Early studies on the physiological effects of melatonin typically reported hypnotic 'side-effects'. Later studies, specifically addressing this action, failed to reliably replicate hypnotic effects using standard polysomnography. This difference may be related to differences in the basic physiological action of melatonin compared with more conventional hypnotics. It is suggested that melatonin exerts a hypnotic effect through thermoregulatory mechanisms. By lowering core body temperature, melatonin reduces arousal and increases sleep-propensity. Thus, in humans, one role of melatonin is to transduce the light-dark cycle and define a window-of-opportunity in which sleep-propensity is enhanced. As such, melatonin is likely to be an effective hypnotic agent for sleep disruption associated with elevated temperature due to low circulating melatonin levels. The combined circadian and hypnotic effects of melatonin suggest a synergistic action in the treatment of sleep disorders related to the inappropriate timing of sleep and wakefulness. Adjuvant melatonin may also improve sleep disruption caused by drugs known to alter normal melatonin production (e.g., beta-blockers and benzodiazepines). If melatonin is to be developed as a successful clinical treatment, differences between the pharmacological profile following exogenous administration and the normal endogenous rhythm should be minimized. Continued development as a useful clinical tool requires control of both the amplitude and duration of the exogenous melatonin pulse. There is a need to develop novel drug delivery systems that can reliably produce a square-wave pulse of melatonin at physiological levels for 8-10 hr duration.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-079X.1993.tb00503.x

Melatonin and sleep in humans.

An intrinsic body clock residing in the suprachiasmatic nucleus (SCN) within the brain regulates a complex series of rhythms in humans, including sleep/wakefulness. The individual period of the endogenous clock is usually >24 hours and is normally entrained to match the environmental rhythm. Misalignment of the circadian clock with the environmental cycle may result in sleep disorders. Among these are chronic insomnias associated with an endogenous clock which runs slower or faster than the norm [delayed (DSPS) or advanced (ASPS) sleep phase syndrome, or irregular sleep-wake cycle], periodic insomnias due to disturbances in light perception (non-24-hour sleep-wake syndrome and sleep disturbances in blind individuals) and temporary insomnias due to social circumstances (jet lag and shift-work sleep disorder). Synthesis of melatonin (N-acetyl-5-methoxytryptamine) within the pineal gland is induced at night, directly regulated by the SCN. Melatonin can relay time-of-day information (signal of darkness) to various organs, including the SCN itself. The phase-shifting effects of melatonin are essentially opposite to those of light. In addition, melatonin facilitates sleep in humans. In the absence of a light-dark cycle, the timing of the circadian clock, including the timing of melatonin production in the pineal gland, may to some extent be adjusted with properly timed physical exercise. Bright light exposure has been demonstrated as an effective treatment for circadian rhythm sleep disorders. Under conditions of entrainment to the 24-hour cycle, bright light in the early morning and avoidance of light in the evening should produce a phase advance (for treatment of DSPS), whereas bright light in the evening may be effective in delaying the clock (ASPS). Melatonin, given several hours before its endogenous peak at night, effectively advances sleep time in DSPS and adjusts the sleep-wake cycle to 24 hours in blind individuals. In some blind individuals, melatonin appears to fully entrain the clock. Melatonin and light, when properly timed, may also alleviate jet lag. Because of its sleep-promoting effect, melatonin may improve sleep in night-shift workers trying to sleep during the daytime. Melatonin replacement therapy may also provide a rational approach to the treatment of age-related insomnia in the elderly. However, there is currently no melatonin formulation approved for clinical use, neither are there consensus protocols for light or melatonin therapies. The use of bright light or melatonin for circadian rhythm sleep disorders is thus considered exploratory at this stage.

Circadian rhythm sleep disorders: pathophysiology and potential approaches to management.

Chronobiotics—drugs that shift rhythms

BACKGROUND: Melatonin is an important regulator of the sleep-wake cycle. A prolonged-release formulation of melatonin (PR-M) that essentially mimics the profile of the endogenous production of the hormone is effective in the treatment of insomnia in patients aged 55 years and older. Because hypnotics result in impairments of various cognitive skills, it is important to examine the cognitive effects associated with the use of PR-M. OBJECTIVES AND METHODS: The effects of therapeutic oral doses of PR-M (2 mg), zolpidem (10 mg) and their combination administered at bedtime on cognitive functions in healthy subjects aged 55 years and older (12 males + 4 females, age 59.4 +/- 3.2 years) were assessed in a randomized, double-blind, placebo-controlled, and four-way crossover study. Psychomotor functions, memory recall, and driving skills were assessed at 1 and 4 h following administration and the next morning. RESULTS: Compared to placebo, PR-M alone did not impaired performances on any cognitive tasks. Zolpidem significantly impaired psychomotor and driving performance 1 h and 4 h post-dosing, and early memory recall; these impairment were exacerbated with PR-M co-administration. No effects on next morning psychomotor or driving performance were observed except that the decline in memory recall after zolpidem was more pronounced in the next day. No pharmacokinetic interactions were found. CONCLUSIONS: This study extends previous researches showing impairment of cognitive functions by zolpidem within 5 h post-administration. Further, PR-M use was not found associated with impairment of psychomotor functions, memory recall, and driving skills, and point to a pharmacodynamic interaction between melatonin and GABA-A modulators. Language: en

/pdf/effects-of-prolonged-release-melatonin-zolpidem-and-their-1q33oz3hcv.pdf

Effects of prolonged‐release melatonin, zolpidem, and their combination on psychomotor functions, memory recall, and driving skills in healthy middle aged and elderly volunteers

The perceptual-cognitive mechanisms and neural correlates of Absolute Pitch (AP) are not fully understood. The aim of this fMRI study was to examine the neural network underlying AP using a pitch memory experiment and contrasting two groups of musicians with each other, those that have AP and those that do not. We found a common activation pattern for both groups that included the superior temporal gyrus (STG) extending into the adjacent superior temporal sulcus (STS), the inferior parietal lobule (IPL) extending into the adjacent intraparietal sulcus (IPS), the posterior part of the inferior frontal gyrus (IFG), the pre-supplementary motor area (pre-SMA), and superior lateral cerebellar regions. Significant between-group differences were seen in the left STS during the early encoding phase of the pitch memory task (more activation in AP musicians) and in the right superior parietal lobule (SPL)/intraparietal sulcus (IPS) during the early perceptual phase (ITP 0–3) and later working memory/multimodal encoding phase of the pitch memory task (more activation in non-AP musicians). Non-significant between-group trends were seen in the posterior IFG (more in AP musicians) and the IPL (more anterior activations in the non-AP group and more posterior activations in the AP group). Since the increased activation of the left STS in AP musicians was observed during the early perceptual encoding phase and since the STS has been shown to be involved in categorization tasks, its activation might suggest that AP musicians involve categorization regions in tonal tasks. The increased activation of the right SPL/IPS in non-AP musicians indicates either an increased use of regions that are part of a tonal working memory (WM) network, or the use of a multimodal encoding strategy such as the utilization of a visual-spatial mapping scheme (i.e., imagining notes on a staff or using a spatial coding for their relative pitch height) for pitch information.

/pdf/perceiving-pitch-absolutely-comparing-absolute-and-relative-2zbhri8726.pdf

Perceiving pitch absolutely: comparing absolute and relative pitch possessors in a pitch memory task.

It has been suggested that melatonin may have therapeutic potential for alleviating jet lag. In an attempt to define further the effects of low pharmacological doses of melatonin on the human body, 5 mg of melatonin was given orally to one subject in a blind experiment. The electrocardiogram (ECG) was recorded together with simple reaction time (SRT) responses over a 5-h period after taking melatonin. The main part of the project was carried out under artificial domestic lighting conditions and involved ten evening sessions.



Microprocessor analysis of the ECG of one subject clearly showed that melatonin had the effect of lengthening the RR interval, that between the peak of the P wave and the onset of the R wave, and the interval between the onset of the R wave and the peak of the T wave. A model to explain the cubic curve, which was fitted by regression analysis to the data, implies that the natural evening increase in melatonin may also increase these intervals. The results suggest that melatonin may affect both the phase and the amplitude of the observed ECG phenomenon.



Analysis of more than 40,000 SRT responses to both visual and auditory stimuli implied that these responses might also be lengthened by melatonin. Frequency histograms of the responses and observations on premature and missed responses were not able to reproduce the results of other workers who found that higher doses (240 mg) of melatonin decreased the number of incorrect responses to simple reaction time tasks.

Effect of melatonin on the human electrocardiogram and simple reaction time responses.

The accuracy and consistency of absolute pitch (AP) judgments have been measured on three subjects in two longitudinal studies separated by twenty years. The drifts and cyclical variations observed in the earlier study still persisted, and an investigation of two other subjects, one of whom was first studied forty years ago, suggests that they might undergo similar cyclical variations in their pitch perception. Pitch judgments also varied during the day. The detailed observations of these nonrandom fluctuations have been used to determine a value for the underlying consistency of the AP estimates. When the effects of the daytime variations and longer-term drifts were removed, the values for this consistency, as measured by the standard deviation, were calculated to be 3.1, 3.4, 3.7, 4.4, and 4.5 Hz for the five subjects. When an oscillator was used to produce the estimate, the consistency of the judgments was observed to depend on the accuracy of those judgments.

Accuracy and consistency of absolute pitch

The absolute pitch ability (AP) of three female and two male subjects has been investigated over many years. The pitch estimates of A4 (440 Hz) of four of the subjects varied by up to a semitone during the longitudinal study. The fifth subject showed no noticeable variation in his estimates of A4. Standard deviations calculated from the data showed no significant variation with age.

Vernon Thomas Wynn

Papers

Effect of melatonin on the human electrocardiogram and simple reaction time responses.

Accuracy and consistency of absolute pitch

Absolute pitch revisited.