Melatonin's antioxidant activity may reduce damage caused by some types of Parkinson's disease, may play a role in preventing cardiac arrhythmia and may increase longevity. Melatonin has been studied for the treatment of cancer, immune disorders, cardiovascular diseases, depression, seasonal affective disorder(SAD), circadian rhythm sleep disorders and sexual dysfunction...
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Melatonin is a natural compound produced by the Pineal gland and by other tissue.
Melatonin is involved in numerous aspects of biological and physiological regulation, such as the body's internal clock.
Melatonin Molecule and Cancer see below
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Research shows that Melatonin may improve brain function and may also be one of the most powerful anti-aging hormones yet discovered.
Researchers are also studying its effect on preventing or helping Alzheimer's and Parkinson's disease.
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Melatonin exists naturally in the human body and is involved in setting mammallian circadian rhythms.
By setting our internal clock supplemental Melatonin may benefit those with disruptive sleep for a variety of reasons.
Additionally frequent travelers may find melatonin useful in helping to normalize sleep schedules.
By promoting a more restful sleep fatigue may also go to the wayside.
As a naturally-occuring hormone Melatonin is involved in setting our bodys natural physiologic cycles.
Melatonin Antioxidant and Free Radical
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Melatonin was first identified forty years ago and is now recognized as one of life's most beneficial molecules.
Humans secrete it naturally from the pineal gland (a pea-sized structure located at the center of the brain), in response to light hitting the eyes.
Physiologists recognize Melatonin as the hormone that keeps us in sync with the rhythms of the day as well as the season.
Through its effect on other hormones, it helps determine when people sleep, animals breed, birds migrate and even when dogs shed their coats.
Melatonin is rapidly gaining recognition as one of the most effective anti-oxidants available.
Interpreting the true greatness of this dietary supplement may take years, the most common way of taking Melatonin is simply before going to sleep - as many people who take it will tell you they get exactly what they expect!
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Melatonin supplements have been clinically shown to be an effective treatment for jet lag, sleep disorders and moodiness.
Melatonin appears to be involved in the natural biorhythm of the body, that is known as the ''circadian'' rhythm.
This refers to the internally built clock that signals the secretion of various nutrients at different times to regulate all body functions.
Melatonin plays a key role as the biological timekeeper.
It also seems to function in controlling periods of sleepiness and wakefulness.
Background: Melatonin is naturally secreted by the pineal gland located at the base of the brain.
The body's natural production of Melatonin produces peak levels in the early morning (between 2:00 and 4:00 am) and its lowest levels in the afternoon.
Melatonin has also been shown to inhibit several types of cell abnormalities.
It seems to not only inhibit the start, but also the metastasis of these cell irregularities.
The production of Melatonin decreases as we get older.
A decrease in Melatonin levels can lead to a compromised immune system and an increase in cell disorders, heart dysfunction and high blood pressure.
Many medical researchers believe a Melatonin supplementation may help with these conditions.
Reason to Use: Sleep Disorders. Jet Lag. Depression. Superior Anti-Oxidant. Poor Mood.
Duration of Therapy: When used for jet lag, apply 24 hours before trip and then daily for 5 days in total.
Special Advantages: Melatonin also plays a unique roll as a powerful anti-oxidant.
Unlike other anti-oxidants, the extremely small size of the Melatonin molecule allows it to penetrate the cell membrane.
Researchers have discovered that the pineal gland is the body's ''time clock'' and regulates the bodys rate of aging.
Melatonin given to 18 month-old mice (the human equivalent of 60 years) has been shown to dramatically reverse aging, extending their life an additional 50%.
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Melatonin can be taken as a dietary supplement to support normal sleep.
Melatonin is a natural biorhythm regulating metabolite that is secreted by the brain’s pineal gland and has beneficial effects on sleep and jet lag.
Melatonin Pineal Gland
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Melatonin is a metabolic hormone made in the pineal gland, retina, and intestines.
Melatonin is released into the blood stream by the pineal gland (which resides in the brain) to set your body’s biological clock and initiate sleep.
Darkness stimulates the pineal gland and causes it to produce more melatonin.
Daylight stops your body’s production of melatonin. Melatonin helps to promote healthy sleep patterns.
Melatonin also protects cells from free radical damage, and directs the release of growth and sex hormones.
Melatonin and Weight Loss see below
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Melatonin supports healthy sleep patterns.
The body naturally releases melatonin in response to changes in light, with melatonin levels rising at night.
It is in this way that melatonin helps promote sleep.
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Melatonin (also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring compound found in animals, plants, and microbes. In animals, circulating levels of the hormone melatonin vary in a daily cycle, thereby allowing the entrainment of the circadian rhythms of several biological functions.
Many biological effects of melatonin are produced through activation of melatonin receptors, while others are due to its role as a pervasive and powerful antioxidant, with a particular role in the protection of nuclear and mitochondrial DNA.
In mammals, melatonin is secreted into the blood by the pineal gland in the brain. Known as the "hormone of darkness", it is secreted in darkness in both day-active (diurnal) and night-active (nocturnal) animals.
It may also be produced by a variety of peripheral cells such as bone marrow cells, lymphocytes and epithelial cells. Usually, the melatonin concentration in these cells is much higher than that found in the blood but it does not seem to be regulated by the photoperiod.
Melatonin-rich plant feed, such as rice, ingested by chicks has been shown to reach and bind to melatonin receptors in their brains. No food has been found to elevate plasma melatonin levels in humans.
Products containing melatonin have been available over-the-counter as a dietary supplement in the United States since the mid-1990s. In many other countries, the over-the-counter sale of this neurohormone is not permitted or requires a prescription, and the U.S. Postal Service lists unapproved melatonin preparations among items prohibited by Germany. In 2008, a prolonged release form of melatonin (Circadin®) by Lundbeck has been approved in European countries and Israel as a prescription drug for the treatment of insomnia.
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In humans - Circadian rhythm
In humans, melatonin is produced by the pineal gland, a gland about the size of a pea, located in the center of the brain but outside the blood-brain barrier. The melatonin signal forms part of the system that regulates the sleep-wake cycle by chemically causing drowsiness and lowering the body temperature, but it is the central nervous system (to be more specific, the SCN) that controls the daily cycle in most components of the paracrine and endocrine systems rather than the melatonin signal (as was once postulated).
Infants' melatonin levels become regular in about the third month after birth, with the highest levels measured between midnight and 08:00 (8 AM).
In humans, 90% of melatonin is cleared in a single passage through the liver, a small amount is excreted in urine, and a small amount is found in saliva.
Production of melatonin by the pineal gland is inhibited by light and permitted by darkness. For this reason melatonin has been called "the hormone of darkness". Its onset each evening is called the Dim-Light Melatonin Onset (DLMO). Secretion of melatonin as well as its level in the blood, peaks in the middle of the night, and gradually falls during the second half of the night, with normal variations in timing according to an individual's chronotype. Terman et al. devised a formulation that mimics that gradual washout (vs. the spikes in blood concentration and rapid washout associated with most over-the-counter melatonin tablets). When used several hours before sleep, the compound shifts the circadian clock earlier, thus promoting earlier sleep onset and morning awakening.
It is principally blue light, around 460 to 480nm, that suppresses melatonin, increasingly with increased light intensity and length of exposure. Until recent history, humans in temperate climates were exposed to few hours of (blue) daylight in the winter; their fires gave predominantly yellow light. Wearing glasses that block blue light in the hours before bedtime may avoid melatonin loss. Kayumov et al.showed that light containing only wavelengths greater than 530 nm does not suppress melatonin in bright-light conditions. Use of blue-blocking goggles the last hours before bedtime has also been advised for people who need to adjust to an earlier bedtime, as melatonin promotes.
Besides its function as synchronizer of the biological clock, melatonin also exerts a powerful antioxidant activity. The discovery of melatonin as an antioxidant was made in 1993. In many less complex life forms, this is its only known function. Melatonin is an antioxidant that can easily cross cell membranes and the blood-brain barrier. Melatonin is a direct scavenger of OH, O2−, and NO. Unlike other antioxidants, melatonin does not undergo redox cycling, the ability of a molecule to undergo reduction and oxidation repeatedly. Redox cycling may allow other antioxidants (such as vitamin C) to act as pro-oxidants, counterintuitively promoting free radical formation. Melatonin, on the other hand, once oxidized, cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals. Therefore, it has been referred to as a terminal (or suicidal) antioxidant.
Recent research indicates that the first metabolite of melatonin in the melatonin antioxidant pathway may be N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (or AFMK) rather than the common, excreted 6-hydroxymelatonin sulfate. AFMK alone is detectable in unicellular organisms and metazoans. A single AFMK molecule can neutralize up to 10 ROS/RNS (reactive oxygen species/reactive nitrogen species) since many of the products of the reaction/derivatives (including melatonin) are themselves antioxidants. This capacity to absorb free radicals extends at least to the quaternary metabolites of melatonin, a process referred to as "the free radical scavenging cascade". This is not true of other, conventional antioxidants.
In animal models, melatonin has been demonstrated to prevent the damage to DNA by some carcinogens, stopping the mechanism by which they cause cancer. It also has been found to be effective in protecting against brain injury caused by ROS release in experimental hypoxic brain damage in newborn rats. Melatonin's antioxidant activity may reduce damage caused by some types of Parkinson's disease, may play a role in preventing cardiac arrhythmia and may increase longevity; it has been shown to increase the average life span of mice by 20% in some studies.
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While it is known that melatonin interacts with the immune system, the details of those interactions are unclear. There have been few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on small, incomplete clinical trials. Any positive immunological effect is thought to result from melatonin acting on high affinity receptors (MT1 and MT2) expressed in immunocompetent cells. In preclinical studies, melatonin may enhance cytokine production, and by doing this counteract acquired immunodeficiences. Some studies also suggest that melatonin might be useful fighting infectious disease including viral, such as HIV, and bacterial infections, and potentially in the treatment of cancer.
Endogenous melatonin in human lymphocytes has been related to interleukin-2 (IL-2) production and to the expression of IL-2 receptor. This suggests that melatonin is involved in the clonal expansion of antigen-stimulated human T lymphocytes. When taken in conjunction with calcium, it is an immunostimulator and is used as an adjuvant in some clinical protocols; conversely, the increased immune system activity may aggravate autoimmune disorders. In rheumatoid arthritis patients, melatonin production has been found increased when compared to age-matched healthy controls.
Although it has not yet been clearly demonstrated whether melatonin increases non-specific immunity with resulting contraindication in autoimmune diseases, an increase in the production of IL-2 and IL-1 was noted in cultured splenocytes.
Some supplemental melatonin users report an increase in vivid dreaming. Extremely high doses of melatonin (50 mg) dramatically increased REM sleep time and dream activity in both people with and without narcolepsy. Many psychoactive drugs, such as cannabis and lysergic acid diethylamide (LSD), increase melatonin synthesis. It has been suggested that nonpolar (lipid-soluble) indolic hallucinogenic drugs emulate melatonin activity in the awakened state and that both act on the same areas of the brain.
Individuals with autism spectrum disorders (ASD) may have lower than normal levels of melatonin. A 2008 study found that unaffected parents of individuals with ASD also have lower melatonin levels, and that the deficits were associated with low activity of the ASMT gene, which encodes the last enzyme of melatonin synthesis.
Melatonin has been studied for the treatment of cancer, immune disorders, cardiovascular diseases, depression, seasonal affective disorder(SAD), circadian rhythm sleep disorders and sexual dysfunction. Studies by Alfred J. Lewy at Oregon Health & Science University and other researchers have found that it may ameliorate circadian misalignment and SAD. Basic research indicates that melatonin may play a significant role in modulating the effects of drugs of abuse such as cocaine.
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Circadian rhythm disorders
Exogenous melatonin taken in the evening is, together with light therapy upon awakening, the standard treatment for delayed sleep phase syndrome (DSPS) and non-24-hour sleep-wake syndrome. It appears to have some use against other circadian rhythm sleep disorders as well, such as jet lag and the problems of people who work rotating or night shifts. Melatonin reduces sleep onset latency to a greater extent in people with DSPS than in people with insomnia.
Taken 30 to 90 minutes before bedtime, melatonin supplementation acts as a mild hypnotic. It causes melatonin levels in the blood to rise earlier than the brain's own production accomplishes. This usage is now commonly used in sleep and relaxation drinks.
A very small dose taken several hours before bedtime in accordance with the phase response curve for melatonin in humans (PRC) doesn't cause sleepiness but, acting as a chronobiotic (affecting aspects of biological time structure), advances the phase slightly and is additive to the effect of using light therapy upon awakening. Light therapy may advance the phase about one to two-and-a-half hours and a small oral dose melatonin, timed correctly some hours before bedtime, can add about 30 minutes to the advance achieved with light therapy.
Learning, memory and Alzheimer's
Melatonin receptors appear to be important in mechanisms of learning and memory in mice, and melatonin can alter electrophysiological processes associated with memory, such as long-term potentiation (LTP). The first published evidence that melatonin may be useful in Alzheimer's disease was the demonstration that this neurohormone prevents neuronal death caused by exposure to the amyloid beta protein, a neurotoxic substance that accumulates in the brains of patients with the disorder. Melatonin also inhibits the aggregation of the amyloid beta protein into neurotoxic microaggregates that, it seems, underlie the neurotoxicity of this protein, causing death of neurons and formation of neurofibrillary tangles, the other neuropathological landmark of Alzheimer's disease.
Melatonin has been shown to prevent the hyperphosphorylation of the tau protein in rats. Hyperphosphorylation of tau protein can also result in the formation of neurofibrillary tangles. Studies in rats suggest that melatonin may be effective for treating Alzheimer's disease. These same neurofibrillary tangles can be found in the hypothalamus in patients with Alzheimer's, adversely affecting their bodies' production of melatonin. Those Alzheimer's patients with this specific affliction often show heightened afternoon agitation, called sundowning, which has been shown in many studies to be effectively treated with melatonin supplements in the evening.
A randomized placebo-controlled trial, showed that low-dose (0.5 mg) melatonin supplementation to elderly patients admitted to acute Medicine services, significantly reduced delirium.
Research shows that after melatonin is administered to ADHD patients on methylphenidate, the time needed to fall asleep is significantly reduced. Furthermore, the effects of the melatonin after three months showed no change from its effects after one week of use.
A research team in Italy has found that melatonin supplementation in the evening in perimenopausal women produces an improvement in thyroid function and gonadotropin levels, as well as restoring fertility and menstruation and preventing the depression associated with the menopause. However, at the same time, some resources warn women trying to conceive not to take a melatonin supplement. One study reported that three mg of melatonin taken in the evening raised prolactin levels in six out of seven women. Melatonin also lowers FSH levels. It is believed that these hormonal changes could in some women impair fertility.
Melatonin has a very low toxicity in rats. Rat maternal toxicity: The no observable adverse effect level (NOAEL) and lowest observed adverse effect level (LOAEL) were 100 and 200 mg/kg/day, respectively, and the developmental toxicity NOAEL was >= 200 mg/kg/day.
Several clinical studies indicate that supplementation with melatonin is an effective preventive treatment for migraines and cluster headaches.
Melatonin has been shown to be effective in treating one form of depression and seasonal affective disorder, and is being considered for bipolar and other disorders in which circadian disturbances are involved. It has been observed that bipolar disorder might have, as a "trait marker" (something that is characteristic of being bipolar, that does not change with state), supersensitivity to light, i.e., a greater decrease in melatonin secretion in response to light exposure at night. This could be contrasted with drug-free recovered bipolar patients not showing light hypersensitivity.
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A systematic review of unblinded clinical trials involving a total of 643 cancer patients using melatonin found a reduced incidence of death. Another clinical trial is due to be completed in 2012. Melatonin levels at night are reduced to 50% by exposure to a low-level incandescent bulb for only 39 minutes, and it has been suspected that women with the brightest bedrooms have an increased risk for breast cancer. Reduced melatonin production has been proposed as a likely factor in the significantly higher cancer rates in night workers.
Melatonin presence in the gallbladder has many protective properties, such as converting cholesterol to bile, preventing oxidative stress, and increasing the mobility of gallstones from the gallbladder. It also decreases the amount of cholesterol produced in the gallbladder by regulating the cholesterol that passes through the intestinal wall. In guinea pigs, melatonin administration restored normal function by reducing inflammation after induced Cholecystitis, whether administered before or after onset of inflammation. Concentration of melatonin in the bile is 2–3 times higher than the otherwise very low daytime melatonin levels in the blood across many diurnal mammals, including humans.
Amyotrophic lateral sclerosis
In animal models, melatonin has been shown to ameliorate glutamate-induced neuronal death, it is presumed due to its antioxidant effects. In a clinical safety study involving 31 ALS patients, high-dose rectal melatonin (300 mg/day for 2 years) was shown to be tolerated well.
Melatonin is involved in energy metabolism and body weight control in small animals. Many studies show that chronic melatonin supplementation in drinking water reduces body weight and abdominal fat in experimental animals, especially in the middle-aged rats. It is interesting to note that the weight loss effect of melatonin does not require the animals to eat less and to be physically more active. A potential mechanism is that melatonin promotes the recruitment of brown adipose tissue (BAT) as well as enhances its activity. This effect would raise the basal metabolic rate by stimulating thermogenesis, heat generation through uncoupling oxidative phosphorylation in mitochondria. Whether the results of animal studies can be extrapolated to human obesity is a matter of future clinical trials, since substantially active BAT has been identified in adult humans.
Protection from radiation
Radioactive fallout from nuclear accidents is potentially a worldwide problem and we are ill-equipped to protect against this low dose and persistent ionizing radiation, for example, after cesium-137 ingestion or inhalation. Both animal and human studies have shown melatonin to be potentially radioprotective. Moreover, it is a more efficient protector than amifostine, a commonly used agent for this purpose.
The mechanism of melatonin in protection of ionizing radiation is thought to involve scavenging of free radicals. It is estimated that nearly 70% biological damages caused by ionizing radiation are attributed to the free radical, especially the hydroxyl radical attacking to DNA, proteins and cellular membrane. Melatonin has been suggested as a radioprotective agent, with the proposed advantages of being broadly protective, readily available, orally self-adminsted, and without major known side effects.
It is believed that melatonin has some effects for sexual development in higher organisms., and is involved in the seasonal timing of reproduction in rodents.
Melatonin increases proliferation of cultured neural stem cells obtained from mice nervous tissue.
Melatonin was used in to treat Periodic Limb Movement Disorder, a common neurological condition, which, when severe, adversely affects sleep and causes excessive daytime fatigue, in a small trial conducted by Kunz D and Bes F. In this condition, the sufferer is affected by mini arousals during sleep and limb movements that occur in a frequent rhythmic fashion. This often involves leg kicking, but sometimes also involves arm movement. Those affected are often not aware of the condition, and partners are often the first to notice the condition. 7 out of the 9 participants in the trial showed significant improvement.
In recent trial for use in IBS treatment, melatonin relieved some symptoms, as published in 2010.
Veterinarians may recommend melatonin for dogs suffering from aggression or separation anxiety.
Use as medication
The hormone melatonin is used to treat circadian rhythm sleep disorders and some types of insomnia.
Studies have found that the use of melatonin can help entrain the circadian clock to environmental cycles and have beneficial effects for the treatment of certain forms of insomnia (2004). Prolonged release melatonin has shown good results in treating insomnia in older adults (2007).
A 2004 review found that melatonin significantly increased total sleep time in people suffering from sleep restriction. Other studies have found that for certain types of sleep disorders, melatonin is not effective. A 2006 review found that although it is safe for short term use (of three months or less), there is "no evidence that melatonin is effective in treating secondary sleep disorders or sleep disorders accompanying sleep restriction, such as jet lag and shiftwork disorder."
In a 2005 study, researchers concluded that while "there is some evidence to suggest that melatonin is effective in treating delayed sleep phase syndrome", ... "There is evidence to suggest that melatonin is not effective in treating most primary sleep disorders with short-term use (4 weeks or less)."
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Melatonin tablets/capsules often contain three to ten times the amount needed to produce physiologic nocturnal blood melatonin levels for a more rapid sleep onset. Studies suggest that smaller doses (for example 0.3 mg as opposed to 3 mg) are just as effective.
Large doses of melatonin can even be counterproductive: Lewy et al. provide support to the "idea that too much melatonin may spill over onto the wrong zone of the melatonin phase-response curve" (PRC). In one of their blind subjects, 0.5 mg of melatonin was effective while 20 mg was not. Solomon Labs tested initial doses of 30 and 60 milligrams and found very little efficacy even at those levels.
Availability and safety
Legal availability of melatonin varies in different countries, ranging from being available without prescription (e.g., in most of North America) to being available only on prescription or not at all (although its possession and use may not be illegal). The hormone may be administered orally, as capsules, tablets or liquid, sublingually, or as transdermal patches.
Melatonin appears to cause very few side-effects in the short term, up to three months, when healthy people take it at low doses. A systematic review in 2006 looked specifically at efficacy and safety in two categories of melatonin usage: first, for sleep disturbances that are secondary to other diagnoses and, second, for sleep disorders such as jet lag and shift work that accompany sleep restriction.
The study concluded that There is evidence that melatonin is safe with short term use.
A similar analysis by the same team a year earlier on the efficacy and safety of exogenous melatonin in the management of primary sleep disorders found that: There is evidence to suggest that melatonin is safe with short-term use (3 months or less).
Some unwanted effects in some people, especially at high doses (~3 mg/day or more) may include: headaches, nausea, next-day grogginess or irritability, hormone fluctuations, vivid dreams or nightmares, and reduced blood flow.
While no large, long-term studies that might reveal side-effects have been conducted, there do exist case reports about patients having taken melatonin for years.
Melatonin can cause somnolence (drowsiness), and, therefore, caution should be shown when driving, operating machinery, etc.
In individuals with auto-immune disorders, there is concern that melatonin supplementation may ameliorate or exacerbate symptoms due to immunomodulation.
Individuals experiencing orthostatic intolerance, a cardiovascular condition that results in reduced blood pressure and blood flow to the brain when a person stands, may experience a worsening of symptoms when taking melatonin supplements, a study at Penn State College of Medicine's Milton S. Hershey Medical Center suggests. Melatonin can exacerbate symptoms by reducing nerve activity in those experiencing the condition, the study found.
The use of melatonin derived from animal pineal tissue may carry the risk of contamination or the means of transmitting viral material.
The synthetic form of this medication does not carry this risk. *
* Read an article in Wikipedia with references and links Mar 28, 2011
* * Read a more current article with references and links Feb 29, 2012
* * Melatonin. (2012, February 28). In Wikipedia, The Free Encyclopedia.
Retrieved 19:44, February 29, 2012, from
Melatonin is a natural hormone which induces sleep, regulates metabolic rate, may increase longevity, and prevents free radical damage.
Melatonin assists the body to normalize sleep disruptions thereby helping alleviate the fatigue that often accompanies chronic lack of sleep.
Melatonin is a metabolic hormone made in the pineal gland, retina, and intestines.
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