Melatonin (N-acetyl-5 methoxytryptamine) is a human hormone produced in and released from the pineal gland; a pea-sized gland located just beneath the brain. The pineal gland is an adaptive organ, which maintains and regulates cerebral homeostasis by “fine tuning” biological rhythms through the mediation of melatonin. Melatonin is termed a chronobiotic - an agent that helps maintain normal circadian rhythms. Melatonin was identified in 1958 and was thought to be biosynthesized only in the pineal gland.  However, scientists now know that melatonin is also found in the retina, Harderian glands, and gastrointestinal tract. Melatonin is converted from the neurotransmitter serotonin, via 5-hydroxytryptophan decarboxylation.
The exact mechanism of action for melatonin has still not been fully elucidated. New functions and applications for this wide-reaching hormone continue to be discovered. Melatonin is vital to the synchronization of hormone secretion and neurotransmitter release throughout the body; this cycle of release is termed the circadian rhythm. Melatonin release is light sensitive, with secretion inhibited by natural light and stimulated by darkness. Electromagnetic radiation and x-ray also affects melatonin levels. Not only does melatonin act as a clock-keeper, it also contributes to sleep and wake cycles, blood pressure, body temperature, mood, immune, and adrenal function; also possessing anti-oxidative activity. 
Melatonin has specific effects on particular hormones. Melatonin increases levels of progesterone (while it decreases estrogen), gonadotropin releasing hormone (GnRH), thyroxine, coticosteroids, aldosterone, and ACTH. Melatonin has a half-life of 20 to 50 minutes, but it has long-lasting effects due to the cascade it initiates. As mentioned, melatonin is very sensitive to light and radiation. In addition, melatonin levels can be increased by rigorous exercise, hypoglycemia and stress; and decreased by aging and artificial light. 
Melatonin is a hormone and therefore no food sources of this molecular compound exist. Again, melatonin is converted in the body from serotonin, therefore an adequate supply of tryptophan, a serotonin precursor is necessary for its production.
Tryptophan is found in highest amounts in brown rice, cottage cheese, meat, peanuts, and soy proteins.  Because only small amounts of tryptophan are actually converted to serotonin, dietary sources of tryptophan are not sufficient to achieve the therapeutic effect of melatonin. Nutritional supplementation considered the most effective option.
Melatonin is most popularly known for treating insomnia. It appears that melatonin is most effective in treating this disorder when plasma levels are low; a common characteristics in the elderly. Taking melatonin within 90 - 120 minutes of bedtime improved sleep in elderly subjects when compared to placebo.  Subjects experienced less trouble falling asleep, had more refreshing sleep, less waking, and longer durations of sleep. Another study observed improved sleep in elderly patients in response to an eight week course of nightly administrations using melatonin.  The most interesting part of the study was that the effect on sleep patterns lasted when melatonin was discontinued. A double-blind placebo controlled study in the elderly confirmed these prior studies over a shorter treatment period as well. 
An additional benefit of melatonin in treating sleep disorders is for sleep problems induced by benzodiazepine discontinuation.  A double-blind, placebo-controlled study of a time-released melatonin preparation, demonstrated that sleep quality scores were improved in the melatonin group, and 79% of the patients who were taking it continued to do so at the six-month follow up, citing good sleep quality.
Another popular application for melatonin is in treating jet lag. A double-blind, placebo-controlled study demonstrated improvement in feelings of fatigue and jet lag in the group taking melatonin.  Melatonin was taken three days prior to a transcontinental flight which traveled greater than 12 time zones, continuing this supplementation until three days after arrival. The dosage level was 5 milligrams taken between 22:00 and 24:00 hours calculated at the destination.
The efficacy of melatonin treatment for patients suffering from migraine headaches cannot be fully established until double-blind placebo trials are carried out. However, two small studies exist that support the use of melatonin for migraine treatment. Nocturnal infusion of 20 micrograms of melatonin (from 21:00 to 01:00 h) evoked plasma melatonin levels slightly higher than a physiological secretion peak.  Headache relief was noted the morning after melatonin infusion in 4 out of 6 of the patients, with 3 patients describing decreased pulsatility of pain. No adverse effects were noted.
Another small, but clinically significant study examined the occurrence of headache and its change after treatments with 5 milligrams of melatonin.  Thirty patients with delayed sleep phase syndrome were given melatonin 5 hours before the endogenous nocturnal plasma melatonin concentration had reached 10 pg/mL. Individual results were as follows:
- Three women (aged 14, 14, and 23 years) included in the trial suffered from chronic tension-type headaches as well. Their headache disappeared within 2 weeks after the start of treatment with melatonin.
- One 54-year-old man suffered from disabling migraine attacks without aura, twice a week. After starting melatonin treatment, only three migraine attacks were reported in 12 months.
- A 60-year-old man complained of cluster headache episodes lasting about 2 months, twice a year, for over a twenty year period. In the year since starting melatonin treatment, only one 5-day cluster episode occurred.
As with the previous study, no adverse effects of melatonin administration were observed.
The authors suggest that melatonin’s effectiveness may be due to the modification of vascular and nociceptive systems or to its chronobiological action, which adjusts the patient’s biological clock to his/her lifestyle. Considering no adverse reactions had been noted in these two studies, melatonin may offer a tremendous benefit in treatment versus current prescription and non-prescription medications.
Other conditions for which melatonin may be beneficial include; cataracts, various types of cancer, hypertension in type 1 diabetes mellitus, epilepsy, androgenetic alopecia in women, benign prostatic hypertrophy, anxiolytic and sedative for surgery, and essential hypertension. [12-20]
Most studies use a dose of 1 - 2 milligrams daily. The timing of the dose is quite important for addressing sleep-wake cycles and has been most effective when taken within 90 - 120 minutes. Higher doses are required in some conditions such as cancer and Parkinson’s disease.
Melatonin is available in a time-released preparation which has shown improved results on sleep maintenance in a study of elderly individuals with insomnia.
Symptoms of melatonin deficiency include; insomnia in the elderly, anxiety, immune dysfunction, lower basal body temperature, and disturbances in the progesterone/estrogen ration resulting in premenstrual type symptoms.  Melatonin levels can be tested either directly by measuring plasma levels (although there is a great deal of variation due to circadian patterns of release), or by urinary breakdown products.
Melatonin is generally considered a safe therapeutic substance when taken in recommended doses. The majority of studies reveal the absence of adverse effects in patients taking melatonin. Melatonin supplementation should be avoided when there is excessive drowsiness or if a patient has seasonal affective disorder, because of the potential to aggravate symptoms. Adverse effects include drowsiness and lethargy if taken during waking hours. To minimize any side effects of night time melatonin supplementation, wide spectrum light therapy in the morning can be employed. 
Melatonin, when taken at a dosage level of 8 milligrams daily has produced significant alterations in the circadian rhythm of other hormones, as evidenced by measurements of cortisol and prolactin levels over a four day period. 
1. Murray M and Pizzorno J. Encyclopedia of Natural Medicine, 2nd Ed. Prima Publishing, Rocklin, CA 1998:173-174.
2. Reiter RJ et al. A review of the evidence supporting melatonin’s role as an antioxidant. J Pineal Res 1995;18(1)1-11.
3. Powell, D. Endocrinology and Naturopathic Therapies. Bastyr University, Kenmore, WA 2002;28-30.
4. Balch PA. Prescription for Nutritional Healing: The A-Z Guide to Supplements, 2nd Ed. Penguin Putnam, Inc. New York, NY 2002;120-121.
5. Shaffer M. Melatonin could help elderly sleep better. Med Tribune July 22;1993:15.
6. Field R. Melatonin may relieve sleep-cycle disorders. Med Tribune Apr 8; 1993:2
7. Garfinkel D et al. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet 1995;346:541-544.
8. Garfinkel D et al. Facilitation of benzodiazepine discontinuation by melatonin: a new clinical approach. Arch Intern Med 1999;159:2456-2460.
9. Petrie K et al. Effect of melatonin on jet lag after long haul flights. Br Med J 1989;298:705-707.
10. Claustrat B, Brun J, Geoffriau M, Zaidan R, Mallo C, Chazot G. Nocturnal plasma melatonin profile and melatonin kinetics during infusion in status migrainosus. Cephalalgia 1997;17(4):511-7; discussion 487
11. Nagtegaal JE; Smits MG; Swart AC; Kerkhof GA; van der Meer YG. Melatonin-responsive headache in delayed sleep phase syndrome: preliminary observations. Headache 1998;38(4):303-7
12. Reiter RJ et al. Oxygen radical detoxification processes during aging: the functional importance of melatonin. Aging Clinical Exp Res 1995;7:340-351.
13. Lissoni P et al. Randomized study of the pineal hormone melatonin versus supportive care alone in advanced nonsmall cell cancer resistant to a first line chemotherapy containing cisplatin. Oncology 1992;49:336-339.
14. Lissoni P et al. A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms. Cancer 1994;73:699-701.
15. Cavallo A et al. Blood pressure response to melatonin in type 1 diabetes. Pediatr Diabetes. 2004;5(1):26-31.
16. Gupta M et al. A randomized, double-blind, placebo controlled trial of melatonin add-on therapy in epileptic children on valproate monotherapy: effect on glutathione peroxidase and glutathione reductase enzymes. Br J Clin Pharmacol. 2004;58(5):542-7.
17. Fischer TW et al. Melatonin increases anagen hair rate in women with androgenetic alopecia or diffuse alopecia: results of a pilot randomized controlled trial. Br J Dermatol. 2004;150(2):341-5.
18. Drake MJ, Mills IW, Noble JG. Melatonin pharmacotherapy for nocturia in men with benign prostatic enlargement. J Urol. 2004;171(3):1199-202.
19. Acil M et al. Perioperative effects of melatonin and midazolam premedication on sedation, orientation, anxiety scores and psychomotor performance. Eur J Anaesthesiol. 2004;21(7):553-7.
20. Scheer FA et al. Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension. Hypertension. 2004;43(2):192-7.
21. Mallo C et al. Effects of a four day melatonin treatment on the 24h plasma melatonin, cortisol and prolactin profiles in humans. Acta Endocrinologia 1995;119:474-480.