Does melatonin improve sleep? Efficacy of melatonin.
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Circadian Rhythm↗
Biomedical subjects
Josephine Arendt
Publications and source records attributed to Josephine Arendt.
Alerting effects of light are sensitive to very short wavelengths.
In humans a range of non-image-forming (NIF) light responses (melatonin suppression, phase shifting and alertness) are short wavelength sensitive (440-480 nm). The aim of the current study was to assess the acute effect of three different short wavelength light pulses (420, 440 and 470 nm) and 600 nm light on subjective alertness. Healthy male subjects (n = 12, aged 27 +/- 4 years, mean +/- S.D.) were studied in 39, 4-day laboratory study sessions. The subjects were maintained in dim light (<8 lx) and on day 3 they were exposed to a single 4-h light pulse (07:15-11:15 h). Four monochromatic wavelengths were administered at two photon densities: 420 and 440 nm at 2.3 x 10(13)photons/cm(2)/s and 440, 470 and 600 nm at 6.2 x 10(13)photons/cm(2)/s. Subjective mood and alertness were assessed at 30 min intervals during the light exposure, using four 9-point VAS scales. Mixed model regression analysis was used to compare alertness and mood ratings during the 470 nm light to those recorded with the other four light conditions. There was a significant effect of duration of light exposure (p < 0.001) on alertness but no significant effect of subject. Compared to 470 nm light, alertness levels were significantly higher in 420 nm light and significantly lower in the 600 nm light (p < 0.05). These data (420 nm>470 nm>600 nm) suggest that subjective alertness may be maximally sensitive to very short wavelength light.
Adult↗
Melatonin and human rhythms.
Melatonin signals time of day and time of year in mammals by virtue of its pattern of secretion, which defines 'biological night.' It is supremely important for research on the physiology and pathology of the human biological clock. Light suppresses melatonin secretion at night using pathways involved in circadian photoreception. The melatonin rhythm (as evidenced by its profile in plasma, saliva, or its major metabolite, 6-sulphatoxymelatonin [aMT6s] in urine) is the best peripheral index of the timing of the human circadian pacemaker. Light suppression and phase-shifting of the melatonin 24 h profile enables the characterization of human circadian photoreception, and circulating concentrations of the hormone are used to investigate the general properties of the human circadian system in health and disease. Suppression of melatonin by light at night has been invoked as a possible influence on major disease risk as there is increasing evidence for its oncostatic effects. Exogenous melatonin acts as a 'chronobiotic.' Acutely, it increases sleep propensity during 'biological day.' These properties have led to successful treatments for serveal circadian rhythm disorders. Endogenous melatonin acts to reinforce the functioning of the human circadian system, probably in many ways. The future holds much promise for melatonin as a research tool and as a therapy for various conditions.
Biological Clocks↗
Sleep and circadian phase in a ship's crew.
Numerous factors influence the increased health risks of seamen. This study investigated sleep (by actigraphy) and the adaptation of the internal clock in watch-keeping crew compared to day workers, as possible contributory factors. Fourteen watch keepers, 4 h on, 8 h off (0800-1200/2000-2400 h, 1200-1600/2400-0400 h, 1600-2000/0400-0800 h) (fixed schedule, n = 6; rotating by delay weekly, n = 8), and 12 day workers participated during a voyage from the United Kingdom to Antarctica. They kept daily sleep diaries and wore wrist monitors for continuous recording of activity. Sleep parameters were derived from activity using the manufacturer's software and analyzed by repeated-measures ANOVA using SAS 8.2. Sequential urine samples were collected for 48 h weekly for 6-sulphatoxymelatonin measurement as an index of circadian rhythm timing. Individuals working watches of 1200-1600/2400-0400 h and 1600-2000/0400-0800 h had 2 sleeps daily, analyzed separately as main sleep (longest) and 2nd sleep. Main sleep duration was shorter in watch keepers than in day workers (p < 0.0001). Objective sleep quality was significantly compromised in rotaters compared to both day workers and fixed watch keepers, the most striking comparisons being sleep efficiency (percentage desired sleep time spent sleeping) main sleep (p < 0.0001) and sleep fragmentation (an index of restlessness) main sleep (p < 0.0001). The 2nd sleep was substantially less efficient than was the main sleep (p < 0.0001) for all watch keepers. There were few significant differences in sleep between the different watches in rotating watch keepers. Circadian timing remained constant in day workers. Timing of the 6-sulphatoxymelatonin rhythm was later for the watch of 1200-1600/2400-0400 h than for all others (1200-1600/2400-0400 h, 5.90 +/- 0.85 h; 1600-2000/0400-0800 h, 1.5 +/- 0.64 h; 0800-1200/ 2000-2400 h, 2.72 +/- 0.76 h; days, 2.09 +/- 0.68 h [decimal hours, mean +/- SEM]: ANOVA, p < 0.01). This study identifies weekly changes in watch time as a cause of poor sleep in watch keepers. The most likely mechanism is the inability of the internal clock to adapt rapidly to abrupt changes in schedule.
Adult↗
Human circadian rhythms: physiological and therapeutic relevance of light and melatonin.
Ocular light plays a key role in human physiology by transmitting time of day information. The production of the pineal gland hormone melatonin is under the control of the light-dark cycle. Its profile of secretion defines biological night and it has been called the 'darkness hormone'. Light mediates a number of non-visual responses, such as phase shifting the internal circadian clock, increasing alertness, heart rate and pupil constriction. Both exogenous melatonin and light, if appropriately timed, can phase shift the human circadian system. These 'chronobiotic' effects of light and melatonin have been used successfully to alleviate and correct circadian rhythm disorders, such as those experienced following travel across time zones, in night shift work and in circadian sleep disorders. The effectiveness of melatonin and light are currently being optimized in terms of time of administration, light intensity, duration and wavelength, and melatonin dose and formulation. The aim of this review is not to replicate information that has been reported in a number of reviews of the human circadian timing system and the role of melatonin and light, but rather to extract findings relevant to the field of clinical biochemistry.
Biological Clocks↗
Melatonin as a chronobiotic.
Melatonin, hormone of the pineal gland, is concerned with biological timing. It is secreted at night in all species and in ourselves is thereby associated with sleep, lowered core body temperature, and other night time events. The period of melatonin secretion has been described as 'biological night'. Its main function in mammals is to 'transduce' information about the length of the night, for the organisation of daylength dependent changes, such as reproductive competence. Exogenous melatonin has acute sleepiness-inducing and temperature-lowering effects during 'biological daytime', and when suitably timed (it is most effective around dusk and dawn) it will shift the phase of the human circadian clock (sleep, endogenous melatonin, core body temperature, cortisol) to earlier (advance phase shift) or later (delay phase shift) times. The shifts induced are sufficient to synchronise to 24 h most blind subjects suffering from non-24 h sleep-wake disorder, with consequent benefits for sleep. Successful use of melatonin's chronobiotic properties has been reported in other sleep disorders associated with abnormal timing of the circadian system: jetlag, shiftwork, delayed sleep phase syndrome, some sleep problems of the elderly. No long-term safety data exist, and the optimum dose and formulation for any application remains to be clarified.
Animals↗
Short-wavelength sensitivity of the human circadian system to phase-advancing light.
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Adult↗
Melatonin: characteristics, concerns, and prospects.
Melatonin is of great importance to the investigation of human biological rhythms. Its rhythm in plasma or saliva provides the best available measure of the timing of the internal circadian clock. Its major metabolite 6-sulphatoxymelatonin is robust and easily measured in urine. It thus enables long-term monitoring of human rhythms in real-life situations where rhythms may be disturbed, and in clinical situations where invasive procedures are difficult. Melatonin is not only a "hand of the clock"; endogenous melatonin acts to reinforce the functioning of the human circadian system, probably in many ways. Most is known about its relationship to sleep and the decline in core body temperature and alertness at night. Current perspectives also include a possible influence on major disease risk, arising from circadian rhythm disruption. Melatonin clearly has the ability to induce sleepiness and lower core body temperature during "biological day" and to change the timing of human rhythms when treatment is appropriately timed. It can entrain free-running rhythms and maintain entrainment in most blind and some sighted people. Used therapeutically it has proved a successful treatment for circadian rhythm disorder, particularly the non-24-h sleep wake disorder of the blind. Numerous other clinical applications are under investigation. There are, however, areas of controversy, large gaps in knowledge, and insufficient standardization of experimental conditions and analysis for general conclusions to be drawn with regard to most situations. The future holds much promise for melatonin as a therapeutic treatment. Most interesting, however, will be the dissection of its effects on human genes.
Blindness↗
Melatonin advances the circadian timing of EEG sleep and directly facilitates sleep without altering its duration in extended sleep opportunities in humans.
The rhythm of plasma melatonin originating from the pineal gland and driven by the circadian pacemaker located in the suprachiasmatic nucleus is closely associated with the circadian (approximately 24 h) variation in sleep propensity and sleep spindle activity in humans. We investigated the contribution of melatonin to variation in sleep propensity, structure, duration and EEG activity in a protocol in which sleep was scheduled to begin during the biological day, i.e. when endogenous melatonin concentrations are low. The two 14 day trials were conducted in an environmental scheduling facility. Each trial included two circadian phase assessments, baseline sleep and nine 16 h sleep opportunities (16.00-08.00 h) in near darkness. Eight healthy male volunteers (24.4 +/- 4.4 years) without sleep complaints were recruited, and melatonin (1.5 mg) or placebo was administered at the start of the first eight 16 h sleep opportunities. During melatonin treatment, sleep in the first 8 h of the 16 h sleep opportunities was increased by 2 h. Sleep per 16 h was not significantly different and approached asymptotic values of 8.7 h in both conditions. The percentage of rapid eye movement (REM) sleep was not affected by melatonin, but the percentage of stage 2 sleep and sleep spindle activity increased, and the percentage of stage 3 sleep decreased. During the washout night, the melatonin-induced advance in sleep timing persisted, but was smaller than on the preceding treatment night and was consistent with the advance in the endogenous melatonin rhythm. These data demonstrate robust, direct sleep-facilitating and circadian effects of melatonin without concomitant changes in sleep duration, and support the use of melatonin in the treatment of sleep disorders in which the circadian melatonin rhythm is delayed relative to desired sleep time.
Adult↗
A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference.
STUDY OBJECTIVES: To investigate the link between extreme diurnal preference, delayed sleep phase syndrome, and a length polymorphism in Per3. DESIGN: Subjects were genotyped using polymerase chain reaction. PATIENTS OR PARTICIPANTS: Subjects with defined diurnal preference as determined by the Horne-Ostberg questionnaire and patients with delayed sleep phase syndrome. MEASUREMENTS AND RESULTS: The Per3 polymorphism correlated significantly with extreme diurnal preference, the longer allele associating with morningness and the shorter allele with eveningness. The shorter allele was strongly associated with the delayed sleep phase syndrome patients, 75% of whom were homozygous. CONCLUSION: The length of the Per3 repeat region identifies a potential genetic marker for extreme diurnal preference.
Adolescent↗
Phase advancing human circadian rhythms with short wavelength light.
The photoreceptor(s) responsible for photoresetting of the human circadian system have not been identified. The aim of the present study was to assess the ability of short wavelength light to alter the timing of circadian rhythms. Eleven male subjects were studied in 15 4-day trials with a single 4 h light pulse administered on day 3, immediately after habitual wake time. The magnitude of the phase shifts in the melatonin acrophase and offset were similar after white (4300 microW/cm(2)) and short wavelength (28 microW/cm(2)) light exposure even though the white light pulse contained 185-fold more photons than the short wavelength light. This finding suggests short wavelength sensitivity of the photoreceptors mediating synchronization of human circadian rhythms.
Adult↗
Circadian aspects of postprandial metabolism.
Time-dependent variations in the hormonal and metabolic responses to food are of importance to human health, as postprandial metabolic responses have been implicated as risk factors in a number of major diseases, including cardiovascular disease. Early work reported decreasing glucose tolerance in the evening and at night with evidence for insulin resistance at night. Subsequently an endogenous circadian component, assessed in constant routine (CR), as well as an influence of sleep time, was described for glucose and insulin. Plasma triacylglycerol (TAG), the major lipid component of dietary fat circulating after a meal, also appears to be influenced by both the circadian clock and sleep time with higher levels during biological night (defined as the time between the onset and offset of melatonin secretion) despite identical hourly nutrient intake. These time-dependent differences in postprandial responses have implications for shiftworkers. In the case of an unadapted night shift worker, meals during work time will be taken during biological night. In simulated night shift conditions the TAG response to a standard meal, preceded by either a low-fat or a high-fat premeal, was higher after a nighttime meal than during a daytime meal, and the day/night difference was larger in men than in women. In real night shift workers in Antarctica, insulin, glucose, and TAG all showed an increased response after a nighttime meal (second day of night shift) compared to a daytime meal. Night shift workers are reported to have an approximately 1.5 times higher incidence of heart disease risk and also demonstrate higher TAG levels compared with matched dayworkers. As both insulin resistance and elevated circulating TAG are independent risk factors for heart disease, it is possible that meals at night may contribute to this risk.
Blood Glucose↗
Does melatonin improve sleep in older people? A randomised crossover trial.
STUDY OBJECTIVE: to determine whether melatonin will improve quality of sleep in healthy older people with age-related sleep maintenance problems. DESIGN: a double blind randomised placebo controlled crossover trial in healthy older volunteers. SETTING: a largely urban population, Auckland, New Zealand. PARTICIPANTS: participants were part of the larger Possible Role of Melatonin in Sleep of Elders study. People 65 years or more of age were recruited through widespread advertising. We screened 414 potential participants by mail using the Pittsburgh Sleep Quality Index, and selected 194 for clinic interview. Exclusions included depression, cognitive impairment, hypnosedative medications, sleep phase abnormalities, medical and/or environmental problems that might impair sleep. Twenty normal and 20 problem sleepers were randomly allocated for this study from a larger sample of 60 normal and 60 problem sleepers. MEASUREMENTS AND RESULTS: 24-hour urine 6-sulphatoxymelatonin was measured to estimate melatonin secretion in each participant. Five milligrams of melatonin, or matching placebo were each taken at bedtime for 4 weeks, separated by a 4-week washout period. Sleep quality was measured using sleep diaries, the Leeds Sleep Evaluation Questionnaire, and actigraphy. There was a significant difference between the groups in self-reported sleep quality indicators at entry, but no difference in melatonin secretion. Melatonin did not significantly improve any sleep parameter measured in either group. CONCLUSION: 5 mg of fast release melatonin taken at bedtime does not improve the quality of sleep in older people with age-related sleep maintenance problems.
Aged↗
The effects of low-dose 0.5-mg melatonin on the free-running circadian rhythms of blind subjects.
Exogenous melatonin (0.5-10 mg) has been shown to entrain the free-running circadian rhythms of some blind subjects. The aim of this study was to assess further the entraining effects of a daily dose of 0.5 mg melatonin on the cortisol rhythm and its acute effects on subjective sleep in blind subjects with free-running 6-sulphatoxymelatonin (aMT6s) rhythms (circadian period [tau] 24.23-24.95 h). Ten subjects (9 males) were studied, aged 32 to 65 years, with no conscious light perception (NPL). In a placebo-controlled, single-blind design, subjects received 0.5 mg melatonin or placebo p.o. daily at 2100 h (treatment duration 26-81 days depending on individuals' circadian period). Subjective sleep was assessed from daily sleep and nap diaries. Urinary cortisol and aMT6s were assessed for 24 to 48 h weekly and measured by radioimmunoassay. Seven subjects exhibited an entrained or shortened cortisol period during melatonin treatment. Of these, 4 subjects entrained with a period indistinguishable from 24 h, 2 subjects continued to free run for up to 25 days during melatonin treatment before their cortisol rhythm became entrained, and 1 subject appeared to exhibit a shortened cortisol period throughout melatonin treatment. The subjects who entrained within 7 days did so when melatonin treatment commenced in the phase advance portion of the melatonin PRC (CT6-18). When melatonin treatment ceased, cortisol and aMT6s rhythms free ran at a similar period to before treatment. Three subjects failed to entrain with initial melatonin treatment commencing in the phase delay portion of the PRC. During melatonin treatment, there was a significant increase in nighttime sleep duration and a reduction in the number and duration of daytime naps. The positive effect of melatonin on sleep may be partly due to its acute soporific properties. The findings demonstrate that a daily dose of 0.5 mg melatonin is effective at entraining the free-running circadian systems in most of the blind subjects studied, and that circadian time (CT) of administration of melatonin may be important in determining whether a subject entrains to melatonin treatment. Optimal treatment with melatonin for this non-24-h sleep disorder should correct the underlying circadian disorder (to entrain the sleep-wake cycle) in addition to improving sleep acutely.
Adult↗
Melatonin phase-shifts human circadian rhythms with no evidence of changes in the duration of endogenous melatonin secretion or the 24-hour production of reproductive hormones.
The pineal hormone melatonin is a popular treatment for sleep and circadian rhythm disruption. Melatonin administered at optimal times of the day for treatment often results in a prolonged melatonin profile. In photoperiodic (day length-dependent) species, changes in melatonin profile duration influence the timing of seasonal rhythms. We investigated the effects of an artificially prolonged melatonin profile on endogenous melatonin and cortisol rhythms, wrist actigraphy, and reproductive hormones in humans. Eight healthy men took part in this double-blind, crossover study. Surge/sustained release melatonin (1.5 mg) or placebo was administered for 8 d at the beginning of a 16-h sleep opportunity (1600 h to 0800 h) in dim light. Compared with placebo, melatonin administration advanced the timing of endogenous melatonin and cortisol rhythms. Activity was reduced in the first half and increased in the second half of the sleep opportunity with melatonin; however, total activity during the sleep opportunities and wake episodes was not affected. Melatonin treatment did not affect the endogenous melatonin profile duration, pituitary/gonadal hormone levels (24-h), or sleepiness and mood levels on the subsequent day. In the short term, suitably timed sustained-release melatonin phase-shifts circadian rhythms and redistributes activity during a 16-h sleep opportunity, with no evidence of changes in the duration of endogenous melatonin secretion or pituitary/gonadal hormones.
Adult↗
Human circadian phase in 12:12 h, 200: <8 lux and 1000: <8 lux light-dark cycles, without scheduled sleep or activity.
The light levels required to maintain human circadian phase in the absence of other strong time cues are not defined. We investigated circadian phase in two groups of men, living in partial temporal isolation, exposed to 12 h:12 h light:dark cycles of: (A) 200: <8 lux, broad spectrum white light for 14 days; and (B) 1000: <8lux for 14 days. The rhythm variables measured were urinary 6-sulphatoxymelatonin, rectal temperature, activity and rest (actigraphy and sleep logs). In 200: <8 lux four/six individuals showed phase delays. Exposure to 1000: <8 lux appeared to maintain synchronisation of rest-activity to 24 h, but with a significant overall phase advance of 0.81 h in temperature. These observations suggest that domestic intensity light does not maintain phase without scheduled sleep/activity, possibly due to indirect effects on behaviour influencing light exposure.
Adolescent↗
The 3111 Clock gene polymorphism is not associated with sleep and circadian rhythmicity in phenotypically characterized human subjects.
Mutations in clock genes are associated with abnormal circadian parameters, including sleep. An association has been reported previously between a polymorphism (3111C), situated in the 3'-untranslated region (3'-UTR) of the circadian gene Clock and evening preference. In the present study, this polymorphism was assessed in: (1) 105 control subjects with defined diurnal preference, (2) 26 blind subjects with free-running circadian rhythms and characterized with regard to circadian period (tau) and (3) 16 delayed sleep phase syndrome patients. The control group was chosen from a larger population (n = 484) by Horne-Ostberg questionnaire analysis, from which three subgroups were selected (evening, intermediate and morning preference). Data from sleep diaries completed by 90% of these subjects showed a strong correlation between preferred and estimated timings of sleep and wake. The mean timings of activities for the evening group were at least 2 h later than the morning group. Genetic analysis showed that, in contrast with the previously published finding, there was no association between 3111C and eveningness. Neither was there an association between 3111C and tau, nor a significant difference in 3111C frequency between the normal and delayed sleep phase syndrome groups. To assess the effect of this polymorphism on messenger RNA (mRNA) translatability, luciferase reporter gene constructs containing the two Clock polymorphic variants in their 3'-UTR were transfected into COS-1 cells and luciferase activity measured. No significant difference was observed between the two variants. These results do not support Clock 3111C as a marker for diurnal preference, tau, or delayed sleep phase syndrome in humans.
Alleles↗