WHAT IS THE PROPER DOSE OF MELATONIN?
The Life Extension Foundation regularly profiles and evaluates important new products on the market, often making them available directly to you, as well as to Foundation members at a discount via the Life Extension Buyers Club.
Based on published reports indicating significant disease prevention potential, melatonin has become a popular dietary supplement in the United States. There is a debate, however, as to what the optimal nightly dose of melatonin should be.
A recent study tested ten milligrams of melatonin for 28 consecutive nights on human volunteers. At this high dose, there was no evidence of toxicity and those receiving the melatonin (10 mg) had a better sleep score compared to the placebo group.[ 1]
Some experts, however, advocate that low-dose melatonin is better than higher doses. These scientists point to another study on human subjects where only 300 micrograms of melatonin induced better sleep than 3000 micrograms (3 mg) over a seven day period.[ 2]
A review of all the published literature reveals that a wide range of melatonin doses have been used to produce better sleep patterns in human subjects.[ 3-31]
The Life Extension Foundation introduced melatonin to its members in 1992. The dosage unit of the first melatonin supplement offered was 3 milligrams (mg). Over the years, The Foundation has introduced new melatonin supplements starting in dosage units of 500 micrograms and going up to 10 milligrams.
In the January 1996 issue of Life Extension magazine, an article was published suggest-hag that lower doses of melatonin might enable some people to sleep better. This article was based on anecdotal reports from some members who stated they had better sleep patterns when taking 500 microgram melatonin rather than higher doses.
To ascertain what dosage units Foundation members find most effective, we did a computer survey of melatonin purchases over the last 12 months. The chart below shows the percentage of overall melatonin sales for the least to most popular doses of melatonin chosen.
As can be seen above, the majority of Foundation members prefer the 3 mg doses. Even though most people are buying the 3 mg size, some are taking two of these capsules at bedtime, meaning they are consuming a total of 6 mg of melatonin nightly.
Based on studies indicating that melatonin may provide anti-aging effects throughout the body, it is easy to understand why members would want higher amounts of melatonin. One recent report discusses the role of melatonin in reversing partially degraded body proteins that lead to lipofuscin (age-pigments), cataract and cross-linked collagen. The scientist who wrote this article stated that the night-time rise in melatonin is one way the body "cleans" itself of partially glycated proteins.[ 32] If this hypothesis is correct, it provides a new mechanism to help explain how melatonin protects against such a wide range of age-related diseases.
For those who are not sleeping well, despite taking higher doses of melatonin, it is important to emphasize that there is a logical basis for some people using lower doses to induce better sleep.
The age-related decline in melatonin production
As people age, their sleep quality often undergoes significant deterioration, commonly characterized by frequent and longer-lasting nighttime awakenings. In many older people, sleep disturbance is correlated with a decline in melatonin secretion. A number of published studies also show that decreased melatonin production is associated with the onset of a host of degenerative diseases.[ 53-57]
In older people, peak nighttime melatonin levels are only 30 to 40 (picograms per milliliter of blood),[ 58] whereas younger people often secrete 100 to 200 (picograms per milliliter of blood) at night.[ 59] This age-related decline in melatonin secretion has been demonstrated in all but one[ 60] of more than 20 studies that have examined this issue.
The vast majority of melatonin is produced in the pineal gland. During normal aging, calcification of the pineal tissue is thought to cause the decline in melatonin synthesis.
A number of studies show that melatonin deficiency may be an underlying cause of insomnia in older people. When melatonin is administered to humans in clinical trials, it induces sleep sooner and produces better sleep patterns compared to placebo.[ 61-64]
Low-dose melatonin for sleep
In response to several studies showing that doses as low as 300 micrograms of melatonin can induce an enhanced state of drowsiness and provide a better quality of sleep, The Life Extension Buyers Club is offering members the option of using very low-dose melatonin supplements. For those who have tried higher dose melatonin supplements and not found effective relief from insomnia, these lower dose supplements may prove effective.
Unlike Canada, Europe and Japan, where melatonin is regulated as a drug, citizens of the United States can buy pharmaceutical-grade melatonin at extraordinarily low prices.
When it comes to ascertaining the ideal dose of melatonin, there appears to be a wide range of individual variability. Most people use 3 mg of melatonin at night to induce better sleep and saturate their body with high levels of melatonin. There will be some people, on the other hand, who may find they sleep better by taking only 1/10 this amount, i.e. 300 mcg of melatonin.
Mainstream scientists often raise concern that melatonin sold in health food stores may not meet pharmaceutical standards of purity. That is why the Life Extension Buyers Club restricts its purchases of melatonin to European sources that produce only 99.99% or better purity.
Melatonin's multi-modal effects
Melatonin may help prevent a number of age-related degenerative diseases. What follows are titles from just a few of the many published articles indicating the importance of maintaining youthful levels of melatonin.
A significant correlation between melatonin deficiency and endometrial cancer. Gynecol Obstet Invest 1998; 45( 1):62-5.
Melatonin and regulation of the cardiovascular system. Therapie 1998 Sep-Oct;53( 5):459-65.
Effect of melatonin on sleep quality of COPD intensive care patients: a pilot study. Chronobiol Int 2000 Jan;17( 1):71-6.
Pharmacology and physiology of melatonin in the reduction of oxidative stress in vivo. Biol Signals Recept 2000 May-Aug; 9( 3-4):160-71.
Is carbonyl detoxification an important anti-aging process during sleep? Med Hypotheses 2000 Apr;54( 4):519-22.
Differential growth inhibitory effect of melatonin on two endometrial cancer cell lines. J Pineal Res 2000 28( 4):227-33.
Melatonin as biological response modifier in cancer patients Anticancer Res 1998 Mar-Apr; 18(2B): 1329-32.
Melatonin deficiency: Its role in oncogenesis and age-related pathology. Journal of Orthomolecular Medicine (Canada) 1990, 5/1 ( 22-24).
Cataractogenesis and lipid peroxidation in newborn rats treated with buthionine sulfoximine: preventive actions of melatonin. J Pineal Res 1997 Apr;22( 3): 117-23.
Melatonin improves sleep quality of patients with chronic schizophrenia. J Clin Psychiatry 2000 May;61 ( 5):373-7.
Effect of melatonin on proliferative activity and apoptosis in colon mucosa and colon tumors induced by 1,2-dimethylhydrazine in rats. Exp Toxicol Pathol 2000;52( 1):71-6.
Influence of melatonin on proliferation and antioxidant system in Ehrlich ascites carcinoma cells. Cancer Left 2000; 151( 2):119-25.
1. de Lourdes M, et al. Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. Pineal Res 2000 Nov;29(4): 193-200.
2. Harrison's Online http://www.medscape.com/HOL/public/HOL-journal.html. Effects of Melatonin on Sleep. Richard J. Wurtman, Cecil H. Green Distinguished Professor and Director, Clinical Research Center, MIT, Cambridge, MA [Copyright [Copyright] 1998, 1999, 2000 by The McGraw-Hill Companies, Inc. Reproduced with permission of The McGraw-Hill Companies.]
3. Dawson D, et al. Effect of sustained nocturnal transbuccal melatonin administration on sleep and temperature in elderly insomniacs. J Biol Rhythms 1998 Dec;13(6):532-8.
4. Suhner A, et al. Comparative study to determine the optimal melatonin dosage form for the alleviation of jet lag. Chronobiol Int 1998 Nov;15(6):655-66.
5. Sack RL, et al. Entrainment of free-running circadian rhythms by melatonin in blind people. N Engl J Med 2000 Oct 12;343(15):1070-7.
6. Dalton EJ, et al. Use of slow-release melatonin in treatment-resistant depression. J Psychiatry Neurosci 2000 Jan;25(1):48-52.
7. Matsumoto M. The hypnotic effects of melatonin treatment on diurnal sleep in humans. Psychiatry Clin Neurosci 1999 Apr;53(2):243-5.
8. Zhdanova IV, et al. Effects of a low dose of melatonin on sleep in children with Angelman syndrome. J Pediatr Endocrinol Metab 1999 Jan-Feb;12(1):57-67.
9. Jan JE, et al. Melatonin treatment of non-epileptic myoclonus in children. Dev Med Child Neurol 1999 Apr;41 (4):255-9.
10. Miyamoto A, et al. Serum melatonin kinetics and long-term melatonin treatment for sleep disorders in Rett syndrome. Brain Dev 1999 Jan;21 (1):59-62.
11. Domzal TM, et al. [Melatonin in sleep rhythm disorders after cerebral stroke]. Pol Merkuriusz Lek 2000 Jun;8(48) :411-2.
12. Garfinkel D, et al. Facilitation of benzodiazepine discontinuation by melatonin: a new clinical approach. Arch Intern Med 1999 Nov 8; 159(20):2456-60.
13. Brusco LI, et al. Effect of melatonin in selected populations of sleep-disturbed patients. Biol Signals Recept 1999 Jan-Apr;8(l-2):126-31.
14. Fauteck J, et al. Melatonin in epilepsy: first results of replacement therapy and first clinical results. Biol Signals Recept 1999 Jan-Apr;8(1-2): 105-10.
15. Dagan Y, et al. Rapid reversal of tolerance to benzodiazepine hypnotics by treatment with oral melatonin: a case report. Eur Neuropsychopharmacol 1997 May;7(2):157-60.
16. Pillar G, et al. Melatonin treatment in an institutionalised child with psychomotor retardation and an irregular sleep-wake pattern. Arch Dis Child 1998 Jul;79(1):63-4.
17. Gordon N. The therapeutics of melatonin: a paediatric perspective. Brain Dev 2000 Jun;22 (4):213-7.
18. Kunz D, et al. Melatonin as a therapy in REM sleep behavior disorder patients: an open-labeled pilot study on the possible influence of melatonin on REM-sleep regulation. Mov Disord 1999 May;14(3):507-11.
19. Jean-Louis G, et al. Melatonin effects on sleep, mood, and cognition in elderly with mild cognitive impairment. J Pineal Res 1998 Oct;25(3):177-83.
20. Kato M, et al. Melatonin treatment for rhythm disorder. Psychiatry Clin Neurosci 1998 Apr;52(2):262-3.
21. Okawa M, et al. Melatonin treatment for circadian rhythm sleep disorders. Psychiatry Clin Neurosci 1998 Apr;52 (2):259-60.
22. Melatonin treatment for circadian rhythm sleep disorders. Does exogenous melatonin improve day sleep or night alertness in emergency physicians working night shifts? Ann Emerg Med 1998 Jun;31 (6):699-704.
23. Avery D, et al. Guidelines for prescribing melatonin. Ann Med 1998 Feb;30(1):122-30.
24. Shochat T, et al. Melatonin--the key to the gate of sleep. Ann Med 1998 Feb;30(1): 109-14.
25. Rosenberg SI, et al. Effect of melatonin on tinnitus. Laryngoscope 1998 Mar; 108 (3) :305-10.
26. Hughes RJ, et al. Sleep-promoting and hypothermic effects of daytime melatonin administration in humans. Sleep 1997 Feb;20(2):124-31.
27. Lushington K, et al. Daytime melatonin administration in elderly good and poor sleepers: effects on core body temperature and sleep latency. Sleep 1997 Dec;20(12): 113544.
28. Kunz D, et al. Melatonin effects in a patient with severe REM sleep behavior disorder: case report and theoretical considerations. Neuropsychobiology 1997 ;36 (4) :2114.
29. Jan JE, et al. Use of melatonin in the treatment of paediatric sleep disorders. J Pineal Res 1996 Nov;21 (4): 193-9.
30. Middleton B, et al. Complex effects of melatonin on human circadian rhythms in constant dim light. J Biol Rhythms 1997 Oct; 12 (5):467-77.
31. Nakamura K, et al. Daily melatonin intake resets circadian rhythms of a sighted man with non-24-hour sleep-wake syndrome who lacks the nocturnal melatonin rise. Psychiatry Clin Neurosci 1997 Jun;51 (3): 121-7.
32. Yin D. Is carbonyl detoxification an important anti-aging process during sleep? Med Hypotheses 2000 Apr;54(4):519-22.
33. Yu Q, et al. Melatonin inhibits apoptosis during early B-cell development in mouse bone marrow. J Pineal Res 2000 Sep;29(2):86-93.
34. Anisimov VN, et al. Melatonin and colon carcinogenesis. III Effect of melatonin on proliferative activity and apoptosis in colon mucosa and colon tumors induced by 1, 2-dimethylhydrazine in rats. Exp Toxicol Pathol 2000 52(1):71-6.
35. Lissoni P, et al. Immunoendocrine therapy with low-dose subcutaneous interleukin-2 plus melatonin of locally advanced or metastatic endocrine tumors. Oncology 1995 52(2):163-6.
36. Aldeghi R, et al. Low-dose interleukin-2 subcutaneous immunotherapy in association with the pineal hormone melatonin as a first-line therapy in locally advanced or metastatic hepatocellular carcinoma. Eur J Cancer 1994 30A(2):167-70.
37. Neri B, et al. Melatonin as biological response modifier in cancer patients. Anticancer Res 1998 Mar-Apr;18(2B):1329-32.
38. Lissoni P, et al. A randomized study of chemotherapy with cisplatin plus etoposide versus chemoendocrine therapy with cisplatin, etoposide and the pineal hormone melatonin as a first-line treatment of advanced non-small cell lung cancer patients in a poor clinical state. J Pineal Res 1997 Aug;23(1):15-9.
39. Kanishi Y, et al. Differential growth inhibitory effect of melatonin on two endometrial cancer cell lines. J Pined Res 2000 28(4):227-33.
40. El-Missiry MA, et al. Influence of melatonin on proliferation and antioxidant system in Ehrlich ascites carcinoma cells. Cancer Lett 2000 151 (2):119-25.
41. Reiter RJ, et al. Pharmacology and physiology of melatonin in the reduction of oxidative stress in vivo. Biol Signals Recept 2000 May-Aug;9(34):160-71.
42. Scalbert E, et al. [Melatonin and regulation of the cardiovascular system]. Therapie 1998 Sep-Oct;53(5):459-65.
43. Fontenot J.M., et al. Melatonin deficiency: Its role in oncogenesis and age-related pathology. Journal of Orthomolecular Medicine (Canada) 1990, 5/1 (22-24).
44. Li ZR, et al. Cataractogenesis and lipid peroxidation in newborn rats treated with buthionine sulfoximine: preventive actions of melatonin. J Pineal Res 1997 Apr;22(3): l17-23Erratum in: J Pineal Res 1997 Nov;23(4):230.
45. Srinivasan V. Melatonin, biological rhythm disorders and phototherapy. Indian J Physiol Pharmacol 1997 Oct;41 (4):309-28.
46. McArthur AJ, et al. Sleep dysfunction in Rett syndrome: a trial of exogenous melatonin treatment. Dev Med Child Neurol 1998 Mar;40(3): 186-92.
47. Dagan Y, et al. Evaluating the role of melatonin in the long-term treatment of delayed sleep phase syndrome (DSPS). Chronobiol Int 1998 Mar; 15 (2): 181-90.
48. Nagtegaal JE, et al. Traumatic brain injury-associated delayed sleep phase syndrome. Funct Neurol 1997 Nov-Dec;12(6):345-8.
49. Nagtegaal JE, et al. Effects of melatonin on the quality of life in patients with delayed sleep phase syndrome. J Psychosom Res 2000 Jan;48(1):45-50.
50. Shilo L, et al. Effect of melatonin on sleep quality of COPD intensive care patients: a pilot study. Chronobiol Int 2000 Jan;17(1):71-6.
51. Shamir E, et al. Melatonin improves sleep quality of patients with chronic schizophrenia. J Clin Psychiatry 2000 May;61 (5):373-7.
52. Grin W, et al. A significant correlation between melatonin deficiency and endometrial cancer. Gynecol Obstet Invest 1998;45(1):62-5.
53. Hoyos M, et al. Serum cholesterol and lipid peroxidation are decreased by melatonin in diet-induced hypercholesterolemic rats. J Pineal Res 2000 Apr;28(3):150-5.
54. Vollrath L., et al. Day/night serotonin levels in the pineal gland of male BALB/c mice with melatonin deficiency. Acta Endocrinologica (Denmark) 1988, 117/1 (93-98).
55. O'Hare J.P., et al. Does melatonin deficiency cause the enlarged genitalia of the fragile-X syndrome? Clinical Endocrinology (United Kingdom) 1986, 24/3 (327-333).
56. Scalbert E, et al. [Melatonin and regulation of the cardiovascular system]. Therapie 1998 Sep-Oct;53(5):459-65.
57. Garcia-Maurino S, et al. Melatonin activates Th1 lymphocytes by increasing IL-12 production. Life Sci 1999;65(20):2143-50.
58. Waldhauser F, et al. Alterations in nocturnal serum melatonin levels in humans with growth and aging. J Clin Endocrinol Metab 1988 Mar;66(3) :648-52.
59. Brzezinski A. Melatonin in humans. N Engl J Med 1997 Jan 16;336(3):186-95.
60. Zeitzer JM, et al. Do plasma melatonin concentrations decline with age? Am J Med 1999 Nov;107(5):432-661.
61. Garfinkel D, et al. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet 1995 Aug 26;346(8974):5414.
62. Saletu B. [Melatonin--a natural hypnotic]? Wien Klin Wochenschr 1997 Oct 3;109(18):714-21.
63. Zisapel N. The use of melatonin for the treatment of insomnia. Biol Signals Recept 1999 Jan-Apr;8(1-2):84-9.
64. Blaicher W, et al. Melatonin in postmenopausal females. Arch Gynecol Obstet 2000 Feb;263 (3): 116-8.