Poor compensatory function for sleep loss as a pathogenic factor in patients with delayed sleep phase syndrome

OBJECTIVE: Delayed sleep phase syndrome (DSPS) is a condition in which the patient is unable to reset or phase-advance his/her sleep timing properly after transient sleep delay and consequently shows persistent sleep phase delay. Prior studies suggested that DSPS is associated with a phase delay in the circadian pacemaker, but there was no evidence to explain the patient's inability to reset sleep phase. SUBJECTS AND METHODS: We used an ultra-short sleep-wake schedule together with simultaneous measurement of dim light melatonin rhythm after 24-hour sleep deprivation to allow the differential observation of diurnal sleep propensity fluctuation both from circadian and homeostatic aspects in 11 patients with DSPS (17-37 years; 8 men, 3 women) and 15 healthy controls (19-32 years; 8 men, 7 women). SETTING: NA. PATIENTS OR PARTICIPANTS: NA. INTERVENTIONS: NA. RESULTS: DSPS patients showed less ability to compensate for previous sleep loss during their circadian day and first hours of their circadian nighttime determined by dim light melatonin onset compared with controls, while controls compensated for previous sleep loss at most circadian times. Though shapes of dim light melatonin rhythm did not differ between the groups, phase angle between melatonin and sleep propensity rhythms was wider in DSPS patients than in controls. CONCLUSIONS: These findings suggest that poor compensatory function for sleep loss predisposes DSPS patients to failure to reset their sleep phase. Our results provide implications for understanding not only the pathophysiology of DSPS but also the biological basis for why some people can change their sleep schedule easily according to personal or social demands while others cannot.     

Daytime exposure to bright light, as compared to dim light, decreases sleepiness and improves psychomotor vigilance performance

STUDY OBJECTIVES: This study examined the effects of bright light exposure, as compared to dim light, on daytime subjective sleepiness, incidences of slow eye movements (SEMs), and psychomotor vigilance task (PVT) performance following 2 nights of sleep restriction. DESIGN: The study had a mixed factorial design with 2 independent variables: light condition (bright light, 1,000 lux; dim light, < 5 lux) and time of day. The dependent variables were subjective sleepiness, PVT performance, incidences of SEMs, and salivary melatonin levels. SETTING: Sleep research laboratory at Monash University. PARTICIPANTS: Sixteen healthy adults (10 women and 6 men) aged 18 to 35 years (mean age 25 years, 3 months). INTERVENTIONS: Following 2 nights of sleep restriction (5 hours each night), participants were exposed to modified constant routine conditions. Eight participants were exposed to bright light from noon until 5:00 pm. Outside the bright light exposure period (9:00 am to noon, 5:00 pm to 9:00 pm) light levels were maintained at less than 5 lux. A second group of 8 participants served as controls for the bright light exposure and were exposed to dim light throughout the entire protocol. MEASUREMENTS AND RESULTS: Bright light exposure reduced subjective sleepiness, decreased SEMs, and improved PVT performance compared to dim light. Bright lights had no effect on salivary melatonin. A significant positive correlation between PVT reaction times and subjective sleepiness was observed for both groups. Changes in SEMs did not correlate significantly with either subjective sleepiness or PVT performance. CONCLUSIONS: Daytime bright light exposure can reduce the impact of sleep loss on sleepiness levels and performance, as compared to dim light. These effects appear to be mediated by mechanisms that are separate from melatonin suppression. The results may assist in the development of treatments for daytime sleepiness.     

Timed exposure to bright light improves sleep and alertness during simulated night shifts.

Many of the health and safety problems reported by shift workers result from the chronic sleep deprivation associated with shorter, fragmented daytime sleep. This reduction in the quality and duration of sleep has been attributed to a change in the phase relationship between the work period and the circadian system, timing the propensity for sleep and wakefulness. This study examined the extent to which appropriately timed exposure to bright light would accelerate the circadian readjustment of physiological parameters thought to contribute to impaired performance in shift workers. A control (n = 7) and treatment group (n = 6) underwent a 3-day transition to simulated night work. The treatment group received a single 4-hour pulse of bright light (6,000 lux) between 2400 and 0400 hours on the first night shift and dim light (less than 200 lux) for the remainder of the study. The control group received dim light throughout. By the third night shift, the phase position of the core body temperature rhythm for the treatment group had delayed by 5-6 hours whereas the control group had delayed by only 2-3 hours. When compared to the control group, the greater delay in core temperature rhythm for the treatment group was associated with significantly higher alertness across the night shift and improved sleep quality during the day. By the third day sleep, mean sleep efficiency in the treatment group was not significantly different from normal night sleep. Similarly, onshift alertness was improved relative to the control group. The treatment group did not show the typical decline in alertness observed in the control group between 0300 and 0700 hours. These data indicate that a single 4-hour pulse of bright light between midnight and 0400 hours is effective in ameliorating the sleep and alertness problems associated with transition to night shift.     

Larger phase angle between sleep propensity and melatonin rhythms in sighted humans with non-24-hour sleep-wake syndrome

STUDY OBJECTIVES: This study was aimed to clarify phase angle between sleep propensity and the circadian pacemaker in patients with non-24-hour sleep-wake syndrome (Non-24). DESIGN AND SETTING: A case-control study was underaken. PARTICIPANTS: Sighted patient with Non-24 (4 males and 1 female, aged 16 to 39 y), and sex- and age-matched healthy controls (12 males and 3 females, aged 19 to 35 y) participated the study. MEASUREMENT AND INTERVENTION: Following an actigraphic assessment of the sleep-wake cycle in their homes, the participants entered an ultra-short sleep-wake schedule together with simultaneous measurement of dim light melatonin rhythm after 24-hour sleep deprivation. RESULTS: The period of the sleep-wake cycle observed at home was longer in the Non-24 patients (25.12 hours) than in the controls (24.02 hours, p<0.0001). The interval from sleep propensity (SP) onset to the melatonin midpoint (MLmid) was significantly shorter in the Non-24 patients than in the controls. The interval from the MLmid to the SP offset was significantly longer in the Non-24 patients than in the controls. CONCLUSIONS: It was postulated that Non-24 sufferers' delayed SP onset relative to the circadian pacemaker may accelerate the light-induced phase-delay, leading to sleep-wake cycle that is longer than 24 hours.     

Responsiveness of the aging circadian clock to light

The present study assessed whether advances in sleep times and circadian phase in older adults might be due to decreased responsiveness of the aging circadian clock to light. Sixteen young (29.3 ± 5.6 years) and 14 older adults (67.1 ± 7.4 years) were exposed to 4 h of control dim (10 lux) or bright light (3500 lux) during the night. Phase shifts of the melatonin rhythm were assessed from the nights before and after the light exposure. Bright light delayed the melatonin midpoint in both young and older adults (p < 0.001). Phase delays for the older subjects were not significantly different from those of the young subjects for either the bright or dim light conditions. The magnitude of phase delays was correlated with both sleep offset and phase angle in the older, but not the younger subjects. The present results indicate that at light intensities commonly used in research as well as clinical practice older adults are able to phase delay to the same extent as younger subjects.     

Effects of evening bright light exposure on melatonin, body temperature and sleep

SUMMARY  Five male subjects were exposed to a single 2-h period of bright (2500 lux) or dim (<100 lux) light prior to sleep on two consecutive nights. The two conditions were repeated the following week in opposite order. Bright light significantly suppressed salivary melatonin and raised rectal temperature 0.3°C (which remained elevated during the first 1.5 h of sleep), without affecting tympanic temperature. Bright light also increased REM latency, NREM period length, EEG spectral power in low frequency, 0.75-8 Hz and sigma, 12–14 Hz (sleep spindle) bandwidths during the first hour of sleep, and power of all frequency bands (0.5–32 Hz) within the first NREMP. Potentiation of EEG slow wave activity (0.5-4.0 Hz) by bright light persisted through the end of the second NREMP. The enhanced low-frequency power and delayed REM sleep after bright light exposure could represent a circadian phase-shift and/or the effect of an elevated rectal temperature, possibly mediated by the suppression of melatonin.     

A three pulse phase response curve to three milligrams of melatonin in humans

Exogenous melatonin is increasingly used for its phase shifting and soporific effects. We generated a three pulse phase response curve (PRC) to exogenous melatonin (3 mg) by administering it to free-running subjects. Young healthy subjects (n = 27) participated in two 5 day laboratory sessions, each preceded by at least a week of habitual, but fixed sleep. Each 5 day laboratory session started and ended with a phase assessment to measure the circadian rhythm of endogenous melatonin in dim light using 30 min saliva samples. In between were three days in an ultradian dim light (< 150 lux)-dark cycle (LD 2.5 : 1.5) during which each subject took one pill per day at the same clock time (3 mg melatonin or placebo, double blind, counterbalanced). Each individual's phase shift to exogenous melatonin was corrected by subtracting their phase shift to placebo (a free-run). The resulting PRC has a phase advance portion peaking about 5 h before the dim light melatonin onset, in the afternoon. The phase delay portion peaks about 11 h after the dim light melatonin onset, shortly after the usual time of morning awakening. A dead zone of minimal phase shifts occurred around the first half of habitual sleep. The fitted maximum advance and delay shifts were 1.8 h and 1.3 h, respectively. This new PRC will aid in determining the optimal time to administer exogenous melatonin to achieve desired phase shifts and demonstrates that using exogenous melatonin as a sleep aid at night has minimal phase shifting effects.     

Sleep propensity free-runs with the temperature, melatonin and cortisol rhythms in a totally blind person.

In previous studies, we found that many totally blind people have free-running melatonin rhythms, but that free-running melatonin rhythms were not necessarily associated with periodic insomnia and daytime sleepiness. Thus, it was not clear if the circadian sleep propensity rhythm was free-running with the other circadian rhythms. In the present study, we report that the sleep propensity rhythm (as defined by an ultrashort sleep-wake schedule) free-ran with the melatonin, temperature and cortisol rhythms in a 44-year-old totally blind man even though he maintained a conventional sleep schedule and did not complain of clinically significant insomnia or excessive daytime sleepiness.     

The 24-h growth hormone rhythm in men: sleep and circadian influences questioned

The 24-h rhythm of growth hormone (GH) is thought to be controlled primarily by sleep processes with a weak circadian component. This concept has been recently questioned in sleep-deprived persons. To test the notion of a high sleep-dependency of GH release, we established simultaneous 24-h rhythms of GH and melatonin, a circadian marker, in night workers who form a model for challenging sleep and circadian processes. Ten day-active subjects and 11 night workers were studied during their usual sleep-wake schedule, with sleep from 23:00 to 07:00 hours and 07:00 to 15:00 hours, respectively. Experiments were conducted in sleep rooms under continuous nutrition, bed rest, and dim light. Melatonin and GH were measured every 10 min over 24 h. In day-active subjects, melatonin and GH showed the well-known 24-h profiles, with a major sleep-related GH pulse accounting for 52.8 +/- 3.5% of the 24-h GH production and the onset of the melatonin surge occurring at 21:53 hours +/- 18 min. In night workers, melatonin showed variable circadian adaptation, with the onset of secretion varying between 21:45 and 05:05 hours. The sleep-related GH pulse was lowered, but the reduction was compensated for by the emergence of large individual pulses occurring unpredictably during waking periods, so that the total amount of GH secreted during the 24 h was constant. One cannot predict the degree of GH adaptation from the highly variable melatonin shift. These results argue against the concept that sleep processes exert a predominant influence on GH release whatever the conditions. When sleep and circadian processes are misaligned, the blunting of the sleep-related GH pulse is counteracted, as in sleep-deprived persons, by a compensatory mechanism promoting GH pulses during wakefulness.     

Effect of a single 3-hour exposure to bright light on core body temperature and sleep in humans

Seven human subjects were exposed to bright light (BL, approx. 2500 lux) and dim light (DL, approx. 6 lux) during 3 h prior to nocturnal sleep, in a cross-over design. At the end of the BL exposure period core body temperature was significantly higher than at the end of the DL exposure period. The difference in core body temperature persisted during the first 4 h of sleep. The latency to sleep onset was increased after BL exposure. Rapid-eye movement sleep (REMS) and slow-wave sleep (SWS; stage 3 + 4 of non-REMS) were not significantly changed. Eight subjects were exposed to BL from 20.30 to 23.30 h while their eyes were covered or uncovered. During BL exposure with uncovered eyes, core body temperature decreased significantly less than during exposure with covered eyes. We conclude that bright light immediately affects core body temperature and that this effect is mediated via the eyes.     

Complete or partial circadian re-entrainment improves performance, alertness, and mood during night-shift work

STUDY OBJECTIVES: To assess performance, alertness, and mood during the night shift and subsequent daytime sleep in relation to the degree of re-alignment (re-entrainment) of circadian rhythms with a night-work, day-sleep schedule. DESIGN: Subjects spent 5 consecutive night shifts (11:00 pm-7:00 am) in the lab and slept at home in darkened bedrooms (8:30 am-3:30 pm). Subjects were categorized by the degree of re-entrainment attained after the 5 night shifts. Completely re-entrained: temperature minimum in the second half of daytime sleep; partially re-entrained: temperature minimum in the first half of daytime sleep; not re-entrained: temperature minimum did not delay enough to reach daytime sleep. SETTING: See above. PARTICIPANTS: Young healthy adults (n = 67) who were not shift workers. INTERVENTIONS: Included bright light during the night shifts, sunglasses worn outside, a fixed dark daytime sleep episode, and melatonin. The effects of various combinations of these interventions on circadian re-entrainment were previously reported. Here we report how the degree of re-entrainment affected daytime sleep and measures collected during the night shift. MEASUREMENTS AND RESULTS: Salivary melatonin was collected every 30 minutes in dim light (<20 lux) before and after the night shifts to determine the dim light melatonin onset, and the temperature minimum was estimated by adding a constant (7 hours) to the dim light melatonin onset. Subjects kept sleep logs, which were verified by actigraphy. The Neurobehavioral Assessment Battery was completed several times during each night shift. Baseline sleep schedules and circadian phase differed among the 3 re-entrainment groups, with later times resulting in more re-entrainment. The Neurobehavioral Assessment Battery showed that performance, sleepiness, and mood were better in the groups that re-entrained compared to the group that did not re-entrain, but there were no significant differences between the partial and complete re-entrainment groups. Subjects slept almost all of the allotted 7 hours during the day, and duration did not significantly differ among the re-entrainment groups. CONCLUSIONS: In young people, complete re-entrainment to the night-shift day-sleep schedule is not necessary to produce substantial benefits in neurobehavioral measures; partial re-entrainment (delaying the temperature minimum into the beginning of daytime sleep) is sufficient. The group that did not re-entrain shows that a reasonable amount of daytime sleep is not enough to produce good neurobehavioral performance during the night shift. Therefore, some re-alignment of circadian rhythms is recommended.     

Total sleep deprivation induces an acute and transient increase in NK cell activity in healthy young volunteers.

STUDY OBJECTIVES: To investigate the effects of one night's total sleep deprivation (TSD) on NK cell activity, with rigorous control of circadian phase of sampling points as well as physical exercise level in association with sleep deprivation. DESIGN: The mean sleep onset time of each subject before starting the study was defined as his 0000 h. This study was composed of a Sleep-Sleep session (sleep times, 00:00 h - 08:00 h and 24:00 h - 32:00 h) and a Sleep-Wake session (sleep time, 00:00 h - 08:00 h) with TSD (24:00 h - 32:00 h) placed in a cross-over design with 2-week interval between each session. In each session, the subjects were rested in the supine position under dim light from - 06:00 h to 36:00 h (for 42 hours). SETTING: University-based sleep and chronobiology laboratory PARTICIPANTS: 10 healthy adult men (mean age, 20.9 y; age range, 19-23 y) INTERVENTIONS: NA. MEASUREMENTS AND RESULTS: NK cell activity was measured every 4 hours from 12:00 h. NK cell activity during TSD (at 28:00 h) has been revealed to significantly increase (p=0.01) compared with the corresponding value in the Sleep-Sleep session. This effect was weaker at their usual waking time 32:00 h (p=0.07), and disappeared until 36:00 h (4 hours after awakening). The circadian rhythm phases (dim light melatonin onset time) were coincident between the 2 sessions. CONCLUSIONS: The present findings suggest that one night TSD induces an acute and transient increase in NK cell activity that is not influenced by the effects of circadian rhythm or the amount of physical exercise undertaken during TSD.     

Sleep propensity and sleep architecture after bright light exposure at three different times of day

SUMMARY  The aim of this work was to study the effects of bright light-induced circadian phase shifts on sleep propensity and sleep architecture while the timing of the sleep/wake cycle is kept constant. Twenty-three normal subjects underwent an 11-day study including: (i) baseline sleep and vigilance evaluation; (ii) baseline evaluation of the circadian temperature rhythm with a 40-h constant routine; (iii) five hours of bright light exposure on each of three days; (iv) post-treatment sleep and vigilance evaluation; (v) post-treatment circadian rhythm evaluation with a second 40-h constant routine. Subjects were divided into three groups: eight subjects were exposed to bright light in the morning ('Morning group'), eight subjects were exposed in the evening ('Evening group'), and seven subjects were exposed in the afternoon ('Afternoon group'). After light exposure, the Morning group showed an advance of 1.23 h in the phase of the temperature rhythm, the Evening group showed a delay of 1.62 h, and the Afternoon group showed a non-significant advance of 0.5 h. In support of expectations, early-night sleep propensity was decreased by evening bright light, was increased in almost all subjects exposed to morning bright light, and was not changed by afternoon bright light exposure. The phase shift created by bright light exposure did not seem to be large enough to have a systematic effect on sleep consolidation or on REM sleep parameters in any of the three groups, suggesting that these variables are less sensitive to alterations in phase of the circadian oscillator than early-night sleep propensity.     

Effects of light exposure and sleep displacement on dim light melatonin onset

The purpose of the study was to induce in two different ways, a phase-angle difference between the circadian pacemaker and the imposed sleep-wake cycle in humans, we intended to: (i) shift the circadian pacemaker by exposure to bright light and keep the timing of the sleep-wake cycle fixed; and (ii) keep the timing of the circadian pacemaker fixed by a constant light-dark cycle and displace sleep. We monitored dim light melatonin onset (DLMO), core body temperature and sleep. DLMO was delayed significantly after 3 days of a 3-h delayed sleep-phase when compared with 3 days of sleep at a normal or 3-h advanced sleep-phase. The shifts in DLMO were not accompanied by shifts in body temperature, changes in waking-up time or by a change in the duration of the first rapid eye movement (REM) sleep episode. Three days of light exposure in the morning or evening resulted in shifts in DLMO of similar magnitude, but this was accompanied by shifts in the rhythm of body temperature, changes in waking-up time and in the duration of the first REM sleep episode. We conclude that the changes observed after light exposure reflect shifts in the circadian pacemaker. In contrast, we propose that the changes observed in DLMO after sleep displacement are not mediated by the circadian pacemaker. These results raise some doubts about the reliability of DLMO as a marker of circadian phase in cases of sleep disturbances. Finally, we initiate a search for changes in sleep that might be responsible for the unexpected effects on DLMO.     

Circadian rhythms of early morning awakening insomniacs

SUMMARY It has been suggested that two types of insomnia, sleep onset insomnia and early morning awakening insomnia, may be caused by delays and advances respectively of circadian rhythms. Evidence supports the circadian rhythm phase delay of sleep onset insomniacs. The present study investigated the phase timing of circadian rhythms of early morning awakening insomniacs compared with a group of age matched good sleepers. A 24-h bed rest laboratory session was used to evaluate the endogenous core body temperature and urinary melatonin rhythms. Objective and subjective sleepiness were also measured every 30 min across the session with 10 min multiple sleep latency tests and Stanford Sleepiness Scale. Maximum and minimum phases of each individual's rhythm were identified using two-component cosine curve fitting. Compared with the good sleepers, the insomniacs had significant phase advances of 2 4 h for the temperature and melatonin rhythms. However, the 0-4 h advances of the sleepiness rhythms were not significant. This latter unexpected result was explained on the basis of variability of sleepiness measures. It was suggested that early morning awakening insomnia arises from phase advanced circadian rhythms which evoke early arousal's from sleep.     

Prediction of melatonin efficacy by pretreatment dim light melatonin onset in children with idiopathic chronic sleep onset insomnia

Research has shown efficacy of melatonin treatment to advance sleep-wake rhythms in insomnia. In healthy adults, direction and magnitude of the phase shift depends on the timing of administration relative to the phase position of the circadian system. Therefore, in the present study we investigated whether in children with chronic sleep onset insomnia (SOI) efficacy of melatonin treatment in the early evening could be predicted from dim light melatonin onset (DLMO), a phase marker of the circadian system. We combined data of two previously published double blind, randomized, placebo-controlled trials in 110 participants, aged 6-12 years. Sleep was actigraphically estimated, and saliva collected, at baseline and in the third week of a 4-week treatment period with 5 mg melatonin or placebo at 18:00 or 19:00 hours. Primary outcome measures were pre- to post-treatment changes in dim light melatonin onset (DeltaDLMO), sleep onset (DeltaSO), sleep latency (DeltaSL), and total sleep duration (DeltaTSD). Melatonin advanced DLMO with +1:12 h (P < 0.001), SO with +0:42 h (P = 0.004), SL decreased with 25 min (P = 0.019), and TSD did not change significantly, as compared with placebo. In the melatonin-treated group, but not in the placebo-treated group, pretreatment DLMO was significantly related to DeltaDLMO [F(1, 29) = 7.28, P = 0.012] and DeltaSO [F(1, 25) = 7.72, P = 0.010]. The time interval between treatment administration and pretreatment DLMO (INT) was only significantly related to DeltaSO [F(1,26) = 5.40, P = 0.028]. The results suggest that in children with SOI, the efficacy of early evening melatonin to advance sleep onset and endogenous melatonin onset increases the later the pretreatment DLMO is.     

Effects of light intensity on the circadian temperature and feeding rhythms in the squirrel monkey

The circadian rhythms of body temperature and feeding appear to be timed by separate pacemakers. Tonic administration of light has been used to investigate the response of the pacemaker timing behavioral rhythms; however, the response of the body temperature rhythm has not been similarly examined. This study investigates the circadian timing of the body temperature rhythm under conditions of different light intensity. We simultaneously recorded the patterns of both feeding and body temperature in squirrel monkeys free-running in an environment free of external time cues. In each lighting condition, the periods of the body temperature and feeding rhythms were identical. In constant bright light the rhythm periods were longer than when the animals were exposed to constant dim light. In addition, the variability of the periods was dependent on light intensity. The feeding rhythm period variance of animals in constant bright light was smaller than when in dim light. Conversely, the period of the free-running body temperature rhythm exhibited more variability in bright light than in dim light. Further, in each condition, there were changes in phase angle relationship between feeding and body temperature which were qualitatively similar to those observed in humans, although quantitatively smaller in magnitude. Thus, in the squirrel monkey, tonic light studies reveal that the mean circadian period of the body temperature and feeding rhythms are similar. However, changes in phase relationship, and differential rhythm period stabilities suggest differences in the period of the underlying, tightly coupled pacemakers.     

Melatonin rhythms in night shift workers.

For some time, it has remained uncertain whether the circadian rhythms of permanent night shift workers are adapted to their night-active schedule. Previous studies of this question have often been limited by "masking" (evoked) effects of sleep and activity on body temperature and cortisol, used as marker rhythms. In this study, the problem of masking was minimized by measuring the timing of melatonin production under dim light conditions. Nine permanent night shift workers were admitted to the Clinical Research Center (CRC) directly from their last work shift of the week and remained in dim light while blood samples were obtained hourly for 24 hours. Melatonin concentrations were measured in these samples using a gas-chromatographic mass-spectrometric method. Sleep diaries were completed for two weeks prior to the admission to the CRC. Overall, the onset of the melatonin rhythm was about 7.2 hours earlier (or 16.8 hours later) in the night workers compared to day-active controls. It was not possible to know whether the phase of the melatonin rhythm was the result of advances or delays. In night shift workers, sleep was initiated (on average) about three hours prior to the onset of melatonin production. In contrast, day-active subjects initiated sleep (on average) about three hours after their melatonin onset. Thus, the sleep times selected by night shift workers may not be well-synchronized to their melatonin rhythm, assumed to mark the phase of their underlying circadian pacemaker.     

Advancing circadian rhythms before eastward flight: a strategy to prevent or reduce jet lag

STUDY OBJECTIVES: To develop a practical pre-eastward flight treatment to advance circadian rhythms as much as possible but not misalign them with sleep. DESIGN: One group had their sleep schedule advanced by 1 hour per day and another by 2 hours per day. SETTING: Baseline at home, treatment in lab. PARTICIPANTS: Young healthy adults (11 men, 15 women) between the ages of 22 and 36 years. INTERVENTIONS: Three days of a gradually advancing sleep schedule (1 or 2 hours per day) plus intermittent morning bright light (one-half hour approximately 5000 lux, one-half hour of <60 lux) for 3.5 hours. MEASUREMENTS AND RESULTS: The dim light melatonin onset was assessed before and after the 3-day treatment. Subjects completed daily sleep logs and symptom questionnaires and wore wrist activity monitors. The dim light melatonin onset advanced more in the 2-hours-per-day group than in the 1-hour-per-day group (median phase advances of 1.9 and 1.4 hours), but the difference between the means (1.8 and 1.5 hours) was not statistically significant. By the third treatment day, circadian rhythms were misaligned relative to the sleep schedule, and subjects had difficulty falling asleep in the 2-hours-per-day group, but this was not the case in the 1-hour-per-day group. Nevertheless, the 2-hours-per-day group did slightly better on the symptom questionnaires. In general, sleep disturbance and other side effects were small. CONCLUSIONS: A gradually advancing sleep schedule with intermittent morning bright light can be used to advance circadian rhythms before eastward flight and, thus, theoretically, prevent or reduce subsequent jet lag. Given the morning light treatment used here, advancing the sleep schedule 2 hours per day is not better than advancing it 1 hour per day because it was too fast for the advance in circadian rhythms. A diagram is provided to help the traveler plan a preflight schedule.     

Hypnotic activity of melatonin

OBJECTIVE: To establish the effect of melatonin upon nocturnal and evening sleep. METHODS: Experiment I: The effect of melatonin (0.1, 0.5, 1.0, 5.0, and 10 mg), ingested at 23:30, was studied on nocturnal sleep (23:30-07:30) and core body temperature in 8 healthy volunteers. Performance was measured 8.5 h post-ingestion. On completion of the experiment dim light melatonin onsets (DLMO) were determined. Experiment II: The effect of melatonin (0.5, 1.0, 5.0, and 10 mg), ingested at 18:00, was studied on evening sleep (18:00-24:00) and core body temperature in 6 healthy volunteers. Performance was measured 6.5 h post-ingestion. Each experiment was placebo-controlled and double-blind with a cross-over design with temazepam (20 mg) as an active control. RESULTS: Experiment I: Melatonin (5 mg) reduced the duration of stage 3 in the first 100 min of sleep. Melatonin (0.1 mg) reduced body temperature 6.5 to 7 h post-ingestion. Temazepam increased stage 2, reduced wakefulness and stage 1, and increased the latency to REM sleep. Temazepam reduced body temperature 4.5 to 6.5 h post-ingestion. There were no changes in performance compared with placebo. DLMO occurred between 20:40 and 23:15. Experiment II: Melatonin (all doses) increased total sleep time (TST), sleep efficiency index (SEI) and stage 2, and reduced wakefulness. Temazepam increased TST, SEI, stage 2 and slow-wave sleep, and reduced wakefulness. There were no changes in body temperature or performance compared with placebo. CONCLUSION: Melatonin given at 23:30 has no significant clinical effect on nocturnal sleep in healthy individuals. Hypnotic activity of melatonin when given in the early evening (presumably in the absence of endogenous melatonin) is similar to 20 mg temazepam.