Melatonin in Medicine

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.

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)."

Dosage

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.

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.

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.

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.

Delirium

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.

ADHD

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.

Fertility

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.

Toxicology

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.

Headaches

Several clinical studies indicate that supplementation with melatonin is an effective preventive treatment for migraines and cluster headaches.

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.

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.

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.

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. 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.

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.

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. 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

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 against ionizing radiation is thought to involve scavenging of free radicals. It is estimated that nearly 70% of biological damage caused by ionizing radiation is attributable to the free radical, especially the hydroxyl radical that attacks DNA, proteins, and cellular membranes.

Melatonin has been suggested as a radioprotective agent, with the proposed advantages of being broadly protective, readily available, orally self-administered, and without major known side effects.

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.

In recent trial for use in IBS treatment, melatonin relieved some symptoms, as published in 2010.

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.

Dietary supplement

In the USA, because it is sold as a dietary supplement, sometimes combined with other ingredients, such as vitamins and herbal extracts, and not as a drug, the Food and Drug Administration (FDA) regulations that apply to medications are not applicable to melatonin. In addition, the industry has been required to report to the FDA "all serious dietary supplement related adverse events" and the FDA has, within the cGMP guidelines, recently begun enforcement of that requirement.

Food Products

As reported in the New York Times in May 2011, melatonin is sold in grocery stores, convenience stores, and clubs in both beverage and snack forms. The FDA is considering whether these food products can continue to be sold with the label "dietary supplements". On January 13, 2010, they issued a warning letter to Innovative Beverage, creators of several beverages marketed as "relaxation drinks," stating that melatonin is not approved as a food additive.

Pediatrics

While the packaging of melatonin often warns against use in children, at least one long-term study does assess effectiveness and safety in children. No serious safety concerns were noted in any of the 94 cases studied by means of a structured questionnaire for the parents. With a mean follow-up time of 3.7 years, long-term medication was effective against sleep onset problems in 88% of the cases.

Prolonged release

Melatonin is available as a prolonged-release prescription drug, trade-name Circadin, manufactured by Neurim Pharmaceuticals. The European Medicines Agency (EMA) has approved Circadin 2 mg (prolonged-release melatonin) for patients aged 55 or over, as monotherapy for the short-term treatment (up to 13 weeks) of primary insomnia characterized by poor quality of sleep.