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MELATONIN



Table of Contents
image Melatonin and The Inhibition of Fibroblasts
image Transdermal Delivery of Melatonin
image Melatonin secretion related to side-effects of beta-blockers from the central nervous system
image Oxidative damage caused by free radicals produced during catecholamine autoxidation: Protective effects of O-methylation and melatonin
image Protective effect of melatonin against hippocampal DNA damage induced by intraperitonealadministration of kainate to rats
image Neuroprotection by melatonin from kainate-induced excitotoxicity in rats
image The hypothermic effect of melatonin on core body temperature: Is more better?
image The zinc pool is involved in the immune reconstituting effect of melatonin in pinealectomized mice
image Melatonin and the endocrine role of the pineal organ
image Brief report: Circadian melatonin, thyroid-stimulating hormone, prolactin, and cortisol levels in serum of young adults with autism
image Effects of melatonin and thyroxine replacement on thyrotropin, luteinizing hormone, and prolactin in male hypothyroid hamsters
image Suppression of UV-induced erythema by topical treatment with melatonin (N-acetyl-5-methoxytryptamine). A dose response study
image Melatonin reduces mortality from Aleutian disease in mink (Mustela vison).
image Gastroprotective activity of melatonin and its precursor, L-tryptophan, against stress-induced and ischaemia-induced lesions is mediated by scavenge of oxygen radicals.
image Melatonin: media hype or therapeutic breakthrough?
image Prevention of cytokine-induced hypotension in cancer patients by the pineal hormone melatonin.
image Mechanisms of action of ECT in Parkinson's disease: possible role of pineal melatonin.
image Pineal melatonin functions: possible relevance to Parkinson's disease.
image Locus coeruleus-pineal melatonin interactions and the pathogenesis of the "on-off" phenomenon associated with mood changes and sensory symptoms in Parkinson's disease.
image Pineal melatonin and sensory symptoms in Parkinson disease.
image [Neuroendocrine and psychopharmacologic aspects of the pineal function. Melatonin and psychiatric disorders]
image Studies on the antiinflammatory, immunoregulatory, and analgesic actions of melatonin
image Melatonin effects on behavior: Possible mediation by the central GABAergic system
image Nocturnal plasma melatonin profile and melatonin kinetics during infusion in status migrainosus
image Nocturnal melatonin excretion is decreased in patients with migraine without aura attacks associated with menses
image Urinary melatonin excretion throughout the ovarian cycle in menstrually related migraine
image Nocturnal plasma melatonin levels in migraine: A preliminary report
image The influence of the pineal gland on migraine and cluster headaches and effects of treatment with picoTesla magnetic fields.
image Is migraine due to a deficiency of pineal melatonin?
image Melatonin in humans physiological and clinical studies.
image Treatment of circadian rhythm disorders - Melatonin
image The Mel(1a) melatonin receptor gene is expressed in human suprachiasmatic nuclei
image Circadian sleep-wake disorders
image Melatonin and jet lag
image Melatonin efficacy in aviation missions requiring rapid deployment and night operations
image Melatonin: Between facts and fantasy
image Melatonin: A master hormone and a candidate for universal panacea
image Use of melatonin in circadian rhythm disorders and following phase shifts
image Adapting to phase shifts, II. Effects of melatonin and conflicting light treatment
image Chronobiotics - Drugs that shift rhythms
image Phase shifting the human circadian clock using melatonin
image A double-blind trial of MELATONIN as a treatment for jet lag in international cabin crew.
image MELATONIN and jet lag: confirmatory result using a simplified protocol
image Role of biological clock in human pathology
image Melatonin marks circadian phase position and resets the endogenous circadian pacemaker in humans.
image The role of pineal gland in circadian rhythms regulation.
image Light, melatonin and the sleep-wake cycle.
image Circadian rhythms, jet lag, and chronobiotics: an overview.
image [Chronobiological sleep disorders and their treatment possibilities]
image Chronopharmacological actions of the pineal gland.
image Some effects of MELATONIN and the control of its secretion in humans.
image Daily melatonin intake resets circadian rhythms of a sighted man with non-24-hour sleep-wake syndrome who lacks the nocturnal melatonin rise
image A sighted man with non-24-hour sleep-wake syndrome shows damped plasma melatonin rhythm
image Case study: The use of melatonin in a boy with refractory bipolar disorder
image Rapid reversal of tolerance to benzodiazepine hypnotics by treatment with oral melatonin: A case report
image Improvement of sleep quality by controlled-release melatonin in benzodiazepine-treated elderly insomniacs
image Melatonin - a chronobiotic and soporific hormone
image Evaluation of the antioxidant activity of melatonin in vitro
image Nocturnal melatonin secretion and sleep after doxepin administration in chronic primary insomnia
image Melatonin: From the hormone to the drug?
image Inhibition of melatonin secretion onset by low levels of illumination
image Melatonin replacement corrects sleep disturbances in a child with pineal tumor
image Melatonin replacement therapy of elderly insomniacs
image Improvement of sleep equality in elderly people by controlled-release melatonin
image Sleep-inducing effects of low doses of melatonin ingested in the evening
image Melatonin rhythms in night shift workers
image Effect of melatonin replacement on serum hormone rhythms in a patient lacking endogenous melatonin
image Melatonin administration in insomnia
image Immune effects of preoperative immunotherapy with high-dose subcutaneous interleukin-2 versus neuroimmunotherapy with low-dose interleukin-2 plus the neurohormone melatonin in gastrointestinal tract tumor patients.
image The immunoneuroendocrine role of melatonin.
image Melatonin reduces the severity of dextran-induced colitis in mice.
image Melatonin affects proopiomelanocortin gene expression in the immune organs of the rat.
image Serial transplants of DMBA-induced mammary tumors in Fischer rats as model system for human breast cancer. IV. Parallel changes of biopterin and melatonin indicate interactions between the pineal gland and cellular immunity in malignancy.
image Inhibitory effect of melatonin on production of IFN gamma or TNF alpha in peripheral blood mononuclear cells of some blood donors.
image Specific binding of 2-[125I]iodomelatonin by rat splenocytes: characterization and its role on regulation of cyclic AMP production.
image Pineal-opioid system interactions in the control of immunoinflammatory responses.
image Evidence for a direct action of melatonin on the immune system.
image The immuno-reconstituting effect of melatonin or pineal grafting and its relation to zinc pool in aging mice.
image Multiple sclerosis: the role of puberty and the pineal gland in its pathogenesis.
image Modulation of human lymphoblastoid interferon activity by melatonin in metastatic renal cell carcinoma. A phase II study.
image Modulation of 2[125I]iodomelatonin binding sites in the guinea pig spleen by melatonin injection is dependent on the dose and period but not the time.
image Binding of [125I]-labelled iodomelatonin in the duck thymus.
image Characteristics of 2-[125I]iodomelatonin binding sites in the pigeon spleen and modulation of binding by guanine nucleotides.
image Pinealectomy ameliorates collagen II-induced arthritis in mice.
image 2[125I]iodomelatonin binding sites in spleens of guinea pigs.
image Melatonin: a chronobiotic with anti-aging properties?
image Effect of dose and time of melatonin injections on the diurnal rhythm of immunity in chicken.
image The pineal neurohormone melatonin stimulates activated CD4+, Thy-1+ cells to release opioid agonist(s) with immunoenhancing and anti-stress properties.
image Alterations of pineal gland and of T lymphocyte subsets in metastatic cancer patients: preliminary results.
image Endocrine and immune effects of melatonin therapy in metastatic cancer patients.
image Melatonin modulation of estrogen-regulated proteins, growth factors, and proto-oncogenes in human breast cancer.
image Melatonin inhibition of MCF-7 human breast-cancer cells growth: influence of cell proliferation rate.
image Modulation of cancer endocrine therapy by melatonin: a phase II study of tamoxifen plus melatonin in metastatic breast cancer patients progressing under tamoxifen alone.
image Modulation of estrogen receptor mRNA expression by melatonin in MCF-7 human breast cancer cells.
image Melatonin modulates growth factor activity in MCF-7 human breast cancer cells.
image Role of pineal gland in aetiology and treatment of breast cancer.
image A review of the evidence supporting melatonin's role as an antioxidant.
image Treatment of cancer chemotherapy-induced toxicity with the pineal hormone melatonin.
image Treatment of cancer-related thrombocytopenia by low-dose subcutaneous Interleukin-2 plus the pineal hormone melatonin: A biological phase II study
image Type 2 Th cells as target of the circadian melatonin signal: Relevance in local immunity
image Hematopoietic rescue via T-cell-dependent, endogenous granulocyte- macrophage colony-stimulating factor induced by the pineal neurohormone melatonin in tumor-bearing mice
image Randomized study with the pineal hormone melatonin versus supportive care alone in advanced nonsmall cell lung cancer resistant to a first-line chemotherapy containing cisplatin
image Melatonin increase as predictor for tumor objective response to chemotherapy in advanced cancer patients
image Modulation of the length of the cell cycle of the MCF-7 human breast cancer cells by melatonin
image Melatonin blocks the stimulatory effects of prolactin on human breast cancer cell growth in culture.
image Differences between pulsatile or continuous exposure to melatonin on MCF-7 human breast cancer cell proliferation.
image Effects of melatonin on cancer: studies on MCF-7 human breast cancer cells in culture.
image Neuroimmunotherapy of advanced solid neoplasms with single evening subcutaneous injection of low-dose interleukin-2 and melatonin: preliminary results.
image Tissue changes in glutathione metabolism and lipid peroxidation induced by swimming are partially prevented by melatonin
image Modulation of tumor necrosis factor-alpha (TNF-alpha) toxicity by the pineal hormone melatonin (MLT) in metastatic solid tumor patients
image A biological study on the efficacy of low-dose subcutaneous interleukin-2 plus melatonin in the treatment of cancer-related thrombocytopenia.
image Melatonin prevents death of neuroblastoma cells exposed to the Alzheimer amyloid peptide.
image Daily rhythm of serum melatonin in patients with dementia of the degenerate type.
image The mystery of Alzheimer's disease and its prevention by melatonin.
image Chrono-neuroendocrinological aspects of physiological aging and senile dementia.
image A phase II study of tamoxifen plus melatonin in metastatic solid tumour patients

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Melatonin efficacy in aviation missions requiring rapid deployment and night operations

Aviation Space and Environmental Medicine (USA), 1996, 67/6 (520-524)

Background: The rapid deployment of Army aviation personnel across time zones, combined with missions beginning immediately upon arrival, results in desynchronization of physiological and cognitive performance rhythms. Implementation of effective countermeasures enhances safely, health, well- being, and mission completion. The naturally occurring hormone melatonin has been suggested as an effective countermeasure for jet lag and shift lag because of its influence on the human circadian timing system and its hypnotic properties. Method: The efficacy of melatonin (10 mg) in maintaining stable sleep/wake cycles of Army aircrews was tested during a training mission involving rapid deployment to the Middle East and night operations. Cognitive performance was tested before and after travel; activity rhythms were recorded continuously for 13 d. Results: Melatonin treatment advanced both bedtimes and rise times (2-3 h) and maintained sleep durations between 7-8 h. Placebo treatment was mostly associated with longer advances in rise times than bedtimes resulting in shorter sleep durations (5-7 h). Upon awakening, the melatonin group exhibited significantly fewer errors (mean: 7.45) than the placebo group (mean: 14.50) in a dual task vigilance test. Conclusion: Melatonin can be a useful treatment for the prevention of sleep disruptions and cognitive degradation, even in uncontrolled sleeping environments characteristic of military deployments.



Melatonin: Between facts and fantasy

TW Neurologie Psychiatrie (Germany), 1996, 10/5 (384-386+389-390)

Melatonin is involved in the regulation of seasonal and circadian fluctuations of other hormones and in the synchronization of many aspects of circadian rhythmicity to the light-dark-cycle. In addition melatonin may act as a modulator of intracellular signal transduction. It is also a potent scavenger of reactive oxygen species and may thus protect cells and tissues against radical-mediated damage. Animal and cell culture experiments suggest that melatonin may have beneficial effects on certain aspects of aging and age-associated diseases. Of particular interest are reports on the influence of melatonin on the brain and the immune system. More research data and clinical studies are needed to define possible sites and mechanisms of these actions and to identify possible side effects of long-term melatonin treatment especially in elderly and diseased subjects. Serious concerns are raised about the use of uncontrolled, impure or partially degraded melatonin preparations.



Melatonin: A master hormone and a candidate for universal panacea

Indian Journal of Experimental Biology (India), 1996, 34/5 (391-402)

The molecule of melatonin seems to have been evolutionarily conserved. Its presence has been demonstrated in almost all groups of organisms, from plants, protozoa to people. During evolution, melatonin is claimed to have mediated dark adaptation. The universal presence of melatonin may be because it is lipophilic in nature which enables it to cross all biological (lipid membrane) barriers to diffuse into every compartment of the cell, and because it serves as an antioxidant and is used as a free radical scavenger. In vertebrates, the pineal gland is the single largest source of melatonin production although, especially in non-mammalian vertebrates, other organs (e.g. retina, harderian gland etc.) may contribute significantly to the blood melatonin levels. In invertebrates, on the other hand, the pineal gland is absent and, therefore, melatonin secretion is clearly derived from another source(s). Regardless of the site of synthesis and the nature of organisms (diurnal, nocturnal or crepuscular), melatonin is secreted in the night and melatonin biosynthetic pathway remains essentially the same. Tryptophan, an amino acid derived from dietary sources, undergoes a series of enzymatic reactions to produce melatonin. The rhythm in melatonin secretion is generated endogenously by the circadian pacemaker(s) in the suprachiasmatic nuclei (SCN), and regulated by environmental light:dark cycle. Melatonin through its action on the SCN synchronizes disrupted or free-running circadian rhythms, and regulates a variety of daily and seasonal changes in the physiology and behaviour of animals. Emerging scientific evidence for the role of melatonin as therapeutic agent in the treatment of circadian rhythm-associated sleep disorders in persons having normal social working hours and shift workers, in jet lag, in immunological functions etc. have considerably increased interest in this hormone molecule. The role of melatonin in organisms physiology has now been widely recognized, and the wealth of information accumulated in the past two decades indicate it to be the best hormone candidate to be investigated for a universal panacea.



Use of melatonin in circadian rhythm disorders and following phase shifts

Acta Neurobiologiae Experimentalis (Poland), 1996, 56/1 (359-362)

Following abrupt phase shifts (real or simulated time zone changes, night shift work) there is desynchronisation between the internal circadian rhythms (including melatonin) and the external environment with consequent disturbances in sleep, mood and performance. In humans the pineal hormone melatonin has phase-shifting and resynchronising properties with regard to a number of circadian rhythms. Suitably timed melatonin administration hastened adaptation to phase shift and significantly improved self-rated jet lag in large numbers of time zone travellers. Preliminary results in night shift workers showed improved daytime sleep and night-time alertness. In simulated experiments, appropriately timed melatonin improved subjective sleep, alertness and performance and facilitated the readaptation of the melatonin rhythm following a rapid 9 h advance phase shift. Melatonin has also been assessed in circadian rhythm disorders with disturbed sleep (blindness and delayed sleep phase insomnia). Compared with placebo, melatonin significantly improved sleep and synchronised the sleep wake cycle in some blind subjects. Melatonin treatment significantly advanced the sleep onset time in delayed sleep phase insomnia. Taken together these findings suggest that melatonin is of benefit in facilitating adaptation to forced phase shifts and in conditions of circadian rhythm disturbance.



Adapting to phase shifts, II. Effects of melatonin and conflicting light treatment

Physiology and Behavior (USA), 1996, 59/4-5 (675-682)

The effects of melatonin (MT) and placebo (P) on adaptation to a rapid 9-h advance phase shift, in the presence and absence of inappropriate bright light (BL) exposure were examined. Volunteers were initially subjected to a gradual 9-h delay phase shift over 5 days (D1-D5) using a combination of bright light and darkness/sleep. Readaptation to a subsequent rapid 9-h advance phase shift was studied using: 1) MT, 5 mg, 2300 h, D6-D8, 2) BL, 2,000 lx, 0800-1200 h, D7-D8, 3) MT + BL and 4) P, 2300 h, D6-D8. MT treatment was timed to phase advance and BL to phase delay. BL delayed the 6-sulphatoxymelatonin rhythm in five out of seven subjects. Two subjects delayed and five phase advanced with both MT and MT + BL. MT consistently improved subjective sleep, alertness, and performance even in the presence of inappropriate BL and before phase readaptation had occurred. BL improved alertness and performance transiently. The beneficial effects of MT are not wholly mediated through an effect on the biological clock.



Chronobiotics - Drugs that shift rhythms

Pharmacology and Therapeutics (USA), 1996, 69/1 (15-36)

A chronobiotic is defined and levels of action within the mammalian circadian pacemaker system, such as the retina, retinohypothalamic tract, geniculohypothalamic tract, suprachiasmatic nuclei, output and feedback systems are identified. Classes of drug that include the indoleamines, cholinergic agents, peptides, and benzodiazepines, which might act as chronobiotics within these levels, are evaluated. Particular emphasis is placed on the indole, melatonin (MLT). The clinical circumstances for use of chronobiotics in sleep disturbances of the circadian kind, such as jet lag, shift work, delayed sleep-phase syndrome, advanced sleep-phase syndrome, irregular and non-24-hr sleep-wake cycles, are described under reorganized headings of disorders of entrainment, partial entrainment, and desynchronization. Specific attention is given to the blind and the aged. Both human and animal studies suggest that MLT has powerful chronobiotic properties. MLT shows considerable promise as a prophylactic and therapeutic alternative or supplement to the use of natural and artificial bright light for resetting the circadian pacemaker. Throughout this discussion, the hypnotic and hypothermic versus the chronobiotic actions of MLT are raised. Finally, problems in the design of delivery systems for MLT are discussed.



Phase shifting the human circadian clock using melatonin

Behavioural Brain Research (Netherlands), 1996, 73/1-2 (131-134)

Melatonin is produced only during nighttime darkness. Its onset during the evening is a useful marker for circadian phase position, when melatonin levels are sampled frequently and under conditions of dim light or darkness. This marker is termed the dim light melatonin onset (DLMO). Recently, we have described a phase response curve (PRC) to melatonin in humans that is about 12 h out of phase with the PRC to light. Exogenous melatonin administration and bright light exposure can be used to shift circadian rhythms according to their respective PRCs. These phase-resetting agents can be used alone or together to treat circadian phase disorders, which include advanced and delayed sleep phase syndrome, shift work maladaptation, jet lag and winter depression. Endogenous melatonin may function to augment entrainment of circadian rhythms by the light-dark cycle.



A double-blind trial of MELATONIN as a treatment for jet lag in international cabin crew.

Biol Psychiatry (UNITED STATES) Apr 1 1993

This study investigated the efficacy of oral MELATONIN in alleviating jet lag in flight crew after a series of international flights. The optimal time for taking MELATONIN in this group was also investigated. In a double-blind placebo-controlled trial, 52 international cabin crew were randomly assigned to three groups; early MELATONIN (5 mg started 3 days prior to arrival until 5 days after return home); late MELATONIN (placebo for 3 days then 5 mg MELATONIN for 5 days); and placebo. Daily ratings showed a trend in jet lag, mood, and sleepiness measures toward an improved recovery in the late MELATONIN group and a worse recovery in the early MELATONIN group as compared to placebo. Retrospective ratings made 6 days after arrival showed the late MELATONIN group reported significantly less jet lag and sleep disturbance following the flight compared to placebo. The late MELATONIN group also showed a significantly faster recovery of energy and alertness than the early MELATONIN group, which reported a worse overall recovery than placebo. These findings show MELATONIN may have potential benefits for international aircrew.



MELATONIN and jet lag: confirmatory result using a simplified protocol

Biol Psychiatry (UNITED STATES) Oct 15 1992, 32 (8) p705-11

This study replicates the alleviation of jet-lag with MELATONIN in a simplified protocol for eastward flight. At 22-n hr (n is the time-lag between the North American departure point and France), subjects took either MELATONIN (8 mg, n = 15), or placebo (n = 15) on the day of the return flight and for 3 consecutive days. On day 8, self-ratings significantly discriminated between MELATONIN and placebo for global treatment efficacy, morning fatigue, and evening sleepiness.



Role of biological clock in human pathology

Presse Med (FRANCE) Jun 17 1995, 24 (22) p1041-6

Most of the vegetative, hormonal and behavioural functions of the human organism operate under the biological control of a circadian clock which responds to environmental and social stimuli, synchronizing the organism's physiology to daily and seasonal rhythms. The underlying anatomic structures are located in the suprachiasmatic nucleus and the pineal gland. Although the precise physiologic mechanisms involved are still under study, MELATONIN is known to play a major role. Normal function of the circadian clock is disrupted in jet-lag, night-shift work, and blindness as well as in rare cases of lesions to the pineal gland leading to a shift in biological rhythms including hormone secretion and control of body temperature, for example. Several signs of impaired function have been identified: various types of sleep disorders, memory and concentration impairment, dysphoria, asthenia, irritability. Seasonal recurrence of such signs and frequent depressive complications are also suggestive of a disorder in the circadian clock. Knowledge of specific clinical signs and biological parameters will undoubtedly lead to the discovery of other disease states dependant on the circadian clock and to the development of therapeutic strategies capable of regulating the organism's chronobiology.



Melatonin marks circadian phase position and resets the endogenous circadian pacemaker in humans.

Ciba Found Symp (NETHERLANDS) 1995, 183 p303-17; discussion 317-21

Measuring the dim light MELATONIN onset (DLMO) is a useful and practical way to assess circadian phase position in humans. As a marker for the phase and period of the endogenous circadian pacemaker, the DLMO has been shown to advance with exposure to bright light in the morning and to delay with exposure to bright light in the evening. This 'phase response curve' (PRC) to light has been applied in the treatment of winter depression, jet lag and shift work, as well as circadian phase sleep disorders. Exogenous MELATONIN has phase-shifting effects described by a PRC that is about 12 h out of phase with the PRC to light. That is, MELATONIN administration in the morning causes phase delays and in the afternoon causes phase advances. All of the circadian phase disorders that have been successfully treated with appropriately timed exposure to bright light can be treated with appropriately scheduled MELATONIN administration. MELATONIN administration is more convenient and therefore may be the preferred treatment.



The role of pineal gland in circadian rhythms regulation.

Bratisl Lek Listy (SLOVAKIA) Jul 1994, 95 (7) p295-303

In the presented article we try to find a synthesis of the current knowledge on circadian rhythms. We pick up the most prominent oscillations in human physiology and review the current knowledge of their regulation. Circadian oscillations in the parameters of internal environment are driven by the pineal gland. A biochemical pathway in the pineal transforms tryptophan through serotonin to the final product--the indolamine MELATONIN. Its plasma level is high at night and low during the day. MELATONIN, easily penetrating through biological barriers, thus carries phase of day information to all peripheral tissues. Light exposure of retina alters (via neural pathways connecting retina to pineal gland) the amount of serotonin metabolized to MELATONIN. This physiological mechanism of adjustment of the endogenous clock to the solar day can be altered in some circumstances, leading to pathologic symptoms. The best known diseases caused by breakdown in circadian regulation are seasonal affective disorders and jet-lag syndrome.



Light, melatonin and the sleep-wake cycle.

J Psychiatry Neurosci (CANADA) Nov 1994, 19 (5) p345-53

Blood levels of the pineal hormone MELATONIN are high at night and low during the day. Its secretion is regulated by a rhythm-generating system located in the suprachiasmatic nucleus of the hypothalamus, which is in turn regulated by light. MELATONIN is regulated not only by that circadian oscillator but acts as a darkness signal, providing feedback to the oscillator. MELATONIN has both a soporific effect and an ability to entrain the sleep-wake rhythm. It also has a major role in regulating the body temperature rhythm. MELATONIN rhythms are altered in a variety of circadian rhythm disorders. MELATONIN treatment has been reported to be effective in treatment of disorders such as jet lag and delayed sleep phase syndrome.



Circadian rhythms, jet lag, and chronobiotics: an overview.

Chronobiol Int (UNITED STATES) Aug 1994, 11 (4) p253-65

This overview considers the origins of jet lag in terms of altered circadian rhythmicity. The properties required of a chronobiotic--an agent to cause phase adjustment of the body clock--are discussed, and an account is given of the major candidates at the present time: light, MELATONIN, activity, and benzodiazepines. It is concluded that current knowledge indicates that a combination of factors is likely to be most effective.



[Chronobiological sleep disorders and their treatment possibilities]

Ther Umsch (SWITZERLAND) Oct 1993, 50 (10) p704-8

A temporal discrepancy between the endogenous sleep-wake cycle and the daily structure of the surrounding social network are characteristic for chronobiological sleep disturbances. Activity rhythms that are in abnormal relation to the environment are more frequent than commonly assumed. They can arise either from external causes (such as shift-work or jet-lag) or as a result of internal changes promoting abnormal sleep behaviour. Structuring daily activities by paying attention to natural daylight (dawn and dusk) and to the social routine strengthen the synchronizing effect of external timekeepers necessary for the concordance between inner and outer rhythmic phenomena. Treatment of chronobiological sleep/wake-cycle disturbances require correct diagnosis and modification of their causes, particularly changes in habits consolidating such disturbances. Early recognition of a chronobiological sleep disorder can reduce the risk of misuse of sleeping pills, caffeine and nicotine. Recently developed treatment approaches such as bright light, the pineal hormone MELATONIN and vitamin B12 have provided promising results.



Chronopharmacological actions of the pineal gland.

Drug Metabol Drug Interact (ENGLAND) 1990, 8 (3-4) p189-201

In all mammalian species studied to date, the pineal gland shows a pronounced circadian rhythm with high activity at night and very low activity in daytime, as reflected in the output of its hormone, MELATONIN. The pineal is one of the few organs which can synthesize MELATONIN and, under normal circumstances, is virtually the only source of circulating MELATONIN. Pineal activity is tightly controlled by the light/dark cycle, in such a manner that MELATONIN can convey information to the organism on the length of the dark phase of the photoperiod. In seasonal breeding species, the 24 hour pattern of secretion of MELATONIN shows seasonal changes which are crucial for determining the timing of seasonal changes in bodily function. In man, alterations in pineal function are of significance in jet-lag, shift work and in affective disorder. (41 Refs.)



Some effects of MELATONIN and the control of its secretion in humans.

Ciba Found Symp (NETHERLANDS) 1985, 117 p266-83

Whether or not the pineal gland has a significant physiological role in humans is not known. There has nevertheless been speculation about the potential therapeutic use of MELATONIN (in view of its hypnotic and possible zeitgeber properties) in conditions such as insomnia and jet lag, and in shift-workers. Our work concerns the effects of MELATONIN administration in humans and the interactions between MELATONIN and other circadian variables. Chronic (one month), timed (1700 h), low-dose (2 mg daily) MELATONIN administration to normal subjects without environmental control consistently increased evening fatigue and slightly modified the 24 h prolactin rhythm without effect on cortisol, growth hormone, luteinizing hormone, thyroxine, testosterone or self-rated mood. In five out of 11 subjects the endogenous MELATONIN rhythm was advanced by one to three hours. During fractional desynchronization of circadian rhythms by increasing imposed 'day' length (26-29 h, 24 days, 500 lux), 5 mg MELATONIN per os at lights-out in two subjects resulted in better entrainment of the fatigue rhythm to the zeitgeber than in five out of six control subjects, without major consistent effects on other measured circadian variables. Using a new radioimmunoassay for 6-hydroxymelatonin sulphate (aMT6s), the major MELATONIN metabolite, we have shown that the urinary aMT6s rhythm is closely correlated to that of MELATONIN in plasma and is completely suppressed by an acute dose of atenolol (100 mg per os), a peripheral beta-adrenergic antagonist. During fractional desynchronization by increasing imposed 'day' length in one subject and decreasing imposed 'day' length in two subjects, the urinary aMT6s rhythm behaved similarly to that of core temperature. The results suggest that fatigue (or alertness) may be entrained by MELATONIN, but whether critical performance rhythms can be suitably manipulated remains to be clarified. It is likely that MELATONIN production is linked to the so-called 'strong' circadian oscillator.



Daily melatonin intake resets circadian rhythms of a sighted man with non-24-hour sleep-wake syndrome who lacks the nocturnal melatonin rise

Psychiatry and Clinical Neurosciences (Japan), 1997, 51/3 (121-127)

Effects of daily melatonin intake on the circadian rhythms of sleep and wakefulness, rectal temperature and plasma cortisol were examined in a sighted man who had suffered from the non-24-hour sleep-wake syndrome. The subject lacked the nocturnal melatonin rise in plasma, but showed robust circadian rhythms in rectal temperature and plasma cortisol. The sleep-wake rhythm free-ran with a period longer than 24 hours. Daily melatonin intake at 21:00 h concentrated sleep episodes in the nocturnal period (24:00-8:00 h), and increased the length of the episodes. A single oral dose (3 mg) of melatonin increased plasma melatonin levels to about 1300 pg/mL within one hour and remained at pharmacological levels for approximately 6 hours. The trough of rectal temperature and the circadian rise of plasma cortisol were fixed to the early morning A higher dose of melatonin (6 mg) did not improve the general feature. After the cessation of melatonin intake, the sleep-wake rhythm began to free-run together with the circadian rhythms in rectal temperature and plasma cortisol. It is concluded that daily intake of melatonin at early night time resets the circadian rhythms in a sighted man who lacked the nocturnal melatonin rise and showed free running circadian rhythms in routine life.



A sighted man with non-24-hour sleep-wake syndrome shows damped plasma melatonin rhythm

Psychiatry and Clinical Neurosciences (Japan), 1997, 51/3 (115-119)

Twenty-four-hour profiles of plasma melatonin, cortisol and rectal temperature were measured longitudinally in a sighted man who has been suffering from sleep disorders for more than 10 years. The sleep-wake rhythm of this subject free-ran, despite his routine life, and occasionally showed a sign of internal desynchronization, where sleep was lengthened up to 30 h. These states were classified into the non-24-hour sleep-wake syndrome. Plasma melatonin concentrations in the subjective night remained at a low level and showed a damped circadian rhythm. At the same time, robust circadian rhythms were detected in plasma cortisol and rectal temperature, indicating that the circadian pacemaker was intact. The causal relationship between the damping of nocturnal melatonin rise and a failure of entrainment of the sleep wake cycle is discussed.



Case study: The use of melatonin in a boy with refractory bipolar disorder

Journal of the American Academy of Child and Adolescent Psychiatry (USA), 1997, 36/6 (822-825)

The authors describe the clinical course of a 10-year-old boy with bipolar disorder diagnosed at age 5 years. Lithium, carbamazepine, and valproic acid were ineffective or caused intolerable side effects. A trial of melatonin led to rapid relief of insomnia and aborted a manic episode. He has continued to take melatonin and adjunctive alprazolam for 15 months without recurrence of insomnia or mania. Affective disorders involving circadian dysregulation may respond to interventions that restore a normal sleep-wake cycle. Literature supporting this hypothesis is cited.



Rapid reversal of tolerance to benzodiazepine hypnotics by treatment with oral melatonin: A case report

European Neuropsychopharmacology (Netherlands), 1997, 7/2 (157-160)

A 43 year old woman had suffered from insomnia for the past 11 years and was being treated with benzodiazepines. All attempts to stop benzodiazepine treatment resulted in withdrawal symptoms and a renewal of the insomnia. Treatment with 1 mg of controlled release melatonin enabled the patient to completely cease any benzodiazepine use within two days, with an improvement in sleep quality and no side effects. Examination of urinary 6- sulphatoxymelatonin levels before the melatonin treatment indicated that the levels were very low and lacked the typical circadian rhythm of excretion. Reexamination of 6-sulphatoxymelatonin levels during melatonin treatment revealed the existence of a normal circadian rhythm of excretion. This case may suggest that some of the people suffering from insomnia and addicted to benzodiazepines may successfully undergo withdrawal from these drugs and improve their sleep by means of treatment with melatonin. The results of this single case study warrant further investigation of a larger population by means of a double-blind placebo-drug study.



Improvement of sleep quality by controlled-release melatonin in benzodiazepine-treated elderly insomniacs

Archives of Gerontology and Geriatrics (Ireland), 1997, 24/2 (223-231)

Benzodiazepines are widely used in the elderly population for the initiation of sleep. However, very frequently, complaints about poor sleep maintenance persist despite benzodiazepine treatment. Melatonin, a hormone produced by the pineal gland at night, is involved in the regulation of the sleep/wake cycle. Melatonin production decreases with age and can also be inhibited by benzodiazepines. We have recently reported on the association between insomnia and impaired melatonin output in the elderly. In the present study we have investigated the efficacy of melatonin replacement therapy in improving sleep in 21 elderly subjects who have been taking benzodiazepines and had low melatonin output. In a randomized, double-blind, crossover designed study the subjects were treated for three weeks with 2 mg per night of controlled-release melatonin and for 3 weeks with placebo, 2 h before desired bedtime with a 1-week washout period between treatment periods. Subjects' sleep was assessed by wrist actigraphy. Melatonin treatment significantly increased sleep efficiency and total sleep time and decreased wake after sleep onset, sleep latency, number of awakenings and fragmental index, as compared to placebo. The results of our study indicate that melatonin replacement therapy can improve sleep quality in the elderly and that the beneficial effects are augmented in the presence of benzodiazepines.



Melatonin - a chronobiotic and soporific hormone

Archives of Gerontology and Geriatrics (Ireland), 1997, 24/2 (167-173)

In this report we review evidence that melatonin, a hormone produced by the pineal gland during the hours of darkness, plays a major role in the synchronization of the sleep/wake cycle. The production of melatonin is regulated by a structure located in the hypothalamus called the suprachiasmatic nucleus (SCN). The activity of the SCN is strongly affected by changes in illumination and, as a consequence, melatonin levels are high during darkness and low in the light and it, therefore, reflects the cycle. Changes in sleep/wake patterns are among the hallmarks of biological aging. Complaints of difficulty in initiating and maintaining sleep, and daytime drowsiness, are more common in the elderly than in any other age group. In this report, we review evidence that impaired meltonin secretion is associated with sleep disorders in old age. Circulating melatonin levels have been found to be significantly lower in elderly insomniacs than in age-matched controls, and their onset and peak times delayed. In view of these findings, we investigated the effects of melatonin treatment on melatonin-deficient insomnia in the elderly. From the results of our study, it seems likely that melatonin replacement therapy may be beneficial in the initiation and maintenance of sleep in this population.



Evaluation of the antioxidant activity of melatonin in vitro

Free Radical Biology and Medicine (USA), 1996, 21/3 (307-315)

Melatonin is being increasingly promoted as a treatment for 'jet lag' and insomnia and has been suggested to act as an antioxidant in vivo. The antioxidant and potential pro-oxidant activities of melatonin were investigated in vitro. Melatonin was able to scavenge hypochlorous acid (HOCl) at a rate sufficient to protect catalase against inactivation by this molecule. Melatonin could also prevent the oxidation of 5-thio-2- nitrobenzoic acid by HOCl. Melatonin decreased the peroxidation of ox-brain phospholipids with a calculated IC50 of (210 plus or minus 2.3) microM. In contrast, serotonin which also scavenged HOCl, was much more effective in decreasing phospholipid peroxidation (IC50 15 plus or minus 5 microM). Both compounds reacted with trichloromethylperoxyl radical (CCl3O2) with rate constants of (2.7 plus or minus 0.2) x 108 and (1.2 plus or minus 0.1) x 108 M-1 s-1 respectively. Melatonin did not scavenge superoxide radical and weakly protected DNA against damage by the ferric bleomycin system. By contrast serotonin was weakly pro-oxidant in the ferric-bleomycin system and strongly pro-oxidant in the Fe3+- EDTA/H2O2-deoxyribose system. Solubility restrictions precluded examination of melatonin in this system. Our data show that melatonin exerts only limited direct antioxidant activities.



Nocturnal melatonin secretion and sleep after doxepin administration in chronic primary insomnia

Pharmacopsychiatry (Germany), 1996, 29/5 (187-192)

Nocturnal melatonin secretion and polysomnographic sleep patterns were investigated in ten patients with chronic primary insomnia (age 41.3 plus or minus 9.5 years) and in five healthy subjects (age 27.2 plus or minus 0.7 years) after either a single intravenous administration of 25 mg doxepin or placebo in a randomized, double-blind, and cross-over setting. In the patient group a third session was performed after a three-week open oral treatment with 25 mg doxepin daily. The single-dose administration of doxepin did not affect plasma melatonin concentrations in either the patients or the healthy subjects. After three weeks of oral doxepin intake by the patients, the area under the curve of total nocturnal plasma melatonin concentration was significantly increased by 26% and the peak values were increased by 30%. Both after the single i.v. treatment as well as after long-term oral administration, doxepin also significantly improved sleep latency, total sleep time, and sleep efficiency in the insomniacs as well as the healthy subjects, whereas the nocturnal wake time was decreased. These findings indicate that this tricyclic antidepressant not only improves sleep but also preserves the secretion of a hormone which is believed to play a special role in the circadian sleep-wake rhythm. Long-term doxepin treatment of chronic insomniac patients not only improves sleep but also restores nocturnal melatonin secretion in these patients.



Melatonin: From the hormone to the drug?

Pathologie Biologie (France), 1996, 44/7 (645-653)

Melatonin is an indole hormone that is produced by the pineal gland, mainly at night, with a peak around 3.00 a.m. under normal environmental conditions. This endogenic secretion cycle is generated by the suprachiasmatic nuclei in response to the day/night alternation. Light either suppresses or entrains melatonin production according to the time of light exposure. Melatonin can be viewed as the 'hand' of the internal clock and is regulated via the central nervous and sympathetic systems. Melatonin synchronizes biological cycles, particularly the temperature and sleep/wake cycles. Exogenous melatonin can influence the endogenous secretion of melatonin according to a phase response curve, an effect that provides a rationale for the use of melatonin to treat disorders of biological rhythms (rapid time-zone change syndrome, delayed sleep phase syndrome, desynchronization in blind subjects or shift workers, insomnia in the elderly). Other therapeutic indications are being considered (immune function disorders). Improvements in galenic forms (sustained-release presentations) or the development of analogs would be significant advances.



Inhibition of melatonin secretion onset by low levels of illumination

Journal of Sleep Research (United Kingdom), 1996, 5/2 (77-82)

Melatonin is a hormone released during darkness under the control of the hypothalamic circadian pacemaker. It has been shown that melatonin is suppressed by light as a function of intensity, with low levels of illumination producing small effects and more intense light greater, but not complete inhibition. The studies which lead to these conclusions administered light subsequent to the secretion pattern being well established. Light as low as 250 lux administered during the normal onset of secretion can reduce melatonin to below detectable levels. The onset of melatonin secretion was delayed for at least an hour during 250 lux exposure and did not rise until termination of light exposure (two hours after control melatonin onset) with higher illumination (500, 1000 and 2500 lux). This tentatively indicates that duration of the inhibition is intensity dependent. It is suggested that the experimental paradigm used in the present study may be a more realistic representation of the effect of normal light exposure (both natural and artificial) on the circadian system,and that findings may be pertinent to the aetiology of certain sleep onset insomnias, which would include delayed sleep phase syndrome (DSPS) and adaptation to shift work.



Melatonin replacement corrects sleep disturbances in a child with pineal tumor

Neurology (USA), 1996, 46/1 (261-263

A child with a germ cell tumor involving the pineal region had marked suppressed melatonin secretion associated with severe insomnia. Exogenous melatonin (3 mg in the evening) for 2 weeks restored sleep continuity, as demonstrated by objective monitoring of rest-activity cycles. This case report provides direct evidence of the essential role of melatonin in normal sleep.



Melatonin replacement therapy of elderly insomniacs

Sleep (USA), 1995, 18/7 (598-603)

Changes in sleep-wake patterns are among the hallmarks of biological aging. Previously, we reported that impaired melatonin secretion is associated with sleep disorders in old age. In this study we investigated the effects of melatonin replacement therapy on melatonin-deficient elderly insomniacs. The study comprised a running-in, no-treatment period and four experimental periods. During the second, third and fourth periods, subjects were administered tablets for 7 consecutive days, 2 hours before desired bedtime. The tablets were either 2 mg melatonin administered as sustained- release or fast-release formulations, or an identical-looking placebo. The fifth period, which concluded the study, was a 2-month period of daily administration of 1 mg sustained-release melatonin 2 hours before desired bedtime. During each of these five experimental periods, sleep-wake patterns were monitored by wrist-worn actigraphs. Analysis of the first three 1-week periods revealed that a 1-week treatment with 2 mg sustained-release melatonin was effective for sleep maintenance (i.e. sleep efficiency and activity level) of elderly insomniacs, while sleep initiation was improved by the fast-release melatonin treatment. Sleep maintenance and initiation were further improved following the 2-month 1-mg sustained-release melatonin treatment, indicating that tolerance had not developed. After cessation of treatment, sleep quality deteriorated. Our findings suggest that for melatonin-deficient elderly insomniacs, melatonin replacement therapy may be beneficial in the initiation and maintenance of sleep.



Improvement of sleep equality in elderly people by controlled-release melatonin

Lancet (United Kingdom), 1995, 346/8974 (541-544)

Melatonin, produced by the pineal gland at night, has a role in regulation of the sleep-wake cycle. Among elderly people, even those who are healthy, the frequency of sleep disorders is high and there is an association with impairment of melatonin production. We investigated the effect of a controlled-release formulation of melatonin on sleep quality in 12 elderly subjects (aged 76 (SD 8) years) who were receiving various medications for chronic illnesses and who complained of insomnia. In all 12 subjects the peak excretion of the main melatonin metabolite 6-sulphatoxymelatonin during the night was lower than normal and/or delayed in comparison with non-insomniac elderly people. In a randomised, double-blind, crossover study the subjects were treated for 3 weeks with 2 mg per night of controlled-release melatonin and for 3 weeks with placebo, with a week's washout period. Sleep quality was objectively monitored by wrist actigraphy. Sleep efficiency was significantly greater after melatonin than after placebo (83 (SE 4) vs 75 (3)%, p<0.001) and wake time after sleep onset was significantly shorter (49 (14) vs 73 (13) min, p<0.001). Sleep latency decreased, but not significantly (19 (5) vs 33 (7) min, p=0.088). Total sleep time was not affected. The only adverse effects reported were two cases of pruritus, one during melatonin and one during placebo treatment; both resolved spontaneously. Melatonin deficiency may have an important role in the high frequency of insomnia among elderly people. Controlled-release melatonin replacement therapy effectively improves sleep quality in this population.



Sleep-inducing effects of low doses of melatonin ingested in the evening

Clinical Pharmacology and Therapeutics (USA), 1995, 57/5 (552-558)

We previously observed that low oral doses of melatonin given at noon increase blood melatonin concentrations to those normally occurring nocturnally and facilitate sleep onset, as assessed using an involuntary muscle relaxation test. In this study we examined the induction of polysomnographically recorded sleep by similar doses given later in the evening, close to the times of endogenous melatonin release and habitual sleep onset. Volunteers received the hormone (oral doses of 0.3 or 1.0 mg) or placebo at 6, 8, or 9 PM. Latencies to sleep onset, to stage 2 sleep, and to rapid eye movement (REM) sleep were measured polysomnographically. Either dose given at any of the three time points decreased sleep onset latency and latency to stage 2 sleep. Melatonin did not suppress REM sleep or delay its onset. Most volunteers could clearly distinguish between the effects of melatonin and those of placebo when the hormone was tested at 6 or 8 PM. Neither melatonin dose induced 'hangover' effects, as assessed with mood and performance tests administered on the morning after treatment. These data provide new evidence that nocturnal melatonin secretion may be involved in physiologic sleep onset and that exogenous melatonin may be useful in treating insomnia.



Melatonin rhythms in night shift workers

SLEEP (USA), 1992, 15/5 (434-441)

For some time, it has remained uncertain whether the circadian rhythms of permanent night shift workers are adapted to their night-active schedule. Previous studies of this question have often been limited by 'masking' (evoked) effects of sleep and activity on body temperature and cortisol, used as marker rhythms. In this study, the problem of masking was minimized by measuring the timing of melatonin production under dim light conditions. Nine permanent night shift workers were admitted to the Clinical Research Center (CRC) directly from their last work shift of the week and remained in dim light while blood samples were obtained hourly for 24 hours. elatonin concentrations were measured in these samples using a gas-chromatographic mass-spectrometric method. Sleep diaries were completed for two weeks prior to the admission to the CRC. Overall, the onset of the melatonin rhythm was about 7.2 hours earlier (or 16.8 hours later) in the night workers compared to day-active controls. It was not possible to know whether the phase of the melatonin rhythm was the result of advances or delays. In night shift workers, sleep was initiated (on average) about three hours prior to the onset of melatonin production. In contrast, day-active subjects initiated sleep (on average) about three hours after their melatonin onset. Thus, the sleep times selected by night shift workers may not be well-synchronized to their melatonin rhythm, assumed to mark the phase of their underlying circadian pacemaker.



Effect of melatonin replacement on serum hormone rhythms in a patient lacking endogenous melatonin

BRAIN RES. BULL. (USA), 1991, 27/2 (181-185)

A potentially confounding variable inherent in studies designed to examine the effect of melatonin administration in humans is the presence of an endogenous melatonin rhythm in the experimental subjects. The effects of exogenous melatonin administration on serum hormone rhythms was recently examined in a male patient who lacked detectable circulating levels of endogenous melatonin. The patient's pineal gland had been destroyed five years previously in the course of treatment for a pineal astrocytoma. On three separate occasions, over approximately a one-year period, the patient was given daily oral melatonin replacement (2 mg/day, 1 mg/day and 0.5 mg/day). These experiments were designed to assess the effects of exogenous melatonin on serum growth hormone, prolactin, cortisol and testosterone rhythms. Analysis of blood samples collected every 2-4 hours for 24-hour periods both before and during melatonin replacement revealed that the exogenous melatonin rhythm was associated with improvements in self-reported sleep and mood ratings. Melatonin administration produced robust nocturnal peaks in serum growth hormone and prolactin levels immediately following ingestion of the hormone, while serum cortisol and testosterone rhythms were not influenced. These results suggest that melatonin may modulate the coordination and enhancement of selected biological rhythms in man.



Melatonin administration in insomnia

NEUROPSYCHOPHARMACOLOGY (USA), 1990, 3/1 (19-23)

Ten patients with persistent insomnia were randomized in a double-blind design and the effects of 1-mg and 5-mg oral dosages of melatonin on the lectroencephalogram-recorded sleep were examined. Subjects showed no changes in either the onset or duration of sleep, nor any effect on mood or alertness the following day. A significant increase in rapid-eye movement (REM) latency was noted at the 1-mg dose, though no other parameter of REM sleep was affected. The patients reported less sleep on both melatonin conditions. Despite this perception of decrease, overall subjective quality was reported to be improved.

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