© 1991-2010 Jerry Emanuelson

Chapter 3

MELATONIN - The Sleep Cycle Hormone

The hormone melatonin is the primary controller of circadian (day/night) bio-rhythms.  Some studies indicate that it may also be a central regulator of the hormonal component of the aging process.  It is likely that this is only partly true.

Most of the melatonin in the human body (except for the intestine) is secreted by the pineal gland, a small pine-cone-shaped gland located near the center of the brain.  The pineal gland receives information from the optic nerve about the ambient light level and adjusts its melatonin output accordingly.

Bright light suppresses the output of melatonin.  Ordinary indoor lighting does not.  After sunset, the pineal gland responds to the decreased light levels by greatly increasing its output of melatonin.  After a few hours, blood melatonin levels reach a point where sleep is induced.  Melatonin levels usually peak two to four hours after the onset of sleep and decrease gradually during the remaining sleep period.  Daylight inhibits the production of melatonin, and levels of melatonin usually reach a minimum sometime during the afternoon.

Irregularities in melatonin production can cause sleep problems, lethargy and mood disorders.

Production of melatonin usually becomes more sluggish with increasing age.  The total amount of melatonin produced is decreased substantially and the day/night cycling often becomes less pronounced.

Melatonin is a powerful antioxidant; more importantly, it is one of the few antioxidants that can penetrate into the cell's mitochondria.  The mitochondria is the energy-producing part of a cell that contains its own DNA.  The fact that nearly all of the antioxidants in nutritional supplements do not enter the mitochondria is believed to be the main reason that ordinary antioxidants do not noticably extend lifespan and only minimally slow the aging process.  Melatonin does appear to protect the mitochondria from oxidation damage.

(Alpha lipoic acid or R-lipoic acid may be superior to melatonin in protecting mitochondria from oxidative damage, especially when combined with acetyl-l-carnitine.)

Some animal studies have shown that melatonin reverses stress related suppression of the immune system.  A number of animal studies have shown that melatonin reduces the incidence of some types of cancer, especially estrogen-mediated cancers such as breast cancer.  Experiments to confirm these effects in humans have not yet been completed.  Some researchers suspect, however, that the melatonin suppression due to artificial lighting during this century may be a contributor to the rise in breast cancer rates since sufficiently bright artificial light will suppress melatonin production.  This does not mean that one should avoid artificial lighting.  It is just as important to have several waking hours with low melatonin levels as it is to have several hours in the period just before and during sleep with high melatonin levels.

In laboratory mice, oral melatonin in one experiment increased life span to 931 days compared to a life span of 755 days for mice on an identical regimen without supplemental melatonin.

Melatonin has been safely used in humans for years, principally to reset biological clocks.  Many people have found melatonin to be very useful in jet lag and other situations where the day/night cycle of the human body must be quickly reset.  It has been shown to be useful in the insomnia associated with aging.  It has other potential uses as a natural sleeping pill and (in conjunction with other therapies) in the treatment of Seasonal Affective Disorder and some forms of depression.

One important development in melatonin research has been the use of melatonin in combination with estrogen or progestin.  Research has been done in hopes of producing an estrogen-free birth control pill that would have significantly fewer side effects (both long-term and short-term) than current birth control pills.  Although the research yielded encouraging results, no company was able to bring a product to market on the basis of the research.

A combination of melatonin and natural estrogen for estrogen replacement therapy has undergone limited testing for use in post-menopausal women.  Melatonin seems to multiply the effectiveness of estrogen and allow reduction in estrogen dosage to about 25 percent of what is normally required without a large dose of melatonin, however the interaction of melatonin and estrogen is very complex.

Although melatonin is absorbed when taken in capsule form, among different individuals, there is at least a 25:1 ratio in how well it is absorbed.  (One study indicated a 300:1 ratio.)  The average oral dose is about 3 daily 30 minutes to 3 hours before sleep.  Because of the very wide range of individual variations in oral melatonin absorption, melatonin tablets are available in doses of 0.3 mg. to 10 mg.  Only individual experimentation can determine the proper dosage and timing for any particular individual.

It is important that melatonin not be taken shortly after awakening.  If the timing of melatonin dosing is incorrect, it can severely disrupt sleep patterns.  In susceptible individuals, incorrect timing of the melatonin dose may also induce mania or depression.  Some individuals absorb melatonin much more slowly than others, and some melatonin pills take longer to dissolve than others.  Most people who experience lethargy or depressed mood after taking melatonin are experiencing a problem with timing.

In people with Seasonal Affective Disorder (SAD) or Delayed Sleep Phase Syndrome (DSPS) a therapy that is often quite effective is the combination of bright light to suppress melatonin at one end of the 24-hour cycle and oral melatonin at the opposite end of the cycle.  Melatonin alone is not effective in Seasonal Affective Disorder, and may even make the problem worse.

(SAD is usually manifested by lethargy or depression in the winter.  Those with DSPS are night-owls in the extreme, with natural sleep onset times well after midnight and natural awakening times typically late morning or early afternoon.)

There are large individual variations in the levels of lighting that suppress melatonin production.  The human melatonin suppression mechanism seems to be slightly more sensitive to the green portion of the visible spectrum.  Fluorescent lights are usually used for therapeutic melatonin suppression because they are much more cost-effective, especially when very bright lighting is necessary.  Although even the cheapest fluorescent lights will work for this purpose, many people are uncomfortable with ordinary fluorescent lighting.  This problem can usually be alleviated by using a broad spectrum light to reduce perceived glare and a high-frequency electronic ballast to eliminate flicker.  Compact fluorescent lights are also available with a broad (daylight) spectrum of natural color.

Propanolol (Inderal), a common medication for reducing high blood pressure, also inhibits the production of melatonin, and may be useful for inducing proper melatonin cycling.  Many individuals have reported success in treating their Seasonal Affective Disorder by taking propanolol in the morning and melatonin at night.  People who are using long-acting beta blockers along with an alpha blocker for the treatment of high blood pressure may be almost completely surpressing their natural melatonin production.  One significant exception to this is carvedilol, a unique combination alpha and beta blocker, which does not seem to suppress melatonin release.

It has recently been found that low frequency electromagnetic fields may inhibit the production and biological activity of melatonin.  This includes the magnetic fields induced by 60-cycle household power.  The extent of this problem is a very controversial subject.  The only problem most people are likely to encounter in this regard is when using electric blankets.  Some electric blankets surround an individual with sufficient low-frequency electromagnetic fields that melatonin may be inhibited exactly when it is needed most.  All of the newer electric blankets on the market, though, have been specifically designed to minimize this problem.

Virtually all of the melatonin supplements sold in the United States use pure synthetic melatonin mixed with an inert substance such as micronized cellulose.  In the past, some of the melatonin supplements sold in Europe have reportedly been made from the pineal glands of cattle.  (I have some doubts about the accuracy of those reports.)  This "natural" melatonin has caused some concern because many European cattle have been afflicted with slow acting viral infections of the brain or with prion diseases.  Many of these "slow viruses" are difficult to kill with conventional sterilization methods used on glandular tissue and the abnormal proteins called prions are even more difficult to suppress.  So far, there have been no reported cases of viral brain diseases in humans taking European melatonin supplements, but there is a very real risk in using the "natural" product.  All of the melatonin products now found in health food stores are the synthetic product.  The sale of melatonin is severely restricted in some countries.

No significant adverse effects of synthetic melatonin supplements have been reported.  Animal experiments, however, indicated a somewhat shortened life span if regular supplementation is begun when the animals are too young.  This suggests it may be unwise for persons under about age 35 to use melatonin every night.  There seems to be no problem with occasional use, though, by adults of any age.

Several books were published during 1995 that provide an excellent overview of melatonin and information about the practical aspects of using melatonin supplements.  Two of the best books are listed below.  Both books also contain numerous references to the scientific studies reported in medical journals.  Anyone planning to use melatonin supplements on a regular basis should purchase and read at least one of these books.

(In my opinion, the Reiter and Robinson book is the best.  The Pierpaoli and Regelson book reports on anti-aging studies that are potentially the most important, but these studies leave many important unanswered questions.)


Book:  The Melatonin Miracle  by Walter Pierpaoli, M.D. and William Regelson, M.D. [Simon & Schuster] 1995

Book:  Stay Young the Melatonin Way  by Steven J. Bock, M.D. [Dutton, division of Penguin Books] 1995.


Also see:

Magri, F. et al. Changes in Endocrine Circadian Rhythms as Markers of Physiological and Pathological Brain AgingChronobiology International. 1997 July; volume 14, issue 4, pp. 386-396.

Girgert, R, et al. Membrane-bound Melatonin Receptor MT1 Down-Regulates Estrogen Responsive Genes in Breast Cancer CellsJournal of Pineal Research. 2009 August; volume 47, issue 1: pp. 23-31.

Viswanathan A.N., et al. Circulating Melatonin and the Risk of Breast and Endometrial Cancer in WomenCancer Letters. 2009 August 18; volume 281, issue 1: pp. 1-7.

Dopfel, R.P., et al. Nutritional and Lifestyle Correlates of the Cancer-Protective Hormone MelatoninCancer Detection and Prevention. 2007. volume 31, issue 2: pp. 140-8.

Zawiliska, J.B., Skene, D.J. and Arendt, J.  Physiology and Pharmacology of Melatonin in Relation to Biological Rhythms..  Pharmacology Reports. 2009, May-June. Vol. 61. Issue 3. pp. 383-410.

Reid, K.J., and Zee, P.C.  Circadian Rhythms Disorders.  Seminars in Neurology. 2009, September. Vol. 29. Issue 4. pp. 393-405.

Sullivan, S.S. and Guilleminault, C.  Emerging drugs for insomnia: new frontiers for old and novel targets.  Expert Opinion on Emerging Drugs. 2009, September. Vol. 14. Issue 3. pp. 411-422.

Kalpakcioglu B. and Senel K.  The Role of Melatonin in Rheumatic Diseases.  Infectious Disorders Drug Targets. 2009, August. Vol. 9. Issue 4. pp. 453-456.

Odaci, E. and Kaplan, S.  Chapter 16: Melatonin and Nerve Regeneration..  International Review of Neurobiology. 2009. Vol. 87. pp. 317-335.

Reuter, R.J., Tan, D.X. and Korkman, A.  The circadian melatonin rhythm and its modulation: possible impact on hypertension.  Journal of Hypertension. 2009, August, Vol. 27. Supplement 6. pp. S17-S20.

Reiter R.J., Paredes S.D., Manchester L.C. and Tan D.X.  Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin  Critical Reviews in Biochemistry and Molecular Biology. 2009, July-August. Vol. 44. Issue 4. pp. 175-200.

Reiter, R.J.  The Pineal Gland and Melatonin in Relation to Aging: A Summary of the Theories and of the Data.  Experimental Gerontology. 1995, May-August. Vol. 30. Issues 3-4. pp. 199-212.

Schachter, F.  Causes, Effects, and Constraints in the Genetics of Human Longevity.  American Journal of Human Genetics. 1998, May. Vol. 62. Issue 5. pp. 1008-1014.

Samantaray S., Das, A., Thakore, N.P., Matzelle, D.D., Reiter, R.J., Ray, S.K.and Banik, N.L.  Therapeutic Potential of Melatonin in Traumatic Central Nervous System Injury.  Journal of Pineal Research. 2009, September. Vol. 47. Issue 2. pp. 134-142.

Stoschitzky K, Sakotnik A, Lercher P, Zweiker R, Maier R, Liebmann P, Lindner W.  Influence of beta-blockers on melatonin release.  European Journal of Clinical Pharmacology. 1999. April. Vol. 55. Issue 2. pp.111-115.

Stoschitzky K, Koshucharova G, Zweiker R, Maier R, Watzinger N, Fruhwald FM, Klein W.  Differing beta-blocking effects of carvedilol and metoprolol.  European Journal of Heart Failure. 2001. June. Vol. 3. Issue 3. pp. 343-349.


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