Melatonin

Melatonin, 5-methoxy-N-acetyltryptamine, is a hormone found in all living creatures from algae[1] to humans, at levels that vary in a diurnal cycle.

Many biological effects of melatonin are produced through activation of melatonin receptors,[2] while others are due to its role as a pervasive and extremely powerful antioxidant[3] with a particular role in the protection of nuclear and mitochondrial DNA.[4]

Melatonin was released into the general health supplement market in the United States in 1993, and met with good consumer acceptance and enthusiasm.[5]

In higher animals, melatonin is produced by pinealocytes in the pineal gland (located in the brain) and also by the retina, lens and GI tract. It is naturally synthesized from the amino acid tryptophan (via synthesis of serotonin) by the enzyme 5-hydroxyindole-O-methyltransferase.

Production of melatonin by the pineal gland is under the influence of the suprachiasmatic nucleus (SCN) of the hypothalamus which receives information from the retina about the daily pattern of light and darkness.

Melatonin is also synthesized by various plants, such as rice, and ingested melatonin has been shown to be capable of reaching and binding to melatonin binding sites in the brains of mammals.[6][7]

A study indicates that patients with nocturnal asthma may experience adverse effects from melatonin supplements. According to the study “Immunomodulatory Effects of Melatonin in Asthma”, even small amounts of supplemental melatonin worsen the symptoms of the inflammatory disease asthma by causing the body to release chemicals which provoke inflammation. The inflammatory chemicals include increased production of interleukin-1, interleukin-6, and tumor necrosis factor-alpha [8].

Melatonin produced in the pineal gland acts as an endocrine hormone since it is released into the blood. By contrast, melatonin produced by the retina and the gastrointestinal (GI) tract acts as a paracrine hormone.

Biological clock

See also: Phase response curve

In humans, melatonin is produced by the pineal gland, a gland about the size of a pea, that is located in the center of the brain, on the dorsal surface of diencephalon. The melatonin signal forms part of the system that regulates the circadian cycle, but it is the Central nervous system that controls the daily cycle in most components of the paracrine and endocrine systems[9][10] rather than the melatonin signal (as was once postulated).

Normally, the 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." The secretion of melatonin peaks in the middle of the night, and gradually falls during the second half of the night. Until recent history, humans in temperate climates were exposed to up to eighteen hours of darkness in the winter. In this modern world, artificial lighting typically reduces this to eight hours or less per day all year round. Even low light levels inhibit melatonin production to some extent, but over-illumination can create significant reduction in melatonin production. Reduced melatonin production has been proposed as a likely factor in the significantly higher cancer rates in night workers,[11] and the effect of modern lighting practice on endogenous melatonin has been proposed as a contributory factor to the larger overall incidence of some cancers in the developed world.[12] As inadequate as blood concentrations may be in brightly-lit environments, some scientists now believe that people's overnight output of melatonin can be further jeopardized each time they interrupt their sleep and turn on a bright light (suggesting that the lower brightness level of a nightlight would be safer). Others suggest that such short exposures do no harm.[13]

Although the primary site of melatonin's action in humans is the melatonin receptors, it first evolved as an antioxidant. In many lower life forms, it serves only this purpose.[14]

Melatonin is a powerful antioxidant that can easily cross cell membranes and the blood-brain barrier.[3] 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, 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.[15]

Recent research indicates that the beginning of 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 neuralize up to 10 ROS/RNS since many of the products of the reaction/derivatives (including melatonin) are themselves antioxidants, and so on. 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.[14]

In animal models, melatonin has been demonstrated to prevent the damage to DNA by some carcinogens, stopping the mechanism by which they cause cancer.[16]

The antioxidant activity of melatonin 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.[17][18][19]

Immune system
While it is clear that melatonin interacts with the immune system,[20][21] 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.

Melatonin is an immunoregulator that can enhance T cell production. 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.

Many supplemental melatonin users have reported an increase in the vividness or frequency of dreams. High doses of melatonin (50mg) dramatically increased REM sleep time and dream activity in both narcoleptics and normal people.[22]

Many psychoactive drugs, such as LSD and cocaine, increase melatonin synthesis.[22] 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.[22]

In a 2005 editorial of the British Journal of Psychiatry, Ben Sessa suggested that psychotropic drugs be readmitted in the field of scientific enquiry and therapy.[23] Melatonin, being two endogenous hallucinogenic indoles like N,N-dimethyltryptamine (DMT), is likely to be research priorities in this reemerging field of psychiatry.[24]

Melatonin appears to have some use against circadian rhythm sleep disorders, such as jet lag and delayed sleep phase syndrome. It has been studied for the treatment of cancer, immune disorders, cardiovascular diseases, depression, seasonal affective disorder (SAD), and sexual dysfunction. A study by Alfred J. Lewy and other researchers at Oregon Health & Science University found that it may ameliorate SAD and circadian misalignment,[25] but as of 2006 it is known to affect the timing of endogenous melatonin production, raising the risk that it can exacerbate both clinical depression and SAD.[26] Basic research indicates that melatonin may play a significant role in modulating the effects of drugs of abuse such as cocaine.[27]

Melatonin has been shown to reduce tissue damage in rats due to ischemia in both the brain[28] and the heart;[29] however, this has not been tested in humans.

Melatonin receptors appear to be important in mechanisms of learning and memory in mice,[30] and melatonin can alter electrophysiological processes associated with memory, such as long-term potentiation (LTP). Melatonin has been shown to prevent the hyperphosphorylation of the tau protein in rats. Hyperphosphorylation of tau protein can result in the formation of neurofibrillary tangles, a pathological feature seen in Alzheimer's disease. Thus, melatonin may be effective for treating Alzheimer's Disease.[31] These same neurofibrillary tangles can be found in the hypothalamus in patients with Alzheimer's, adversely affecting their body's 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.[32]

ADHD is most commonly treated with methylphenidate which may cause insomnia in approximately 94% of its users. Research shows that after melatonin is administered to the patients, the time needed to fall asleep is significantly reduced. Before the melatonin was administered, the time needed to fall asleep ranged from 15 minutes to 240 minutes. After the melatonin was administred, the time needed to fall asleep ranged from 15 minutes to 64 minutes. Furthermore, the effects of the melatonin after three months showed no change from its effects after one week of use.[33]

Recent research has concluded that melatonin supplementation in perimenopausal women produces a highly significant improvement in thyroid function and gonadotropin levels, as well as restoring fertility and menstruation and preventing the depression associated with the menopause.[34]

Some resources warn women trying to conceive not to take a melatonin supplement.[35]

Melatonin has been shown to be effective in treating one form of depression, Seasonal Affective Disorder. [1]

Some studies have shown that melatonin has potential for use in the treatment of various forms of cancer, HIV, and other viral diseases; however, further testing is necessary to confirm this.[38]

Histologically speaking, it is also believed that melatonin has some effects for sexual growth in higher organisms. (*Quoted from Ross Histology and Wheather's Functional Histology.)

The primary motivation for the use of melatonin as a supplement is as a natural aid to better sleep, with other incidental benefits to health and well-being due to its role as an antioxidant and its stimulation of the immune system and several components of the endocrine system.

Victor Herbert, M.D., J.D., of the Mt. Sinai School of Medicine, cites studies from Massachusetts Institute of Technology that say melatonin pills sold as supplements contain three to 10 times the amount needed to produce the desirable physiologic nocturnal blood melatonin level for enhancement of nighttime rest. Dosages are designed to raise melatonin levels for several hours to enhance quality of sleep, but some studies suggest that smaller doses are just as effective at improving sleep quality.[39] High dose melatonin can even be counterproductive: Lewy & al[40] provide support to the "idea that too much melatonin may spill over onto the wrong zone of the melatonin phase-response curve." In their study, 0.5 mg of melatonin was effective while 20 mg wasn't. A practical implication of these results is that effective melatonin supplementation (for sleep problems) thus becomes very accessible: it costs a fraction of what most researchers thought it might cost. Melatonin supplementation for sleep problems is available without prescription in most cases in the United States. Melatonin supplements are available as oral supplements and transdermal melatonin or "melatonin sleep patch".

Melatonin is involved in the regulation of body weight, and may be helpful in treating obesity (especially when combined with calcium).[41]

Melatonin is practically nontoxic and exhibits almost no short-term side effects. However, melatonin derived from animal sources may be contaminated with viral material; synthetic melatonin may be taken to avoid this risk.[42] No studies have been conducted yet to determine whether there are any long-term side effects.

Even though it is seen as a relatively safe, benign drug, especially to herbal enthusiasts, it can cause some unwanted side effects, especially at high doses. The bodies of people under age 35 are usually able to produce an adequate supply of melatonin on their own.[citation needed] Ingesting melatonin supplements can cause hormone fluctuations,[2] irritability,[3] reduced blood flow (see below), and increased sleep disturbances, including vivid nightmares.[4]

Melatonin taken in combination with monoamine oxidase inhibitors (MAOIs) can lead to overdose because MAOIs inhibit the breakdown of melatonin by the body. Exogenous melatonin normally does not affect the endogenous melatonin profile in the short or medium-term, merely advancing the phase of endogenous melatonin production in time.

In individuals with auto-immune disorders, there is concern that melatonin supplementation may exacerbate symptoms due to stimulation of the immune system.[43]

Melatonin causes somnolence, and therefore should not be taken within five hours[citation needed] before driving, operating machinery, etc. As melatonin is almost always taken at the end of the waking day, this is generally not an issue.

Individuals who experience 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 the symptoms by reducing nerve activity in those who experience the condition, the study found.[44]

Melatonin has been classified as a dietary supplement and made freely available in the USA.[45]

Many animals use the variation in duration and quantity of melatonin production in each day as a seasonal clock.[46] In seasonal breeders which do not have long gestation periods, and which mate during longer daylight hours, the melatonin signal controls the seasonal variation in their sexual physiology, and similar physiological effects can be induced by exogenous melatonin in animals including mynah birds[47] and hamsters.[48] 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.

Melatonin is also related to the mechanism by which some amphibians and reptiles change the color of their skin.[49][50]