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 Delta-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.

SUMMARY 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 sleepwake/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.k e y w o r d s circadian, constant routine, heart rate, heart rate variability, light, melatonin, sleep

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.

The literature on pencil and paper tests and the effects of psychotropic drugs is reviewed. Performance at digit symbol substitution, symbol copying, letter cancellation, arithmetic, logic and cognitive processing with a relatively constant level of triazolam was compared with placebo. Analysis of variance, covariance analysis and principal component analysis were applied to the data. Pencil and paper tests which measure various skills are useful for detecting drug effects. Letter cancellation, arithmetic and DSST appear to be most sensitive, although logic and symbol copying may be useful.

In humans, the pineal hormone melatonin can phase shift a number of circadian rhythms (e.g., "fatigue", endogenous melatonin, core body temperature) together with the timing of prolactin secretion. It is uncertain, however, whether melatonin can fully entrain all human circadian rhythms. In this study, the authors investigated the effects of daily melatonin administration on sighted individuals kept in continuous very dim light. A total of 10 normal, healthy males were maintained in two separate groups in partial temporal isolation under constant dim light (< 8 lux) with attenuated sound and ambient temperature variations but with knowledge of clock time for two periods of 30 days. In these circumstances, the majority of individuals free run with a mean period of 24.3 h. In a double-blind, randomized crossover design, subjects received 5 mg melatonin at 20:00 h on Days 1 to 15 (Melatonin 1st) followed by placebo on Days 16 to 30 (Placebo 2nd) or vice versa (Placebo 1st, Melatonin 2nd) during Leg 1 with treatment reversed in Leg 2. The variables measured were melatonin (as 6-sulphatoxymelatonin), rectal temperature, activity, and sleep (actigraphy and logs). In the experiment, 9 of the 10 subjects free ran with Placebo 1st, whereas Melatonin 1st stabilized the sleep-wake cycle to 24 h in 8 of 10 individuals. In addition, 2 individuals showed irregular sleep with this treatment. In some subjects, there was a shortening of the period of the temperature rhythm without synchronization. Melatonin 2nd induced phase advances (5 of 9 subjects), phase delays (2 of 9 subjects), and stabilization (2 of 9 subjects) of the sleep-wake cycle with subsequent synchronization to 24 h in the majority of individuals (7 of 9). Temperature continued to free run in 4 subjects. Maximum phase advances in core temperature were seen when the first melatonin treatment was given approximately 2 h after the temperature acrophase. These results indicate that melatonin was able to phase shift sleep and core temperature but was unable to synchronize core temperature consistently. In the majority of subjects, the sleep-wake cycle could be synchronized.

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.

SUMMARYThe 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.

1 Effects of the heterocyclic amphetamine derivatives, pemoline (20 and 40 mg), prolintane hydrochloride (5 and 10 mg), methylphenidate hydrochloride (10 and 20 mg) and fencamfamine hydrochloride (10 and 20 mg), and of caffeine anhydrous (100, 200 and 300 mg) on sleep, were compared with placebo in six young adults (20-31 years) using electroencephalography for sleep measures and analogue scales for subjective assessments of well-being and sleep quality. The