Wake-Up Call for Melatonin 

Melatonin is an exciting subject. Remember all the media hoopla two years ago? The Melatonin Miracle . . . The Aging Clock . . . Nature's Sleeping Pill . . . et cetera. The truth is . . . the "hype" is real. Melatonin does virtually everything they say it does. The scientific literature is solid. To start off, melatonin is a supplement that you can experience. It produces noticeable and positive effects. It helps improve sleep. It enhances immune function. It's a powerful antioxidant. And it's also one of the few supplements with a patina that extends out to the horizon. To wit, several animal studies even indicate that melatonin may help to roll back the aging clock, and extend mean lifespan and possibly maximum lifespan. With this kind of press, many people thought melatonin was the "answer" to all their health problems.


From reviewing the literature on
melatonin, it becomes clear that
a dividing line must be drawn
between what is a physiologic
and what is a pharmacologic dose.

Now that the publicity storm has passed, it is time to reassess the value of this pineal hormone and especially the controversy concerning the right amounts to take. To get the most out of supplementing with melatonin, it is necessary to know that some advantages are not achievable except at higher pharmacological doses. It is also necessary that dosing at these levels may mean foregoing other, perhaps more important long-range benefits. There may be one optimal dose (higher level) for protection against excessive cell proliferation (which could lead to cancer), and another (higher level) dose for antioxidant optimality and yet another (lower or higher level) for enhancing the prospects of increased longevity.

Because our concern has always been the long-run, it behooves us to determine the optimal amount for long-term outcome. Is that amount physiologic (in a range with which our body is accustomed) or is it pharmacologic (in a range that is many multiples higher than the body normally experiences)? What are the known risks? What do we know and what don't we know?

Perhaps the easiest way to investigate this is to review the functional benefits of melatonin and to cite the amounts used in the literature. A chart follows. 

AMOUNT USED EXPERIMENTAL SUBJECTS(positive responders) RESEARCH CITATION (comments on findings)
Promote better sleep (Physiologic) 
300 mcg - 5 mg (oral)
12 (12) Zhdanova IV, Wurtman RJ, Morabito C, Piotrovska VR, Lynch HJ. Effects of low oral doses of melatonin, given 2-4 hours before habitual bedtime, on sleep in normal young humans. Sleep 1996;19:423-431.

Comments: Sleep promotion without hangover.

Avoid jet lag (Physiologic) 
1-10 mg (oral)
20 (20) Comperatore CA, Lieberman HR, Kirby AW, Adams B, Crowley JS. Melatonin efficacy in aviation missions requiring rapid deployment and night operations. Aviat Space Environ Med 1996;67:520-52.

Comments: More rapid acclimation across the board.

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(7):526-530.

Comments: Taking 5 mg of melatonin before flight day did not help but taking it after increased recovery and alertness.

Memory maintenance (Physiologic) 
6 mg (oral)
10 (10) Jean-Louis G, von Gizycki H, Zizi F. Melatonin effects on sleep, mood, and cognition in elderly with mild cognitive impairment. J Pineal Res. 1998 Oct;25(3):177-183.

Comments: The ability to remember previously-learned items improved by taking 5 mg melatonin. There was also a significant reduction in depressed moods.

Immune enhancement (Pharmacologic) 
10-40 mg (oral)
Little benefit Fraschini F, Demartini G, Esposti D, Scaglione F. Melatonin involvement in immunity and cancer. Biol Signals Recept 1998 Jan;7(1):61-72.

Comments: Melatonin found to exert direct and/or indirect stimulatory effects on immunity.

Antioxidant protection (Pharmacologic) 15 (13*) Abuja PM, Liebmann P, Hayn M, Schauenstein K, Esterbauer H. Antioxidant role of melatonin in lipid peroxidation of human LDL. FEBS Lett. 1997 Aug 18;413(2):289-293.

Comments: The data in this study does not support a direct physiological relevance of melatonin as an antioxidant in lipid peroxidation processes because it is too weak at low levels.

Lifespan increase (in animals) (Pharmacologic) 12 (4*) 
10 (20%**) 
15 (6 mos***)
Oaknin-Bendahan S, Anis Y, Nir I, Zisapel N. Effects of long-term administration of melatonin and a putative antagonist on the aging rat. NeuroReport.1995; 6: 785-788.

Comments: At specie survival age, 43% of controls remained, while 87% of melatonin-consuming rats survived (with better health).

* Alive at specie life expectancy age

Lifespan increase, mean or maximal (in animals) (Physiologic); 
perhaps as low as 300 mcg; data not clear
12 (4*) 
10 (20%**) 
15 (6 mos***)
Pierpaoli W, Regelson W. Pineal control of aging: effect of melatonin and pineal grafting on aging mice. Proc Natl Acad Sci. 1994;91:787-791.

Comments: Survival and youthfulness prolonged in all groups of mice (male and female) when melatonin given at night (but not daytime) and whether started earlier or later in life.

* Outliving controls

** Percent survival beyond controls

*** Absolute duration of survival increase = 6 months)

Prevention and treatment of cancer (Pharmacologic)
40 mg-700 mg
30 (16) 
14 (14) 
40 (6)
Lissoni P, Meregalli S, Nosetto L, et al. Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology1996;53:43-6.

Comments: Melatonin may prolong the survival time and improve the quality of life of patients affected by glioblastoma, a type of brain tumor.

Lissoni P, Barni S, Meregalli S, et al. Modulation of cancer endocrine therapy by melatonin: a phase II study of tamoxifen alone. Br J Cancer. 1995;71:854-6.

Comments: Tamoxifen plus melatonin appeared to slow breast cancer for 14 women.

Gonzalez R, Sanchez A, Ferguson JA, et al. Melatonin therapy of advanced human malignant melanoma. Melanoma Res1991;1:237-43.

Comments: Six of 40 patients with advanced malignant melanoma treated with high doses of melatonin (up to 700 mg per day) had transient decreases in the size of some tumor masses.

From reviewing the literature it becomes clear that a dividing line must be drawn between what is a physiologic and what is a pharmacologic dose. The total amount of melatonin produced in the human body is not known (at least four other areas other than the pineal gland are thought to produce melatonin also), but most researchers agree that the pattern of concentration in the blood stream during the nighttime peak is reflective of systemic production and availability. It is important to note that bioavailability of melatonin varies depending on a number of factors but primarily whether it is ingested orally or sublingually. In the former instance perhaps only 33% gets absorbed through the average gastrointestinal tract.1 Therefore, a 1 mg capsule of melatonin may only deliver 333 mcg of melatonin, or within the range of 100 to 600 mcg. There is a wide difference when melatonin is sublingually absorbed. The amount delivered to general circulation may be much higher, perhaps 50% or more. This means that a 1 mg sublingual tablet (the equivalent in sublingual drops) will deliver 500 mcg or more. Sublingual delivery is faster too.

Depending on your age, we know that all it takes to increase the nighttime levels of melatonin to that of a healthy young adult [see Figure 1] is an oral dose of between 100 mcg to 1 mg of melatonin.2 We do not yet know what much higher -- a 5 mg oral dose can elevate blood levels by up to 100 times higher than normal -- long-term levels of melatonin will do; ie, whether there are any significant risks associated with its continued ingestion at pharmacological levels. No serious side effects or risks have been reported in association with the ingestion of melatonin to date. However, the dose-dependent physiological effects (e.g., hypothermia, increased sleepiness, decreased alertness, and possibly birth control or other reproductive effects) of this hormone has not yet been properly evaluated in people who take large doses for prolonged periods of time. Remember, our goal is long-term health and not, for example, hitting the most home runs in a single season [see Creatine All Over Again - November 1998] and then fizzling out.

We recommend using the saliva test to determine if the amount of melatonin in your body, at average nighttime peak levels, is consistent with youthful-adult levels. This test is scientifically based and reliable if used properly.3 With this issue we are now offering a low-dose capsule containing just 300 mcg of melatonin.

In an important dose study, adult rats were treated with either melatonin, a melatonin antagonist, ML-23, a combination of the two, or a placebo.4 Survival rates were significantly prolonged in the group receiving melatonin which also had increased density of binding sites for melatonin in the brain's medulla-pons and hypothalamus. Strangely, the melatonin antagonist ML-23, without or with melatonin, also prolonged the lifespan of the aged animals. ML-23 treatment greatly increased binding sensitivity in the medulla-pons, whereas this increase was prevented by melatonin supplementation. In the melatonin group, density of receptors increased but sensitivity went down. This study seems to strongly imply that there is a happy middle ground in just the right amount of melatonin. Too much melatonin can decrease sensitivity and result in receptor shutdown. Less melatonin may be more in the long run.


  1. Di WL, Kadva A, Johnston A, Silman R. Variable bioavailability of oral melatonin. N Engl J Med. 1997;336:1028-1029.
  2. Dollins AB, Zhdanova IV, Wurtman RJ, Lynch HJ, Deng MH. Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance. Proc Natl Acad Sci. 1994;91:1824-1828.
  3. Shirakawa S, Tsuchiya S, Tsutsumi Y, Kotorii T, Uchimura N, Sakamoto T, Yamada S. Time course of saliva and serum melatonin levels after ingestion of melatonin. Psychiatry Clin Neurosci. 1998;52:266-267.
  4. Oaknin-Bendahan S, Anis Y, Nir I, Zisapel N. Effects of long-term administration of melatonin and a putative antagonist on the aging rat. Neuroreport 1995;6:785-788.