Melatonin:
ª chemistry:
Melatonin is an amino acid based (indole) hormone, produced in the brain by the pineal gland. Its amino acid precursor, tryptophan, is also the precursor to the neurotransmitter serotonin.
ª metabolism:
Melatonin is regulated by numerous environmental and body cycles. The largest regulatory influence is that of the daily cycle of light and darkness; melatonin production begins to slowly rise with nightfall, reaching its maximum between midnight and 3 AM.
Melatonin is metabolized by the liver after a half-life of 30-50 minutes.
Many other cycles influence melatonin production as well, such as the annual cycle of longer and shorter days and the monthly female reproductive cycle, and many events tied to these cycles are linked to melatonin.
ª function:
Melatonin functions as a hormonal interface between the body and the environment; it sets the biological clock. After its synthesis is triggered by various external environmental cues, it activates bodily functions associated with those cues. The most notable example is the circadian (24-hour) cycle of sleep and waking, in which darkness triggers melatonin production, which helps to engender a feeling of sleepiness.
Melatonin acts on multiple systems, and appears to be high on the hierarchy of regulatory hormones (it regulates hormones that regulate hormones.) For example, it appears to be such as powerful regulator of gonadotropins (the hormones which regulate the production of sex hormones such as estrogen and progesterone) that it is a crucial element in the timing of the female reproductive cycle, with appropriate levels necessary for ovulation. It also introduces subtle changes according to external rhythms; for example, varying melatonin levels over the course of the year result in higher estrogen in the spring and summer, and higher progesterone in the fall and winter.
The immune system is influenced by melatonin; receptors have been reported on T and B lymphocytes, and melatonin has demonstrated immune-enhancing properties in many animal studies. The immune-suppressive activity of corticosteroids may also be moderated by melatonin.
Various studies have shown a correlation between melatonin and longer life span. One proposed rationale for this is that the ratio of serotonin to melatonin increases as a person ages, increasing the production of various chemicals that are linked with aging. Studies have also shown that melatonin decreases the internal carotid pulsability index of premenopausal women (Cagnacci, Arangino et al) and, applied topically, can reduce skin damage inflicted by UV radiation. (Bangha, Elsner, and Kistler) Research does not support supplementation as a remedy for the effects of aging; it is probably more beneficial to protect oneself from influences that inhibit melatonin.
Melatonin also functions as an powerful antioxidant. Supplementation for this purpose may be inappropriate, however, because the antioxidant effects may be offset by hormonal disruption caused by taking large doses.
ª requirements:
RDA: No U.S. RDA has been established.
Under normal circumstances, a healthy body can synthesize all it needs.
ª food sources:
Melatonin appears in foods only in trace amounts.
ª deficiency:
Deficiency may result from a number of factors, including age, artificial light, drugs, and a variety of electrical fields (ranging from high-tension wires to electric blankets.) Melatonin sensitivity to these stimuli varies between individuals.
A change in schedule such as an airplane flight across time zones or a change in work shift may disrupt the melatonin rhythm, causing sleep problems. Although this is not a deficiency per se, it can frequently be corrected by appropriate supplementation.
ª therapeutics:
Alzheimer's disease: In vitro, melatonin has been found to protect neurons against ß-amyloid toxicity, inhibit amyloid formation, and has shown antioxidative properties. In a case report, Brusco et al describe the results of treating a pair of elderly, male twins with Alzheimer's disease. The one brother who was prescribed 6 mg of melatonin each evening. After three years assessment of both twins indicated that the one taking melatonin was at a higher functional level than his brother, with substantially less impairment of memory and speech. Further, the brother using melatonin daily melatonin showed significantly less progression of the cognitive and behavioral signs typical of Alzheimer's disease progression. In contrast, the twin who had not taken the melatonin showed marked deterioration.
(Brusco LI, et al. J Pineal Res 1998 Dec;25(4):260-263.)
Cluster headaches: A drop in nocturnal melatonin has been linked with cluster headaches, and melatonin supplementation has shown a low but significant preventive capacity for cluster headaches. (Leone et al)
Depression: Some studies showing melatonin to be an effective treatment for depression were flawed. Melatonin is unlikely to produce significant positive effects in the treatment of depression in most patients, especially if the patient is not already melatonin-deficient. Badly timed use of melatonin can worsen depression. However, some patients with SAD (seasonal affective disorder, a form of depression associated with the shortening of the days in autumn) have been shown to have disrupted melatonin cycles, and have been treated effectively with light therapy. Several other mental illnesses have possible links to melatonin disruption or deficiency, but research is so far inconclusive as to exact relationships.
Insomnia: Melatonin plays an important role in the induction of sleep. Low melatonin secretion at night can be a cause of insomnia. Several double-blind trials show melatonin supplementation is very effective in promoting sleep. However, it appears that the sleep-promoting effects of melatonin supplementation are most apparent if melatonin levels are low. Melatonin supplementation does not act as a simple sedative like a sleeping pill; only if this sleep-producing hormone is deficient will supplementation be helpful with insomnia. Further, melatonin acts to regulate or alter sleep rhythms and not as a sedative, so its effect may be stronger with problems getting to sleep initially than with sleep disturbances once asleep.
Jet lag: Several studies demonstrate that melatonin is very effective in relieving jet lag. Recommendations vary: some recommend taking melatonin a few days before traveling, especially eastward, in order to match the new sleep cycle, whereas some recommend just one dose in the evening upon arrival. A study involving international airline crews found an optimal dosage to be 5 mg of melatonin in the evening for five days after arrival.
Cancer: Melatonin has been shown to inhibit several types of cancers, especially hormone-related cancers like breast cancer and prostate cancer. (Bartsch and Bartsch) This may be due to its ability to reduce the number of cellular estrogen receptors, which reduces the production of cell-multiplication factors. The immune-modulating properties of melatonin seem to convey additional anti-cancer properties. It has been shown to support the use of interleukin-2 in anti-cancer therapy, especially under conditions of controlled lighting. Many animal studies have demonstrated an increase in tumor growth rates in animals whose pineal glands have been removed.
While interferon and interleukin 2 (IL-2) are often ineffective when used alone, in combination with melatonin they exhibit very good results. In one study of patients with advanced solid neoplasms, 80 patients received either IL-2 alone (3 million International Units per day 6 days a week for 4 weeks) or in combination with melatonin (40 milligrams per day orally at 8:00 P.M.). A complete response was obtained in 3 out of 41 patients treated with IL-2 plus melatonin and in none of the patients receiving IL-2 alone. A partial response was achieved in 8 out of 41 patients treated with IL-2 and melatonin compared to only I in the IL-2-only group. The survival rate after 1 year was 19 out of 41 in the IL-2 and melatonin group compared to only 6 out of 30 in the IL-2 group. In another study of 100 patients with metastatic solid tumors, for whom no standard therapy was available, the percentage of survival at 1 year was significantly higher in patients treated with IL-2 and melatonin than in those receiving the supportive care alone (21 out of 52 versus 5 out of 48).
Similar results have been shown with melatonin in combination with interferon, tumor necrosis factor, and tamoxifen, and when melatonin was used alone. These preliminary results are quite encouraging because approximately 30 percent of the patients taking anywhere from 10 to 50 milligrams daily (at 8:00 P.M.) experienced improvements in survival time and quality-of-life assessments. (Lissoni et al, Brit J Cancer 7l(4):854-56, 1995)
However, although melatonin can increase survival time in these studies, the results are good but not earth-shattering. For example, in one study of patients with solid tumors with brain metastasis, 15 out of 24 patients (63 percent) died within I year in the melatonin group compared to 21 out of 26 (88 percent) in the group receiving supportive care only. (Lissoni et al. Cancer 73:699-701, 1994.) These studies, although randomized, are not double-blind; therefore, a placebo response may be partially responsible for some of the improvements noted.
Rett Syndrome: Melatonin has been shown to improve sleep efficiency and decrease sleep latency in young girls with Rett syndrome. However, response varied between individuals and long-term effects of supplementing children with melatonin are unknown. (McArthur and Budden)
ª dosage:
Melatonin is appropriate for supplementation when low melatonin levels are suspected, as occurs in some cases of insomnia and jet lag. The amount of melatonin necessary to produce benefit in these cases is largely unknown.
A dosage of 3 milligrams at bedtime is more than enough-dosages as low as 0.1 milligrams and 0.3 milligrams can produce a sedative effect when melatonin levels are low.
1-3 mg of melatonin may be taken one to two hours before bedtime.
Generally, melatonin should not be taken during the day as it may disrupt circadian rhythms and/or cause drowsiness.
Higher dosages may be required to produce the anticancer benefits noted above.
ª forms:
Melatonin is available in tablet, capsule, and sublingual tablet forms.
There is no definitive evidence that any of these forms is substantially superior to another.
An argument focusing on absorption might favor of the sublingual form.
The time-release form might best duplicate the body's normal releasing of melatonin for several hours per night; studies using time-release melatonin have reported good results.
ª side effects:
Few side effects have been reported with melatonin.
There have been reports of sleepwalking, grogginess upon waking, excessive drowsiness, and disorientation.
Appropriate timing of dosage is important.
Grogginess and depression have been exacerbated by the melatonin use during the day.
ª toxicity:
No toxicity of melatonin has been reported other than the side-effects mentioned above.
Caution is advised given the limited knowledge of hormones and their interactions and the multiple influences melatonin exerts on other regulatory hormones.
Persistent use is not advised.
ª contraindications:
Melatonin may cause seizures in children, and make attacks more frequent if the child already suffers from them. (Sheldon SH. Lancet 1998 Apr 25;351(9111):1254.)
Due to melatonin's multiple, and as yet poorly understood, impact on many key hormones and their feedback systems, certain individuals should not use melatonin supplements.
Some highly experimental animal trials suggest that supplementation of melatonin may be contraindicated for patients suffering from autoimmune disorders such as rheumatoid arthritis, lupus or multiple sclerosis. Also, it may counteract corticosteroid drugs.
Use during the day may result in fatigue and decreased alertness.
Melatonin readily crosses the placenta and its fetal effects are unknown; therefore, melatonin supplementation during pregnancy is not recommended.
Melatonin supplementation may inhibit ovulation, so should not be used by women who are trying to get pregnant.
ª interactions:
Vitamin B-12 can influence melatonin secretion. The low vitamin B-12 status of many elderly patients may be related to their levels of melatonin. The beneficial effects of melatonin on sleep-wake cycles may be enhanced by daily supplementation of 1.5 mg of Vitamin B-12 (methylcobalamin), presumably because of improved melatonin secretion.
NSAIDs (non-steroidal anti-inflammatory drugs) such as aspirin, ibuprofen, and indomethacin can inhibit production of melatonin, due to their inhibition of prostaglandin synthesis. (Murphy, PJ)
Fluoxetine (Prozac) has been shown to decrease melatonin levels.
"Beta blocker" drugs inhibit melatonin production. Cardiac beta blockers are especially adept at blocking production of melatonin, probably because the beta-1 receptors blocked in the heart are the same as the beta-1 receptors in the pineal gland that trigger melatonin production.
Melatonin may counteract corticosteroids; melatonin supplementation is not recommended for those taking corticosteroids for anti-inflammatory or immunosuppressive purposes.
Melatonin may help to ease withdrawal symptoms from benzodiazepine insomnia treatment by re-establishing a regular sleep cycle. (Dagan et al)
Doses of 1-2 mg of melatonin have shown various effects (raising and lowering during follicular and luteal phases) on levels of LH in premenopausal women. TSH levels appear unaffected, while prolactin secretion is increased. Prolactin secretion is also increased in men. (Cagnacci et al: Fertil Steril 63(5):996-999, May 1995; Terzolo et al; Chiodera et al.)
Evening ethanol consumption, studied in quantities mimicking social consumption, has been found to inhibit melatonin secretion. (Ekman et al)
Melatonin may potentiate interferon and interleukin 2 (IL-2) as used in chemotherapy.
footnotes
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