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Abstracts

Abstracts

Ageing & Melatonin

Ageing

Melatonin is a very potent and efficient endogenous free radical scavenger. Pineal indolamine reacts with toxic hydroxyl radicals and can provide an immediate protection against oxidative damage to biomolecules within every cellular compartment. Melatonin acts as a primary non-enzymatic antioxidative defense against the destruction caused by hydroxyl free radicals. Melatonin and structurally related tryptophan metabolites are principally involved in the prevention of oxidative stress in a diverse range of organisms.

Melatonin can retard the rate of ageing and the time of onset of age-related diseases. The activation of central excitatory amino acid receptors can suppress melatonin synthesis and is accompanied by a reduced detoxification rate of hydroxyl radicals. Aged animals and humans are melatonin-deficient and more sensitive to oxidative stress.

New therapies investigating stimulants of melatonin synthesis, such as magnesium, may lead to therapeutic approaches for the prevention of diseases related to premature ageing.

"Melatonin, Hydroxyl Radical-Mediated Oxidative Damage, and Ageing: A Hypothesis", Poeggeler, B., et al, Journal of Pineal Research, 1993;14:151-168.

The pineal hormone melatonin is a potent free radical scavenger. In particular, it quenches what is generally considered the most toxic and damaging free radical produced in the organism, the hydroxyl radical (OH). Melatonin production in the pineal gland declines progressively with age such that in elderly humans (and old animals) the levels of melatonin are a fraction of that in young individuals.

A prominent theory of aging claims that the anatomical and functional degeneration that organs undergo during aging is a consequence of accumulated free radical damage. This being so, melatonin may well play a significant role in aging processes.

If the drop in melatonin which normally occurs as animals age could be prevented, perhaps the aging process would also be delayed? Also, supplemental administration of melatonin may be beneficial in delaying age-related degenerative conditions. Certainly, free radical damage has been implicated in a number of neurodegenerative disorders. Theoretically, melatonin administration may forestall these as well.

"Pineal function during aging: attenuation of the melatonin rhythm and its neurobiological consequences." Reiter-RJ. Acta-Neurobiol-Exp-Warsz. 1994; 54 Suppl: 31-9

It is believed that pineal calcification may be age-associated and that the well-demonstrated age-related decline in melatonin biosynthesis may be an expression of an alteration in calcium homeostasis in the pinealocyte. Prior correlations of melatonin to calcium deposition and age were made on the basis of radiological or semiquantitative analysis.

In this postmortem study calcium deposits measured by atomic absorption spectrometry correlated positively with age in day and night. Nighttime pineal melatonin content was higher than daytime melatonin levels.

Calcium, calcification, and melatonin biosynthesis in the human pineal gland: a postmortem study into age-related factors. Schmid-HA; Requintina-PJ; Oxenkrug-GF; Sturner-W. J-Pineal-Res. 1994 May; 16(4): 178-83.

Senile dementia

Senile dementia

The circadian pattern of melatonin and cortisol secretion was evaluated in two groups of elderly subjects with Alzheimer's and the other without cognitive impairment.

The melatonin circadian profile was clearly flattened in the two groups of elderly subjects by comparison with young controls, due to the selective impairment of melatonin nocturnal secretion. In both elderly groups, but particularly in demented patients, plasma cortisol levels were significantly higher.

Chrono-neuroendocrinological aspects of physiological aging and senile dementia. Dori-D; Casale-G; Solerte-SB; Fioravanti-M; Migliorati-G; Cuzzoni-G; Ferrari-E. Chronobiologia. 1994 Jan-Jun; 21(1-2): 121-6.

Dementia (Melatonin)

Dementia

Elderly inpatients (#14) with dementia showing sleep and behavior disorders and controls (#10) were carefully observed for 2 months. Four weeks of morning light therapy markedly improved sleep and behavior disorders in the dementia group which suggests that sleep and behavior disorders are related to decreases in the amplitude of the sleep-wake rhythm and decreases in the levels of melatonin secretions. Morning light therapy significantly increased total and nocturnal sleep time and decreased daytime sleep time.

Results indicate that morning bright light is a powerful synchronizer that can normalize disturbed sleep and substantially reduce the frequency of behavior disorders in elderly people with dementia.

Morning bright light therapy for sleep and behavior disorders in elderly patients with dementia. Mishima-K; Okawa-M; Hishikawa-Y; Hozumi-S; Hori-H; Takahashi-K. Acta-Psychiatr-Scand. 1994 Jan; 89(1): 1-7.

Behavior (elderly)

Behavior (elderly)

Inpatients (#14) with dementia showing sleep and behavior and control elderly people (#10) were carefully observed for 2 months.
Four weeks of morning light therapy markedly improved sleep and behavior disorders in the dementia group. Sleep and behavior disorders in the dementia group are related to decreases in the amplitude of the sleep-wake rhythm and decreases in the levels of melatonin secretions.

Morning light therapy significantly increased total and nocturnal sleep time and significantly decreased daytime sleep time.

Morning bright light is a powerful synchronizer that can normalize disturbed sleep and substantially reduce the frequency of behavior disorders in elderly people with dementia.

"Morning bright light therapy for sleep and behavior disorders in elderly patients with dementia." Mishima-K; Okawa-M; Hishikawa-Y; Hozumi-S; Hori-H; Takahashi-K. Acta-Psychiatr-Scand. 1994 Jan; 89(1): 1-7.

Alaska

Alaska

The diurnal variations in the secretory patterns of melatonin, cortisol and testosterone were studied in a Fairbanks, Alaska population who were unadapted to the extreme light variations of the North.

Results indicate a delayed phase secretory pattern when compared to the normal pattern at lower latitudes. These findings imply possible underlying physiological causes for the high incidence of behavior disorders such as depression and alcoholism in Alaska and circumpolar environments in general.

Diurnal and seasonal rhythms of melatonin, cortisol and testosterone in interior Alaska. Levine-ME; Milliron-AN; Duffy-LK. Arctic-Med-Res. 1994 Jan; 53(1): 25-34.

Anorexia and Bulimia

Anorexia and Bulimia

Although the exact physiological role of melatonin in humans is unclear, it appears to be implicated in reproductive physiology, especially in terms of the onset of menarche. Low levels of melatonin also occur in depression.

The influence of weight loss, binging and purging, and depression on melatonin is discussed.

"Melatonin disturbances in anorexia nervosa and bulimia nervosa." Kennedy-SH, Int-J-Eat-Disord. 1994 Nov; 16(3): 257-65.

Alcoholism & Melatonin

Alcoholism

Changes in central neurotransmission and in hypothalamo-pituitary function occur in both ethanol (ETOH) intake and withdrawal. Melatonin (MLT) secretion is regulated by the noradrenergic system, which is activated upon ETOH withdrawal. Experimental evidence exist that pineal gland may have a role in ETOH intake and preference in rats. Twenty-four hour urinary excretion of MLT was found to be increased during ETOH intake in chronic alcoholics.

Twenty-four hour plasma MLT mean levels on acute withdrawal were higher than after 14 days abstinence and than those found in controls. Large interindividual differences prevented the detection of statistical significance. The cosinor analysis disclosed the loss of circadian periodicity in the acute withdrawal. Significant 24h periodicity was restored after 14 days abstinence.

Melatonin and cortisol circadian secretion during ethanol withdrawal in chronic alcoholics. Fonzi-S; Solinas-GP; Costelli-P; Parodi-C; Murialdo-G; Bo-P; Albergati-A; Montalbetti-L; Savoldi-F; Polleri-A. Chronobiologia. 1994 Jan-Jun; 21(1-2): 109-12.

Arctic

Arctic

The 24-hr rhythm of salivary melatonin was measured in persons living in the city of Tromso (70 degrees N) at the following times of the year: in January at a day length of 2 hr of twilight, in June under continuous sunshine, and in March and September at about 12 hr light and 12 hr darkness.

The hormone patterns varied widely between individuals, but, in general, they were consistent within most individuals between the seasons. Highest peak values occurred in January when the mean level was also significantly higher than at any other time of year. The lowest mean levels occurred in June. Although individual rhythms were not always apparent, the mean patterns showed significantly elevated melatonin concentrations during the night at all seasons.

It is assumed that the delayed melatonin peak in June may be associated with a tendency among people to shift their activity/rest rhythm and that the pineal sensitivity to light is reduced in the morning in summer.

Melatonin rhythms in Arctic urban residents. Stokkan-KA; Reiter-RJ. J-Pineal-Res. 1994 Jan; 16(1): 33-6.

Behavior (student)

Behaviour (student)

An male high school student with school refusal and circadian rhythm disturbance is reported. He was treated with methyl B12 and melatonin, which normalized the circadian rhythm. Desynchronization of the biorhythms, particularly the circadian rhythm, may be one of the important causes of school refusal in Japan, and melatonin and methyl B12 might be useful for treatment of the condition.

A school refusal case with biological rhythm disturbance and melatonin therapy. Tomoda-A; Miike-T; Uezono-K; Kawasaki-T. Brain-Dev. 1994 Jan-Feb; 16(1): 71-6.

Blindness

Blindness

Complete blindness generally results in the loss of synchronization of circadian rhythms to the 24-hour day and in recurrent insomnia. However, some blind patients maintain circadian entrainment. Do some blind patients' eyes convey sufficient photic information to entrain the hypothalamic circadian pacemaker and suppress melatonin secretion, despite an apparently complete loss of visual function?

The visual subsystem that mediates light-induced suppression of melatonin secretion remains functionally intact in some sightless patients. The absence of photic input to the circadian system thus constitutes a distinct form of blindness, associated with periodic insomnia, that afflicts most but not all patients with no conscious perception of light.

"Suppression of melatonin secretion in some blind patients by exposure to bright light." Czeisler-CA; Shanahan-TL; Klerman-EB; Martens-H; Brotman-DJ; Emens-JS; Klein-T; Rizzo-JF. N-Engl-J-Med. 1995 Jan 5; 332(1): 6-11.

Blindness/Breast Cancer

Blindness/Breast Cancer

Evaluated the hypothesis of increased light exposure and the rates of breast cancer.

All hospital discharges in the National Hospital Discharge Survey from 1979 to 1987 were evaluated revealing that blind women were half as likely to have breast cancer as women who were not profoundly blind. This effect diminished with age.

"Profound Bilateral Blindness and The Incidence of Breast Cancer." Hahn, Robert A.. Epidemiology, May 1991;2(3):208-210.

Breast Cancer (EMF)

Breast Cancer (EMF)

Reviewed postmenopausal women (#382) with breast cancer compared to controls (#439) for electric blanket use over a ten year period. There was a slight increased risk of breast cancer in electric blanket users.

It has been suggested that chronic exposure to electromagnetic fields may increase the risk of breast cancer by suppressing the normal nocturnal rise in pineal melatonin. In animal models electromagnetic fields have reduced melatonin levels. Melatonin has been shown to reduce the rate of breast tumor growth in animal models and has been administered to patients with cancer to inhibit cell proliferation.

"Electric Blankets Appear to Increase Risk of Breast Cancer." Vena, John E. et al. AFP, October 1990;1065.

Cancer & Melatonin

Cancer

According to this in vitro study, melatonin may inhibit growth of human breast and ovarian cancer cells. Researchers treated breast and ovarian tumors with melatonin, pineal extract (extract from the gland that produces melatonin), and chemotherapeutic drugs. Pineal extract inhibited growth of all tumors, melatonin inhibited growth of 1 out of 6 breast tumors, and melatonin also inhibited growth of 2 out of 3 ovarian tumors. Researchers conclude that anti-cancer pineal extract components must be identified, and that melatonin may be helpful for some cases of ovarian or breast cancer.

Bartsch H, et al: Effect of melatonin and pineal extracts on human ovarian and mammary tumor cells in a chemosensitivity assay, Life Sci 2000 Nov 3;67(24):2953-60


Recent studies have shown the existence of reciprocal links between cytokine activity and immunomodulating neurohormones or neuropeptides. In particular, the pineal hormone melatonin (MLT) appears to influence IL-2 activity in cancer.

The stimulatory effect of tumor necrosis factor-alpha (TNF) on MLT secretion and the inhibitory action of MLT on TNF release, would suggest the existence of feed-back mechanisms operating between the pineal gland and TNF released from macrophages in human neoplasms.

Role of the pineal gland in the control of macrophage functions and its possible implication in cancer: a study of interactions between tumor necrosis factor-alpha and the pineal hormone melatonin. Lissoni-P; Bami-S; Tancini-G; Brivio-F; Tisi-E; Zubelewicz-B; Braczkowski-R. J-Biol-Regul-Homeost-Agents. 1994 Oct-Dec; 8(4): 126-9.


The pineal neurohormone melatonin (MLT) may enhance the antitumor activity of IL-2.

This preliminary study suggests that advanced solid neoplasms resistant to IL-2 may become responsive to IL-2 therapy by a concomitant administration of the pineal hormone MLT, which could act by enhancing IL-2 antitumor immune effect and/or by increasing the susceptibility of cancer cells to the cytolysis mediated by IL-2-induced cytotoxic lymphocytes.

Efficacy of the concomitant administration of the pineal hormone melatonin in cancer immunotherapy with low-dose IL-2 in patients with advanced solid tumors who had progressed on IL-2 alone. Lissoni-P; Barni-S; Cazzaniga-M; Ardizzoia-A; Rovelli-F; Brivio-F; Tancini-G. Oncology. 1994 Jul-Aug; 51(4): 344-7.



Metastatic hepatocellular carcinoma

Metastatic hepatocellular carcinoma

Experimental studies have showed that hepatocellular carcinoma (HCC) cells are susceptible to cytolysis of interleukin (IL)-2-activated lymphocytes. Moreover, previous studies demonstrated that the pineal neurohormone melatonin (MLT) may enhance IL-2 efficacy.

Neuroimmunotherapy with low-dose IL-2 plus MLT is a new well-tolerated and effective therapy of advanced HCC.

Low-dose interleukin-2 subcutaneous immunotherapy in association with the pineal hormone melatonin as a first-line therapy in locally advanced or metastatic hepatocellular carcinoma. Aldeghi-R; Lissoni-P; Barni-S; Ardizzoia-A; Tancini-G; Piperno-A; Pozzi-M; Ricci-G; Conti-A; Maestroni-GJ. Eur-J-Cancer. 1994; 30A(2): 167-70

Renal cell carcinoma

Renal cell carcinoma

Numerous attempts to identify active cytotoxic agents for the treatment of metastatic renal cell carcinoma (RCC) have proved disappointing. However, several recent developments in biologic therapy of neoplastic disease have substantially improved the prospects for the treatment of advanced RCC.

Melatonin (MLT), a hormone regulated by the pineal gland, has been shown to act on the immune system by causing the release of cytokines from activated T-cell populations.

Modulation of human lymphoblastoid interferon activity by melatonin in metastatic renal cell carcinoma. A phase II study. Neri-B; Fiorelli-C; Moroni-F; Nicita-G; Paoletti-MC; Ponchietti-R; Raugei-A; Santoni-G; Trippitelli-A; Grechi-G. Cancer. 1994 Jun 15; 73(12): 3015-9.

Cholesterol Metabolism

Cholesterol Metabolism

Nocturnal melatonin levels are reduced in a patients with multiple sclerosis (MS). Their high incidence of hypercholesterolemia may be linked to dysfunction of the pineal gland since pinealectomy in rats was reported to be associated with elevation of blood cholesterol levels.

There was a significantly higher serum cholesterol level in patients who had low nocturnal plasma melatonin levels compared to patients with normal melatonin levels.

As serum cholesterol levels were statistically unrelated to TG levels, it suggests a specific association between pineal melatonin and cholesterol metabolism. The pineal gland may exert a cholesterol reducing effect and melatonin could be used therapeutically in the treatment of hypercholesterolemia.

"The relationship between melatonin secretion and serum cholesterol in patients with multiple sclerosis." Sandyk-R; Awerbuch-GI. Int-J-Neurosci. 1994 May; 76(1-2): 81-6.

There is some indirect evidence that the pineal hormone melatonin can suppress plasma levels of cholesterol in hypercholesterolemic rats. We have examined the effects of the hormone on cellular cholesterol metabolism in freshly isolated human mononuclear leukocytes. The data provide evidence that melatonin can modulate cholesterol metabolism in human cells.

"Melatonin inhibits LDL receptor activity and cholesterol synthesis in freshly isolated human mononuclear leukocytes." Muller-Wieland-D; Behnke-B; Koopmann-K; Krone-W, Biochem-Biophys-Res-Commun. 1994 Aug 30; 203(1): 416-21.

Circadian Rhythm

Circadian Rhythm

Methylcobalamin (3 mgs per day) was given to 9 healthy subjects for 4 weeks in a crossover, placebo-controlled trial. It was found that the 24 hour melatonin rhythm was significantly phase-advanced in the "vitamin B12" trial as compared to the placebo trial. The 24 hour mean level of plasma melatonin was much lower in the vitamin B12 trial than the placebo trial. In those taking the vitamin B12, the nocturnal melatonin levels during bright light exposure were significantly lower. Vitamin B12 did not affect the timing of sleep.

Vitamin B12 phase-advances the circadian rhythm by increasing melatonin and thereby increases the sensitivity of plasma melatonin to bright light and sensitivity of the circadian clock to light.

"Effects of Vitamin B12 on Plasma Melatonin Rhythm in Humans: Increased Light Sensitivity Phase-Advances the Circadian Clock." Honma, K. et al. Experientia, 1992;48:716720.

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 penetrates biological barriers, thus carries phase of day information to all peripheral tissues. Light exposure of the retina alters (via neural pathways connecting retina to pineal gland) the amount of serotonin metabolized to melatonin.

If the endogenous clock is altered, it may lead to pathologic symptoms. The best known are: seasonal affective disorders and jet-lag syndrome.

"The role of pineal gland in circadian rhythms regulation." Kral'-A, Bratisl-Lek-Listy. 1994 Jul; 95(7): 295-303.

Reentrainment of human circadian rhythm to an 8-h advanced schedule of sleep and social contacts was assessed under two different conditions: with and without bright light (4,000-6,000 lx).

The maximum phase-advance shift by three consecutive light pulses was observed when the first pulse was applied approximately 4 h after the onset of melatonin rise. By contrast, the maximum phase shift of a similar extent was detected at 1 h after the onset of melatonin rise, when ordinary room light (300-500 lx) at the time corresponding to bright light was regarded as a dim light pulse.

Bright light accelerates the reentrainment of human circadian rhythm, and bright light and social schedule have differential effects on the reentrainment.

Differential effects of bright light and social cues on reentrainment of human circadian rhythms. Honma-K; Honma-S; Nakamura-K; Sasaki-M; Endo-T; Takahashi-T. Am-J-Physiol. 1995 Feb; 268(2 Pt 2): R528-35.

Shift work and rapid travel across several time zones leads to desynchronization of internal circadian rhythms from the external environment and from each other with consequent problems of behaviour, physiology and performance. Field studies of travellers and shift workers are expensive and difficult to control.

This investigation used simulation in a laboratory environment.

This method of determining MT secretion is comparable and gives reliable assessments of the MT circadian phase position even after a phase-shift. Significant phase-shifts of similar magnitude can be induced in both MT and alertness rhythms using moderate intensity bright light at night.

Phase-shifts in melatonin, 6-sulphatoxymelatonin and alertness rhythms after treatment with moderately bright light at night. Deacon-SJ; Arendt-J. Clin-Endocrinol-Oxf. 1994 Mar; 40(3): 413-20.

Clinical Uses

Clinical Uses

Supports melatonin as a therapeutic agent. Of benefit to: jet lagged travelers, shift workers, blind people and elderly people with sleep disturbances.

Melatonin can inhibit the growth of human breast cancer cell lines in vitro. Therefore, this pill may also be used to help protect against breast cancer.

Melatonin is a simple derivative of tryptophan and serotonin and is cheap to make. Toxilogical studies will require millions of dollars.

"Melatonin: Hormone of Darkness." Short, R.V. Editorial, British Medical Journal, 1993;307.

Daytime Levels

Daytime Levels

It is well established that in healthy humans oral intake of 5- or 8-methoxypsoralen (5- and 8-MOP) is followed by a significant increase in plasma melatonin concentrations.

Patients were exposed to UVA light treatments.

8-methoxypsoralen increases daytime plasma melatonin levels in humans through inhibition of metabolism. Garde-E; Micic-S; Knudsen-K; Angelo-HR; Wulf-HC. Photochem-Photobiol. 1994 Nov; 60(5): 475-80.

Dopamine

Dopamine

The catecholamine dopamine (D) is involved in the regulation of LH and PRL secretion, whereas a dysregulated noradrenergic system may contribute significantly to symptoms encountered in affective disorders.

AMPT significantly attenuates nocturnal M secretion. M is a good marker for characterizing the effectiveness of AMPT in inhibiting sympathetic NE activity.

Inhibition of presynaptic catecholamine synthesis with alpha-methyl-para-tyrosine attenuates nocturnal melatonin secretion in humans. Zimmermann-RC; Krahn-L; Klee-G; Delgado-P; Ory-SJ; Lin-SC. J-Clin-Endocrinol-Metab. 1994 Oct; 79(4): 1110-4.

Dysthymia

Dysthymia

The present study investigated pre- and post-treatment 24-h urinary metabolites of monoamines and melatonin as a function of response to treatment in primary early onset dysthymic patients.

Data support the view that there is a biological substrate for certain subgroups of dysthymia, part of which may involve serotonergic systems.

Primary early onset dysthymia, biochemical correlates of the therapeutic response to fluoxetine: II. Urinary metabolites of serotonin, norepinephrine, epinephrine and melatonin. Ravindran-AV; Bialik-RJ; Brown-GM; Lapierre-YD. J-Affect-Disord. 1994 Jun; 31(2): 119-23.

Endocrine Tumors

Endocrine Tumors

Recent evidence has shown that endocrine tumors are under an endocrine and immune regulation, and that biotherapies with interferon or the long-acting somatostatin analog, octreotide, may be effective in the control of tumor growth and clinical symptomatology..

"Immunoendocrine therapy with low-dose subcutaneous interleukin-2 plus melatonin of locally advanced or metastatic endocrine tumors." Lissoni-P; Barni-S; Tancini-G; Mainini-E; Piglia-F; Maestroni-GJ; Lewinski-A. Oncology. 1995 Mar-Apr; 52(2): 163-6.

Epilepsy & Melatonin

Epilepsy

Urinary excretion of 6-sulfatoxymelatonin (aMT.6S), the hepatic metabolite of melatonin, was measured in patients (#30) with untreated active epilepsy and in controls.

Melatonin production in untreated patients with active epilepsy is increased and has a circadian pattern with a phase difference as compared with that of normal subjects.

Melatonin response in active epilepsy. Schapel-GJ; Beran-RG; Kennaway-DL; McLoughney-J; Matthews-CD. Epilepsia. 1995 Jan; 36(1): 75-8.

The pineal gland is a complex neuroendocrine organ with pronounced effects on central nervous system activity. Previous studies have suggested an anti-convulsant role formelatonin, so we studied diurnal variations in plasma melatonin in children with febrile or epileptic convulsions and normal children. There were significant changes in melatonin levels during convulsions, consistent with the hypothesis.

Day-night variations in melatonin secretion by the pineal gland during febrile and epileptic convulsions in children. Molina-Carballo-A; Munoz-Hoyos-A; Rodriguez-Cabezas-T; Acuna-Castroviejo-D. Psychiatry-Res. 1994 Jun; 52(3): 273-83.

Plasma melatonin was measured in epileptic infants and children (39 controls, 28 with epileptic convulsions, and 51 with febrile convulsions).

In both febrile and epileptic children, melatonin levels were significantly increased in comparison with normal children.

Effects of febrile and epileptic convulsions on daily variations in plasma melatonin concentration in children. Molina-Carballo-A; Acuna-Castroviejo-D; Rodriguez-Cabezas-T; Munoz-Hoyos-A. J-Pineal-Res. 1994 Jan; 16(1): 1-9.

Free Radical Scavanger

Free Radical Scavanger

This reviews the new finding that melatonin is the most potent free radical scavenger. It specifically scavenges the most damaging free radical, the hydroxyl radical, and has easy access to every portion of the cell.

Clearly, the pineal gland must be considered an important organ.

"Antioxidant Capacity of Melatonin: A Novel Action Not Requiring a Receptor." Reiter, R.J. et al. Neuroendocrinology Letter, 1993;15(1+2)103-116.

Hypertension & Melatonin

Hypertension

The nocturnal production of melatonin synthesis has been associated with circadian mechanisms of the organization of sleep. It is well known that the synthesis of melatonin is under the control of pineal beta 1-adrenoreceptors. The effect of ten weeks treatment with the beta-adrenoreceptor (beta-AR) blockers: propranolol and ridazolol on melatonin synthesis and on sleep quality was examined in patients (#42) suffering from essential hypertension.

A significant 50 percent reduction of sulfatoxymelatonin was measured. No relationship between these reductions and changes in sleep factors was found. The results indicate that a reduced nightly amplitude of melatonin has minor significance for the organization of physiological sleep.

Influence of chronic beta-adrenoreceptor blocker treatment on melatonin secretion and sleep quality in patients with essential hypertension. Rommel-T; Demisch-L. J-Neural-Transm-Gen-Sect. 1994; 95(1): 39-48.

Hypnotic

Hypnotic

Examined effects of very low doses of melatonin (0.1-10 mg, orally) or placebo, administered at 11.45 h, on sleep latency and duration, mood, performance, oral temperature, and changes in serum melatonin levels in healthy male volunteers(#20).

The 0.1- and 0.3-mg doses generated peak serum melatonin levels that were within the normal range of nocturnal melatonin levels in untreated people. All melatonin doses tested significantly increased sleep duration, as well as self-reported sleepiness and fatigue, relative to placebo.

Orally administered melatonin can be a highly potent hypnotic agent. The physiological increase in serum melatonin levels, at around 2100 h daily, may be signal normal sleep onset.

"Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance." Dollins-AB; Zhdanova-IV; Wurtman-RJ; Lynch-HJ; Deng-MH. Proc-Natl-Acad-Sci-U-S-A. 1994 Mar 1; 91(5): 1824-8.

Insomnia (Melatonin)

Insomnia

Fatal familial insomnia (FFI) is a disease characterized by loss of sleep activity due to selective thalamic degeneration. To assess the secretory pattern of melatonin (MT) in FFI.

Plasma MT concentrations gradually decreased as the disease progressed. Complete rhythm obliteration was achieved in the most advanced stage.

Thalamic lesions of FFI appear to determine a progressive disruption of the sleep/wake cycle accompanied by decreased circulating levels of MT, with progressive alterations in the circadian rhythm of this hormone. On the other hand, decreased secretion of MT may contribute to the sleep disturbances of FFI.

Progressive disruption of the circadian rhythm of melatonin in fatal familial insomnia. Portaluppi-F; Cortelli-P; Avoni-P; Vergnani-L; Maltoni-P; Pavani-A; Sforza-E; Degli-Uberti-EC; Gambetti-P; Lugaresi-E. J-Clin-Endocrinol-Metab. 1994 May; 78(5): 1075-8.

Jet Lag

Jet Lag

There have been some reports of melatonin being beneficial in alleviating the subjective symptoms of jet lag, while accelerating the resynchronization following transmeridian flight. Daily administration of melatonin has similarly been able to show benefit in entraining rhythms in blind subjects. High affinity "receptors" for melatonin have been found in the SCN of several mammals. The entraining effect of melatonin has been shown to depend on the presence of an intact SCN.

It is thought that administered melatonin mimics the ability of the endogenous hormone to act as an internal zeitgeber.. A jet lag pill is still in the future. A pharmacologic agent is likely to emerge from a greater knowledge of neurotransmitter mechanisms involved in the entrainment process.

"Can Pharmacologic Agents Be Used Effectively in the. Alleviation of Jet-Lag?" Redfern, P.H.. Drugs, 1992;43(2);147153.

The effects of four-day round flights (Helsinki-Los Angeles-Seattle-Helsinki) were studied flight attendants (#35).

Results indicate that the restitution time of five days at the home base is proper for recovery, if a four day round flight over 10 time zones takes four days or less. The resynchronization rate of salivary hormones after westward, outgoing flights is faster than the resynchronization rate after the eastward return flights.

"The effect of four-day round trip flights over 10 time zones on the circadian variation of salivary melatonin and cortisol in airline flight attendants." Harma-M; Laitinen-J; Partinen-M; Suvanto-S. Ergonomics. 1994 Sep; 37(9): 1479-89.

The properties required of a chronobiotic--an agent to cause phase adjustment of the body clock--are discussed. Current knowledge indicates that a combination of factors is likely to be most effective.

"Circadian rhythms, jet lag, and chronobiotics: an overview." Redfern-P; Minors-D; Waterhouse-J. Chronobiol-Int. 1994 Aug; 11(4): 253-65.

Light Therapy

Light Therapy

After 7 days of morning bright light (2500 lx) or dim light (50 lx) treatment, levels of serotonin and melatonin were assessed for 24 hour rhythms in 39 unmedicated inpatients with nonseasonal affective disorder (depression) and 40 healthy men and women.

Bright light led to a more than 50%decrease in the Hamilton Rating Scale for depression score in 4 of 19 patients, and dim light in 1 of 17 patients. After light treatment the subjects' melatonin levels did not change significantly. These findings suggest the involvement of serotonergic mechanisms following light therapy.

"Blood Serotonin, Serum Melatonin and Light Therapy in Healthy Subjects and in Patients With Nonseasonal Depression." Rao, M.L. et al. ACTA Psychiatr Scand, 1992;86:127-132.

Patients (#8) with winter depression were compared to controls (#5) and morning light was significantly better than evening light in reducing depressive symptoms.

At baseline there was a tendency towards the onset of melatonin production to be later in the patients than in the controls. The morning light moved the melatonin onset significantly earlier in patients but not the controls.

Patients with winter depression have circadian rhythms that are delayed and bright light therapy benefits winter depression from earlier secretion of melatonin.

"Morning vs. Evening Light Treatment For Winter Depression: Evidence That the Therapeutic Effects of Light Are Mediated By Circadian Phase Shifts." Sack, Robert L. et al. Archives of General Psychiatry, April 1990;47:343-351.

Patients (#12) with seasonal affective disorder (SAD) and controls (#11) were exposed to 2,000 lux and 300 lux of artificial full spectrum lighting on consecutive nights during the winter. Suppression of melatonin secretion was measured.

The SAD group showed significant seasonal variation in sensitivity to light. There was a supersensitivity in the winter but a subsensitivity to light in the summer. There was an abnormal seasonal variation and suppression of melatonin by light in SAD patients but not in matched controls.

"Seasonal Affective Disorder and Season-Dependent Abnormalities of Melatonin Suppression By Light." Thompson, C. et al, The Lancet, September 22, 1990;336:703-706.

SAD

SAD

In winters 1990-1991 and 1991-1992 women with and without seasonal affective disorder, winter type, were treated by light at 2500 lux either in the morning (0800h-1000h) or afternoon (1600h-1800h). In winter before light treatment, melatonin levels in serum in daytime (1200h and 1600h) were higher in patients compared to controls. This difference disappeared in the summer, or after light treatment in the winter.

The decline in melatonin levels correlated with the decline in specific SAD symptoms of hyperphagia and carbohydrate craving. In winter, neither patients nor controls showed significant diurnal variations in levels of whole blood serotonin. In both patients and controls, levels of serotonin were higher in summer as compared with winter, especially at 2000h. Data suggest that elevated daytime melatonin can be a state marker of winter depression and that seasonal change of photoperiod may also affect the circadian amplitude and daytime levels of blood serotonin.

"Diurnal and seasonal variations of melatonin and serotonin in women with seasonal affective disorder." Danilenko-KV; Putilov-AA; Russkikh-GS; Duffy-LK; Ebbesson. Arctic-Med-Res. 1994 Jul; 53(3): 137-45.

Schizophrenia & Melatonin

Schizophrenia

Circadian rhythm abnormalities have been described mostly with respect to manic-depressive illness; little information is available concerning circadian rhythms and schizophrenia or their influence on neuroleptic drugs.

Results suggest that circadian changes, such as phase are not only present in depression but also in schizophrenia.

Circadian rhythm of tryptophan, serotonin, melatonin, and pituitary hormones in schizophrenia. Rao-ML; Gross-G; Strebel-B; Halaris-A; Huber-G; Braunig-P; Marler-M. Biol-Psychiatry. 1994 Feb 1; 35(3): 151-63.

Secretion

Secretion

A single physiological dose of melatonin (20 micrograms for 3 h given intravenously at different times of the day (04.00-12.00, 16.00 and 20.00 h) was able to shift the endogenous plasma melatonin profile of healthy volunteers under entrained conditions according to a phase-response curve (PRC).

Results support the paradigm of melatonin as an endogenous synchronizer.

Melatonin is able to influence its secretion in humans: description of a phase-response curve. Zaidan-R; Geoffriau-M; Brun-J; Taillard-J; Bureau-C; Chazot-G; Claustrat-B. Neuroendocrinology. 1994 Jul; 60(1): 105-12.

SIDS

SIDS

It is hypothesized that melatonin, by its actions on porphyrin and nitric oxide biosynthesis, produces an increase in cyclic guanosine monophosphate.

Melatonin increases cyclic guanosine monophosphate: biochemical effects mediated by porphyrins, calcium and nitric oxide. Relationships to infant colic and the Sudden Infant Death Syndrome. Weissbluth-M. Med-Hypotheses. 1994 Jun; 42(6): 390-2.

Sudden Infant Death Syndrome (SIDS) is the unexpected, and after autopsy, unexplained death of an apparently healthy infant. SIDS exhibits circannual, circadian, and ontogenetic features which may reflect an impaired maturation of the photoneuroendocrine system caused by a genetic absence or mutation of the enzyme N-acetyltransferase which is the rate-limiting enzyme for the biosynthesis of the hormone melatonin in the pineal gland.

The failure of normal pineal gland development and subsequent impaired production of its main secretory product, melatonin, may cause a lethal imbalance in the chemical interactions among serotonin, progesterone, and catecholamines. The result of this chemical imbalance, culminating in SIDS, involves the neurotoxic and cardiomyotoxic effects of abnormally elevated catecholamines and intracellular calcium ions.

Sudden infant death syndrome: a genetically determined impaired maturation of the photoneuroendocrine system. A unifying hypothesis. Weissbluth-L; Weissbluth-M. J-Theor-Biol. 1994 Mar 7; 167(1): 13-25.

Skin color

Skin color

Previous studies have shown the pineal hormone melatonin to influence mammalian coat color and amphibian skin color when administered exogenously. It has also been suggested that melatonin can be employed effectively to inhibit progress of neoplastic disease in both animals and humans. The present study investigates the effect of melatonin on human skin color in an effort to uncover its mechanism of action as an antimelanoma agent.

Conclude that melatonin has no effect on human skin pigmentation, and that the demonstrated effectiveness of melatonin in mediating malignant melanoma growth is not related to suppression of normal melanogenesis.

Effect of melatonin on human skin color. McElhinney-DB; Hoffman-SJ; Robinson-WA; Ferguson-J. J-Invest-Dermatol. 1994 Feb; 102(2): 258-9.

Sleep Disorders & Melatonin

Sleep Disorders

An Israeli study showed how individuals, who could not fall asleep until five in the morning and then not able to wake up before noon, could reset their biological clock to a normal sleep cycle.

This was done by taking melatonin at dosages of 1 to 2 mgs per day taken orally about 2 hours before the desired bedtime.

Once a patient achieves the desired bedtime, the melatonin can be stopped.

The exact mechanism of how melatonin corrects the biological clock is unknown.

"Melatonin May Relieve Sleep-Cycle Disorders." Field, Roger, Medical Tribune, April 8, 1993;2.


Sleep disorders (Children)

Sleep disorders (Children)

Children (#15) with severe, chronic sleep disorders were given 2 to 10mg of oral melatonin at bedtime. All had failed to respond to conventional management. Nine patients had ocular or cortical visual impairment.

The health, behavioural and social benefits of treatment were significant, with no adverse side-effects. While the response was not always complete, melatonin has an important role in the treatment of chronic sleep disorders.

"The treatment of sleep disorders with melatonin." Jan-JE; Espezel-H; Appleton-RE. Dev-Med-Child-Neurol. 1994 Feb; 36(2): 97-107.

Sleep-wake cycle

Sleep-wake cycle

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 disorders such as jet lag and delayed sleep phase syndrome.

Light, melatonin and the sleep-wake cycle. Brown-GM. J-Psychiatry-Neurosci. 1994 Nov; 19(5): 345-53.

Sleep-wake regulation

Sleep-wake regulation

Investigated the hypnotic effects of 5 mg melatonin (or placebo) administered at 1200, 1700, 1900 and 2100 hours. Young adults (#18) were studied with the 7/13 ultrashort sleep-wake paradigm after an overnight sleep deprivation.

Melatonin significantly increased sleep propensity, the spectral power in the theta, delta and spindles bands and subjective sleepiness. It significantly decreased the power in the alpha and beta bands and oral temperature. The latency to maximum effect varied linearly from 3 hours 40 minutes at 1200 hours to 1 hour at 2100 hours.

Melatonin possesses a time-dependent hypnotic effect and may participate in sleep-wake regulation.

"Melatonin possesses time-dependent hypnotic effects." Tzischinsky-O; Lavie-P. Sleep. 1994 Oct; 17(7): 638-45.

Smokers and Melatonin

Smokers

Melatonin secretion is required to be a potential inhibitor of the development and growth of tumors, and cigarette smoking is a well established risk factor for cancer at various sites.

Data showed higher melatonin circulating levels in smokers (17.44 +/- 1.8 pg/ml) than in nonsmokers (9.77 +/- 1.4 pg/ml). The causes, mechanism and meaning of this phenomenon are still unknown. Possibly, higher melatonin levels in smokers is an attempt to counterbalance cellular growth stimulus, a natural "brake" mechanism to restrain the proliferation of normally differentiated tissues: smoke is a prominent risk factor for several different tumors.

Daytime circulating melatonin levels in smokers. Tarquini-B; Perfetto-F; Poli-R; Tarquini-R. Tumori. 1994 Jun 30; 80(3): 229-32.

Subarctic melatonin

Subarctic melatonin

Secretion of the hormone melatonin shows a circadian rhythm and is inhibited by light. Light therapy with phase shifting of the melatonin rhythm has been used as treatment of sleeping problems and seasonal affective disorders (SAD). Exercise has also been shown to suppress the melatonin secretion. A change in habitual level of activity should be thought of as a possible help for treating midwinter insomnia and SAD.

Evening melatonin in January after changes in hours of habitual exercise during fall among youths living in the subarctic. Weydahl-A. Arctic-Med-Res. 1994 Jul; 53(3): 146-51.

Synthesis (Melatonin)

Synthesis

Hydroxyindole-O-methyltransferase (HIOMT) catalyzes the last step in the metabolic pathway that synthesizes the hormone melatonin. We have found HIOMT mRNA present in small amounts in human retina and in relatively high abundance in the pineal gland.

Structural analysis of the human hydroxyindole-O-methyltransferase gene. Presence of two distinct promoters. Rodriguez-IR; Mazuruk-K; Schoen-TJ; Chader-GJ. J-Biol-Chem. 1994 Dec 16; 269(50): 31969-77.

Target sites

Target sites

A pre-requisite to understanding the physiological mechanisms of action for melatonin is the identification of the target sites where the hormone acts.

New melatonin analogues will greatly aid our understanding of the pharmacology of the melatonin receptor both in terms of the development of potent melatonin receptor antagonists and for the definition of receptor sub-types. The wide species and phylogenic diversity of melatonin binding sites in the brain has probably generated more questions than answers.

The localization of melatonin receptors to the suprachiasmatic nucleus of the hypothalamus is consistent with circadian effects within the foetus and the adult.

Melatonin receptors: localization, molecular pharmacology and physiological significance. Morgan-PJ; Barrett-P; Howell-HE; Helliwell-R. Neurochem-Int. 1994 Feb; 24(2): 101-46.

Thermoregulation

Thermoregulation

Melatonin plays an important role in seasonal thermoregulatory adjustments of animals including torpor and hibernation. Furthermore, melatonin has a crucial role in circadian thermoregulatory adjustments of body temperature (Tb). Melatonin appears to send signals to the preoptic area of the anterior hypothalamus (PoAH) where it adjusts the set point of Tb consistent with the metabolic rate of the animal. This new function for melatonin as a transducer mediating information about energy balance has been suggested in this review. Melatonin also adjusts the activity of the biological clock in vertebrates.

Function of melatonin in thermoregulatory processes. Saarela-S; Reiter-RJ. Life-Sci. 1994; 54(5): 295-311.

Time of death

Time of death

A method for the estimation of time of death (TOD), was evaluated by measuring the melatonin (MT) content of pineal bodies (PBs), sera and urine samples from cadavers(#85).

Estimation of time of death by quantification of melatonin in corpses. Mikami-H; Terazawa-K; Takatori-T; Tokudome-S; Tsukamoto-T; Haga-K. Int-J-Legal-Med. 1994; 107(1): 42-51.

Tourette's

Tourette's

Despite current intensive research, the pathophysiology of tardive dyskinesia (TD), a serious neurological side effect of neuroleptic treatment, is poorly understood. Suggest that the pineal gland exerts a protective effect which mitigates against the development of TD and, by inference, that reduced melatonin secretion may relate to the pathophysiology of TD.

Studied the association of TD with pineal calcification (PC) on CT scan in chronic schizophrenic patients. Revealed a significant association between TD and PC and may provide a neuroradiological marker of TD.

Since PC may reflect diminished secretory activity of the gland, these findings support the hypothesis that the pathophysiology of TD is linked to disturbances of melatonin secretion.

Disturbances in melatonin secretion may also be relevant to the pathophysiology of Tourette's syndrome.

The relationship of pineal calcification and melatonin secretion to the pathophysiology of tardive dyskinesia and Tourette's syndrome. Sandyk-R; Kay-SR. Int-J-Neurosci. 1991 Jun; 58(3-4): 215-47.

Transdermal delivery

Transdermal delivery

A transdermal delivery device (TDD)1 was applied to four human subjects to investigate whether melatonin (MT) could penetrate through human skin.

Although an intersubject variability in both plasma MT concentration and urinary excretion rate of 6-STMT was noted, it was evident that MT can be delivered transdermally in human subjects.

Preliminary evaluation of transdermal delivery of melatonin in human subjects. Lee-BJ; Parrott-KA; Ayres-JW; Sack-RL. Res-Commun-Mol-Pathol-Pharmacol. 1994 Sep; 85(3): 337-46.

Temperature

Temperature

Appropriately administered melatonin is able to: phase-shift circadian rhythms, induce transient sleepiness and suppress core body temperature.

Melatonin induced a significant suppression of temperature suppression suggesting that it is an integral part of the phase-shifting mechanism.

Acute phase-shifting effects of melatonin associated with suppression of core body temperature in humans. Deacon-S; English-J; Arendt-J. Neurosci-Lett. 1994 Aug 29; 178(1): 32-4.

Uveitis (Melatonin)

Uveitis

Experimental models of autoimmune uveitis are consistently associated with pinealitis.

Results suggest a possible neuroendocrine-immune interaction in uveitis patients.

Neuroendocrine alterations in uveitis patients. Wollmann-HA; Pleyer-U; Friedel-S; Zierhut-M; Thiel-HJ; Gupta-D. Graefes-Arch-Clin-Exp-Ophthalmol. 1994 May; 232(5): 297-301.

Activity & Melatonin

Activity

To determine whether a single episode of physical activity is capable of inducing rapid phase shifts in human circadian rhythms.
Profiles of plasma cortisol, thyrotropin (TSH), and melatonin as well as body temperature were monitored continuously to derive estimations of circadian phase position.

Data demonstrate that nonphotic stimuli may exert phase-shifting effects on the human circadian pacemaker.

Nocturnal exercise phase delays circadian rhythms of melatonin and thyrotropin secretion in normal men. Van-Reeth-O; Sturis-J; Byrne-MM; Blackman-JD; L'Hermite-Baleriaux-M; Leproult-R; Oliner-C; Refetoff-S; Turek-FW; Van-Cauter-E. Am-J-Physiol. 1994 Jun; 266(6 Pt 1): E964-74.

Winter depression

Winter depression

The phase of circadian rhythms can be shifted by exposure to light. Most patients with winter depression are suggested to have a phase delay in their circadian rhythms. The efficacy of light in treatment of winter depression is thought to be associated with the phase shifting effect of light.

In addition to light, melatonin and serotonin can cause phase shifts of the rhythms. The concerted action of these indoleamines may underly the finding that light has an antidepressant effect, independently of time of day or circadian phase of an individual.

Involvement of melatonin and serotonin in winter depression. Partonen-T. Med-Hypotheses. 1994 Sep; 43(3): 165-6.

Propranolol, 60 mg or less, was administered daily between 5:30 and 6:00 a.m. to patients (#33) with winter depression.

Findings are consistent with the hypothesis that duration of nocturnal melatonin secretion is the critical seasonal time cue in humans.

Early-morning administration of short-acting beta blockers for treatment of winter depression. Schlager-DS. Am-J-Psychiatry. 1994 Sep; 151(9): 1383-5.

Melanocyte (Melatonin)

Melanocyte

The pineal, serotoninergic and pigmented neurons are associated with light-dependent sleep/arousal, serving as a biological clock with a circadian rhythm. This rhythm is maintained by melatonin which serves to recognise the 'dark' phase. The neural network that responds to seasonal variations in day/night length has not been identified.

The present study demonstrates that melanocytes in human skin respond to changes in the duration of UV exposure, and can serve as a biological calendar. These responses are mediated by two indoleamines, serotonin and melatonin.

Higher melatonin levels correspond to long nights and short days (short UV pulse), while high serotonin levels in the presence of melatonin reflect short nights and long days (long UV exposure). This is responsible for coat colour changes from pure white in winter to complete repigmentation in summer.

Indoleamines and the UV-light-sensitive photoperiodic responses of the melanocyte network: a biological calendar? Iyengar-B. Experientia. 1994 Aug 15; 50(8): 733-6.

Melanoma & Melatonin

Melanoma

To determine the effect of oral melatonin in divided doses on plasma melatonin levels in patients with metastatic melanoma.

Divided oral doses of melatonin were well tolerated and maintained plasma melatonin levels 25-80 times higher than endogenous peak values.

Serum melatonin levels in melanoma patients after repeated oral administration. Kane-MA; Johnson-A; Nash-AE; Boose-D; Mathai-G; Balmer-C; Yohn-JJ; Robinson-WA. Melanoma-Res. 1994 Feb; 4(1): 59-65.

Migraine and Melatonin

Migraine

Nocturnal urinary melatonin excretion was significantly decreased throughout an ovarian cycle in migraine without aura patients (#12) compared to healthy controls (#8). Normal increases in urinary melatonin excretion during the luteal phase were less pronounced in the migraine patients. Melatonin excretion was further decreased during headache. The data indicate impaired pineal function in migraine.

"Urinary melatonin excretion throughout the ovarian cycle in menstrually related migraine." Murialdo-G; Fonzi-S; Costelli-P; Solinas-GP; Parodi-C; Marabini-S; Fanciullacci-M; Polleri-A. Cephalalgia. 1994 Jun; 14(3): 205-9.

The circannual secretion of melatonin in 14 Swedish and 15 Italian patients suffering from episodic cluster headache was compared with matched, healthy controls.

Melatonin concentrations in nocturnal urine were permanently low in cluster headache and there was no consistent change of the melatonin concentration in relation to cluster periods occurring during the study. Lower melatonin levels in cluster headache patients may be related to a larger number of smokers in the patient group.

"Lowered circannual urinary melatonin concentrations in episodic cluster headache." Waldenlind-E; Ekbom-K; Wetterberg-L; Fanciullacci-M; Marabini-S; Sicuteri-F; Polleri-A; Murialdo-G; Filippi-U. Cephalalgia. 1994 Jun; 14(3): 199-204.

Monocytes (Melatonin)

Monocytes

To determine the effects of the pineal hormone melatonin on human monocytes, human monocytes were activated by different concentrations of melatonin.

Data suggest that melatonin activates monocytes and induces their cytotoxic properties, along with the IL-1 secretion.

Activation of human monocytes by the pineal hormone melatonin. Morrey-KM; McLachlan-JA; Serkin-CD; Bakouche-O. J-Immunol. 1994 Sep 15; 153(6): 2671-80.

Mood

Mood

Review article discusses the following variables: prolactin; growth hormone; the hypothalamic-pituitary-thyroid axis (including thyrotropin, triiodothyronine, and thyroxine); the hypothalamic-pituitary-adrenal axis (cortisol, corticotropin, and beta-endorphin); melatonin; sleep; body temperature; and neurotransmitter activity (serotonergic and adrenergic systems).

Melatonin does not appear to vary systematically over the course of the menstrual cycle.

Effects of the menstrual cycle on dependent variables in mood disorder research. Leibenluft-E; Fiero-PL; Rubinow-DR. Arch-Gen-Psychiatry. 1994 Oct; 51(10): 761-81.

MRI

MRI

Production of melatonin, a hormone synthesized and secreted by the pineal body, has been suppressed by electromagnetic fields in some but not all animal studies. Magnetic resonance (MR) imaging at 1.5 T was evaluated for its ability to modulate the level of melatonin in male volunteers (#8). Subjects were exposed between 1:00 and 2:00 AM on different nights.

Subjects exposed to darkness showed a typical increase in melatonin concentration. Subjects exposed to bright light showed a characteristic suppression of melatonin concentration. Those exposed to the MR imaging fields showed an increase in melatonin level similar to that seen in the dark control condition. Light and MR imaging had no significant effects on cortisol levels.

Thus, MR imaging at field strengths known to modulate melatonin levels in rats did not suppress melatonin production in human subjects.

Effect of MR imaging on the normal human pineal body: measurement of plasma melatonin levels. Schiffman-JS; Lasch-HM; Rollag-MD; Flanders-AE; Brainard-GC; Burk-DL Jr. J-Magn-Reson-Imaging. 1994 Jan-Feb; 4(1): 7-11.

Multiple sclerosis & Melatonin

Multiple sclerosis (MS)

Fatigue is one of the most common clinical features of multiple sclerosis (MS) and is a frequent cause of disability. The pathogenesis of fatigue remains obscure. It may result from impaired propagation of action potentials in areas of demyelination. Other contributors may be mental depression, immobility, and physical disability.

Attention has been focused recently on the relationship between MS and the pineal gland and evidence has been presented to implicate the pineal gland and melatonin in the pathogenesis of the disease.

Pineal calcification and its relationship to the fatigue of multiple sclerosis. Sandyk-R; Awerbuch-GI. Int-J-Neurosci. 1994 Jan-Feb; 74(1-4): 95-103.

Multiple sclerosis (MS) is the most common of the demyelinating diseases of the CNS. The clinical course and prognosis of the disease are variable. Characteristically, the illness tends to progress in a series of relapses and remissions.

The pineal gland has been implicated recently in the pathogenesis and clinical course of MS. Since MS is generally a chronic progressive disorder, we predicted an association between duration of illness and the activity of the pineal gland.

Relationship of nocturnal melatonin levels to duration and course of multiple sclerosis. Sandyk-R; Awerbuch-GI. Int-J-Neurosci. 1994 Apr; 75(3-4): 229-37.

Neoplasms

Neoplasms

Experimental studies have shown that the best approach to increase the biological anti-tumour activity of interleukin 2 (IL-2) is not co-administration of another cytokine but the association with immunomodulating neurohormones, in an attempt to reproduce the physiological links between psychoendocrine and immune systems, which play a fundamental role in the regulation of the immune responses; particularly, the association with the pineal neurohormone melatonin (MLT).

Tumour objective regression rate was significantly higher in patients treated with IL-2 and MLT than in those receiving IL-2 alone (11/41 vs 1/39). The survival at 1 year was significantly higher (19/41 vs 6/39, respectively). Finally, the mean increase in lymphocyte and eosinophil number was significantly higher. On the contrary, the mean increase in the specific marker of macrophage activation neopterin was significantly higher in patients treated with IL-2 alone. The treatment was well tolerated in both groups of patients.

The concomitant administration of MLT may increase the efficacy of low-dose IL-2.

A randomised study with subcutaneous low-dose interleukin 2 alone vs interleukin 2 plus the pineal neurohormone melatonin in advanced solid neoplasms other than renal cancer and melanoma. Lissoni-P; Barni-S; Tancini-G; Ardizzoia-A; Ricci-G; Aldeghi-R; Brivio-F; Tisi-E; Rovelli-F; Rescaldani-R; et-al. Br-J-Cancer. 1994 Jan; 69(1): 196-9.

Nightwork

Nightwork

Female nurses (#15) were examined with the aim of evaluating their psychophysical adaptation to one of the most commonly used, rapidly rotating shift systems, the "metropolitan rota" (2-2-2-2), with the length of the shifts modified according to the work load (including night shifts of 10h) and with the start of the morning shift delayed (to 7 a.m.).

Results showed that this rapidly rotating shift system (including 2 consecutive night shifts) does not significantly alter the normal circadian rhythms of the body, particularly as concerns performance levels, body temperature and hormone excretion.

Evaluation of a rapidly rotating shift system for tolerance of nurses to nightwork. Costa-G; Ghirlanda-G; Tarondi-G; Minors-D; Waterhouse-J. Int-Arch-Occup-Environ-Health. 1994; 65(5): 305-11.

Night workers

Night workers

There is strong evidence to suggest that circadian psychophysiological adaptation processes are modified by light, depending on its intensity and timing.

Circadian rhythms of melatonin and cortisol were analysed from salivary samples collected for 24 hr at 2 hr intervals.

Group comparison revealed a marked difference of the mean melatonin concentrations at night, and at 0700.

Different patterns of light exposure in relation to melatonin and cortisol rhythms and sleep of night workers. Koller-M; Harma-M; Laitinen-JT; Kundi-M; Piegler-B; Haider-M. J-Pineal-Res. 1994 Apr; 16(3): 127-35.

NSAIDS

NSAIDS

Previous studies have demonstrated that some nonsteroidal anti-inflammatory drugs (NSAIDs), specifically aspirin and indomethacin, have acute negative effects on sleep in humans and animals.

Aspirin and ibuprofen disrupted sleep in comparison to placebo by increasing the number of awakenings and percentage of time spent in stage wake, and by decreasing sleep efficiency. Ibuprofen also delayed the onset of the deeper stages of sleep. Acetaminophen did not differ significantly from placebo.

However, every index of objective sleep reflected slight, albeit nonsignificant, sleep disruption for each drug group relative to placebo.

The mechanisms of sleep disruption after NSAID administration may relate to direct and indirect consequences of inhibiting prostaglandin synthesis, including decreases in prostaglandin D2, suppression of nighttime melatonin levels, and changes in body temperature.

Nonsteroidal anti-inflammatory drugs affect normal sleep patterns in humans. Murphy-PJ; Badia-P; Myers-BL; Boecker-MR; Wright-KP Jr. Physiol-Behav. 1994 Jun; 55(6): 1063-6.

Opioids

Opioids

Several studies have demonstrated involvement of the pineal gland in the regulation of neuropeptide secretion and activity. Both opioid peptides and melatonin (MLT) play an important role in neuromodulation of the immunity. Moreover, the immune effects of MLT are mediated by endogenous opioid peptides, which may be produced by both the endocrine system and the immune cells. In addition, the immune dysfunctions that characterize some human diseases, such as cancer, depend not only on the immune system per se, but also at least in part, on altered secretion of immunomodulating neurohormones, including MLT and opioid peptides. Therefore, the exogenous administration of neurohormones could potentially improve the immune status in humans.

The mean increase in T lymphocytes, natural killer cells, and eosinophils was significantly higher in patients treated with IL-2 plus MLT than in those who received IL-2 alone.

Pineal-opioid system interactions in the control of immunoinflammatory responses. Lissoni-P; Barni-S; Tancini-G; Fossati-V; Frigerio-F. Ann-N-Y-Acad-Sci. 1994 Nov 25; 741: 191-6.

Posture

Posture

Melatonin is extensively used as a circadian rhythm marker and thus any factors influencing its concentrations other than endogenous rhythmicity must be assessed. We report here the effects of posture on melatonin concentrations in plasma and saliva.

Healthy subjects (#7) remained sitting until 24:00 h and in dim light (< 10 lux) until 01:30 h. From 24:00 h, they assumed a different postural position: standing or supine. Plasma and salivary melatonin concentrations, measured by radioimmunoassay, increased when moving from a supine to a standing position and decreased when these positions were reversed. These changes, as seen with other blood components, can be explained through the influence of gravity which causes a decrease in plasma volume on standing and an increase in plasma volume on lying down.

Posture influences melatonin concentrations in plasma and saliva in humans. Deacon-S; Arendt-J. Neurosci-Lett. 1994 Feb 14; 167(1-2): 191-4.

Radiation & Melatonin

Radiation

Cells in human peripheral blood were treated in vitro with increasing concentrations of melatonin (0.5 or 1.0 or 2.0 mM) for 20 min at 37 +/- 1 degrees C and then exposed to 150 cGy gamma-radiation from a 137Cs source.

The lymphocytes which were pre-treated with melatonin exhibited a significant and concentration-dependent decrease in the frequency of radiation-induced chromosome damage.

Melatonin at 2.0 mM (a 500 x lower concentration) was as effective in decreasing the radiation-induced chromosome damage as dimethyl sulfoxide at 1.0 M. This may have implications for human protection against damage due to endogenously produced free radicals and also to free radical producing physical and chemical mutagens and carcinogens.

Melatonin protects human blood lymphocytes from radiation-induced chromosome damage. Vijayalaxmi; Reiter-RJ; Meltz-ML. Mutat-Res. 1995 Jan; 346(1): 23-31.

Receptors

Receptors

Currently, the melatonin receptor is depicted as a membrane-associated protein, linked to a guanine nucleotide-binding protein (G-protein), and thus represents a member of a receptor superfamily, acting through G-proteins in the first step of their signal-transduction pathways. Although on a number of occasions specific binding of radioactive melatonin has been demonstrated in a wide variety of tissues and organs, to date, high affinity G-protein-regulated melatonin binding sites, suggestive for a functional melatonin receptor, have been convincingly confirmed in the brain only.

Two sites have been consistently found to express high density of melatonin receptors: the pars tuberalis of the adenohypophysis and the hypothalamic suprachiasmatic nuclei (SCN).

High affinity melatonin receptors in the vertebrate brain: implications for the control of the endogenous oscillatory systems. Fraschini-F; Stankov-B. Chronobiologia. 1994 Jan-Jun; 21(1-2): 89-92.


Oncostatic effect

Oncostatic effect

The pineal hormone, melatonin, has an inhibitory effect on the cell growth of human breast cancer. Assessed the interaction of melatonin with 5-fluorouracil (5-FU) on estrogen-sensitive MCF7 and estrogen-insensitive HBC4 cell lines.

Melatonin inhibited MCF7 cell growth dose-dependently. 5-FU also demonstrated an inhibitory effect on MCF7 cell growth and a maximal inhibition of growth by 24% was acquired at a concentration of 500 ng/ml. By contrast, the inhibitory effect of melatonin was reduced by the co-administration of 5-FU, independently of 5-FU concentration. Melatonin and/or 5-FU exhibited no effect on HBC4 cells. This indicates that 5-FU should be handled with care for treatment of estrogen sensitive-breast cancer.

5-Fluorouracil attenuates an oncostatic effect of melatonin on estrogen-sensitive human breast cancer cells (MCF7). Furuya-Y; Yamamoto-K; Kohno-N; Ku-Y; Saitoh-Y. Cancer-Lett. 1994 Jun 15; 81(1): 95-8.

Growth Hormone Secretion

Growth hormone secretion

Melatonin may induce the secretion of growth hormone (GH) during exercise. Seven men participated in a randomized double blind, placebo- controlled study. They took either melatonin or placebo and performed bicycle exercises. GH secretion levels were higher in the melatonin group than those in the control group during exercise. Hence, melatonin may modulate pituitary secretion and directly influence the GH secretion levels during exercise.

Meeking DR, Wallace JD, Cuneo RC, Forsling M, Russell-Jones DL: Exercise-induced GH secretion is enhanced by the oral ingestion of melatonin in healthy adult male subjects, Eur J Endocrinol 1999 Jul; 1 41(1): 22-26

Morphine

Morphine

According to this study, melatonin may reverse the development of tolerance and dependence on morphine. The inhibitory effect of melatonin on morphine was observed in mice during a 10-day trial. Combination of melatonin and morphine slowed down tolerance and dependence. The mechanism of this action may involve peripheral benzodiazepine receptors.

Raghavendra V, Kulkarni SK: Reversal of morphine tolerance and dependence by melatonin: possible role of central and peripheral benzodiazepine receptors, Brain Res 1999 Jul 10; 834(1-2): 178-181

Universal Regulator

Universal regulator

Melatonin may act as the universal regulator of biological rhythms, as a widely used hormone in intercellular relationships. Recent studies indicate that melatonin was found the retina, gut mucosa, cerebellum, airway epithelium, liver, kidney, adrenals, thymus, thyroid, pancreas, ovary, carotid body, placenta and endometrium. In essence, melatonin is found in just about every organ system of the human body and may be an important part of the intercellular relationships within the human body.

Kvetnoy IM: Extrapineal melatonin: location and role within diffuse neuroendocrine system, Histochem J 1999 Jan; 31(1): 1-12

Neurological Diseases

Neurological diseases

Melatonin may be a detriment in treating neurological diseases, especially Parkinson's disease. In this study, intracerebroventricular implants of slow release melatonin, pinealectomy (PX), or constant light (LL) were administered to rats. The results show that behavioral impairment was found among rats treated with melatonin. Thus, exposure to melatonin may produce harmful effects on neurological disorders.

Willis GL, Armstrong SM: A therapeutic role for melatonin antagonism in experimental models of Parkinson's disease, Physiol Behav 1999 Jul; 66(5): 785-95

Angelman Syndrome

Angelman syndrome

Melatonin may promote sleep and significantly decrease motor activity among children with insomnia as a symptom of Angelman syndrome (AS). During this study, thirteen AS children were administered melatonin before their bedtime. Analysis of the clinical data indicated that motor activity declined significantly and the sleep cycle was prolonged during the melatonin treatment. Melatonin may be used as a supplement for insomnia resulting from Angelman syndrome.

Zhdanova IV, Wurtman RJ, Wagstaff J: Effects of a low dose of melatonin on sleep in children with Angelman syndrome, J Pediatr Endocrinol Metab 1999 Jan-Feb; 12(1): 57-67

Muscle Spasms

Muscle spasms

Melatonin may eliminate muscle spasms (myoclonus) that might be resistant to other anticonvulsant medicines. In a clinical trial, over 200 children who had sleep deprivation due to myoclonus were administered 3-5 mg melatonin. They did not experience myoclonus after treatment and no adverse side effects were reported. However, the researchers note that more information is needed.

Jan JE, Connolly MB, Hamilton D, Freeman RD, Laudon M: Melatonin treatment of non-epileptic myoclonus in children, Dev Med Child Neurol 1999 Apr; 41(4): 255-9


Eye Light Sensitivity

Eye light sensitivity

Melatonin may be correlated a decrease in retinal light sensitivity, according to this study conducted on an older age group. After a trial run for 14 days, the hormone reduced the threshold of the retina's sensitivity to light, possibly through a direct effect on the photoreceptors.

Arushanian EB, Ovanesov KB: Melatonin lowers the threshold of light sensitivity of the human retina, Eksp Klin Farmakol 1999 Mar-Apr; 62(2): 58-60

Advancing Circadian Rhythm

Advancing Circadian Rhythm

To determine the magnitude and direction of phase shifts of human circadian rhythms occurring within 1 day after a single exposure to bright light, plasma thyrotropin, melatonin, and cortisol levels and body temperature were monitored.

The phase shifts in response to light occurred within 24 h and were in the delaying direction for most of the nocturnal "period", with the crossover to phase advances occurring approximately 1 h after the temperature minimum. Phase shifts averaged 1 h, with delays being larger than advances, and were achieved without significant changes in rhythm amplitude. The immediate response of the human circadian clock to a single 3-h light pulse is thus characteristic of "type 1" resetting.

Demonstration of rapid light-induced advances and delays of the human circadian clock using "hormonal" phase markers. Van-Cauter-E; Sturis-J; Byrne-MM; Blackman-JD; Leproult-R; Ofek-G; L'Hermite-Baleriaux-M; Refetoff-S; Turek-FW; Van-Reeth-O. Am-J-Physiol. 1994 Jun; 266(6 Pt 1): E953-63.

Aging Clock

Aging Clock

The pineal organ as a component of the biological clock. Phylogenetic and ontogenetic considerations. Korf-HW. Ann-N-Y-Acad-Sci. 1994 May 31; 719: 13-42.

Several trends are observed in regard to the phylogenetic development of the pineal organ, which are relevant for our understanding of the evolution of biological clock mechanisms.
1. The pineal organ of all vertebrates is capable of producing and releasing melatonin. Melatonin is rhythmically produced and released during darkness and, thus, represents an important neuroendocrine information on the ambient photoperiod.

2. The rhythmic production of melatonin is under control of endogenous oscillators and photoreceptor cells.

The ontogenetic data reviewed support the notion that, in lower vertebrates, melatonin biosynthesis is primarily controlled by intrapineal photoreceptors, whereas, in mammals, it depends on retinal photoreceptors and the sympathetic innervation of the pineal.

The pineal aging clock. Evidence, models, mechanisms, interventions. Pierpaoli-W; Lesnikov-VA. Ann-N-Y-Acad-Sci. 1994 May 31; 719: 461-73.

Aqueous Humor

Aqueous Humor

Aqueous humor flow through the "anterior" chamber of the "eye" undergoes a circadian cycle. The rate of flow during the day is twice as high as the rate of flow at night. The pineal hormone, melatonin, also undergoes a circadian cycle. Melatonin levels are high at night, whereas aqueous humor flow is low. Studied the effect of oral melatonin on aqueous humor flow in humans.

Conclude that melatonin concentrations during the day, comparable with plasma concentrations that occur spontaneously during sleep, do not suppress aqueous humor formation. There is no support for the idea that plasma melatonin, per se, can suppress aqueous formation or that the circadian rhythm of plasma melatonin is primarily responsible for the circadian rhythm of aqueous humor flow.

The effect of melatonin on aqueous humor flow in humans during the day. Viggiano-SR; Koskela-TK; Klee-GG; Samples-JR; Arnce-R; Brubaker-RF. Ophthalmology. 1994 Feb; 101(2): 326-31.

Body Temperature

Body Temperature

Is the biological effect of melatonin in humans directly related to the circulating levels of the "hormone"? The nocturnal decline of body temperature (BT) was observed in early follicular phase women(#16).

Exogenous melatonin restored the full expression of the nocturnal BT decline in the 2 subjects with complete melatonin suppression, but did not modify the BT decline in the 6 subjects with atenolol-induced incomplete melatonin suppression. Our data show that markedly, but not completely attenuated nocturnal melatonin levels are sufficient to exert maximal thermoregulatory effects, indicating rather a threshold- than a dose-response effect of melatonin action on human BT.

Melatonin-induced decrease of body temperature in women: a threshold event. Cagnacci-A; Soldani-R; Romagnolo-C; Yen-SS. Neuroendocrinology. 1994 Nov; 60(5): 549-52.

Brain Metastases

Brain "Metastases"

Unresectable brain metastases remain an untreatable disease. Because of its antitumor cytostatic action and its "anticonvulsant" effect, the pineal hormone melatonin could constitute a new effective agent in the treatment of brain metastases.

The survival at 1 year, free-from-brain-progression "period", and mean survival time were significantly higher in patients treated with melatonin than in those who received the supportive care alone. Conversely, "steroid"-induced "metabolic" and infective complications were significantly more frequent in patients treated with supportive care alone than in those concomitantly treated with melatonin. Melatonin may improve the survival time and quality of life in patients with brain metastases due to solid "tumors".

"A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid "neoplasms"." Lissoni-P; Barni-S; Ardizzoia-A; Tancini-G; Conti-A; Maestroni-G. Cancer. 1994 Feb 1; 73(3): 699-701.

Circadian Patterns

Circadian Patterns

Bright light is known as a strong zeitgeber on human circadian rhythms and influences several "endocrine" and neuroendocrine functions. This study examines the influence of a 3-h bright light stimulus(2500 lux), given at different times during the day (morning or evening), on circadian patterns of cyclic adenosine monophosphate (cAMP), melatonin and cortisol.

Results showed a significant phase advance in the circadian rhythms of melatonin and cortisol when bright light was given in the morning but not when given in the evening. Rhythm in plasma cAMP basically was not affected by either light treatment.

Effects of bright light on circadian patterns of cyclic adenosine monophosphate, melatonin and cortisol in healthy subjects. Lemmer-B; Bruhl-T; Witte-K; Pflug-B; Kohler-W; Touitou-Y. Eur-J-Endocrinol. 1994 May; 130(5): 472-7

Brain Tumors

Brain Tumors

Brain tumours are of different "cell" types, the commonest being tumours of glia called gliomas.

Several epidemiological studies have linked electromagnetic fields (EMFs) to gliomas. Health effects of EMFs have been studied, both in humans and in experimental animals, mainly with negative findings.

Positive experimental evidence linking EMFs to tumours is the effect of EMFs on melatonin production by the "pineal gland". Removal of the pineal gland in rats increases the incidence of tumours.

Electromagnetic fields and brain tumours: a commentary. Hughes-JT. Teratog-Carcinog-Mutagen. 1994; 14(5): 213-7.

Breast Cancer & Melatonin

Breast Cancer

The growth-inhibitory actions of melatonin on human breast tumor cells were examined in the ER-positive, estrogen-responsive MCF-7 human breast tumor cell line.

Melatonin dramatically inhibits the growth of these breast tumor cells and down-regulates ER levels in these cells, suggesting that the modulation of ER may be an important mechanism by which melatonin inhibits breast cancer cell growth.

Melatonin's early regulation of these products suggests a more rapid mechanism than the down--regulation of ER is important.

Melatonin modulation of estrogen-regulated proteins, growth factors, and proto-oncogenes in human breast cancer.

Molis-TM; Spriggs-LL; Jupiter-Y; Hill-SM. J-Pineal-Res. 1995 Mar; 18(2): 93-103.


Melatonin has been shown to have direct oncostatic actions on estrogen-responsive, MCF-7 human breast cancer cells in culture.

The addition of melatonin (10(-9) M) to the cultures of MCF-7 cells with CM from E2 (10(-8) M)-treated cells significantly inhibited the growth stimulatory activity of CM, suggesting that melatonin inhibited cell proliferation by blocking the action of E2-induced autocrine growth stimulatory factors. Conditioned medium from melatonin-treated cells significantly inhibited cell proliferation, while an additional supply of melatonin to these cultures had an even greater inhibitory effect. Melatonin was also active in the complete absence of "serum" as long as cell growth was stimulated by "EGF", an E2-inducible growth factor. The inhibitory effect of melatonin increased as the dose of EGF increased. This non-antiestrogenic inhibitory effect of melatonin was reversed by E2, but not by EGF itself, suggesting that melatonin requires accessible estrogen receptor sites for its inhibitory activity on the growth stimulating action of EGF

Melatonin may inhibit the action and/or release of growth stimulatory factors as well as stimulate the release of growth inhibitory factors in culture.

Melatonin modulates growth factor activity in MCF-7 human breast cancer cells. Cos-S; Blask-DE. J-Pineal-Res. 1994 Aug; 17(1): 25-32.

Studied the different "in vitro" antiproliferative actions of melatonin on MCF-7 cells, depending on whether the cells are exposed to constant hormone concentrations or varying at 12 h intervals, thus simulating a diurnal rhythm.

Differences between pulsatile or continuous exposure to melatonin on MCF-7 human breast cancer cell proliferation. Cos-S; Sanchez-Barcelo-EJ. Cancer-Lett. 1994 Sep 30; 85(1): 105-9.

Melatonin has been shown to have a direct inhibitory effect on the proliferation of estrogen-responsive MCF-7 human breast cancer cells, involving an interaction with estradiol. The anti-proliferative effect of melatonin is reversed by the addition of estradiol to the culture.

Support the notion that melatonin exerts its antitumor effect through a cell-cycle-specific mechanism by delaying the entry of MCF-7 cells into mitosis. This allows the tumor cells to achieve greater differentiation.

Interaction between melatonin and estradiol on morphological and morphometric features of MCF-7 human breast cancer cells. Crespo-D; Fernandez-Viadero-C; Verduga-R; Ovejero-V; Cos-S. J-Pineal-Res. 1994 May; 16(4): 215-22.

Circadian Timing

Circadian Timing

To map the adult human brain with respect to receptor sites for the pineal hormone melatonin, we consistently observed specific binding in the cerebellum. Autoradiography and in vitro binding analysis with 125I-labeled melatonin were used to examine the location and the properties of these binding sites.

These cerebellum binding sites may be functional melatonin receptors.

The adult human cerebellum is a target of the neuroendocrine system involved in the circadian timing. Fauteck-JD; Lerchl-A; Bergmann-M; Moller-M; Fraschini-F; Wittkowski-W; Stankov-B. Neurosci-Lett. 1994 Sep 26; 179(1-2): 60-4.

Compulsive Disorder

Compulsive Disorder

Plasma melatonin, cortisol and "prolactin" ("PRL") levels were measured over a 24-h period in 13 drug-free patients with obsessive-compulsive disorder and in matched healthy subjects. The circadian profiles of melatonin and PRL were altered in patients; the circadian rhythm of cortisol was preserved, although at a higher level compared with normal controls. These changes were significantly related to the severity of the obsessive-compulsive symptoms.

Circadian rhythms of melatonin, cortisol and prolactin in patients with obsessive-compulsive disorder. Monteleone-P; Catapano-F; Del-Buono-G; Maj-M. Acta-Psychiatr-Scand. 1994 Jun; 89(6): 411-5.

Immune System (Melatonin)

Immune System

Pineal melatonin modulates the mammalian "immune system". In vivo studies showed that melatonin enhanced the natural and acquired "immunity" while "in vitro" studies demonstrated its inhibitory influence. The mechanism of melatonin action on the immune system remains unknown.

Immunosuppression with cortisol injection in young ducks decreased the density of the melatonin binding sites in the "thymus". Melatonin receptors may also lie within the lymphoid organs e.g. the "spleen".

Evidence for a direct action of melatonin on the immune system. Poon-AM; Liu-ZM; "Pang"-CS; Brown-GM; Pang-SF. Biol-Signals. 1994 Mar-Apr; 3(2): 107-17.

In Vitro Fertilization

In Vitro Fertilization

To characterize the relationship between the pineal gland hormone, melatonin, and gonadal "hormones".

Results indicate that endogenous estradiol, "progesterone", and "prolactin" do not affect the levels or circadian phase of melatonin secretion in humans.

The pattern of serum melatonin levels during ovarian stimulation for in vitro fertilization. Brzezinski-A; Cohen-M; Ever-Hadani-P; Mordel-N; Schenker-JG; Laufer-N. Int-J-Fertil-"Menopausal"-Stud. 1994 Mar-Apr; 39(2): 81-5.

Intraocular Cues

Intraocular Cues

The vertebrate retina rhythmically synthesizes melatonin, a hormone involved in the regulation of several by environmental lighting conditions. The rhythm of retinal melatonin production, with maximal synthesis at night in darkness, is driven by the photoperiodic environment to which animals are exposed, and is generated by an endogenous circadian clock(s). Dopamine is an established retinal neurotransmitter and paracrine factor, and mediates the action of light on the melatonin generating system in the retina. Special emphasis is given to the characterization of dopamine receptor types involved in the control of retinal melatonin formation.

The role of dopamine in the regulation of melatonin biosynthesis in vertebrate retina. Zawilska-JB. Acta-Neurobiol-Exp-Warsz. 1994; 54 Suppl: 47-56.

Intraocular Pressure (Melatonin)

Intraocular Pressure ("rabbit")

From the evidence available it is clear that melatonin and serotonin receptors exist in the iris/ciliary processes of the rabbit. These receptors may be involved in maintaining the intraocular pressure (IOP). Present information points to the possibility that drugs influencing specific serotonin and/or melatonin receptors may be used to influence IOP in man and thus have a therapeutic effect.

Serotonin and melatonin in the iris/ciliary processes and their involvement in intraocular pressure. Osborne-NN. Acta-Neurobiol-Exp-Warsz. 1994; 54 Suppl: 57-64.

Anorexia Nervosa & Melatonin

Anorexia nervosa

Cultured human peripheral blood mononuclear leukocytes [PBML] from patients with anorexia nervosa [AN] did not respond to light stimulation as PBML of normal controls [NC] did. During winter, visible light increased [3H]thymidine incorporation into DNA of NC-PBML stimulated with phytohemagglutinin [PHA]. This effect was enhanced by 10(-7) M melatonin. PHA-stimulated DNA synthesis of PBML from AN patients failed to respond to photic stimulation during winter, and their proliferative response to melatonin was significantly blunted.

In vitro photic stimulation of NC-PBML reduced melatonin while increasing both serotonin and 5-hydroxyindole 3 -acetic acid [HIAA] production in both basal and PHA-stimulated conditions.

In contrast AN-PBML, that in darkness enhanced the oxidative deamination of serotonin into HIAA more than NC-PBML, did not switch their indole metabolism in response to light. Light did not inhibit the binding of both melatonin and serotonin to AN-PBML as occurred in NC-PBML.

The present data suggests that AN-Pl3ML do not respond to light in vitro, because of a failure in the regulation of serotonin and melatonin metabolism.

Cultured peripheral blood mononuclear leukocytes from anorexia nervosa patients are refractory to visible light. Finocchiaro-LM; Polack-E; NahViod-VE; Glikin-GC. Life-Sci. 1995 Jun 30; 57(6): 559-69.

Bupropion

Bupropion

The mechanism of action of the novel antidepressant bupropion remains unclear after many years of study.

Clinical studies indicate that bupropion enhances noradrenergic functional activity as reflected by an increased excretion of the hydroxy metabolite of melatonin, while at the same time producing a presumably compensatory decrease in norepinephrine turnover. In one study, bupropion elevated plasma levels of the dopamine metabolite homovanillic acid in nonresponders, but not in responders.

Bupropion: a review of its mechanism of antidepressant activity. Ascher-JA; Cole-JO; Colin-JN; Feighner-JP; Ferris-RM; Fibiger-HC; Golden-RN; Martin-P; Potter-WZ; Richelson-E; et-al. J-Clin Psychiatry. 1995 Sep; 56(9): 395-401.

Cancer and Magnetic Fields (Overview)

Cancer and magnetic fields - Overview

Cell studies show that magnetic fields at some frequencies, amplitudes, and wave forms interact with
biological systems. Thus effects have been seen, e.g., on enzymes related to growth regulation, on calcium
balance in the cell, on gene expression, and on pineal metabolism and its excretion of the oncostatic
melatonin. Cellular and physiologic studies thus suggest effects that may be related to cell multiplication
and tumor promotion.

Magnetic fields and cancer: animal and cellular evidence--an overview. Holmberg-B. Environ-Health-Perspect. 1995 Mar; 103 SuppI 2: 63-7.

Circadian Pacemaker

Circadian pacemaker

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' (PRQ 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.

Melatonin marks circadian phase position and resets the endogenous circadian pacemaker in humans. Lewy-AJ; Sack-RL; Blood-ML; Bauer-VK; Cutler-NL; Thomas-KH. Ciba-Found-Symp. 1995; 183: 303-17; discussion 317-21.

Cirrhosis & Melatonin

Cirrhosis

To assess melatonin profile as a marker of output rhythm from the circadian clock and to study sleep diaries as reflections of subjective sleep quality in patients with liver cirrhosis.

Patients with cirrhosis had markedly elevated melatonin levels during daytime hours; in addition, the time of onset of melatonin increase and the time at which melatonin levels peaked were consistently and significantly delayed in these patients. Sleep diaries indicated more nocturnal awakenings and more frequent daytime naps in patients with cirrhosis.

Disruption of the diurnal rhythm of plasma melatonin in cirrhosis. Steindl-PE; Finn-13; Bendok-B; Rothke-S; Zee-PC; Blei-AT. Ann-Intem-Med. 1995 Aug 15; 123(4): 274-7.

Depression & Melatonin

Depression

Melatonin (MT) release from the pineal gland has been used as a marker in major depression. Norepinephrine acts at both alpha and beta adrenergic receptors on the pinealocyte membrane to mediate nocturnal MT release, but in humans the contribution of each receptor class is unclear.

Yohimbine ingestion produced significant rises in pulse rate and the urge to urinate compared to placebo. Clonidine reduced pulse rate, systolic and diastolic blood pressure and increased drowsiness and other measures of sedation following ingestion.

This highlights the limitations of oral neuroendocrine challenge studies.

Melatonin responses to clonidine and yohimbine challenges. Kennedy-SH; Gnam.-W; Ralevski-E;
Brown-GM. J-Psychiatry-Neurosci. 1995 Jul; 20(4): 297-304.

Artificial Light Exposure

Exposure to artificial light         

Humans have conserved mechanisms, like other animals, which detect changes in day length and make corresponding adjustments in the duration of nocturnal periods of secretion of melatonin and of other functions.

Modem men's use of artificial light suppresses responses to seasonal changes in the natural photoperiod that might otherwise occur at this latitude.

Suppression of men's responses to seasonal changes in day length by modem artificial lighting. Wehr-TA; Giesen-HA; Moul-DE; Tumer-EH; Schwartz-PJ. Arn-J-Physiol. 1995 Jul; 269(1 Pt 2): R173-8.

Immune Enhancing Property

Immune enhancing

The concomitant administration of the pineal neurohormone melatonin may amplify the antitumour efficacy of interleukin-2 (IL-2) in humans.

The percentage of survival at 1 year was significantly higher in patients treated with IL-2 and melatonin than in those receiving the supportive care alone (21/52 versus 5/48). Moreover, the performance status improved in 22/52 patients of the immunotherapy group and in only 8/48 patients treated with supportive care. Cancer neuroimmunotherapy with low-dose IL-2 and the pineal hormone melatonin may prolong survival time and improve the quality of life of patients with metastatic solid tumours who do not respond to conventional therapies.

A randomized study of neuroimmunotherapy with low-dose subcutaneous interleukin-2 plus melatonin compared to supportive care alone in patients with untreatable metastatic solid tumour. Lissoni-P; Bami-S; Fossati-V; Ardizzoia-A; Cazzaniga-M; Tancini-G; Frigerio-F. Support-Care-Cancer. 1995 May; 3(3): 194-7.


Demonstrated that the pineal neurohormone melatonin has immunoenhancing properties and can counteract the immunodepression that may follow acute stress, drug treatment, and viral diseases or aging.

T-derived cytokines constitute the main mediators of the immunological effect of melatonin. We have recently found a high affinity (Kd: 346 +/- 24 pM) binding site for 1251-melatonin on T-helper-type 2 lymphocytes in the bone marrow.

The ability of rescuing hernatopoiesis against the toxic action of cancer chemotherapeutic compounds and the presence of high-affinity IL4 receptors on human tumors provide a ftirther promising rationale for the clinical use of melatonin.

T-helper-2 lymphocytes as a peripheral target of melatonin. Maestroni-GJ. J-Pineal-Res. 1995 Mar; 18(2): 84-9.

Light Treatment

Light treatment

Examination of the influence of the light-dark cycle on circadian rhythmicity has been a fundamental aspect of chronobiology since its inception as a scientific discipline. Beginning with Bunning's hypothetical phase response curve in 1936, the impact of timed light exposure on circadian rhythms of literally hundreds of species has been described.

The view that the light-dark cycle was an important zeitgeber for the human circadian system, as well, seemed to be supported by early studies of blind and sighted subjects. Yet, by the early 1970s, based primarily on a series of studies conducted at E'rling-Andechs, Germany, the notion became widely accepted that the light-dark cycle had only a weak influence on the human circadian system and that social cues played a more important role in entrainment.

In 1980, investigators at the National Institute of Mental Health reported that bright light could suppress melatonin production in humans, thereby demonstrating unequivocally the powerful effects of light on the human central nervous system. This finding led directly to the use of timed bright light exposure as a tool for the study and treatment of human circadian rhythms disorders.

Advanced and delayed sleep phase disorders, and the hypersomnia that can accompany winter depression, have been treated successfully by appropriately timed artificial bright light exposure.

Supplemental light exposure in fall and winter can reduce the hypersomnia of winter depression, although the therapeutic effect may be less dependent on timing.

Exposure to bright light may be associated with enhanced subjective alertness, and there is limited evidence of objective changes (EEG, skin conductance levels) that are consistent with true physiological arousal. Such activation appears to be quite transient, and there is little evidence to suggest that bright light-induced activation interferes with subsequent sleep onset. Some depressed patients, however, have experienced insomnia and hypomanic activation following bright-light exposure.

The rationale for the treatment of sleep disorders by scheduled exposure to bright light in seasonal affective disorder, jet lag, shift work, delayed sleep phase syndrome, and the elderly is, in part, based on a conceptual framework developed by nonclinical circadian rhythm researchers working with humans and other species.

In healthy young subjects, light exposure schedules that do not curtail sleep but induce moderate shifts of endogenous circadian phase have been shown to influence the timing of sleep and wakefulness without markedly affecting sleep structure.

Light treatment for sleep disorders: consensus report. 1. Chronology of seminal studies in humans. Campbell-SS; Eastman-Cl; Terman-M; Lewy-AJ; Boulos-Z; Dijk-DJ. J-Biol-Rhythms. 1995 Jun; 10(2): 105-9.

Light treatment for sleep disorders: consensus report. 11. Basic properties of circadian physiology and sleep regulation. Dijk-DJ; Boulos-Z; Eastman-Cl; Lewy-AJ; Campbell-SS; Terman-M. J-Biol-Rhythms. 1995 Jun; 10(2): 113-25.

Light treatment for sleep disorders: consensus report. III. Alerting and activating effects. Campbell-SS; Dijk-DJ; Boulos-Z; Eastman-Cl; Lewy-AJ; Terman-M. J-Biol-Rhythms. 1995 Jun; 10(2): 129-32.

Light treatment for sleep disorders: consensus report. IV. Sleep phase and duration disturbances. Terman-M; Lewy-AJ; Dijk-DJ; Boulos-Z; Eastman-CI; Campbell-SS. J-Biol-Rhythms. 1995 Jun; 10(2): 135-47.

Lhermitte's Sign in Multiple Sclerosis

Lhermitte's sign in multiple sclerosis

Lhermitte's sign, the occurrence of an electrical sensation passing down the back to the legs on flexion of the neck is a common and characteristic feature of multiple sclerosis (MS) which is related to spinal cord lesions affecting the posterior columns and cervical nerve roots. The Lhermitte's sign, which has been reported to occur at some time in up to 25% of MS patients, is seldom painful but is often a cause of distress to the patient and usually a marker of increased disease activity. Treatment with extracranial picotesla range pulsed electromagnetic fields (EMFs) has been found efficacious in the management of various MS symptoms including pain syndromes.

As the cause of the Lhermitte's sign is thought to result from the spread of ectopic excitation in demyelinated plaques in the cervical and thoracic regions of the spinal cord, it is hypothesized that the effects of EMFs are related to the reduction of axonal excitability via a mechanism involving changes in ionic membrane permeability.

Resolution of Lhermitte's sign in multiple sclerosis by treatment with weak electromagnetic fields. Sandyk-R; Dann-LC. Int-J-Neurosci. 1995 Apr; 81(3-4): 215-24.

Menarche

Menarche

The present study investigated the impact of high estrogen doses on melatonin blood concentrations in healthy young girls.

The decrease of melatonin blood concentrations during puberty is not caused by increasing concentrations of estrogens but must be due to some other process.

No effect of ethinylestradiol treatment on melatonin secretion in healthy pubertal girls. Commentz-J; Willig-R. SO: Exp-Clin-Endocrinol-Diabetes. 1995; 103(l): 52-7.

Shiftworkers

Shiftworkers

The effectiveness of a program of scheduled bright light and dark to alter the circadian pacemakers of rotating shiftworkers were evaluated.

The alteration in urinary melatonin levels is the first objective demonstration that the bright light technology can alter the circadian pacemakers of workers in an industrial setting.

An evaluation of scheduled bright light and darkness on rotating shiftworkers: trial and limitations. Budnick-LD; Lerman-SE; Nicolich-MJ. Am-J-Ind-Med. 1995 Jun; 27(6): 771-82.

Sleep (Elderly)

Sleep (elderly)

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.

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.

Improvement of sleep quality in elderly people by controlled-release melatonin. Garfinkel-D; Laudon-M; Nof-D; Zisapel-N. Lancet. 1995 Aug 26; 346(8974): 541-4.

Thrombocytopenia

Thrombocytopenia

The production of cytokines involved in platelet generation, including interleukin (IL)-3, IL-6 and IL- 11, is stimulated by IL-2.

Previous studies showed that IL-2-induced macrophage activation may be counteracted by the pineal hormone melatonin (MLT).

A normalization of the platelet number was achieved in 14/20 (70%) patients. The therapy with low--dose IL-2 plus MLT, in addition to its previously described antitumor activity, may also be effective in the treatment of cancer-related thrombocytopenia.

A biological study on the efficacy of low-dose subcutaneous interleukin-2 plus melatonin in the treatment of cancer-related thrombocytopenia. Lissoni-P; Bami-S; Brivio-F; Rossini-F; Fumagalli-L; Ardizzoia-A; Tancini-G. Oncology. 1995 Sep-Oct; 52(5): 360-2.

Thrombocytopenia is a frequent haematologic complication of IL-2 immunotherapy of cancer. Preliminary results suggest a role of melatonin in the regulation of platelet production, so a study was started to evaluate the influence of the pineal hormone on IL-2-induced thrombocytopenia. Of 25 lung cancer patients, 10 were treated with melatonin alone, 7 received IL-2 alone and 8 patients were concomitantly treated with IL-2 and melatonin. Thrombocytopenia occurred in 3/7 patients treated with IL-2 alone, and in none of those treated with IL-2 plus melatonin; this difference was statistically significant. Platelet number increased during IL-2 plus melatonin, even though not significantly; on the contrary, platelet number decreased during IL-2 alone. Platelet number observed in patients treated with IL-2 plus melatonin was significantly higher than in those who received IL-2 alone. Finally, melatonin alone did not substantially influence platelet number.

These results show that melatonin may abolish IL-2-induced thrombocytopenia. This might be due to an inhibitory effect of melatonin on macrophage-mediated platelet destruction, with a following increase in platelet number due to an enhanced IL-3 production in response to IL-2.

Prevention of interleukin-2-induced thrombocytopenia during the immunotherapy of cancer by a concomitant administration of the pineal hormone melatonin. Bregani-ER; Lissoni-P; Rossini-F; Barni-S; Tancini-G; Brivio-F; Conti-A; Maestroni-GJ. Recenti-Prog-Med. 1995 Jun; 86(6): 231-3.

Seasonal Changes

Seasonal Changes

Infants born in June produce more melatonin than do infants born during the winter, according to this study conducted on a large sample of healthy full-term infants of 8 weeks and 16 weeks old. This increased melatonin production appears to fall off between 8 and 16 weeks of age, as melatonin levels return to normal by 16 weeks of age in both groups. Researchers obtained melatonin levels by nocturnally measuring amounts of a melatonin metabolite (6SMT) from the urine in diapers of participating infants.

Sivan Y, Laudon M, Tauman R, Zisapel N: Melatonin production in healthy infants: evidence for seasonal variations, Pediatr Res 2001 Jan;49(1):63-8

Antiepileptic Effect

Antiepileptic effect

Melatonin may reduce seizure activity in children with epilepsy, according to this study. Six children with severe seizures, ranging in age from 2 to 15 years, were given melatonin in addition to their regular antiepileptic drug regimen for 3 months. The children consumed 3 mg oral melatonin 30 minutes before bedtime for the duration of the study. The parents of the study subjects kept a log of seizure activity before and during the treatment. Five of the children's parents reported significantly less seizure activity during treatment (especially at night). Sleep studies on three of the patients also showed an increase in sleep efficiency from 84.2% to 89.7% during treatment.
        
Peled N, Shorer Z, Peled E, Pillar G: Melatonin effect on seizures in children with severe neurologic deficit disorders, Epilepsia 2001 Sep;42(9):1208-10

Age-related Insomnia

Age-related insomnia

Melatonin may be a useful treatment for age-related insomnia, according to this randomized, double-blind, placebo-controlled study. Varying doses of melatonin (0.1, 0.3, and 3.0 mg) were given to fifteen subjects over the age of fifty with confirmed sleep inefficiency and to fifteen healthy controls for one-week periods. The subjects received melatonin thirty minutes before bedtime and their sleep was monitored by polysomnography the last three nights of each treatment period. The 0.3 mg dose was found to elevate nocturnal melatonin plasma levels in those with age-related insomnia and therefore improved their sleep efficiency. The lowest and highest doses induced hypothermia and prolonged the heightened concentration of melatonin plasma levels. The control subjects were not affected by any of the melatonin treatments.
        
Zhdanova IV, Wurtman RJ, Regan MM, Taylor JA, Shi JP, Leclair OU: Melatonin treatment for age-related insomnia, J Clin Endocrinol Metab 2001 Oct;86(10):4727-30