Melatonin is more than a sleeping pill.

Melatonin (N-acetyl-5-methoxytryptamine [7]) is a lipophilic hormone, mainly produced and secreted at night by the
pineal gland. Melatonin synthesis is under the control of postganglionic sympathetic fibers that innervates the pineal
gland. Melatonin acts via high affinity G protein-coupled membrane receptors. To date, three different receptor subtypes
have been identified in mammals: MT1 (Mel 1a) and MT2 (Mel 1b) and a putative binding site called MT3. [1]

Main and best-known effect of melatonin is restoring the natural cycle of organism functions. It is safe and non-addictive
sleep-inducing drug, which can eliminate disruptions in our circadian rhythm, in such situations as shift working,
changing of time zones (during intercontinental air travelling) or insomnia. It improves mood and quality of sleep. [10]  
However, researhers also have shown that melatonin has chronbiotic activities to resynchronize sleep and circadian
rhythms disturbances and it is also involved in the regulation of seasonal reproduction, body weight and energy balance.

In both diurnal and nocturnal vertebrates, its main product, the hormone melatonin, is synthesized and released in
rhythmic fashion, during the dark portion of the day-night cycle. Melatonin production is controlled by an endogenous
circadian timing system and is also suppressed by light. In lower vertebrates, the pineal gland is photosensitive, and is
the site of a self-sustaining circadian clock. In mammals, including humans, the gland has lost direct photosensitivity, but
responds to light via a multisynaptic pathway that includes a subset of retinal ganglion cells containing the newly
discovered photopigment, melanopsin. The mammalian pineal also shows circadian oscillations, but these damp out
within a few days in the absence of input from the primary circadian pacemaker in the suprachiasmatic nuclei (SCN). The
duration of the nocturnal melatonin secretory episode increases with nighttime duration, thereby providing an internal
calendar that regulates seasonal cycles in reproduction and other functions in photoperiodic species. Although humans
are not considered photoperiodic, the occurrence of seasonal affective disorder (SAD) and its successful treatment with
light suggest that they have retained some photoperiodic responsiveness. [5]

Drs Macchi MM and Bruce JN from Columbia University have suggested the multiple functions of melatonin. In humans,
exogenous melatonin has a soporific effect, but only when administered during the day or early evening, when
endogenous levels are low. Some types of primary insomnia have been attributed to diminished melatonin production,
particularly in the elderly, but evidence of a causal link is still inconclusive. [5]

Melatonin administration also has mild hypothermic and hypotensive effects. A role for the pineal in human reproduction
was initially hypothesized on the basis of clinical observations on the effects of pineal tumors on sexual development.
More recent data showing an association between endogenous melatonin levels and the onset of puberty, as well as
observations of elevated melatonin levels in both men and women with hypogonadism and/or infertility are consistent
with such a hypothesis. [5]

A rapidly expanding literature attests to the involvement of melatonin in immune function, with high levels promoting and
low levels suppressing a number of immune system parameters. The detection of melatonin receptors in various
lymphoid organs and in lymphocytes suggests multiple mechanisms of action. [5]

Melatonin is a powerful antioxidant, and has oncostatic properties via its effects on reproductive hormones. Finally, there
are reports of abnormal daily melatonin profiles in a number of psychiatric and neurological disorders, but it is still to
early to draw any conclusions. [5, 21]

Melatonin Deficiencies
The production of melatonin probably starts to slow at 40 year of ages. Researchers from China found that a step-wise
decrease in the circadian rhythms of saliva melatonin occurred early in life, around 40 yr of ages, in a study of healthy
human subjects. The middle-aged subjects had only 60% of the amplitude of the young subjects. In addition, the
middle-aged subjects showed the longest peak levels duration and the lowest daytime melatonin levels. [2]

Melatonin Benefits
Population worldwide is aging and most of the baby boomers are actively seeking for various ways including using health
supplements to improve their quality of life. One of the popular issues for these baby boomers is insufficient sleep, which
is possibly related to reduced production of melatonin at older ages.

Insomina ...Sleep
Melatonin may facilitate sleep........Administration of melatonin is able: (i) to induce sleep when the homeostatic drive to
sleep is insufficient; (ii) to inhibit the drive for wakefulness emanating from the circadian pacemaker; and (iii) induce
phase shifts in the circadian clock such that the circadian phase of increased sleep propensity occurs at a new, desired
time. Therefore, exogenous melatonin can act as soporific agent, a chronohypnotic, and/or a chronobiotic. Successful
use of melatonin's chronobiotic properties has been reported in other sleep disorders associated with abnormal timing of
the circadian system: jetlag, shiftwork, delayed sleep phase syndrome, some sleep problems of the elderly. [27-29]

According to a paper issued by HHS' Agency for Healthcare Research and Quality, sleep disorders are grouped into two
catalogs. Disorders due to sleep schedule alterations can stem from flying across time zones or working night shifts.
Primary sleep disorders, which include insomnia, can be caused by factors such as stress or drinking too much
caffeinated coffee. Secondary sleep disorders can also include insomnia, but patients in this category also have
underlying mental disorders, such as psychoses or mood and anxiety disorders, neurological conditions such as
dementia and Parkinson's disease, or chronic pulmonary disease. Melatonin supplements do not appear to have much
health benefits on people with secondary sleep disorder, but it does appear to increase sleep efficiency modestly. Sleep
efficiency refers to the percent of time a person is asleep after going to bed. [11] Furthermore, Turk J from St. George's
Hospital Medical School, UK, points out that intractable sleep disturbance is associated to behavioral problems of
children. Melatonin, as a sleep inducer, may also be beneficial and safe adjunct to psychological and social approaches
for severe sleep disturbance in this client group. [31] In an attempt to take advantages of the beneficial opportunities
available through the brain's melatonin system, researchers have developed several melatonin agonists with improved
properties in comparison to melatonin. Some of these agents are now in clinical trials (or even in markets) for treatment
of insomnia or circadian rhythm sleep disorders. [30]

Melatonin is a potent antioxidant. Melatonin scavenges hydroxyl, carbonate and various organic radicals, peroxynitrite
and other reactive nitrogen species. Melatonyl radicals formed by scavenging combine with and, thereby, detoxify
superoxide anions in processes terminating the radical reaction chains. Melatonin also enhances the antioxidant
potential of the cell by stimulating the synthesis of antioxidant enzymes like superoxide dismutase, glutathione
peroxidase and glutathione reductase, and by augmenting glutathione levels. Thus, it provides various health benefits
on various conditions [4, 17] Melatonin plays a beneficial role in the biologic regulation of circadian rhythms, sleep,
mood, reproduction, tumor growth and aging. It may also modulate the activity of various receptors in cancer cells. [18]

Drug Side Effects
Melatonin may reduce side effects of some drugs and metal poisoning. Melatonin has been shown to reduce the toxicity
and increase the efficacy of a large number of drugs which side effects are well documented. Researchers from
University of Texas Health Science Center, San Antonio, summarize the beneficial effects of melatonin when combined
with the following drugs: doxorubicin, cisplatin, epirubicin, cytarabine, bleomycin, gentamicin, ciclosporin, indometacin,
acetylsalicylic acid, ranitidine, omeprazole, isoniazid, iron and erythropoietin, phenobarbital, carbamazepine, haloperidol,
caposide-50, morphine, cyclophosphamide and L-cysteine. The majority of these studies were conducted using animals,
a number of the investigations also used man. [7]

Melatonin prevents poisoning induced by elements like chromium (III) and (VI), iron and copper, through levelling toxic
actions of these ions on organism. The beneficial role of melatonin in these processes relies mainly on scavenging of
arisen free radicals, detoxification of hydrogen peroxide and combining excess of toxic ions into compounds harmless for
organism. [26]

Stroke Melatonin may benefit people suffered from strokes.. Macleod MR and co-workers from National Stroke
Research Institute, Melbourne, Australia, reviewed 14 studies on how melatonin benefited 432 animal models suffered
from focal cerebral ischaemia. They concluded an improvement in outcome with melatonin treatment. [24]

When given at the time of ischemia or reperfusion onset, melatonin reduces neurophysiological deficits, infarct volume,
the degree of neural edema, lipid peroxidation, protein carbonyls, DNA damage, neuron and glial loss, and death of the
animals. Reiter RJ and co-workers from University of Texas Health Science Center suggested that melatonin's protective
actions against these adverse changes are related to its direct free radical scavenging and indirect antioxidant activities,
possibly from its ability to limit free radical generation at the mitochondrial level and because of yet-undefined functions.

Heart Protection
Melatonin may have benefits of heart protection.... Sewerynek E from Medical University of Lodz, Poland suggested that
melatonin may have benefits of heart protection. People with hypertension have lower melatonin levels than those with
normal blood pressure. Researchers reported that melatonin, even in a dose 1 mg, reduced blood pressure and
decreased catecholamine level after 90 min in human subjects. There are evidences of the presence of vascular
melatoninergic receptors/binding sites. Melatonin may reduce blood pressure via the following mechanisms: 1) by a
direct effect on the hypothalamus; 2) as an antioxidant which lowers blood pressure; 3) by decreasing the level of
catecholamines, or 4) by relaxing the smooth muscle in the aorta wall. [9]

People with high LDL-cholesterol levels are also found to have low levels of melatonin. Melatonin was shown to suppress
the formation of cholesterol by 38% and reduce LDL accumulation by 42%. Even a 10-15% reduction in blood
cholesterol concentration resulted in a 20 to 30% decrease in the risk of coronary heart disease, in a study. [9]

Melatonin may have benefits on diabetes....Nishida S from Nihon University School of Medicine, Japan suggested the
beneficial use of melatonin for the treatment of cholesterol/lipid and carbohydrate disorders. Melatonin reduces serum
lipid levels and helps to prevent oxidative stress in diabetic subjects. Long-term melatonin administration to diabetic rats
reduced their hyperlipidemia and hyperinsulinemia, and restored their altered ratios of polyunsaturated fatty acid in
serum and tissues. In a study, melatonin enhanced insulin-receptor kinase and IRS-1 phosphorylation, suggesting the
potential existence of signaling pathway cross-talk between melatonin and insulin. Because TNF-alpha has been shown
to impair insulin action by suppressing insulin receptor-tyrosine kinase activity and its IRS-1 tyrosine phosphorylation in
peripheral tissues such as skeletal muscle cells, it was speculated that melatonin might counteract TNF-alpha-associated
insulin resistance in type 2 diabetes. [23]

Melatonin may benefit people at risk of certain cancers.....Some researchers believe that melatonin may have a
benefit-role in preventing and treating some types of cancers, especially, the hormone-dependent mammary cancer.
[12-14] In various experimental studies, Physiological and pharmacological blood concentrations of melatonin inhibit
tumorigenesis. Studies indicate that melatonin's anticancer effects are exerted via inhibition of cell proliferation and a
stimulation of differentiation and apoptosis. In which, melatonin suppresses cAMP formation and inhibits tumor uptake of
linoleic acid and its metabolism to 13-hydroxyoctadecadienoic acid via a melatonin receptor-mediated mechanism in both
tissue-isolated rat hepatoma 7288 CTC and human breast cancer xenografts. [13]

Researchers found that Nocturnal dietary supplementation with melatonin, at levels contained in a melatonin-rich diet,
inhibits rat hepatoma growth. [13] Thus, one may suggest that light at night may suppress melatonin production and
pose a risk for breast cancer development. However, more studies are needed to confirm this idea.     

Melatonin may benefit people suffered from infertility...Melatonin may benefit male and female infertility in couples with
abnormal melatonin metabolism. Seasonal change may lead to circadian disturbances in reproduction. Melatonin may
also be considered essential to both spermatogenesis and folliculogenesis. Melatonin may exert an inhibitory effect on
the GnRH pulse generator to decrease gonadotropin secretion. Consequently, it may have effects on the pubertal onset
and timing of ovulation. Studies are needed to understand how melatonin used in infertility. [15]

Neural Issues
Melatonin may have benefits of neuro-protection...The etiology of the neurodegenerative diseases which are
characterized by the progressive and irreversible destruction of specific neuronal populations is complex and

Mayo JC and co-workers from University of Oviedo, Spain suggested that melatonin has potent endogenous antioxidant
actions, which may be beneficial to neurodegenerative disorders. It is because neurodegenerative disorders are mainly
caused by oxidative damage, and melatonin has been tested successfully in both in vivo and in vitro models of
Parkinson's disease. Parkinson's disease (PD) is the second most common neurodegenerative disorder after
Alzheimer's disease. It is characterized by a progressive loss of dopamine in the substantia nigra and striatum. However,
over 70% of dopaminergic neuronal death occurs before the first symptoms appear, which makes either early diagnosis
or effective treatments extremely difficult. Only symptomatic therapies have been used, including levodopa (l-dopa), to
restore dopamine content; however, the use of l-dopa leads to some long-term pro-oxidant damage. [16]

Melatonin has been shown to have benefits of neuroprotection in several degenerative disorders, because of its
antioxidant properties. [18] Therapeutic trials with melatonin have been effective in slowing the progression of
Alzheimer's disease. The decline in melatonin production in aged individuals has been suggested as one of the primary
contributing factors for the development of age-associated neurodegenerative diseases, e.g., Alzheimer's disease. [17]

Bone Issues
Melatonin has benefits on bone healthBone formation proceeds through a remodeling process that runs continuously,
involving the resorption of old bone by osteoclasts, and the subsequent formation of new bone by osteoblasts. This is
controlled by growth factors and cytokines produced in bone marrow microenvironment and by the action of systemic
hormones, like parathyroid hormone, estradiol or growth hormone (GH). Cardinali DP and co-workers from Universidad
de Buenos Aires, Argentina suggest that melatonin can be a candidate for hormonal modulation of osteoblast and
osteoclast formation. [19]

Melatonin through its free radical scavenger and antioxidant properties may impair osteoclast activity and bone
resorption. At least in one study melatonin was both inhibitory to osteoclastic and osteoblastic cells. Additionally,
melatonin may impair development of osteopenia associated with senescence by improving non-rapid eye movement
sleep and restoring GH secretion. [19] Nevertheless, more studies are needed to confirm its beneficial role in bone

Melatonin may help headache, a study suggests.Melatonin has a role in the biological regulation of circadian rhythms,
sleep, mood, and ageing. Altered melatonin levels in cluster headache and migraine have been documented. [20] Peres
MF from Albert Einstein Hospital, Brazil, suggests that Melatonin mechanisms are related to headache pathophysiology
in many ways, including its anti-inflammatory effect, toxic free radical scavenging, reduction of proinflammatory cytokine
up-regulation, nitric oxide synthase activity and dopamine release inhibition, membrane stabilization, GABA and opioid
analgesia potentiation, glutamate neurotoxicity protection, neurovascular regulation, serotonin modulation, and the
similarity of chemical structure to that of indomethacin. Treatment of headache disorders with melatonin and other
chronobiotic agents is promising. A double-blind, placebo-controlled trial shows that melatonin is effective in cluster
headache prevention. [20]

Pancreatic and Gastric Ulcers
Melatonin may be a beneficial agent on the pancreatic damage and gastric ulcers. Melatonin is found to be discharged
into the gut lumen and may stimulate pancreatic enzyme secretion, via melatonin-induced release of cholecystokinin.
Melatonin exhibits similar highly protective actions as its precursor L-tryptophan against the damage of both the stomach
and the pancreas and promotes the healing of chronic gastric ulcerations via stimulation of the microcirculation and
cooperation with prostaglandins, nitric oxide, and/or sensory nerves and with their neuropeptides. The beneficial effects
of melatonin results in gastro- and pancreato-protection, prevents various forms of gastritis and pancreatitis through the
activation of specific MT2-receptors and scavenges reactive oxygen species (ROS). Melatonin also counteracts the
increase in the ROS-induced lipid peroxidation and preserves, at least in part, the activity of key anti-oxidizing enzymes
such as superoxide dismutase. [33]

Among various causes of gastric ulceration, lesions caused by stress, alcohol consumption, Helicobacter pylori infection
and use of nonsteroidal antiinflammatory drugs have been shown to be mediated largely through the generation of
reactive oxygen species especially hydroxyl radical (*OH). A number of excellent drugs have been proved useful in
controlling hyperacidity and ulceration but their long term uses are not devoid of disturbing side-effects. Hence,
melatonin may be a beneficial agent to cure gastric hyperacidity and ulcer. [32]

Skin Conditions
Melatonin may have benefits of skin protection Slominski A et al from University of Tennessee, Memphis proposed that
melatonin (synthesized locally or delivered topically) could counteract or buffer external (environmental) or internal
stresses to preserve the biological integrity of the organ and to maintain its home-ostasis. They also suggest that
melatonin could have an beneficial role in protection against solar radiation or even in the management of skin diseases.
Melatonin has been experimentally implicated in skin functions such as hair growth cycling, fur pigmentation, and
melanoma control, and melatonin receptors are expressed in several skin cells including normal and malignant
keratinocytes, melanocytes, and fibroblasts. Melatonin is also able to suppress ultraviolet (UV)-induced damage to skin
cells and shows strong antioxidant activity in UV exposed cells. [22]

Melatonin may have benefits of immuno-stimulatory activities. Melatonin has been shown to prevent paralysis and death
in mice infected with the encephalomyocarditis virus and to decrease viremia. Melatonin also delays the onset of the
disease produced by Semliki Forest virus inoculation and reduces the mortality of West Nile virus-infected mice stressed
by either isolation or dexamethasone injection. Bonilla E and co-workers from Universidad del Zulia, Maracaibo,
Venezuela consider that these observations are related to an increase in the host resistance to the virus via a peripheral
immuno-stimulating activity

Studies have shown that melatonin protects some strains of mink against Aleutian disease, and prevents the reduction of
B- and T-cells as well as Th1 cytokine secretion in mice infected with leukemia retrovirus. In VEE-infected mice,
melatonin postpones the onset of the disease and death for several days and reduces the mortality rate. [34]

Melatonin supplements, which people often take for problems sleeping, appear to be safe when used over a period of
days or weeks, at recommended doses and in conventional formulations*. However, the safety and side effects of
melatonin supplements used over months or even years is unclear. [11]

Atkinson G et al from Loughborough University, UK, points out that the administration of melatonin leads to hypnotic and
hypothermic responses in humans, which can be linked to immediate reductions in short-term mental and physical
performance. Depending on the dose of melatonin, these effects may still be apparent 3-5 hours after administration for
some types of cognitive performance, but effects on physical performance seem more short-lived. [25]

Pregnant women should avoid melatonin, since its teratogenic effect is not known. Patients suffering from non-hormone
dependent tumors, like leukemia, should avoid melanin, since tumor growth was promoted in animal experiments. [3]
*Safety and side effects needed to be evaluated

Researchers worry that melatonin may play a role in rheumatoid arthritis. It is because melatonin may stimulate the
immune system via activating the immature and mature immuno-competent cells, and consequently promote autoimmune
diseases such as rheumatoid arthritis. Clinical studies have shown that subjects suffered from rheumatoid arthritis have
an elevated serum level of melatonin. [6] In one of the early studies, Italian researchers from University of Genova
evaluated melatonin serum levels in 10 rheumatoid arthritis patients and six healthy subjects. They found that melatonin
level was higher in the rheumatoid arthritis patients than in controls. Melatonin progressively increased from 8 p.m. to the
first hours of the morning in both groups. However, melatonin serum level reached the peak at least two hours before in
rheumatoid arthritis patients than in controls. And the melatonin concentration became steadily high lasting 2-3 hours in
the rheumatoid arthritis patients. This ?melatonin concentration plateau? did not happen in the healthy controls. Since
several symptoms of rheumatoid arthritis, such as morning gelling, stiffness, and swelling happen in the early morning,
some researchers believe that rheumatoid arthritis (synovitis) may be related to melatonin's neuro-immunomodulatory
effects. [8] However, more studies are needed to show if there is a cause-effect relationship.
Melatonin has been proved to have multiple benefits, however, its long-term safety or side effects are unclear. Since
prolonged high melatonin serum level is associated to rheumatoid arthritis, selection of a proper dosage form (ie
melatonin release) becomes very important. Discuss with your doctor before taking any supplement.
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melatonin reviews
melatonin side effects and benefits
report adverse side effects to FDA, its website is, or report the adverse side effects to the manufacturer, you should be able to find
the contact information on the label.

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