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Melatonin: Insomnia, Cancer, Jet Lag, Immune Support

James Meschino DC, MS, ROHP
General Feature
Melatonin is a molecule that has been found in every animal and plant studied to date, from human beings to the most primitive one-celled algae that evolved more than three billion years ago.  In each organism, Melatonin’s molecular structure is identical.  This sameness is a rare occurrence in biology.

In all the life forms studied, Melatonin has been produced in the same circadian (daily secretion pattern) rhythm, with higher levels produced at night than during the daytime.

In humans, Melatonin is produced and secreted by the pineal gland in the brain.  It is synthesized from serotonin, which itself is synthesized from 5-hydroxytryptophan and tryptophan.  In the human body Melatonin acts as a hormone, neurotransmitter, antioxidant and immune system modulator.

It is best known for its ability to induce sleep and elevate mood.  Humans produce five to ten times more Melatonin at night than during the day, a circadian rhythm found in animals as well.  Peak amounts occur around two or three o’clock in the morning.

After puberty the body’s production of Melatonin declines.  By age 40 humans produce approximately 60 percent less Melatonin than a 10 year old and by age 70 or 80 Melatonin levels may be undectable.1

With respect to its antioxidant properties, Melatonin is unique in that it is both a water-soluble antioxidant and a fat-soluble antioxidant.  Some studies suggest that as an antioxidant it is twice as effective as Vitamin E, five times as efficient as glutathione, and five hundred times more effective than the synthetic DMSO.  However, Melatonin is produced in picograms (a trillionth of a gram – the smallest amount of any hormone), whereas Vitamin E, and other antioxidants, are present in much higher concentrations.2

Supplementation Studies and Clinical Applications

  1. Insomnia

Low Melatonin secretion at night which commonly accompanies aging, can be a cause of insomnia.  Several double-blind trails show that Melatonin supplementation can be useful in the treatment of insomnia.  Taken within one hour of bedtime, Melatonin has been shown to shorten the time needed to fall asleep, reduce the number of night awakenings, and improve sleep quality.  Low Melatonin levels are an extremely common cause of insomnia in the elderly, who manufacture 90-99 percent less Melatonin than a ten-year old.3-10

  1. Jet Lag

Several double-blind studies demonstrate that Melatonin is very effective in relieving jet lag.  The best approach appears to be taking Melatonin in the first evening after arriving at the new destination (where there is a time zone change).  Shift workers may also take advantage of this strategy to reset the body internal wake-sleep cycle.11-16

  1. Other Considerations

As Melatonin is also an antioxidant, an immune system modulator and a core temperature regulator it is being tested for various other health applications:

  1. Tension and cluster headaches – Some preliminary, double-blind studies suggest that Melatonin supplementation may help in certain cases (1-3 mg at night).17,18 This affect has been attributed to Melatonin’s ability to prevent a rise in core temperature, which is linked to cluster headaches.35,36
  2. Sarcoidosis – Preliminary evidence has shown improvement in patients with sarcoidosis (20 mg at night).19
  3. Adjunctive Cancer Treatment – Early trials indicate that Melatonin supplementation, as an adjunct to cancer treatment may help inhibit the progression of breast cancer, reduce the PSA levels in prostate cancer patients and improve disease-free survival in melanoma patients, as well as patients with brain and lung cancer (20 mg at night). Of course, more research is required before any conclusive statements can be made about this application.20-27  In a study of cancer patients with solid tumors in various organs the intake of Melatonin (40 mg per day) enhanced the effectiveness of interleukin-2 therapy by enhancing its anti-tumor immune effect or by increasing susceptibility of cancer cells to the cytolysis by cytotoxic lymphocytes.37
  4. Immune System and AIDS – Maestroni and Conti demonstrated in 1995 that T-helper-2 lymphocytes possess Melatonin receptors. When Melatonin docks with its receptor on the T-helper cell, a cascade of events is set in motion releasing important signalling agents (cytokines) that strengthen immune function in various ways.  For example, natural killer cell production rose by 240 percent in healthy young men taking 20 mg of Melatonin each night for a period of two months.

Melatonin may also inhibit viral replication and has been shown to increase T-helper cell numbers and natural killer cell numbers in HIV-infected individuals.  Further research is underway to substantiate these findings (20 mg at night).28,29

  1. Birth Control/Contraceptive – Very high doses of Melatonin inhibits ovulation in animals and women. A new birth control is now being tested known as B-Oval.  It contains no estrogen, but rather high dose Melatonin (75 mg) and 0.3 mg of progestin.30

Dosage Ranges
Insomnia and Jet Lag (Shift Workers) – 0.1 mg to 3.0 mg (note 0.1 mg equals 100 mcg), one to two hours before bedtime.  It is best to start with a small dose and work up, based upon improved sleep with no awakening and morning drowsiness.

N.B.  Taking a high dosage of Melatonin (5 – 75 mg) should only be undertaken with knowledge of a physician, who is able to monitor blood work and other parameters, as these dosages are still experimental and long-term safety is unknown at this time.38

Adverse Side Effects and Toxicity
Taking doses that are too high can result in morning grogginess, headaches and/or abdominal cramps.31,32

Melatonin testing in humans and animals indicate that it is very non-toxic.1,33

Contraindications and Drug-Nutrient Interactions
Some cases of depression can be aggravated by Melatonin supplementation.34  Some antidepressant drugs stimulate the production of Melatonin and others, such as fluoxetine (Prozac), may lower Melatonin levels.  It is probably best at this time not to combine Melatonin with any other drug that targets brain chemistry or neurotransmitter levels.35,36

A number of drugs have been shown to deplete Melatonin levels.  Some of these include aspirin, ibuprofen, beta-blockers, calcium channel blockers, sleeping pills, tranquillizers, fluoxetine (Prozac), caffeine, steroids and tobacco.1

The clinical significance of this is yet to be determined, in regards to whether or not patients on these substances require Melatonin supplementation to compensate for the depletion of Melatonin (author’s note).


  1. Reitar RJ, Robinson J.   New York, NY: Bantam Books; 1995.  p. 3-30.
  2. Shida CS, Castrucci AML, Lamy-Freund MT. High melatonin solubility in aqueous medium.  J Pineall Res 1994;16:198-201.
  3. Waldhauser F, Saletu B, Trinchard-Lugan I. Sleep laboratory investigations on hypnotic properties of melatonin.  Psychopharmacol 1990;100:222-6.
  4. Zhdanova IV, Wurtman RJ, Morabito C, Piotrovska VR, Lynch HJ. Sleep-inducing effects of low doses of melatonin ingested in the evening.  Clin Pharmacol Ther 1995;57:552-8.
  5. Dahlitz M, Alverez B, Vignau J, English J, Arendt J, Parkes JD. Delayed sleep phase syndrome response to melatonin. Lancet 1991;337:1121-4.
  6. MacFarlane JG, Cleghorn JM, Brown GM, Streiner DL. The effects of exogenous melatonin on the total sleep time and day-time alertness of chronic insomniacs: A preliminary study.  Biol Psychiatry 1991;30:371-6.
  7. James SP, et al. Melatonin administration in insomnia.  Neuropsychopharmacology 1990;3:19-23.
  8. Nave R, Peled R, Lavie P. Melatonin improves evening napping.  Eur J Pharmacol 1995;275:213-6.
  9. Haimov I, Laudon M, Zisapel N, Souroujon M, Nof D, Shlitner A, et al. Sleep disorders and melatonin rhythms elderly people.  BMJ 1994;309:167.
  10. Hughes RJ, Sack RL, Lewy AJ. The role of melatonin and circadian phase in age-related sleep maintenance insomnia: assessment in a clinical trial of melatonin replacement. Sleep 1998;21:52-68.
  11. Arendt J, Aldhous M, English J, Marks V, Arendt JH, Marks M, et al. Some effects of jet-lag and their alleviation by melatonin. Ergonomics 1987;30:1379-98.
  12. Claustrat B, Brun J, David M, Sassolas G, Chazot G. Melatonin and jet lag: Confirmatory result using a simplified protocol.  Biol Psychiatry 1992;32:705-11.
  13. Petrie K, Conaglen JV, Thompson L, Chamberlain K. Effect of melatonin on jet lag after long haul flights.  Br Med J 1989;298:705-7.
  14. Lino A, Silvy S, Condorelli L, Rusconi AC. Melatonin and jet lag: Treatment schedule.  Biol Psychiatry 1993;34:587.
  15. Petrie K, Dawson AG, Thompson L, Brook R. A double-blind trial of melatonin as a treatment for jet lag in international cabin crew.  Biol Psychiatry 1993;33:526-30.
  16. Folkard S, Arendt J, Clark M.Can melatonin improve shift workers’ tolerance of the night shift: Some preliminary findings.  Chronobio Intern 1993;10,5:315-20.
  17. Nagtegaal JE, Smits MG, Swart AC, Kerkhof GA, van der Meer YG. Melatonin-responsive headache in delayed sleep phase syndrome: Preliminary observations.  Headache 1998;38:303-7.
  18. Leone M, D’Amico D, Moschiano F, et al. Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups.  Cephalagia 1996;16:494-6.
  19. Cagnoni ML, Lombardi A, Cerinic MC, Dedola GL, Pignone A. Melatonin for treatment of chronic refractory sarcoidosis [letter]. Lancet  1995;346(4):1229-30.
  20. Lissoni P, et al. A randomized study with subcutaneous low-dose interleukin 2 alone vs interleukin 2 plus the pineal neurohormone melatonin in advanced solid neoplasms other than renal cancer and melanoma.  Br J Cancer 1994;69:196-9.
  21. Lissoni P, Barni S, Fossati V, Ardizzoia A, Cazzaniga M, Tancini G, et al. A randomized study of neuroimmunotherapy with low-dose subcutaneous interleukin-2 plus melatonin compared to supportive care alone in patients with untreatable matastatic solid tumor.  Support Care Cancer 1995;3(3):194-7.
  22. Neri B, Fiorelli C, Moroni F, Nicita G, Paoletti MC, Ponchieatti R, et al. Modulation of human lymphoblastoid interferon activity by melatonin in metastatic renal cell carcinoma: A phase II study.  Cancer 1994;73(12):3014-9.
  23. Lissoni P, Barni S, Meregalli S, Fossati V, Cazzaniga M, Esposti D, et al.  Modulation of cancer endocrine therapy by melatonin: A phase II study of tamoxifen plus melatonin in metastatic breast cancer patients progressing under tamoxifen alone. Br J Cancer 1995;71(4):854-6.
  24. Lissoni P, Barni S, Ardizzoia A, Paolorossi F, Crispino S, Tancini G, et al. Randomized study with the pineal hormone melatonin versus supportive care alone in advanced non-small cell lung cancer resistant to a first-line chemotherapy containing cisplatin.  Oncology 1992;49:336-9.
  25. Lissoni P, Barni S, Cattaneo G, Tancini G, Esposti G, Esposti D, et al.  Clinical results with the pineal hormone melatonin in advanced cancer resistant to standard antitumor therapies. Oncology 1991;48:448-50.
  26. Lissoni P, Barni S, Ardizzoia A, Tancini G, Conti A, Maestroni G. 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.
  27. Lissoni P, Cazzaniga M, Tancini GE, et al. Reversal of clinical resistance to LHRH analogue in metastatic prostate cancer by the pineal hormone melatonin: efficacy of LHRH analogue plus melatonin in patients progressing on LHRH analogue alone.  Eur Urol 1997;31:178-81.
  28. Maestroni, GJ. T-Helper-2 lympocytes as peripheral target of melatonin signalling.  J Pineal Res 1995;18:84-9.
  29. Reiter RJ, et al. The role of melatonin in the pathophysiology of oxygen radical damage.  In: Advances in Pineal Research.  8.  Moller M, Pevet P, editors.  London: John Libbey and Co.; 1994.  p. 278.
  30. Reitar RJ, Robinson J.   New York, NY: Bantam Books; 1995.  p. 166-7.
  31. Shannon M. Alternative medicines toxicology: A review of selected agents.  Clin Toxicol 1999;37:709-3.
  32. Guardiola-Lemaitre B. Toxicology of melatonin.  J Biol Rythms 1997;12:697-706.
  33. Barchas J, et al. Acute Pharmacology of Melatonin.  Nature 1967;214:919-220.
  34. Rubin RL, et al. Neuroendocrine aspects of primary indogenous depression, XI, Xerum melatonin measures in patients and matched control subjects. Arch Gen Psychiat 1992;49:558-567.
  35. Peres MF, Seabra ML, Zukerman E, Tufik S. Cluster headache and melatonin.  Lancet 2000;355:147[letter].
  36. Blau JN, Engel HO. A new cluster headache precipitant: increased body heat.  Lancet 1999;354:1001-2.
  37. Lissoni P, Barni S, Cazzaniga M, Ardizzoia A, Rovelli F, Brivio F, et al. Efficacy of the concomitant administration of the pineal hormone melatonin in cancer immunotherapy with low-dose IL-2 in patients with advanced solid tumors who had progressed on IL-2 alone.  Oncology 1994;51(4):344-7.
  38. Natural Products Encyclopedia. Melatonin.
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