Barbara M. Stone

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.

Effect of Δ-9-tetrahydrocannabinol and Cannabidiol on Nocturnal Sleep and Early-morning Behavior in Young Adults

Abstract: The effects of cannabis extracts on nocturnal sleep, early-morning performance, memory, and sleepiness were studied in 8 healthy volunteers (4 males, 4 females; 21 to 34 years). The study was double-blind and placebo-controlled with a 4-way crossover design. The 4 treatments were placebo, 15 mg Δ-9-tetrahydrocannabinol (THC), 5 mg THC combined with 5 mg cannabidiol (CBD), and 15 mg THC combined with 15 mg CBD. These were formulated in 50:50 ethanol to propylene glycol and administered using an oromucosal spray during a 30-minute period from 10 pm. The electroencephalogram was recorded during the sleep period (11 pm to 7 am). Performance, sleep latency, and subjective assessments of sleepiness and mood were measured from 8:30 am (10 hours after drug administration). There were no effects of 15 mg THC on nocturnal sleep. With the concomitant administration of the drugs (5 mg THC and 5 mg CBD to 15 mg THC and 15 mg CBD), there was a decrease in stage 3 sleep, and with the higher dose combination, wakefulness was increased. The next day, with 15 mg THC, memory was impaired, sleep latency was reduced, and the subjects reported increased sleepiness and changes in mood. With the lower dose combination, reaction time was faster on the digit recall task, and with the higher dose combination, subjects reported increased sleepiness and changes in mood. Fifteen milligrams THC would appear to be sedative, while 15 mg CBD appears to have alerting properties as it increased awake activity during sleep and counteracted the residual sedative activity of 15 mg THC.

Human circadian rhythms in constant dim light (8 lux) with knowledge of clock time

The light/dark (L/D) cycle is a major synchronizer of human circadian rhythms. In the absence of a strong L/D cycle, synchrony with 24 hours can nevertheless be maintained in a socially structured environment, as shown in Polar regions (Broadway et al. 1987) and by some blind subjects (Czeisler et al. 1995a). The relative contribution of other time cues to entrainment in dim light has not been fully explored. The present study investigated the behaviour of melatonin (assessed as 6‐sulphatoxymelatonin); rectal temperature; activity and sleep (actigraphy and logs) in constant dim light (L/L) with access to a digital clock. 6 normal healthy males were maintained as a group in partial temporal isolation with attenuated sound and ambient temperature for 21 days. All 6 subjects showed free‐running periodicity for 6‐sulphatoxymelatonin and 5/6 subjects for temperature, activity and sleep offset. The average period (tau) was 24.26±0.049, substantially shorter than in previous experiments with a self selected L/D cycle but similar to a recent study conducted in very dim light. One subject maintained a rigid sleep/wake cycle throughout whilst his 6‐sulphatoxymelatonin rhythm free‐ran. Total sleep time, from actigraph data, did not change but sleep efficiency decreased during the experiment. The subjects did not show group synchronization. These results confirm previous data indicating the importance of the L/D cycle in human entrainment and underline the lesser role of social cues and knowledge of clock time. This particular approach will permit the administration of timed medication to sighted humans under free‐running conditions.

Robust circadian rhythm in heart rate and its variability: influence of exogenous melatonin and photoperiod

Heart rate (HR) and heart rate variability (HRV) undergo marked fluctuations over the 24‐h day. Although controversial, this 24‐h rhythm is thought to be driven by the sleep–wake/rest–activity cycle as well as by endogenous circadian rhythmicity. We quantified the endogenous circadian rhythm of HR and HRV and investigated whether this rhythm can be shifted by repeated melatonin administration while exposed to an altered photoperiod. Eight healthy males (age 24.4 ± 4.4 years) participated in a double‐blind cross‐over design study. In both conditions, volunteers were scheduled to 16 h–8 h rest : wake and dark : light cycles for nine consecutive days preceded and followed by 29‐h constant routines (CR) for assessment of endogenous circadian rhythmicity. Melatonin (1.5 mg) or placebo was administered at the beginning of the extended sleep opportunities. For all polysomnographically verified wakefulness periods of the CR, we calculated the high‐ (HF) and low‐ (LF) frequency bands of the power spectrum of the R–R interval, the standard deviation of the normal‐to‐normal (NN) intervals (SDNN) and the square root of the mean‐squared difference of successive NN intervals (rMSSD). HR and HRV variables revealed robust endogenous circadian rhythms with fitted maxima, respectively, in the afternoon (16:36 hours) and in the early morning (between 05:00 and 06:59 hours). Melatonin treatment phase‐advanced HR, HF, SDNN and rMSSD, and these shifts were significantly greater than after placebo treatment. We conclude that endogenous circadian rhythmicity influences autonomic control of HR and that the timing of these endogenous rhythms can be altered by extended sleep/rest episodes and associated changes in photoperiod as well as by melatonin treatment.

MELATONIN AND FRAGMENTED SLEEP PATTERNS

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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.

Modulation of catecholamine transmission and sleep in man

The effect of modulation of catecholamine transmission on sleep in man was studied using mianserin (20 and 40 mg) and nomifensine (50 and 100 mg). It is suggested that reduced wakefulness induced by mianserin during sleep is primarily related to postsynaptic antagonism of alpha adrenoceptors, though a possible synergistic effect with antagonism of histamine H1 receptors cannot be excluded, while increased wakefulness with nomifensine is related to inhibition of the uptake of catecholamines and/or direct or indirect dopaminergic activity. The reduction in rapid eye movement (REM) sleep with both drugs is believed to be a non-specific effect which arises from a disturbance of the balance between monoaminergic and cholinergic influences.

Promoting sleep in shiftworkers and intercontinental travelers.

A number of techniques and treatments can be used to alleviate the sleep disturbance associated with both shiftwork and transmeridian travel. Optimization of the sleeping environment and avoidance of substances such as caffeine and alcohol before sleep are the best initial approach. Timing sleep to coincide with some of the normal sleep period where possible will improve sleep quality in shiftworkers. Similarly, following transmeridian flight, restricting sleep to the nocturnal period in the new time zone will assist adaptation. Hypnotic drugs may be of benefit to alleviate sleep disturbance experienced by shiftworkers or transmeridian travelers. Selection of the most appropriate medication must take into account required duration of action and possible residual effects of the drug on alertness. Hypnotics may be useful, particularly in middle-aged individuals who already have disturbed sleep, on those occasions when poor sleep is anticipated, for example following an eastward flight or after the initial change to night duty. Over-the-counter preparations should be avoided whenever possible unless it is known that they are not associated with residual sequelae.

Irregularity of rest and activity: studies on circadian rhythmicity in man.

1. Rectal temperature, electrolyte excretion and performance were studied in young adults who followed an irregular pattern of work and rest for 9 days in an isolation unit. 2. In the analysis, effects evoked by the pattern of work and rest were separated from the oscillatory component, and rhythms for individual days were examined by the cosinor method. 3. During the schedule, rhythms no longer showed a period of exactly 24 h, and this effect was confirmed by studies using a repeated cycle of irregular work and rest and by studies using constant routines. 4. Temperature and urinary constituents differed in the strength and phase of their rhythms when corrected for evoked effects, as well as in the strength of the evoked effects themselves. 5. There was evidence of deterioration in performance during work periods which exceeded 9 h, but there was no evidence of progressive deterioration in performance over the 9 day schedule.