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

Despite the fact that many physiological and pharmacological actions of melatonin (MEL) have been described, its mechanism of action at the subcellular level remains unclear. It has been suggested that MEL has effects on cellular processes that involve microfilaments and microtubules. In the present study MEL effects on the cytoskeleton were evaluated in MDCK and N1E-115 cells in which the microfilaments have been shown to participate in cell morphology and dome formation (MDCK) and the microtubules in neurite outgrowths. After one day of culture with 10(-11)-10(-7) M MEL MDCK cells showed an increase in the number of elongated cells. After four days with the hormone, an increase in the incidence of MDCK cells contacting neighboring cells through long cytoplasmic elongations was observed. Actin antibody stain showed the appearance of thicker fluorescent fibres beneath the cell membrane and over the nucleus in the MEL treated cells. An increase in dome formation in confluent cells was also observed. In N1E-115 cells MEL (10(-13)-10(-5) M) induced an increase in cell with neurite processes. Neurite outgrowth is clearly seen at 24 h after plating. MEL-treated cells grow in clusters with neurites forming intricate networks. Antitubulin antibody stain showed long fluorescent neurites in the N1E-115 MEL-treated cells. A decrease in N1E-115 neurite formation was observed with either serotonin or 6-hydroxymelatonin (6OH-MEL). However, the number of MDCK cells with cytoplasmic elongations was decreased only after 6OH-MEL. We conclude that MEL action at the cellular level involves a modification of the cytoskeletal organization.

Melatonin effects on the cytoskeletal organization of MDCK and neuroblastoma N1E-115 cells

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.

Josephine Arendt

Papers

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