Zhdanova I.V., Lynch H.J., Wurtman R.J.,1997,
Melatonin: A Sleep-Promoting Hormone
Sleep Vol. 20, No. 10 pp 899-907

Summary: This review discusses the issue of a dual effect of melatonin on sleep: acute sleep promotion that typically occurs within one hour of administration, and the ability to alter the phase of the underlying circadian pacemaker after a repeated melatonin treatment. The authors suggest that both mechanisms are at work, that they are complimentary, and that they may manifest jointly or separately. The review provides some basic information on melatonin, an overview of the literature, and the authors' experience in studying the acute effects of melatonin treatment in humans of different age groups. This review also illustrates the authors' cautious attitude toward melatonin treatment that induces supraphysiologic circulating levels of the hormone.

Wurtman R.J. 00, Editorial: Age-Related Decreases in Melatonin Secretion-Clinical Consequences. The Journal of Clinical Endocrinology and Metabolism Vol. 85, No 6 pp 2135-2136

Bubenik G.A., et al 1998, Prospects of Clinical Utilization of Melatonin. Biological Signals and Receptors Vol. 7 pp 195-219
BioMedNet.com/karger

Abstract: This review summarizes the present knowledge on melatonin in several areas on physiology and discusses various prospects of its clinical utilization. Ever increasing evidence indicates that melatonin has an immunohematopoietic role. In animal studies, melatonin provided protection against gram-negative septic shock, prevented stress induced immunodepression, and restored immune function after a hemorrhagic shock. In human studies, melatonin amplified the antitumoral activity of interleukin-2. Melatonin has been proven as a powerful cytostatic drug in vitro as well as in vivo. In the human clinical field, melatonin appears to be a promising agent either as a diagnostic or prognostic marker of neoplastic diseases or as a compound used either alone or in combination with the standard cancer treatment. Utilizationof melatonin for tratment of rhythm disorders, such as those manifested in jet lag, shift work or blindness, is one of the oldest and the most successful clinical application of this chemical. Low doses of melatonin applied in controlled release preparation were very effective in improving the sleep latency, increasing the sleep efficiency and rising sleep quality scores in elderly, melatonin deficient insomniacs. In the cardiovascular system, melatonin seems to regulate the tone of cerebral arteries; melatonin receptors in vascular beds appear to participate in the regulation of body temperature. Heat loss may be the principal mechanism in the initiation of sleepiness caused by melatonin. The role of melatonin in the development of migraine headaches is at present uncertain but more research could result in new ways of treatment. Melatonin is the major messenger of light dependent periodicity, implicated in the seasonal reproduction of animals and pubertal development in humans. Multiple receptor sites detected in brain and gonadal tissues of birds and mammals of both sexes indicate that melatonin exerts a direct effect on the vertebrate reproductive organs. In a clinical study, melatonin has been used effectively as a female contraceptive with little side effects. Melatonin is one of the most powerful scavengers of free radicals. Because it easily penetrates the blood brain barrier, this antioxidant may, in the future, be used for the treatment of Alzheimer's and Parkinson's diseases, stroke, nitric oxide, neurotoxicity and hyperbaric oxygen exposure. Inthe digestive tract, melatonin reduced the incidence and severity of gastric ulcers and prevented severe symptoms of colitis,such as mucosal lesions and diarrhea.

Abstract: Melatonin (MLT) is a methoxyindole secreted principally by the pineal gland. It is synthesized at night under normal environmental conditions. The endogenous rhythm of secretion is generated by the suprachiasmatic nuclei and entrained by the light/dark cycle. Light is able to both suppress or entrain MLT production on light schedule. The nyctohemeral rhythm of this hormone can be determined by repeated measurement of plasma or saliva MLT or urine sulfatoxy-MLT, the main hepatic metabolite. MLT can be considered as the output (the hand) of the endogenous clock. Since the regulating system follows a central and sympathetic nervous pathway, an abnormality at any level could unspecifically modify the MLT secretion, especially in patients with sympathalgia or dysautonomia. MLT plays the role of an endogenous zeitgeber on core temperature or sleep-wake cycle. Exogenous MLT is able to influence the endogenous secretion of the hormone according to a phase-response curve. There are practical implications for this property in situations when biological rhythms are disturbed (jet-lag syndrome, delayed sleep phase syndrome, insomnia in blind people, shift-work, insomnia in elderly people). Improvement of pharmaceutical forms (controlled release preparations) or development of MLT analogs could lead to decisive progress.

Sack R.L., Hughes R.J., Edgar D.M., Lewy A.J. 1997. Sleep-Promoting Effects of Melatonin: At What Dose, in Whom, Under What Conditions, and by What Mechanisms?
Sleep Vol. 20 No.10 pp 908-915

Summary: Differing conclusions regarding the sleep-promoting effects of melatonin may be the result of the broad range of doses employed (0.1-2000mg), the differing categories of subjects tested (normal subjects, insomniac patients, elderly, etc.), and the varying times of administration (for day-time vs. night-time sleep). We conclude that melatonin may benefit sleep by correcting circadian phase abnormalities and/or by a modest direct soporific effect that is most evident following daytime administration to younger subjects. We speculate that these effects are mediated by interactions  with specific receptors concentrated in the suprachiasmatic nucleus (SCN) that result in resetting of the circadian pacemaker an/or attenuation of an SCN dependent circadian alerting process.

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