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Current and potential medical indications Treatment of circadian rhythm disordersExogenous 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. Preventing ischemic damageMelatonin has been shown to reduce tissue damage in rats due to ischemia in both the brain and the heart; however, this has not been tested in humans. Learning, memory and Alzheimer'sMelatonin 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 which seem to 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. ADHDResearch 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. FertilityA 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. Mood disordersMelatonin has been shown to be effective in treating one form of depression, seasonal affective disorder, and is being considered for bipolar and other disorders where circadian disturbances are involved. It has been observed that bipolar disorder might have, as a "trait marker" (something which 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 people not showing light hypersensitivity. CancerA 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 shown 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. DosageDosages are designed to raise melatonin levels for several hours to enhance quality of sleep, but some studies suggest that smaller doses (for example 0.3mg as opposed to 3mg) 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, 0.5mg of melatonin was effective while 20mg was not.