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What is Melatonin?
Melatonin is a hormone that helps regulate sleep. It also appears to influence other hormones in the body. Melatonin
supplements have become popular as natural sleep aids.
The amount of melatonin we produce is determined by how dark or light our surroundings are. Our eyes have specialized
light-sensitive receptors that relay this message to a cluster of nerves in the brain called the suprachiasmatic nucleus, or
SCN. The SCN sets our internal biological clock, also called our circadian rhythm, which regulates a variety of body
functions including sleep.
Melatonin is made from an amino acid called tryptophan. When our surroundings are dark, the SCN tells the pineal gland to
produce melatonin, which is thought to trigger sleep. Some melatonin is also made in the stomach and intestines.
Melatonin levels were originally thought to decline with age. Early reports said that a person's melatonin levels peaked at
age 20 and gradually decreased to 20% at age 80. This theory was used to explain why many older people have sleep
difficulties. Melatonin supplements became marketed as a "youth hormone," contributing to its rise in popularity. Recent
evidence, however, suggests that melatonin levels don't actually decline with age.
Melatonin Listeni 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.
Melatonin and Medical uses:
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. 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. Melatonin is also a geroprotector.
Melatonin and 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 common 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 of melatonin, timed correctly some hours before bedtime, can add
about 30 minutes to the advance achieved with light therapy.
The World Health Organization in 2007 named late night shift work as a probable cancer-causing agent. Melatonin is an
anti-oxidant and suppressant of tumor development that is produced at night; when someone works in artificial light, they
generally have lower melatonin and may be more likely to develop cancer. Melatonin supplements may simulate the melatonin
production at different times that does not occur during regular sleeping hours for people who work night shifts.
Melatonin 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
Melatonin: Mood disorders:
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.[38] 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.
Melatonin and Cancer:
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 and Gallbladder stones:
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.[45] 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.[45] 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.
Melatonin 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 and Obesity:
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.[49] 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.
Melatonin Other:
Melatonin increases proliferation of cultured neural stem cells obtained from mice nervous tissue.
Melatonin was used 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.
Melatonin In mammals:
Melatonin is produced in the pineal gland, which is outside of the blood-brain barrier, acts as an endocrine hormone since
it is released into the blood.[74] By contrast, melatonin produced by the retina and the gastrointestinal (GI) tract acts as
a paracrine hormone.
Melatonin can suppress libido by inhibiting secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH)
from the anterior pituitary gland, especially in mammals that have a breeding season when daylight hours are long. The
reproduction of long-day breeders is repressed by melatonin and the reproduction of short-day breeders is stimulated by
melatonin. During the night, melatonin regulates leptin, lowering the levels; see leptin.
Light/dark information reaches the suprachiasmatic nuclei (SCN) via retinal photosensitive ganglion cells, intrinsically
photosensitive photoreceptor cells, distinct from those involved in image forming (that is, these light-sensitive cells are
a third type in the retina, in addition to rods and cones). These cells represent approximately 2% of the retinal ganglion
cells in humans and express the photopigment melanopsin.[75] The sensitivity of melanopsin is consistent with that of a
vitamin A-based photopigment, with a peak sensitivity at 484 nm (blue light). This photoperiod cue entrains the circadian
rhythm, and the resultant production of specific "dark"- and "light"-induced neural and endocrine signals that regulate
behavioral and physiological circadian rhythms. Melatonin is secreted in darkness in both day-active (diurnal) and
night-active
Melatonin and Circadian rhythm:
In humans, melatonin is produced by the pineal gland, 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.
Human melatonin production decreases as a person ages. It is believed that as children become teenagers, the nightly
schedule of melatonin release is delayed, leading to later sleeping and waking times.
Melatonin Light dependence:
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 sleepiness.
Melatonin and Antioxidant:
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.[85] 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.[87] 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.
Melatonin and Immune system:
While it is known that melatonin interacts with the immune system,[95][96] 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,[97] and by doing this counteract acquired immunodeficiences. Some studies also suggest that melatonin
might be useful fighting infectious disease[9] 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.[99] 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[citation needed] and is used as an adjuvant in some
clinical protocols[citation needed]; 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.
Melatonin and Dreaming:
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.
Melatonin and Autism:
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.
Multiple small studies have demonstrated that 2 to 10 mg of melatonin may benefit children with ASD who have trouble falling
asleep and/or maintaining sleep. A small 2011 randomized crossover trial found that the administration of melatonin, when
compared to placebo, decreased sleep latency and increased total sleep time, but had no effect on the number of night time
awakenings. At this time, no guidelines exist for the use of melatonin in children with ASD.
Melatonin and Aging:
Research has supported the anti-aging properties of melatonin. Younger children hit their peak melatonin production at
night, and some researchers believe that the level of melatonin peaks earlier as we get older. This may explain why older
adults go to bed earlier, wake up earlier, and have more sleep problems than children do.
Some studies have shown that melatonin plays a crucial part in the aging process and that it may act as an anti-aging agent
when taken by older adults. It has been reported in one study that while elderly people have different gene expression
levels in 100 of 10,000 genes, administration of melatonin may reverse this change in gene expression thus making the genes
of elderly people similar to those of younger people.
One study conducted by researchers of the University of Granada’s Institute of Biotechnology found that consuming melatonin
may neutralize oxidative damage and delay the neurodegenerative process of aging. When small amounts of melatonin were
administered to lab mice, it reduced the oxidative damage caused by aging and delayed the inflammatory process, which in
turn increased the longevity of the mice. The researchers hope these results can also be applied to humans.
Melatonin production:
Along with melanocyte-stimulating hormone, melatonin controls the dispersion of melanin throughout melanocyte cells.[108]
Melatonin controls pigmentation changes by aggregation of melanin into the melanocytes within the skin, causing the skin to
change color. This is responsible for the change in skin color due to amount of sleep or the appearance of those who are
sleep deprived, since melatonin also controls the circadian cycle. This interaction is also responsible for the skin color
of elderly people, since melatonin production reduces with age.
Melatonin and Insomnia:
Studies suggest that melatonin supplements may help people with disrupted circadian rhythms (such as people with jet lag or
those who work the night shift) and those with low melatonin levels (such as some seniors and people with schizophrenia) to
sleep better. A review of clinical studies suggests that melatonin supplements may help prevent jet lag, particularly in
people who cross five or more time zones.
A few clinical studies suggest that when taken for short periods of time (days to weeks) melatonin is more effective than a
placebo in reducing the time it takes to fall asleep, increasing the number of sleeping hours, and boosting daytime
alertness. It' s not clear how well melatonin works, however – some studies suggest that it only reduces the amount of time
to fall asleep by a few minutes.
A number of human studies have measured the effects of melatonin supplements on sleep in healthy people. A wide range of
doses has been used, often taken by mouth 30 - 60 minutes prior to sleep time. Results have been mixed. Some evidence
suggests that melatonin may work best for people over 55 who have insomnia. One study of 334 people aged 55 and older found
that sustained-release melatonin seemed to help people fall asleep faster, sleep better, be more alert in the morning, and
improve quality of life in people with primary insomnia.
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