis of depression involving either monoamines, synaptic remodeling, or immune/inflammatory events. MT1/MT2 receptors can be a potential target for novel antidepressants with impact on concentrations of neurotrophins or neurotransmitters, and reducing levels of pro-inflammatory cytokines. There is an interesting cross-talk mediated via the physical association of melatonin and serotonin receptors into functional heteromers. The antidepressive and neurogenetic effects of MT1/MT2 agonists can also be caused by the inhibition of the acid sphingomyelinase, leading to reduced ceramide, or increasing monoamine oxidase A levels in the hippocampus. Compounds targeting MT1 and MT2 receptors could have potential for new anti-depressants that may improve the quality of therapeutic interventions in treating depression and relieving symptoms. In particular, a combined effect on MT1 and/or MT2 receptors and neurotransmitter systems may be useful, since the normalization of the circadian rhythm through the melatonergic system will probably contribute to improved treatment. In this review, we discuss melatonergic receptors as a potential additional target for novel drugs for depression.
... Foram demonstrados efeitos de sinergismo quando usada em combinação com a terapia de luz.49 As doses aconselhadas variam entre 05mg e 5mg, sendo que formulações de atuação imediata parecem ser as mais eficazes.50 Para atrasos no curso do sono, é recomendado o seu uso numa fase mais tardia do sono ou durante a manhã, pois esta irá avançar o circadiano fazendo com que o corpo pense que a noite chegou mais cedo; para avanços do sono, é recomendada a sua administração à noite.51 ...
Sleep is very important for the proper functioning of the human body and consists of several stages. This text will address the concepts of biological rhythms, the circadian rhythm and body temperature, which is considered the main biological marker of the circadian rhythm. Their disorders have an influence on the athlete’s performance, with jet lag being approached. The diagnosis of these disorders can be made through various subjective and objective methods. Finally, adaptation strategies will be mentioned, addressing physical exercise, diet, and medication, among others.
... 203 As such, melatonin may be used to help realign sleep-wake timing and facilitate daytime sleep for night shift workers 204 or to help overcome jet lag after travel across time zones. 205 Optimizing the timing of melatonin administration is critical to achieving the desired effect, with morning administration leading to delays of the biological clock (shifting sleep later) and evening ...
Risks associated with fatigue that accumulates during work shifts have historically been managed through working time arrangements that specify fixed maximum durations of work shifts and minimum durations of time off. By themselves, such arrangements are not sufficient to curb risks to performance, safety, and health caused by misalignment between work schedules and the biological regulation of waking alertness and sleep. Science-based approaches for determining shift duration and mitigating associated risks, while addressing operational needs, require: 1) a recognition of the factors contributing to fatigue and fatigue-related risks; 2) an understanding of evidence-based countermeasures that may reduce fatigue and/or fatigue-related risks; and 3) an informed approach to selecting workplace-specific strategies for managing work hours. We propose a series of guiding principles to assist stakeholders with designing a shift duration decision-making process that effectively balances the need to meet operational demands with the need to manage fatigue-related risks.
... Melatonin is a neurohormone that is synthesized by the pineal gland during dark periods and regularizes the sleep-wake rhythm [108]. Immediate-release melatonin supplements have provided solid evidence in regularizing circadian rhythm alterations [130], in combination or without BZD assumption. Melatonin elicited an increasing interest as a result of neurobiological studies that found a higher suppression of melatonin in response to light in patients with BD [131]. ...
The onset of prodromal symptoms in subjects who are at familial or clinical risk for bipolar disorder could be considered as an important alarm bell for the development of the disease and should be carefully detected. The management of prodromes in bipolar high-risk patients appears to be an important means of prevention; nevertheless, at the moment, there aren’t clear and widely shared treatment indications. The aim of this review is to summarize the available treatment options (pharmacological, psychosocial and nutraceutical) for the management of prodromal symptoms in subjects who are at familial or clinical risk for bipolar disorder.
... The rapid crossing of time zones causes the internal clock and external event cues to lose synchronization, leading to a variety of physical discomfort symptoms collectively known as jet lag [1]. Jet lag may produce many effects, such as decreased sleep quality at night, daytime drowsiness, decreased alertness, fatigue, increased negative mood, cardiac dysfunction and gastrointestinal upset [2][3][4][5][6]. In addition, jet lag with a phase advance is thought to be more difficult to recover than that with a phase delay, which may be related to the fact that the body's endogenous rhythm phase is slightly longer than 24 h [7]. ...
Light has been found to affect the circadian clock of the human body. This study aims at exploring the proper light scheme for improving performance and alleviating the negative effects of phase-advance jet lag. Herein, the light intervention intensity during an 8-h working time after a simulated eastward flight is set as a variable. 27 healthy young adults participate in a 7-day circadian phase control and 4-day closed circadian conversion experiment. Participants are assigned to three groups according to lighting conditions: (1) control lighting group (CLG), (2) low-intervention group (LIG), and (3) high-intervention group (HIG). The alertness, sleep quality, and circadian phases of the participants are measured during the closed circadian conversion stage. Statistical analysis results show that, compared to CLG, HIG can effectively reduce the effect of the phase-advance jet lag syndrome on alertness during daytime (p = .028), improve short-term memory task performance (p < .001), and reduce visual fatigue (p = .016); besides, the 8-h light intervention during daytime assists in improving sleep quality. The results for dim light melatonin onset (DLMO) evidence that the HIG scheme can advance the circadian phase by 7.17 ± 0.71 h and is thus recommended for adjusting phase-advance jet lag in interior public workplaces. Finally, a model between light stimulus intensity and the circadian phase shift is deduced with a high correlation R² > 0.99.
... In addition, melatonin can be used to aid in entrainment. One strategy suggests evening melatonin therapy dosed at 2 mg or 5 mg upon arrival at the destination bedtime for 4-5 days [82][83][84], or some studies have recommended a more complex regimen initiating melatonin therapy 5 mg in the native time zone at the corresponding destination bedtime for 3 days prior to travel, and continued therapy for 3-4 days in the new time zone [85,86]. ...
Circadian rhythms oscillate throughout a 24-h period and impact many physiological processes and aspects of daily life, including feeding behaviors, regulation of the sleep-wake cycle, and metabolic homeostasis. Misalignment between the endogenous biological clock and exogenous light–dark cycle can cause significant distress and dysfunction, and treatment aims for resynchronization with the external clock and environment. This article begins with a brief historical context of progress in the understanding of circadian rhythms, and then provides an overview of circadian neurobiology and the endogenous molecular clock. Various tools used in the diagnosis of circadian rhythm sleep–wake disorders, including sleep diaries and actigraphy monitoring, are then discussed, as are the therapeutic applications of strategically timed light therapy, melatonin, and other behavioral and pharmacological therapies including the melatonin agonist tasimelteon. Management strategies towards each major human circadian sleep–wake rhythm disorder, as outlined in the current International Classification of Sleep Disorders – Third Edition, including jet lag and shift work disorders, delayed and advanced sleep–wake phase rhythm disorders, non-24-h sleep–wake rhythm disorder, and irregular sleep–wake rhythm disorder are summarized. Last, an overview of chronotherapies and the circadian dysregulation of neurodegenerative diseases is reviewed.
... 167 A Cochrane systematic review found that the short-term use of melatonin can be safe and effective in the prevention of jet lag. 168 It is recommended to take a single dose of 2 to 5 mg 2 to 3 hours before bedtime and up to 4 days after arrival at the traveller's destination. Melatonin decreases the latency of sleep onset and increases sleep efficiency and duration. ...
Introduction: Primary care practitioners and travel medicine physicians are primarily responsible for identifying individuals who may be unfit for overseas travel and consulting with them pre-travel. Pre-existing medical conditions such as cardiovascular disease, chronic respiratory conditions and diabetes mellitus (DM) have the potential to complicate travel journeys. A considerable percentage of travel-associated illness may be due to the decompensation of a pre-existing medical condition. This review seeks to address the challenges faced by travellers with each of these conditions, including recently updated and evidence-based practical approaches for travel with comorbidities.
Methods: Sources for this review were identified through searches of PubMed/Google Scholar for materials published between 1st January 2000 and 31st December 2019, using combinations of search terms.
Results: The volume of literature on travelling with a pre-existing condition exploded with more than 865 associated articles indexed on the PubMed alone as of March 2020. After screening titles, abstracts and, in some cases, the full text version of indexed articles, 121 articles were deemed relevant to the subject matter of this review.
Conclusion: Rational approaches to pre-planning for travel with a medical condition will contribute to the prevention of problems while in transit as well as when at the travel destination. It is imperative for health care providers to be aware of the preventative measures and current recommendations that should be taken before and during travel to protect individuals with a chronic illness. Further research and studies should be directed to protect this vulnerable group of travellers.
... Pineal melatonin release in both diurnal and nocturnal animals starts during sundown and peaks in the middle of the night 128 . The ingestion of melatonin promotes sleep and has been used to lengthen sleep duration in rotating shift workers or to alleviate jet-lagassociated symptoms 129,130 . Although melatonin appears to be neither necessary nor sufficient to maintain circadian rhythms, animal studies indicate that melatonin can synchronize circadian rhythms through the activation of melatonin receptors 131 . ...
Many molecular, physiological and behavioural processes display distinct 24-hour rhythms that are directed by the circadian system. The master clock, located in the suprachiasmatic nucleus region of the hypothalamus, is synchronized or entrained by the light–dark cycle and, in turn, synchronizes clocks present in peripheral tissues and organs. Other environmental cues, most importantly feeding time, also synchronize peripheral clocks. In this way, the circadian system can prepare the body for predictable environmental changes such as the availability of nutrients during the normal feeding period. This Review summarizes existing knowledge about the diurnal regulation of gastrointestinal processes by circadian clocks present in the digestive tract and its accessory organs. The circadian control of gastrointestinal digestion, motility, hormones and barrier function as well as of the gut microbiota are discussed. An overview is given of the interplay between different circadian clocks in the digestive system that regulate glucose homeostasis and lipid and bile acid metabolism. Additionally, the bidirectional interaction between the master clock and peripheral clocks in the digestive system, encompassing different entraining factors, is described. Finally, the possible behavioural adjustments or pharmacological strategies for the prevention and treatment of the adverse effects of chronodisruption are outlined.
... Although the 50 mg dose significantly improved TST by 10 min compared to the 5 mg, it was not considered clinically relevant. Similarly, a systematic review [52] assessing the effectiveness of different oral doses of melatonin for jetlag concluded that doses over 5 mg did not confer any advantage for alleviating jet lag symptoms. It has been suggested that [53] the optimal dose for adults over 55 y should attempt to mimic normal physiological levels of melatonin and the lowest possible dose of immediate release formulation should be used [63]. ...
There is conflicting evidence on the clinical efficacy of exogenous melatonin for the treatment of sleep disorders. This may be due to differences in the pharmacokinetic (PK) properties of melatonin formulations used in clinical trials. The aim of this systematic review was to understand the relationship between melatonin formulations and PK parameters and, where possible, the effects on sleep outcomes. To this purpose, we conducted a systematic review and nineteen papers were included. The studies included three melatonin transdermal formulation, thirteen oral formulations, one topical, two buccal, two intravenous and two nasogastric formulations. Seven studies investigated the effect of the melatonin formulation on sleep and six of them found a significant improvement in one or more sleep parameters. The potential for an improved controlled release formulation that delays maximum concentration (Cmax) was identified. The different formulations and doses affect melatonin PK, suggesting that treatment efficacy maybe affected. Based on the current evidence, we are unable to provide recommendations of specific melatonin formulations and PK parameters for specific sleep disorders. Future studies should systematically investigate how different PK parameters of melatonin formulations affect efficacy treatment of sleep as well as circadian disorders.
... Samuels (2012) suggested that a reduction in the volume and intensity of pre-flight training sessions may help with adaptation following arrival at the destination. Moreover, pharmacological interventions involving melatonin (Herxheimer & Petrie, 2002) and caffeine (Schweitzer et al., 2006) have been shown to be effective in helping people recover a proper circadian rhythm. ...
The study detailed here has sought to assess the physical and technical activity engaged in by football players in the light of the direction of travel in which time zones were crossed as players transferred from training centres to match venues, in the context of matches played at the 2018 FIFA World Cup in Russia. The material consisted of 945 observations of 340 players. Analysed: total distances covered [km], distances covered with high-intensity running (20-25 km/h) [m], numbers of sprints, numbers of shots, numbers of passes, pass accuracy [%] and the official ranking of national teams. Three categories of time-zone shift (training centre → match venue) were taken account of, i.e. (1) West→East (WE), (2) Same Zone (SZ) and (3) East→West (EW). Analysis of results revealed that players in the EW and SZ categories were able to achieve results significantly better than those moving WE (total distances covered H = 11.815(2); p = 0.003; numbers of passes H = 7.630(2); p = 0.022), and this in relation to team placings in the end-of-tournament ranking (H = 18.099(2); p = 0.001). The results will be valuable in searching places for training centres during future FIFA World Cup and UEFA European Championship competitions.
... Strength of evidence Conditional Risk of harm [86][87][88][89][90][91][92][93][94] Mimimal Vitamin A Vitamin A is a micronutrient that is crucial for maintaining vision, promoting growth and development, and protecting epithelium and mucus integrity in the body. Vitamin A is known as an anti-inflammation vitamin because of its critical role in enhancing immune function. ...
As the novel infection with SARS-CoV-2 emerges, objective assessment of the scientific plausibility of nutraceutical and botanical interventions for prevention and treatment is important. We evaluate twelve such interventions with mechanisms of action that modulate the immune system, impair viral replication, and/or have been demonstrated to reduce severity of illness. These are examples of interventions that, mechanistically, can help protect patients in the presence of the prevalent and infectious SARS-CoV-2 virus. While there are limited studies to validate these agents to specifically prevent COVID-19, they have been chosen based upon their level of evidence for effectiveness and safety profiles, in the context of other viral infections. These agents are to be used in a patient-specific manner in concert with lifestyle interventions known to strengthen immune response (see related article in this issue of IMCJ).
... 138 Either preflight, 139 after arrival using melatonin, 140 141 bright light, 142 143 or exercise 144 ; or, a combination of prearrival and postarrival melatonin. 140 141 145 Readers are directed elsewhere for a review of interventions to minimise jet lag after westward and eastward flights. 145 146 There is a pressing need for real-world and robust studies to support the proposed strategies for adjusting the body clock after time zone transitions, for example, randomised controlled trials are required to assess the efficacy of melatonin and the advice on the use of bright light (online supplemental table 1). ...
ABSTRACT
Elite athletes are particularly susceptible to sleep inadequacies, characterised by habitual short sleep (<7 hours/night) and poor sleep quality (eg, sleep fragmentation). Athletic performance is reduced by a night or more without sleep, but the influence on performance of partial sleep restriction over 1–3 nights, a more real-world scenario, remains unclear. Studies investigating sleep in athletes often suffer from inadequate experimental control, a lack of females and questions concerning the validity of the chosen sleep assessment tools. Research only scratches the surface on how sleep influences athlete health. Studies in the wider population show that habitually sleeping <7 hours/night increases susceptibility to respiratory infection. Fortunately, much is known about the salient risk factors
for sleep inadequacy in athletes, enabling targeted interventions. For example, athlete sleep is influenced by sport-specific factors (relating to training, travel and competition) and non-sport factors (eg, female gender, stress and anxiety). This expert consensus culminates with a sleep toolbox for practitioners (eg, covering sleep education and screening) to mitigate these risk factors and optimise athlete sleep. A one-size-fits-all approach to athlete sleep recommendations (eg, 7–9 hours/night) is unlikely ideal for health and performance. We recommend an individualised approach that should consider the athlete’s perceived sleep needs. Research is needed into the benefits of napping and sleep extension (eg, banking sleep).
... Melatonin is a marker rhythm (Fig. 3). The evaluation of the melatonin profile is used to assess the synchronization/desynchronization of patients with certain diseases, such as circadian rhythm sleepwake disorders (Saeed et al., 2019;Selmaoui and Touitou, 2003;Zeitzer et al., 2014), or people performing shift work or night work, or experiencing jet lag (Depner et al., 2018;Herxheimer and Petrie, 2002;Reinberg et al., 2013). Decreased levels of plasma melatonin or of 6-sulfatoxymelatonin, its urinary metabolite, or disruption of melatonin's circadian rhythm have been shown to occur with, e.g., aging (Cugini et al., 2001;Magri et al., 2004;Touitou et al., 2000;Touitou, 2001;Zhao et al., 2002Zhao et al., , 2003, alcohol consumption (Dane and Touitou, 2004;Danel et al., 2009;Reinberg et al., 2010;Swanson et al., 2015) and several diseases such as retinal alterations (Touitou et al., 1986), seasonal affective disorders (Arendt and Middleton, 2018;Nussbaumer--Streit et al., 2019), autism (Gagnon and Godbout, 2018;Tordjman et al., 2005Tordjman et al., , 2012, mood disorders (Carpenter et al., 2017;McIntyre et al., 1989) and cancer (Sulli et al., 2019;Stevens et al., 2014;Touitou et al., 1995Touitou et al., , 1996. ...
White light-emitting diodes (LEDs) will likely become the most used lighting devices worldwide in the future because of their very low prices over the course of their long lifespans which can be up to several tens of thousands of hours. The expansion of LED use in both urban and domestic lighting has prompted questions regarding their possible health effects, because the light that they provide is potentially high in the harmful blue band (400-500 nm) of the visible light spectrum. Research on the potential effects of LEDs and their blue band on human health has followed three main directions: 1) examining their retinal phototoxicity 2) examining disruption of the internal clock, i.e., an out-of-sync clock, in shift workers and night workers, including the accompanying health issues, most concerningly an increased relative risk of cancer; and 3) examining risky, inappropriate late-night use of smartphones and consoles among children and adolescents. Here, we document the recognized or potential health issues associated with LED lighting together with their underlying mechanisms of action. There is so far no evidence that LED lighting is deleterious to human retina under normal use. However, exposure to artificial light at night is a new source of pollution because it affects the circadian clock. Blue-rich light, including cold white LEDs, should be considered a new endocrine disruptor, because it affects estrogen secretion and has unhealthful consequences in women, as demonstrated to occur via a complex mechanism.
PurposePostoperative sleep disturbances are common. Although several studies have examined the effect of melatonin on postoperative sleep disturbances, the results have not reached any definitive conclusion. We sought to conduct a systematic review to compare the effects of melatonin and melatonin agonists on postoperative sleep quality with those of placebo or no treatment in adult patients who underwent surgery under general or regional anesthesia.Methods
We searched MEDLINE, Cochrane Central Register of Controlled Trials, Embase, Web of Science, ClinicalTrials.gov, and the UMIN Clinical Trials Registry up to 18 April 2022. Randomized clinical trials examining the effects of melatonin or melatonin agonists in patients undergoing general or regional anesthesia with sedation for any surgery were eligible for inclusion. The primary outcome was sleep quality measured using a visual analog scale (VAS). The secondary outcomes were postoperative sleep duration, sleepiness, pain, opioid consumption, quality of recovery, and adverse events. A random-effects model was used to combine the results. We assessed study quality with the Cochrane Risk of Bias Tool version 2. We applied a trial sequential analysis to assess the precision of the combined results.ResultsEight studies (516 participants) were analyzed for sleep quality. Of those, four studies used only a short duration of melatonin, either on the night before and the day of surgery or only on the day of surgery. A random-effects meta-analysis showed that melatonin did not improve sleep quality measured by VAS compared with placebo (mean difference, -0.75 mm; 95% confidence interval, -4.86 to 3.35), with low heterogeneity (I2, 5%). Trial sequential analysis revealed that the accrued information size (n = 516) reached the estimated required information size (n = 295). We downgraded the certainty of the evidence because of the high risk of bias. The effect on postoperative adverse events was comparable between the melatonin and control groups.Conclusion
Our results indicate that melatonin supplementation does not improve postoperative sleep quality measured with the VAS compared with placebo in adult patients (GRADE: moderate).Study registrationPROSPERO (CRD42020180167); registered 27 October 2022.
After a flight across multiple time zones, most people show a transient state of circadian misalignment causing temporary malaise known as jetlag disorder. The severity of the elicited symptoms is postulated to depend mostly on circadian factors such as the number of time zones crossed and the direction of travel. Here, we examined the influence of prior expectation on symptom severity, compared to said “classic” determinants, in order to gauge potential psychosocial effects in jetlag disorder.
To this end, we monitored jetlag symptoms in travel-inexperienced individuals (n=90, 18-37y) via detailed questionnaires twice daily for one week before and after flights crossing >3 time zones. We found pronounced differences in individual symptom load that could be grouped into 4 basic symptom trajectories. Both traditional and newly devised metrics of jetlag symptom intensity and duration (accounting for individual symptom trajectories) recapitulated previous results of jetlag prevalence at about 50-60% as well as general symptom dynamics.
Surprisingly, however, regression models showed very low predictive power for any of the jetlag outcomes. The classic circadian determinants, including number of time zones crossed and direction of travel, exhibited little to no link with jetlag symptom intensity and duration. Only expectation emerged as a parameter with systematic, albeit small, predictive value.
These results suggest expectation as a relevant factor in jetlag experience - hinting at potential placebo effects and new treatment options. Our findings also caution against jetlag recommendations based on circadian principles but insufficient evidence linking circadian re-synchronization dynamics with ensuing symptom intensity and duration.
Significance Statement
Jetlag disorder afflicts millions of travelers each year - a nuisance on holiday trips but also a danger in safety and performance-critical operations. For effective prevention and treatment, it is critical to understand what influences jetlag severity, i.e. jetlag symptom intensity and duration. In contrast to what guidelines state, in our study, we did not find that symptom severity could be explained by the number of time zones crossed or travel direction. Rather, travelers’ expectations about how long and strongly they will suffer from jetlag symptoms was the only factor systematically predicting jetlag severity. If this holds true not only for subjective but also objective symptoms, we need to revisit assumptions about how circadian desynchronization relates to experienced jetlag symptoms.
An appreciable number of medicines have a recommended unique single time-of-day or asymmetrical or unequal-interval multiple-daily administration schedule. Many prescription and over-the-counter (OTC) products, according to administration time, can exert positive or negative impact on nighttime sleep and daytime wakefulness. Intuitively, medicines used to manage nighttime sleep and daytime wake disorders should be taken, respectively, at night before bedtime and morning after arising. However, some utilized for other medical conditions, if improperly timed, may compromise nocturnal sleep and diurnal attentiveness. We conducted a comprehensive review of the American Prescribers' Digital Reference, internet version of the Physician's Desk Reference, for the recommended scheduling of medications and OTC remedies that can impact sleep and wakefulness. The search revealed several hundred therapies of various classes -- α2-receptor agonists, antidepressants, barbiturates, central nervous system stimulants, benzodiazepines, dopamine agonists, dopamine norepinephrine reuptake inhibitors, selective norepinephrine reuptake inhibitors, eugeroics, γ-aminobutyric acid modulators, H1 and H3-receptor antagonists, melatonin analogues, OTC melatonin products, non-benzodiazepine benzodiazepine-receptor agonists, dual orexin-receptor antagonists, and serotonin modulators -- that have a recommended unique dosing schedule. The tables and text of this article are intended to guide the proper scheduling of these medicines to optimize desired and/or minimize undesired effects.
Medical research involving US active duty, reservist, and veteran populations can and should improve. Because the US healthcare system is accountable to active duty personnel, reservists, and veterans (ADRV), the US healthcare system must partner to improve healthcare and medical research. Aiming to summarize current issues and opportunities for ADRV research infrastructure alongside healthcare, an exploratory literature review was conducted. Additionally, a broad analysis of search utilizing Cochrane, Google Scholar, and PubMed from the years 2001 to 2021 was undertaken. There are opportunities to refine biomedical, social-behavioral, health service research (HSR), and other research portfolios involving ADRV. There are urgent and serious opportunities to improve the rigor and quality of research. Additionally, there is a clear need for coordinated implementation and translation of research. In this attention to research involving ADRV, the US government, public health, non-profit organizations, private industry, and individuals are birds of a feather. Advancing efforts for research improvement should be handled together.
Circadian rhythms are endogenous self-sustaining oscillations with a period of approximately 24 hours that impart daily rhythms to physiology and behavior. The circadian clock entrains to the 24-hour day-night cycle through environmental time cues such as light exposure and internal time cues such as melatonin secretion. Circadian rhythmicity is a significant determinant of sleep/wake timing, and disruption to the system and its ability to synchronize to the environment can manifest in circadian rhythm sleep-wake disorders (CRSWDs). The resulting sleep disturbances and circadian misalignment negatively impact quality of life, can interfere with occupational and social obligations, adversely impact mental health, and increase the risk of chronic disease. Due to the rarity of CRSWDs in the general population, patients are commonly misdiagnosed or experience a long delay before being correctly diagnosed. Circadian disorders are also difficult to diagnose as there is often overlap with psychiatric or other comorbid conditions. This chapter aims to provide practical and useful information regarding the CRSWDs to improve diagnosis and management of these disorders.
N-[2-(5-methoxy-1H-indol-3-yl) ethyl] or simply melatonin is a biogenic amine produced by pineal gland and recently recognized various other organs. Because of a broad range of biological function melatonin is considered as a therapeutic agent with high efficacy in the treatment of multiple disorders, such as cancer, degenerative disorders and immune disease. However, since melatonin can affect receptors on the cellular membrane, in the nucleus and can act as an anti-oxidant molecule, some unwanted effects may be observed after administration. Therefore, the entrapment of melatonin in biocompatible, biodegradable and safe nano-delivery systems can prevent its degradation in circulation; decrease its toxicity with increased half-life, enhanced pharmacokinetic profile leading to improved patient compliance. Because of this, nanoparticles have been used to deliver melatonin in multiple studies, and the present article aims to cumulatively illustrate their findings.
Importance
Melatonin is commonly used for sleep and jetlag at low doses. However, there is less documentation on the safety of higher doses which are being increasingly used for a wide variety of conditions, including more recently COVID-19 prevention and treatment.
Objective
To investigate the safety of higher doses of melatonin in adults.
Data Sources
Medline, Scopus, Embase and PsycINFO databases from inception until December 2019 with convenience searches until October 2020.
Study Selection
Randomised controlled trials investigating high-dose melatonin (≥10mg) in human adults over 30 years of age.
Data Extraction and Synthesis
2 investigators independently abstracted articles using PRISMA guidelines. Risk of bias was assessed by a committee of 3 investigators. 79 studies were identified with a total of 3861 participants. Studies included a large range of medical conditions. The meta-analysis was pooled data using a random effects model.
Main Outcomes and Measures
The number of adverse events (AEs), serious adverse events (SAEs) and withdrawals due to AEs.
Results
29 studies (37%) made no mention of the presence or absence of AEs. Overall, only 4 studies met the pre-specified low risk of bias criteria for meta-analysis. In that small subset melatonin did not cause a detectable increase in SAEs (Rate Ratio=0.88 [0.52, 1.50], p=0.64) or withdrawals due to AEs (0.93 [0.24, 3.56], p=0.92), but did appear to increase the risk of AEs such as drowsiness, headache, and dizziness (1.40, [1.15, 1.69], p<0.001).
Conclusions and Relevance
Overall, there has been limited AE reporting from large-dose melatonin studies. Based on this limited evidence, melatonin appears to have a good safety profile. Better safety reporting in future long-term trials is needed to confirm this as our confidence limits were very wide due to the paucity of suitable data.
Growing understanding of the finely orchestrated and integrated mechanisms governing sleep and wakefulness allow for new insights into sleep disorders and their pharmacological treatments. While sleep related conditions are many and diverse, this chapter focuses on the common ailments of insomnia and circadian rhythm disorders. We provide a brief overview of these conditions followed by a review of current pathophysiologic understandings for these conditions, which provide context to the subsequent medication review. While an in-depth review of the pharmacologic options is provided, section summaries and tables are included to allow for ease of accessibility and retrieval of the information.
Athletes are increasingly required to travel domestically and internationally, often resulting in travel fatigue and jet lag. Despite considerable agreement that travel fatigue and jet lag can be a real and impactful issue for athletes regarding performance and risk of illness and injury, evidence on optimal assessment and management is lacking. Therefore 26 researchers and/or clinicians with knowledge in travel fatigue, jet lag and sleep in the sports setting, formed an expert panel to formalise a review and consensus document. This manuscript includes definitions of terminology commonly used in the field of circadian physiology, outlines basic information on the human circadian system and how it is affected by time-givers, discusses the causes and consequences of travel fatigue and jet lag, and provides consensus on recommendations for managing travel fatigue and jet lag in athletes. The lack of evidence restricts the strength of recommendations that are possible but the consensus group identified the fundamental principles and interventions to consider for both the assessment and management of travel fatigue and jet lag. These are summarised in travel toolboxes including strategies for pre-flight, during flight and post-flight. The consensus group also outlined specific steps to advance theory and practice in these areas.
The current coronavirus disease 2019 (COVID‐19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), highlights major gaps in our knowledge on the prevention control and cross‐species transmission mechanisms of animal coronaviruses. Transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV), and porcine delta‐coronavirus (PDCoV) are three common swine coronaviruses and have similar clinical features. In absence of effective treatments, they have led to significant economic losses in the swine industry worldwide. We reported that indoles exerted potent activity against swine coronaviruses, the molecules used included melatonin, indole, tryptamine and L‐tryptophan. Herein, we did further systematic studies with melatonin, a ubiquitous and versatile molecule, and found it inhibited TGEV, PEDV, and PDCoV infection in PK‐15, Vero, or LLC‐PK1 cells by reducing viral entry and replication respectively. Collectively, we provide the molecular basis for the development of new treatments based on the ability of indoles to control TGEV, PEDV, and PDCoV infection and spread.
Hintergrund: Im Jahr 2019 wurden weltweit 1,5 Milliarden internationale touristische Reisen gezählt, wobei Deutschland mit 70,8 Millionen Urlaubsreisen von mehr als fünf Tagen Dauer zu den reisefreudigsten Nationen gehörte. Auch ältere und multimorbide Menschen unternehmen heute regelmäßig Fernreisen, welche mit relevanten gesundheitlichen Risiken verbunden sein können. Durch die Beratung von Reisenden und die Umsetzung präventiver Maßnahmen kann das Erkrankungsrisiko deutlich gesenkt werden.
Methode: Es wurde eine selektive PubMed-Recherche zu Publikationen in den Jahren 2000–2020 über reisemedizinische Gesundheitsberatung durchgeführt. Eingeschlossen wurden Leitlinien, Studien und Empfehlungen, die sich vorwiegend mit den präventiven Aspekten der Reisemedizin befassen, eine hohe Praxisrelevanz und einen möglichst hohen Evidenzgrad aufweisen. Bereits publizierte Empfehlungen (basierend auf den GRADE-Kriterien, „Grading of Recommendations, Assessment, Development and Evaluation“) wurden übernommen und solche ohne wissenschaftlichen Studienhintergrund als „Good Clinical Practice“ (GCP) gekennzeichnet.
Ergebnisse: Viele reisemedizinische Empfehlungen basieren weiterhin auf individualisierten, erfahrungs- oder konsensusbasierten Bewertungen. Neben der Erhebung von Anamnese und Impfstatus wird eine Risikoanalyse vorgenommen, die Reisefähigkeit individuell beurteilt sowie ein Prophylaxeplan erstellt. Besonderes Augenmerk gilt der Malariaprophylaxe, dem Vektorschutz und der Reisediarrhö. Spezielle Anforderungen an die Reiseberatung bestehen bei älteren Personen, Kindern, Schwangeren, chronisch Kranken, Langzeit- und Abenteuerreisenden sowie bei Migranten, die aus Malaria-Endemiegebieten stammen und eine Heimreise antreten.
Schlussfolgerung: Durch eine qualifizierte reisemedizinische Beratung lassen sich reiseassoziierte Gesundheitsrisiken minimieren. Viele Empfehlungen sind empirischer Natur und bedürfen weiterer Forschung.
Background: In 2019, 1.5 billion international tourist trips were counted worldwide. Germany, with 70.8 million vacations lasting ≥ 5 days, was one of the populations most willing to travel. These days, even elderly and multimorbid persons regularly travel long-distance, which can be associated with significant health risks. By advising travelers and implementing preventive measures, the risk of illness can be reduced significantly.
Methods: A selective survey of PubMed was performed to identify publications on medical advice for travelers between 2000 and 2020. We included guidelines, studies, and recommendations that mainly deal with the preventive aspects of travel medicine and have a high level of practical relevance and the highest possible level of evidence. Previously published guidelines (based on the GRADE criteria) were adopted, and recommendations not based on the results of scientific studies were characterized as Good Clinical Practice (GCP).
Results: Many medical recommendations for travelers still rely on individualized, experience-based, or consensus-based assessments. Apart from a review of medical history and vaccination status, a risk analysis is performed, travel fitness is evaluated individually, and a prevention plan is designed. Particular attention is devoted to malaria prophylaxis, vector protection, and traveler's diarrhea. Medical advice before travel is especially important for the elderly, children, pregnant women, the chronically ill, long-term and adventure travelers as well as migrants from malaria-endemic areas who are returning home.
Conclusion: The health risks associated with travel can be minimized by specialist medical advice. Many recommendations are empirical in nature and require further research.
Discovered in the 1950s, melatonin is a natural hormone produced by our body. Its secretion is influenced by the alternation of day and night and by environmental factors. Because of its pharmacological properties, it is given many properties, some of which are still to be explored, such as antioxidant effects, oncostatic, antiaging, or a role in the immune system. More recently, more and more research on this molecule has focused on the potential hypnotic power of melatonin, nicknamed “sleep hormone.” Because of its pharmacological properties, it has many properties, some of which are still to be explored, such as antioxidant effects, oncostatic, anti-aging, or a role in the immune system. More recently, more and more research on this molecule has focused on the potential hypnotic power of melatonin, nicknamed “sleep hormone.” Indeed, insomnia is a widespread phenomenon in the population, and we find sleep disorders at any age of life. Insomnia affects nearly a quarter of French people, especially women and the elderly. Melatonin has a certain role in the resynchronization of our biological clock; it is wise to ask if this hormone can bring a benefit in insomnia, in a country that remains the leading consumer of sleeping pills in Europe and at a time when we find more and more a desire to heal by natural methods. Its efficacy has been demonstrated in the treatment of circadian rhythm desynchronization syndromes; this thesis aims to clarify the place that a melatonin intake can occupy in the therapeutic arsenal of the management of insomnia and to recall the advice promoting better sleep.
Uykunun Egzersiz Performansı Üzerine Etkisi: Uyku, Beslenme ve Toparlanma İlişkisi
Amaç: Bu araştırmanın amacı, uykunun egzersiz performansı üzerindeki atletik, fizyolojik ve bilişsel etkileri ile uyku kalitesinin artmasına yardımcı olabilecek beslenme önerilerini incelemektir.
Yöntem: Araştırma, literatür taraması ve içerik analiz yöntemi kullanılarak yapılan derleme türü bir çalışmadır. Çalışmaya ait literatür verileri konuya ışık tutabilecek akademik yayınlar ve nitelikli kitaplardan elde edilmiştir. Bu doğrultuda PubMed, Google Scholar, ScienceDirect veritabanlarında ‘Sleep’, ‘Sleep and Performance’, ‘the importance of sleep’ ve ‘Uyku ve Egzersiz’ anahtar kelimeleri ile tarama yapılarak yayınlanan araştırmalar çalışmanın amacına uygun şekilde incelenmiş ve derlenmiştir.
Bulgular: Çalışmaya dahil edilen literatür veriler, uykunun en temel fizyolojik ihtiyacın çok ötesinde, sporcuların antrenman performansı, toparlanma, bilişsel performans ve dengeli ruh hali gibi en önemli noktalar için kritik bir role sahip olduğunu göstermektedir. Yapılan çalışmalar sporcular için 6-8 saat uykunun yeterli olabileceğini, bir gecelik uyku eksikliğinin performans üzerine direkt olumsuz etkisinin olmayacağını belirtmektedir. Triptofan yönünden zengin besinlerin uyku kalitesini arttırdığı, alkol ve kafein gibi uyarıcıların uyku üzerine olumsuz etkilerinin olabileceği görülmektedir.
Sonuç: Sonuç olarak sporcular için antrenman harici performans gelişimini destekleyen en önemli unsurlardan biri uyku olmaktadır. Hem fiziksel hem de ruhsal etkileri olan uyku, beslenme ve toparlanma ile de doğrudan ilişkisi olması sebebiyle yaşam boyu dikkat edilmesi gereken çok önemli bir fizyolojik ihtiyaçtır.
Effect of Sleep on Exercise Performance: The Relationship Between Sleep, Nutrition and Recovery
Purpose: The aim of this study is to examine the athletic, physiological and cognitive effects of sleep on exercise performance and nutritional recommendations that can help increase sleep quality.
Method: The research is a compilation style study using the literature review and content analysis method. The literature data of the study were obtained from academic publications and qualified books that can shed light on the subject. In this respect, the researches published by scanning the PubMed, Google Scholar, ScienceDirect databases with the keywords 'Sleep', 'Sleep and Performance', 'the importance of sleep' and 'Sleep and Exercise' were examined and compiled in accordance with the purpose of the study.
Results: The literature data included in the study shows that sleep has a critical role in the most important aspects of athletes such as training performance, recovery, cognitive performance and balanced mood, far beyond the most basic physiological needs. Studies indicate that 6-8 hours of sleep may be sufficient for athletes, and lack of sleep for one night will not have a direct negative effect on performance. It is observed that foods rich in tryptophan increase sleep quality, and stimulants such as alcohol and caffeine may have negative effects on sleep.
Conclusion: As a result, sleep is one of the most important factors supporting non-training performance development for athletes. It is a very important physiological need that should be considered throughout life, as it is directly related to sleep, nutrition and recovery, which have both physical and mental effects.
Introduction:
We aimed to investigate the pharmacokinetic properties and safety of melatonin administered by alternative routes of administration.
Methods:
This study employed a cross-over design in healthy female volunteers. Twenty-five milligrams of melatonin was administered intravenously, intravesically, rectally, transdermally, and vaginally. Blood samples were collected at specified time points up to 24 h following intravenous, intravesical, rectal, and vaginal administration, and up to 48 h following transdermal administration. Plasma melatonin concentrations were determined by radioimmunoassay. Sedation was evaluated by a simple reaction-time test, and sleepiness was assessed by the Karolinska Sleepiness Scale. Adverse events were registered for each route of administration.
Results:
Ten participants were included. We documented a mean (SD) time to maximal concentration of 51 (29) min for intravesical, 24 (20) min for rectal, 21 (8) h for transdermal, and 147 (56) min for vaginal administration. The mean (SD) elimination half-life was 47 (6) min for intravenous, 58 (7) min for intravesical, 60 (18) min for rectal, 14.6 (11.1) h for transdermal, and 129 (17) min for vaginal administration. The mean (SD) bioavailability was 3.6 (1.9)% for intravesical, 36.0 (28.6)% for rectal, 10.0 (5.7)% for transdermal, and 97.8 (31.7)% for vaginal administration. No significant changes in reaction times were observed following administration of melatonin by any of the administration routes. Increased tiredness was documented following transdermal administration only. No serious adverse effects were documented.
Conclusion:
Rectally and vaginally administered melatonin may serve as relevant alternatives to standard oral melatonin therapy. Transdermal delivery of melatonin displayed an extended absorption and can be applied if prolonged effects are intended. Intravesical administration displayed, as expected, a very limited bioavailability. Melatonin administered by these routes of administration was safe.
PurposeDiabetes mellitus is a complex metabolic disorder characterized by hyperglycemia occurring as a result of dysregulation and balance of various metabolic pathways. In recent years, circadian misalignment (due to altered sleep/wake, feeding/fasting cycles), has been intimately linked with the development of diabetes mellitus. Herein, we review our knowledge of oxidative stress, circadian rhythms control of metabolism, and the effects of its disruption on homeostasis while emphasizing the importance of melatonin, a nocturnally peaking, pineal hormone, as a potential therapeutic drug for the prevention and treatment of diabetes.Methods
PubMed database was systematically searched for related articles and data from all types of studies, including clinical trials, review articles, and case reports were considered without limiting the study to one specific category.ResultsExperimental and epidemiological evidence indicate melatonin’s multifaceted effects in intermediary metabolism via resynchronization of the circadian rhythms and its deficiency is associated with metabolic derangements. As a chronobiotic, it cures insomnia and sleep disorders caused by shift work or jet lag. The antagonistic relationship between melatonin and insulin highlights its influence in regulating insulin secretion, its action, and melatonin treatment successfully improved glucose homeostasis, energy balance, and overall health in diabetes mellitus. Melatonin’s cytoprotective role as an antioxidant and free radical scavenger, proved useful in combating oxidative stress, preserving beta-cell function, and influencing the development of diabetic complications.Conclusion
The therapeutic application of melatonin as a chronobiotic and cytoprotective agent is of promising significance in diabetes mellitus. Future investigations are encouraged to fully explore the efficacy of this ubiquitous molecule in various metabolic disorders.
The pineal gland is a interface between light-dark cycle and shows neuro-endocrine functions. Melatonin is the primary hormone of pineal gland, secreted at night. The night-time melatonin peak regulates the physiological functions at dark. Melatonin has several unique features as it synchronises internal rhythm with daily and seasonal variations, regulates circadian rhythm and sleep-wake cycle. Physiologically melatonin involves in detoxification of free radicals, immune functions, neuro-protection, oncostatic effects, cardiovascular functions, reproduction, and foetal development. The precise functions of melatonin are exhibited by specific receptors. In relation to pathophysiology, impaired melatonin secretion promotes sleep disorder, cancer progression, type-2 diabetes, and neurodegenerative diseases. Several reports have highlighted the therapeutic benefits of melatonin specially related to cancer protection, sleep disorder, psychiatric disorders, and jet lag problems. This review will touch the most of the area of melatonin-oriented health impacts and its therapeutic aspects.
OBJECTIVE
To evaluate the relationship between melatonin and organ transplantation.
METHODS
A systematic review was performed in PubMed databases using the search terms: “melatonin physiology” or “melatonin therapy” and “transplant pharmacology” or “transplant physiology” or “transplant therapy” or “Transplant therapy”. Experiments on the organs of the reproductive system were not included. After analysis, five articles were selected after reading the title and abstract of 50 manuscripts. The works were divided into two aspects: a) analysis of the influence of the organ transplantation procedure on melatonin production; b) action of melatonin on organ transplantation.
RESULTS
The cardiac transplantation surgical procedure, immunosuppression, and graft did not influence melatonin secretion in rodents, but there was a significant reduction of melatonin in the renal transplantation procedure in patients with renal insufficiency. Melatonin administration in experimental models decreased rejection and improved transplant success.
CONCLUSION
Studies show that melatonin can reduce organ and species dependence, and the use of melatonin decreases graft rejection.
The present study aimed to review the epidemiology, clinical manifestation, laboratory diagnosis, treatment, and future perspectives related to COVID-19 infections. The following electronic databases were used searched: MEDLINE, SCIELO, and LILACS. It became clear that COVID-19 infections occur through exposure to the virus, and both the immunosuppressed and healthy population appear susceptible. The clinical course of COVID-19 is still not clear, although the SARS-CoV-2 infection seems to develop with mild, influenza-like symptoms in the vast majority of subjects, i.e., 10%–15% of COVID-19 patients. Since rRT-PCR tests serve as the gold standard method to confirm a SARS-CoV-2 infection, false-negative results could hinder the prevention and control of the epidemic, particularly considering the test plays a key role in the decision for continued isolated medical observation or discharge. Our findings also indicate that a radical increase in the identification and isolation of currently undocumented infections would be needed to fully control SARS-CoV2.
Objectives
Current options for treating emergent episodes of hypomania and mania in bipolar disorder are limited. Our objective was to compare the effectiveness and safety of add‐on melatonin in hypomania or mania over three weeks as a well‐tolerated therapy.
Methods
A randomised, double‐blind, parallel‐group, three‐week comparison of modified release melatonin (n=21) vs placebo (n=20) in adult bipolar patients aged 18‐65 years. Permuted block randomisation was used with participants and investigators masked to treatment allocation. Trial registration is ISRCTN28988273 and EUdraCT2008‐000281‐23. Approved by the South Central National Research Ethics Service (Oxford REC A) ref: 09/H0604/63.
Results
The trial was negative as there was no significant difference between melatonin and placebo on the primary outcome – mean Young Mania Rating Scale (YMRS) score at Day 21: (mean difference (MD) ‐1.77 ([95%CI:‐6.39 to 2.85]; p=0.447). Significantly fewer patients on melatonin scored 10 or more on the Altman Self Rating Mania Scale (ASRM): (odds ratio (OR) 0.164 [95% CI: 0.0260 to 1.0002]; p=0.05). Quick Inventory of Depression Symptomatology Clinician Version‐16 (QIDS‐C16) scores were not significantly different. (OR 1.77 [95% CI:0.43 to 7.29]; p=0.430). The proportion of patients scoring less than or equal to 5 on the self‐report QIDS‐SR16 at end‐point was greater for the melatonin group (OR 8.35[95% CI:1.04 to 67.23]; p=0.046).
Conclusions
In this small trial melatonin did not effectively treat emerging hypomania or mania as there was no significant difference on the primary outcome. The sample size limitation and secondary outcomes suggest further investigation of melatonin treatment in mood episodes is indicated.
Jet lag and shift lag have similar physiological consequences, but shift lag is a more complex problem. The most severe desynchronization may be experienced by airline personnel making transmeridian flights. Coping strategies for eastward and westward travelers and for shiftworkers are recommended, as are interventions involving melatonin.
To determine whether doses of the pineal hormone melatonin alleviate jet lag.
Double blind, placebo controlled crossover trial.
Long haul return flights from Auckland, New Zealand, to London and back.
Twenty volunteers with experience of transcontinental flights (eight women and 12 men aged 28 to 68).
Melatonin (or placebo) 5 mg three days before flight, during flight, and once a day for three days after arrival.
Symptoms of jet lag.
Visual analogue scale for feelings of jet lag and tiredness; profile of moods states questionnaire for vigour-activity and fatigue-inertia; and retrospective ratings 10 days after arrival of sleep pattern, energy, and daytime tiredness. Feelings of jet lag were less for subjects taking melatonin (mean score 2.15 v 3.4); these subjects took fewer days than the placebo group to establish a normal sleep pattern (2.85 v 4.15), to not feel tired during the day (3.0 v 4.6), and to reach normal energy levels (3.25 v 4.7). Results for fatigue-inertia and vigour-activity were similar. For all subjects jet lag was more severe on the return (westward) than the outward (eastward) journey.
Melatonin can alleviate jet lag and tiredness after long haul flights.
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This study investigated the efficacy of oral melatonin in alleviating jet lag in flight crew after a series of international flights. The optimal time for taking melatonin in this group was also investigated. In a double-blind placebo-controlled trial, 52 international cabin crew were randomly assigned to three groups; early melatonin (5 mg started 3 days prior to arrival until 5 days after return home); late melatonin (placebo for 3 days then 5 mg melatonin for 5 days); and placebo. Daily ratings showed a trend in jet lag, mood, and sleepiness measures toward an improved recovery in the late melatonin group and a worse recovery in the early melatonin group as compared to placebo. Retrospective ratings made 6 days after arrival showed the late melatonin group reported significantly less jet lag and sleep disturbance following the flight compared to placebo. The late melatonin group also showed a significantly faster recovery of energy and alertness than the early melatonin group, which reported a worse overall recovery than placebo. These findings show melatonin may have potential benefits for international aircrew.
To compare the impact of various dosage forms of melatonin and placebo on jet lag symptoms, 320 volunteers who had flights over 6 to 8 time zones were recruited for a double-blind, randomized, placebo-controlled study. The volunteers received either melatonin 0.5-mg fast-release (FR) formulation, melatonin 5-mg FR formulation, melatonin 2-mg controlled-release (CR) formulation, or placebo. The study medication was taken once daily at bedtime during 4 days after an eastward flight. The volunteers completed the Profile of Mood States (POMS), sleep log, and symptoms questionnaires once daily and the Karolinska Sleepiness Scale (KSS) three times daily prior to departure and during the 4 days of medication intake postflight. A total of 234 (73.1%) participants were compliant and completed the study. The FR melatonin formulations were more effective than the slow-release formulation. The 5-mg FR formulation significantly improved the self-rated sleep quality (p < .05), shortened sleep latency (p < .05), and reduced fatigue and daytime sleepiness (p < .05) after intercontinental flight. The lower physiological dose of 0.5 mg was almost as effective as the pharmacological dose of 5.0 mg. Only the hypnotic properties of melatonin, sleep quality and sleep latency, were significantly greater with the 5.0-mg dose.
The goals of this study were to validate a new rating scale for measuring severity of jet lag and to compare the efficacy of contrasting melatonin regimens to alleviate jet lag.
This was a randomized, double-blind trial of placebo and three alternative regimens of melatonin (5.0 mg at bedtime, 0.5 mg at bedtime, and 0.5 mg taken on a shifting schedule) for jet lag. The subjects were 257 Norwegian physicians who had visited New York for 5 days. Jet lag ratings were made on the day of travel from New York back to Oslo (6 hours eastward) and for the next 6 days in Norway. The main outcome measures were scale and item scores from a new, syndrome-specific instrument, the Columbia Jet Lag Scale, that identifies prominent daytime symptoms of jet lag distress.
There was a marked increase in total jet lag score in all four treatment groups on the first day at home, followed by progressive improvement over the next 5 days. However, there were no significant group differences or group-by-time interactions. In addition, there was no group effect for sleep onset, time of awakening, hours slept, or hours napping. Ratings on a summary jet lag item were highly correlated with total jet lag scores (from a low of r = 0.54 on the day of travel to a high of r = 0.80 on day 3). The internal consistency of the total jet lag score was high on each day of the study.
The use of melatonin for preventing jet lag needs further study.
To examine antidepressant augmentation with and hypnotic effects of slow-release melatonin (SR-melatonin) in patients with treatment-resistant depression.
Open-label trial.
Tertiary care outpatient depression clinic.
Nine outpatients who had failed to respond to 2 or more 8-week trials of antidepressant medication.
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.
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.
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.
SR-melatonin may be a useful adjunct for sleep, but does not substantially augment existing antidepressant therapies in some patients with treatment-resistant depression.
The aim of this study was to compare the effectiveness and tolerability of a chronobiotic (melatonin) with a hypnotic (zolpidem) and the combination of both substances to alleviate jet lag symptoms associated with eastward travel.
This double-blind, randomized, placebo-controlled study is based on 137 volunteers flying from Switzerland to the American continent and back (6-9 time zones). The participants either received melatonin 5 mg (n = 35), zolpidem 10 mg (n = 34), a combination thereof (n = 29) or placebo (n = 39) on the eastbound flight back to Switzerland and once daily at bedtime on 4 consecutive days after the flight. The test battery included daily sleep logs, symptoms questionnaires, and the Profile of Mood States (POMS). Also, on the last treatment day, Visual Analog Scales (VAS) were completed to assess overall jet lag ratings and treatment effectiveness. Baseline data were collected on 4 consecutive days 2 wk after the flight. During post-flight treatment and baseline, motor activity was assessed in a subgroup of 49 subjects using wrist-worn ambulatory monitors.
The self-rated sleep quality was significantly improved by zolpidem, especially during the night flight. Subjects taking zolpidem reported significantly less jet lag and zolpidem was rated as the most effective jet lag medication. However, zolpidem and the combination melatonin/zolpidem were less well tolerated than melatonin alone; adverse event reports included nausea, vomiting, amnesia and somnambulia to the point of incapacitation. Confusion, morning sleepiness and nausea were highest in the combination group.
All active treatments led to a decrease of jet lag severity with zolpidem being the most effective treatment, particularly in facilitating sleep on night flights. Potential individual adverse reactions to this hypnotic have to be considered.
Attempting to understand the body’s signals is similar to trying to interpret the noises and sensations of the automobile that we drive. We do not have a computer printout of either the current physiological status of our body or the condition of the various systems of our car. Given this, we are in the position of attempting to understand a large array of ambiguous sensations about which we have at best a modicum of knowledge. Whether we are dealing with human bodies or inanimate cars, the awareness and reporting of symptoms are dependent on psychological or perceptual processes. Throughout this book, a large number of studies have outlined some of the parameters that determine when and why symptoms are reported. Before discussing some of the implications of symptom research, we present the following brief review of our current knowledge about the perception of physical symptoms.
Physical symptoms are fascinating phenomena to examine. We all experience them, use them as signals to guide our behavior, and usually assume that they accurately represent underlying physiological activity. At the same time, we implicitly know that bodily sensations are often vague, ambiguous, and subject to a variety of interpretations. It is not surprising, then, that there is often a disparity between what we think is going on in our bodies and what is objectively occurring. In short, phenomena such as physical symptoms are the stuff of psychology. My own research into physical symptoms started by accident several years ago. In a hastily devised experiment dealing with the effects of noise on behavior, I had to write a post-experimental questionnaire that would be long enough to allow the experimenter time to calibrate some equipment for a later portion of the study. I included some physical symptoms on the questionnaire as fillers. The experiment was a total failure, with the exception of the symptom reports. People's perceptions of symptoms were easily influenced by our manipulations, even though their actual physiological state had not changed. And so began the present inquiry. Despite the pervasiveness, importance, and sheer amount of time and money devoted to discussing and curing common physical symptoms and sensations, very little empirical work has been devoted to examining the psychological and perceptual factors related to sensory experience. Occa sional papers have tested a specific theory, such as cognitive dissonance, wherein physical symptoms served as an interesting dependent measure."
A physiological dose of orally administered melatonin shifts circadian rhythms in humans according to a phase-response curve (PRC) that is nearly opposite in phase with the PRCs for light exposure: melatonin delays circadian rhythms when administered in the morning and advances them when administered in the afternoon or early evening. The human melatonin PRC provides critical information for using melatonin to treat circadian phase sleep and mood disorders, as well as maladaptation to shift work and transmeridional air travel. The human melatonin PRC also provides the strongest evidence to date for a function of endogenous melatonin and its suppression by light in augmenting entrainment of circadian rhythms by the light-dark cycle.
Seventeen healthy volunteers (10 women and 7 men, aged 29-68) were flown from London to San Francisco between 20 November 1985 and 25 January 1986 and remained there for 14 days prior to flight home. Subjects took melatonin (N = 8, 5 women, 3 men) or placebo in a double-blind design, at 18.00h local time for three days before the return flight and at bedtime (22.00-24.00h) in Great Britain for four days. For three days before departure and on days 1-7,14,15, 21 and 22 after their return subjects collected 6-hourly sequential urine samples and kept a daily sleep log. They recorded mood and oral temperature 2 hourly and performed logical reasoning and letter cancellation tests 4 hourly from 08.00h (or wake up time) to 24.00h (or bedtime) whichever was the earlier. Urine was also collected for 48 h prior to departure from the U.S.A‥ On day 7 after their return subjects rated ‘jet lag’ (10 cm visual analogue scale—VAS) from 0 (insignificant) to 100 (very bad). Melatonin significantly improved ‘jet lag’ (p= 0.009). Comparisons by ANOVA between jet-lagged placebo subjects (N = 7) and melatonin (N = 8) showed decreased sleep latency with melatonin (p= 0.0397) which correlated positively with jet lag ratings, p< 0.001. Sleep quality was significantly improved in the melatonin group and correlated negatively with jet-lag ratings (p
The pineal hormone melatonin has clear circadian phase-shifting effects in humans which have recently been formalized as a phase response curve. Its potential use in circadian rhythm disorders has been investigated in field studies of jet lag and shift work and in simulated phase shift. A substantial amount of information indicates that in the majority of subjects it hastens adaptation of both subjective and objective measures to forced shifts in time cues with few reported side-effects. Field studies of its use in adaptation to shift work are sparse and preliminary but the first indications are positive. In some blind subjects with sleep disturbance it can stabilize sleep onset time without necessarily entraining all circadian rhythms and it can advance sleep timing in delayed sleep-phase insomnia. Acute suppression of core body temperature may be an integral part of the phase-shifting mechanism.
A physiological dose of orally administered melatonin shifts circadian rhythms in humans according to a phase-response curve (PRC) that is nearly opposite in phase with the PRCs for light exposure: melatonin delays circadian rhythms when administered in the morning and advances them when administered in the afternoon or early evening. The human melatonin PRC provides critical information for using melatonin to treat circadian phase sleep and mood disorders, as well as maladaptation to shift work and transmeridional air travel. The human melatonin PRC also provides the strongest evidence to date for a function of endogenous melatonin and its suppression by light in augmenting entrainment of circadian rhythms by the light-dark cycle.
This study replicates the alleviation of jet-lag with melatonin in a simplified protocol for eastward flight. At 22-n hr (n is the time-lag between the North American departure point and France), subjects took either melatonin (8 mg, n = 15), or placebo (n = 15) on the day of the return flight and for 3 consecutive days. On day 8, self-ratings significantly discriminated between melatonin and placebo for global treatment efficacy, morning fatigue, and evening sleepiness.
While pinealectomy (Px) has little effect on mammalian circadian rhythms, daily injections of the pineal hormone melatonin in rats have profound effects. These can be classified according to their effects under three categories of desynchronization: external desynchronization, internal desynchronization and phase-shift of the zeitgeber (Aschoff, 1969). Externally desynchronized rats, free-running in constant darkness (DD), can be entrained to a 24-hour regime of melatonin injection. Entrainment depends upon the suprachiasmatic nuclei (SCN) since lesions to the SCN prevent it. Although no animal model for internal desynchronization exists, rats whose circadian rhythms are disrupted or arrhythmic in constant light (LL) are synchronized by daily melatonin injection, and the rate and direction of responses to phase-shift of the zeitgeber can be altered with daily melatonin administration. These and other results suggest melatonin may be useful therapeutically for such human desynchronizations as jet-lag and shiftwork, and preliminary data using human subjects are presented.
This review discusses the effects, in the aerospace environment, of alterations in approximately 24-h periodicities (circadian rhythms) upon physiological and psychological functions and possible therapies for desynchronosis induced by such alterations. The consequences of circadian rhythm alteration resulting from shift work, transmeridian flight, or altered day lengths are known as desynchronosis, dysrhythmia, dyschrony, jet lag, or jet syndrome. Considerable attention is focused on the ability to operate jet aircraft and manned space vehicles. The importance of environmental cues, such as light-dark cycles, which influence physiological and psychological rhythms is discussed. A section on mathematical models is presented to enable selection and verification of appropriate preventive and corrective measures and to better understand the problem of dysrhythmia.
Measuring the dim light melatonin onset (DLMO) is a useful and practical way to assess circadian phase position in humans. As a marker for the phase and period of the endogenous circadian pacemaker, the DLMO has been shown to advance with exposure to bright light in the morning and to delay with exposure to bright light in the evening. This 'phase response curve' (PRC) to light has been applied in the treatment of winter depression, jet lag and shift work, as well as circadian phase sleep disorders. Exogenous melatonin has phase-shifting effects described by a PRC that is about 12 h out of phase with the PRC to light. That is, melatonin administration in the morning causes phase delays and in the afternoon causes phase advances. All of the circadian phase disorders that have been successfully treated with appropriately timed exposure to bright light can be treated with appropriately scheduled melatonin administration. Melatonin administration is more convenient and therefore may be the preferred treatment.
The hypnotic action of melatonin 5 mg p.o. was explored in 15 subjects with psychophysiological insomnia in a double-blind controlled self-report questionnaire study. Melatonin or placebo was taken at 20.00 hours for a 1-week period in random order. Effects on sleep and wakefulness were monitored by visual analogue scale and structured interview. Bedtime, sleep onset time, estimated total sleep and wake time, as well as self-rated sleep quality, were not altered by melatonin, and estimates of next-day function did not change. The period of melatonin, treatment was retrospectively correctly identified by 8 of 15 subjects. Despite unchanged ratings of night sleep quality on the last night of each treatment, 7 of 15 subjects reported that sleep had subjectively improved to a minor extent in the week of active treatment. Side-effects attributed to melatonin included headache and an odd taste in the mouth. These data indicate that melatonin is probably of no clinical value in the management of psychophysiological insomnia.
The rapid deployment of Army aviation personnel across time zones, combined with missions beginning immediately upon arrival, results in desynchronization of physiological and cognitive performance rhythms. Implementation of effective countermeasures enhances safety, health, well-being, and mission completion. The naturally occurring hormone melatonin has been suggested as an effective counter measure for jet lag and shift lag because of its influence on the human circadian timing system and its hypnotic properties.
The efficacy of melatonin (10 mg) in maintaining stable sleep/wake cycles of Army aircrews was tested during a training mission involving rapid deployment to the Middle East and night operations. Cognitive performance was tested before and after travel; activity rhythms were recorded continuously for 13 d.
Melatonin treatment advanced both bedtimes and rise times (2-3 h) and maintained sleep durations between 7-8 h. Placebo treatment was mostly associated with longer advances in rise times than bedtimes resulting in shorter sleep durations (5-7 h). Upon awakening, the melatonin group exhibited significantly fewer errors (mean: 7.45) than the placebo group (mean: 14.50) in a dual-task vigilance test.
Melatonin can be a useful treatment for the prevention of sleep disruptions and cognitive degradation, even in uncontrolled sleeping environments characteristic of military deployments.
Melatonin has clear acute and delayed effects on sleep and circadian rhythms. Decrements in core temperature and alertness have been found at different times of day following low pharmacological and physiological doses of melatonin. When correctly timed, melatonin induces both phase advances and phase delays of the circadian system in humans. When timed to advance, the decrement in temperature and alertness and the degree of shift are closely related to dose. In both simulation and field studies, correctly timed melatonin can alleviate some of the problems of shiftwork and jet lag, notably enhancing sleep and alertness and hastening adaptation of rhythms to the imposed schedule. Performance effects and changes in sleep architecture need to be fully evaluated. The optimization of dose and formulation is also an area that requires further work. Whether or not recently developed melatonin analogs (72) will prove more or less useful than melatonin in adapting to phase shift remains to be seen. If incorrectly timed, melatonin has the potential to induce deleterious effects. While short-term studies indicate that it has very low toxicity, there are no long-term safety data. All of the studies reported here concern healthy adult volunteers and the use of a preparation licensed for human experimental use and available on a named patient basis on prescription. There are no data on uncontrolled preparations available over the counter in some countries. Its effects in pregnancy, interaction with other medications, and many other considerations remain to be addressed. Thus, while melatonin is useful in well-controlled conditions, the indiscriminate use of unlicensed preparations is not advisable.
Melatonin has chronobiotic properties in humans. It is able to phase shift strongly endogenous rhythms, such as core temperature and its own endogenous rhythm, together with the sleep-wake cycle. Its ability to synchronize free-running rhythms has not been fully investigated in humans. There is evidence for synchronization of the sleep-wake cycle, but the available data suggest that it is less effective with regard to endogenous melatonin and core temperature rhythms. When suitably timed, most studies indicate that fast release preparations are able to hasten adaptation to phase shift in both field and simulation studies of jet lag and shift work. Both subjective and objective measures support this statement. However, not all studies have been successful. Careful evaluation of the effects on work-related performance is required. When used to alleviate the non-24-h sleep-wake disorder in blind subjects, again most studies report a successful outcome using behavioral measures, albeit in a small number of individuals. The present data suggest, however, that although sleep-wake can be stabilized to 24 h, entrainment of other rhythms is exceptionally rare.
Subjective, physiological and physical performance variables are affected following travel across multiple time-zones (jet-lag). The objective of the study was to examine the effects of oral melatonin in alleviating jet-lag by investigating its effects on subjects who had flown from London to Eastern Australia, 10 time-zones to the east. Melatonin (5 mg day(-1)) or placebo capsules were administered to 14 experimental (13 males and 1 female) and 17 control subjects (15 males and 2 females), respectively, in a double-blind study; the time of administration was in accord with the current consensus for maximizing its hypnotic effect. Grip strength and intra-aural temperature were measured on alternate days after arrival at the destination, at four different times of day (between the times 07:00 - 08:00 h, 12:00 - 13:00 h, 16:00 - 17:00 h and 19:00 - 20:00 h local time). In addition, for the first 6 - 7 days after arrival in Australia, subjective ratings of jet-lag on a 0 - 10 visual analogue scale and responses to a Jet-lag Questionnaire (incorporating items for tiredness. sleep, meal satisfaction and ability to concentrate) were recorded at the above times and also on retiring (at about midnight). Subjects continued normally with their work schedules between the data collection times. Subjects with complete data (13 melatonin and 13 placebo subjects), in comparison with published data, showed partial adjustment of the diurnal rhythm in intra-aural temperature after 6 days. A time-of-day effect was evident in both right and left grip strength during adjustment to Australian time; there was no difference between the group taking melatonin and that using the placebo. Right and left grip strength profiles on day 6 were adjusted either by advancing or delaying the profiles, independent of whether subjects were taking melatonin or placebo tablets. Subjects reported disturbances with most measures in the Jet-lag Questionnaire but, whereas poorer concentration and some negative effects upon sleep had disappeared after 3 - 5 days, ratings of jet-lag and tiredness had not returned to 'zero' (or normal values), respectively, by the sixth day of the study. Subjects taking melatonin showed no significant differences from the placebo group in perceived irritability, concentration, meal satisfaction, ease in getting to sleep and staying asleep, frequency of bowel motion and consistency of the faeces. These results suggest that, in subjects who, after arrival, followed a busy schedule which resulted in frequent and erratic exposure to daylight, melatonin had no benefit in alleviating jet-lag or the components of jet-lag, and it did not influence the process of phase adjustment.
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