MELATONIN: Agent for Rest and Rejuvenation

For a variety of reasons literally millions of people throughout the world are legitimately crying out: Why am I so tired? And what can I do about it? Onto this stage stepped melatonin. Melatonin is not a foreign substance to the body, but a natural hormone produced in the body and found in certain foods. Even though melatonin supplements have been a commercial success, there is another particularly exciting line of research regarding this hormone. Namely, we are learning that we can boost melatonin production in our own bodies in natural ways, without having to resort to costly supplements. In 1993, newspapers throughout the U.S. carried word of research from the Massachusetts Institute of Technology. Scientists there had demonstrated that small amounts of melatonin acted as a natural sleep aid.(1) Melatonins popularity grew in 1994 when the lay press reported that it could decrease jet lag.(2) Interest in the compound grew further as leading periodicals continued to fan the fire. On August 7, 1995, Newsweek featured melatonin.(3) Since then, the compound has continued to receive rave reviews and has demonstrated its ability to generate sales of millions of dollars for bookstores and health food establishments. When one of the worlds leading melatonin researchers, Dr. Russel J. Reiter, wrote a book in 1995 on the subject, he gave one striking indication of melatonins popularity. He observed that 24 different U.S. companies were then marketing the hormone. Furthermore, a steady stream of new companies was joining the marketing ranks on a monthly basis.(4)

Aging, Healing, and General Repair Perhaps nothing has captured the human imagination as much as the quest for a fountain of youth. Some today are suggesting that medical research may have provided at least a partial candidate for a youth restorer in melatonin. These sentiments grow out of the recognition that melatonin may ease the daily wear and tear that our bodies sustain.
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Consequently, it has been dubbed the fix and rejuvenate nighttime hormone.(5) These healing and general repair effects of melatonin may actually help to delay some of the changes that we normally attribute to aging. There are other lines of evidence that suggest that melatonin may help to slow the aging process. It is well known that human melatonin levels fall throughout life, as depicted in Figure 1: Fall in Melatonin Levels Through Life.(6)

Nighttime levels reach a peak in children between one and five years of age and decrease steadily throughout puberty. By the end of puberty, peak melatonin levels have decreased 75 percent.(7) Levels continue to fall steadily throughout adult life.
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Melatonin's Role as an Antioxidant The most toxic of the oxygen-free radicals is a compound called the hydroxyl radical.(8) Fortunately, melatonin is an effective antioxidant in dealing with this radical. It is even more powerful than the widely touted natural antioxidant called glutathione. In one laboratory model, melatonin emerged as a five-fold more potent antioxidant than glutathione.(9) Melatonin is superior to Vitamin E in handling the toxic peroxyl radical. Overall, the literature indicates that melatonin protects against free radical damage from certain carcinogens, herbicides and radiation.(10)

Preventing or Helping to Fight Cancerous Tumors We have already seen how melatonin as an antioxidant can exert a powerful effect in helping to prevent cancers through this means. However, this hormone appears to have still other anti-cancer properties. Research has demonstrated that melatonin can slow the growth of breast cancer cells.(11) Some of these additional benefits in the area of cancer prevention and treatment may result from the immunostimulating properties of melatonin.

Immune Enhancement Dr. Georges Maestroni and colleagues from Switzerland have performed some fascinating research that looked at the critical role that melatonin performs in the immune system. One of their groundbreaking experiments involved two groups of mice. Both were deliberately infected with a dangerous virus and then subjected to a stressful situation. The only difference was that one group was also injected with melatonin. The results were startling. At the end of thirty days, 92 percent of the mice that had not received melatonin had died. Of those that received melatonin, only 16 percent had died. There was a striking five-fold difference in mortality.(12)
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Further research has illuminated some of the ways in which melatonin exerts its immune-enhancing effects. In another study by Maestronis group, they demonstrated that melatonin can stimulate certain white blood cells called helper T cells to make immune-stimulating compounds.(13) Some of these compounds have the ability to help regulate a key immune system gland, the thymus. They also help in dealing with the effects of stress. In short, these researchers had identified how the brain, the immune system, and the endocrine system all interacted with each other when exposed to stress. They theorized that this newly appreciated interrelationship had a role in helping the immune system to recover after being weakened by high levels of stress hormones or excessive demands.

How to Increase Our Melatonin Levels If a plant foreman desires to improve production on an assembly line, the likelihood of success will be increased if he is thoroughly acquainted with every aspect of the production process. Similarly, if we want to optimize our melatonin levels, we must understand how the body makes this vital hormone. Melatonin production occurs in the pineal gland, a tiny organ that is located in the exact center of the brain.(14) This gland is only about the size of a kernel of corn and has the shape of a miniature pinecone. Its appearance explains the roots of its name: the Latin pinealis is derived from pinea which means pinecone.(15) As a testament to its importance, the pineal gland is the first gland to form during human fetal development. It is clearly distinguishable a mere three weeks after conception.(16)

Regulation of Melatonin Production In spite of what may seem like a very straightforward chemical process, the body carefully regulates melatonin production.(17) The process is largely
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controlled by the light-dark cycle. Optimal melatonin production only occurs at night and is dependent on a dark environment. Nighttime levels generally peak around 2 A.M. to 3 A.M., as depicted in Figure 2: Melatonin Level Variations Throughout the Day.

In those wee hours of the night, melatonin levels are five to ten times higher than during the day.(18) The light-dark regulation of melatonin occurs through an intricate system. The process begins with our eyes and optical nerves which carry information about environmental lighting to an area of the brain called the hypothalamus. Within the hypothalamus lies a small control center (called the Suprachiasmatic Nucleus) that lies above a place where the optic nerves cross after leaving the back of each eye. This control center regulates melatonin production. In a normal daylight situation, the control center is sending messages to the pineal gland that block the release of a key chemical messenger called norepinephrine (NE)
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that is needed for the pineal to make melatonin. The absence of this messenger ensures that no melatonin is made. In order for the gland to produce melatonin, the chemical messenger (NE) must be made and released into the gland. These critical functions of this control center have caused some chronobiologists (those who specialize in research on our timed internal rhythms) to refer to this center (Suprachiasmatic Nucleus) as the body clock. Dr. Russel Reiter has explained further that the control center actually has an internal clock that is either on or off. If the clock is on, it allows the pineal to produce melatonin; if is off, it does not. The clock is on for about 12 hours and off for about 12 hours. Daylight is what keeps this internal clock on schedule. When a person goes to sleep in a dark room, the eyes now initiate a change in pineal regulation. The presence of darkness is perceived by the eyes, which through a series of intricate nerve connections send messages instructing a group of cells (called the Superior Cervical Ganglion) to make that key chemical messenger (norepinephrine) previously mentioned. This group of cells lies near the top of the spinal cord and has direct nerve connections into the pineal gland, so this task sounds as if it could easily be accomplished. However, the key chemical messenger, even though it is produced, cannot be released into the gland until a parallel phenomenon also occurs. At the same time that the group of cells is making the chemical messenger, nerve pathways stimulated by the darkness tell the hypothalamus control center to release its blocking effect on the release of the chemical messenger. It is this combination of messages that leads to an outflow of the messenger into the pineal gland, and the gland then begins to produce melatonin and feeds it into the bloodstream. Light-dark signals are fed through the optical nerves to a control center in the brain where our body clock is located. This clock, in turn, tells the pineal gland not to produce melatonin when the daylight signal is transmitted from the eyes. When the dark signal from the eyes is received by the control center, it triggers the gland to produce melatonin, which is fed into the bloodstream.(19)
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Animal tests indicate that melatonin can also be produced directly by the retina. Under conditions of darkness, this tissue on the back of the eye can act alone in producing melatonin.(20) Melatonin is not stored in the pineal gland; it leaves the gland through simple diffusion.(21) Its half-life is short during the initial few minutes, followed by a second longer phase.(22) As a result we cannot rely on yesterdays melatonin for today. We need a liberal supply of melatonin each evening.

Boosting Melatonin Naturally How can we now apply the understanding of the chemistry and regulation of melatonin in such a way as to increase the production of this vital hormone by our own bodies? The remainder of the chapter will provide answers to this question.

Get Exposure to Bright Light Early in the Day One of the first and highly respected studies probing the daylight/melatonin connection was published in 1988. Researchers in Finland found that rats who were exposed to natural daylight had significantly higher evening melatonin levels than another group of rats who had an equal amount of exposure to artificial light.(23) The difference in melatonin levels of the two groups is shown in Figure 3: Natural Light is Best for Melatonin Production.

Outdoor light is incredibly more intense than the artificial variety. Outdoor light can reach 3000 lux on a bright sunny day.(24) A bright indoor environment may provide only 400 lux, less than 15 percent of daylight brightness.(25) There is an interesting observation regarding a special need for more sunlight as we get older. Consider these three facts: Melatonin appears to slow the aging process. The older we get, the less melatonin output we have. Natural light exposure in daytime increases melatonin output at night.

We conclude that to slow the aging process, we can boost our melatonin output by being exposed to more sunlight, which helps to offset the natural weakening of melatonin production.
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Bright light, such as sunlight, also may increase serotonin production in the daytime which can in turn prevent depression and fatigue.(26)

Avoid Light Exposure at Night Years ago there was recognition that evening light suppressed melatonin production in humans.(27) It is important to avoid light exposure at night while maximizing it during the daytime hours. We know that low intensity light (50 lux) is not a problem but levels of 500 lux and above at night significantly suppress melatonin release. Considering this information, it is prudent to minimize light exposure at night, and where light is necessary in the night time hours (e.g., waking up to use the bathroom), use a light as dim as possible. In Western nations, the habit of staying up late at night is generally associated with significant amounts of light exposure during those hours. From the standpoint of melatonin production, it would be better to go to bed early to take advantage of the nighttime darkness and then rise early. The health advantage of going to bed early was pointed out a century ago by Ellen White, quoted in Figure 14: Sleep is Better Before Midnight.

Exercise Boosts Melatonin An early study by Carr and colleagues looked at seven healthy women. They demonstrated that one hour of exercise on a stationary bicycle could double or triple melatonin levels.(28) Other studies have also demonstrated that physical exercise can boost melatonin levels.(29)

Eat Foods Rich in Melatonin Melatonin is present in many foods. Eating foods rich in natural melatonin (30) can raise melatonin levels in the bloodstream. Foods rich in melatonin are listed in Figure 4: Foods High in Melatonin.(31,32)
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Some habits will result in a lowering of melatonin production. They are listed in Figure 5: Lifestyle Factors that Reduce the Melatonin Peak.

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Research suggests that stress and poor coping skills reduce melatonin production.(33) Thus, finding adequate coping mechanisms for controlling stress is essential in naturally optimizing melatonin levels. Caffeine should be avoided; it stimulates the bodys stress hormone system (the sympathetic nervous system) and tends to weaken melatonin production. It can cut melatonin production for six hours.(34) Insomnia or disturbed sleep is usually the result. Probably the most common drug used in attempting to deal with stressful situations worldwide is alcohol. Alcohol, however, can not be endorsed as a drug to improve a stressed persons melatonin supplies. Alcohol depresses melatonin levels.(35) As little as two mixed drinks taken around 7 PM have been demonstrated to depress melatonin production even five
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or more hours later. Production of melatonin was down as much as 41 percent at 12 midnight. Tobacco appears to be another melatonin depressor. Research indicates that smokers have lower evening melatonin levels than non-smokers.(36) This may help to explain a well-known side effect of smoking: sleep quality generally suffers.

Summing Up Melatonin is a compound with incredible promise. We are just beginning, however, to learn about its side effects. The use of large amounts of melatonin supplements may in some cases pose significant harm. The most prudent approach seems to emphasize natural lifestyle approaches that boost levels of this remarkable hormone. To some this may sound too simple. It may even sound strangely reminiscent of those things our mothers and grandmothers emphasized: a healthful diet, regular physical exercise, regularity in sleeping, avoiding late night activities, sunshine, etc. Despite the simplicity of these measures, medical research is demonstrating their effectiveness. However, there are some things that even mom and grandma did not recognize: the importance of foods high in tryptophan and melatonin, and the dangers of drugs once thought innocent. Our growing understanding of melatonin may, indeed, change the way we attempt to answer that oft-posed question, Why am I so tired? When we struggle with personal fatigue issues, we may find ourselves running down a mental checklist of factors that affect melatonin levels. Such an approach is calculated to help the majority of people safely boost their energy levels, minimize fatigue, and experience a whole host of other benefits.

References 1 Dollins AB, Zhdanova IV, et al. Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature,
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and performance. Proc Natl Acad Sci U S A 1994 Mar 1;91(5):1824-1828. Note: study results were announced to the press in 1993, prior to scientific publication. 2 Petrie K, Dawson AG, et al. A double-blind trial of melatonin as a treatment for jet lag in international cabin crew. Biol Psychiatry 1993 Apr 1;33(7):526-530. 3 Cowley G. Pushing Back Time? Melatonin. Newsweek, August 7, 1995. 4 Reiter RJ, Robinson J. Meet Melatonin, The Life-giving Molecule. In: Melatonin: Your Bodys Natural Wonder Drug. New York, NY: Bantam Books, 1995 p. 4. 5 Gates J. Getting Melatonin Naturally. Nutrition Advocate 1995 Dec;1(6):4, 6. 6 Reiter RJ, Robinson J. The Best Antioxidant. In: Melatonin: Your Bodys Natural Wonder Drug. New York, NY: Bantam Books, 1995 p. 20. 7 Erlich SS, Apuzzo ML. The pineal gland: anatomy, physiology, and clinical significance. J Neurosurg 1985 Sep;63(3):321-341. 8 Reiter RJ, Melchiorri D, et al. A review of the evidence supporting melatonins role as an antioxidant. J Pineal Res 1995 Jan;18(1):1-11. 9 Reiter RJ, Melchiorri D, et al. A review of the evidence supporting melatonins role as an antioxidant. J Pineal Res 1995 Jan;18(1):1-11. 10 Reiter RJ, Melchiorri D, et al. A review of the evidence supporting melatonins role as an antioxidant. J Pineal Res 1995 Jan;18(1):1-11. 11 Blask DE, Hill SM. Effects of melatonin on cancer: studies on MCF-7 human breast cancer cells in culture. J Neural Transm Suppl 1986;21():433-449. 12 Maestroni GJ, Conti A, Pierpaoli W. Pineal melatonin, its fundamental immunoregulatory role in aging and cancer. Ann N Y Acad Sci 1988;521():140-148.
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13 Maestroni GJ, Conti A. Immuno-derived opioids as mediators of the immuno-enhancing and anti-stress action of melatonin. Acta Neurol (Napoli) 1991 Aug;13(4):356-360. 14 Reiter RJ, Robinson J. Meet Melatonin, The Life-giving Molecule. In: Melatonin: Your Bodys Natural Wonder Drug. New York, NY: Bantam Books, 1995 p. 3. 15 Erlich SS, Apuzzo ML. The pineal gland: anatomy, physiology, and clinical significance. J Neurosurg 1985 Sep;63(3):321-341. 16 Reiter RJ, Robinson J. Meet Melatonin, The Life-giving Molecule. In: Melatonin: Your Bodys Natural Wonder Drug. New York, NY: Bantam Books, 1995 p. 4. 17 Erlich SS, Apuzzo ML. The pineal gland: anatomy, physiology, and clinical significance. J Neurosurg 1985 Sep;63(3):321-341. 18 Reiter RJ, Robinson J. The Three-Billion-Year-Old Molecule. In: Melatonin: Your Bodys Natural Wonder Drug. New York, NY: Bantam Books, 1995 p. 17-18. 19 Reiter RJ. The ageing pineal gland and its physiological consequences. Bioessays 1992 Mar;14(3):169-175. 20 Tosini G , Menaker M. Circadian rhythms in cultured mammalian retina. Science 1996 Apr 19;272(5260):419-421. 21 Erlich SS, Apuzzo ML. The pineal gland: anatomy, physiology, and clinical significance. J Neurosurg 1985 Sep;63(3):321-341. 22 Erlich SS, Apuzzo ML. The pineal gland: anatomy, physiology, and clinical significance. J Neurosurg 1985 Sep;63(3):321-341. 23 Laakso ML, Porkka-Heiskanen T, et al. Twenty-four-hour patterns of pineal melatonin and pituitary and plasma prolactin in male rats under natural and artificial lighting conditions. Neuroendocrinology 1988 Sep;48(3):308-313.
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24 Reiter RJ, Robinson J. Back in Sync. In: Melatonin: Your Bodys Natural Wonder Drug. New York, NY: Bantam Books, 1995 p. 161. 25 Reiter RJ, Robinson J. Back in Sync. In: Melatonin: Your Bodys Natural Wonder Drug. New York, NY: Bantam Books, 1995 p. 161. 26 Rao ML, Muller-Oerlinghausen B, et al. The influence of phototherapy on serotonin and melatonin in non-seasonal depression. Pharmacopsychiatry 1990 May;23(3):155-158. 27 Lewy AJ, Wehr TA, et al. Light suppresses melatonin secretion in humans. Science 1980 Dec 12;210(4475):1267-1269. 28 Carr DB, Reppert SM, et al. Plasma melatonin increases during exercise in women. J Clin Endocrinol Metab 1981 Jul;53(1):224-225. 29 Diaz B, Garcia R, et al. Melatonin and gonadotropin hormones in pubertal sportsgirls. Rev Esp Fisiol 1993 Mar;49(1):17-22. 30 Hattori A, Migitaka H, et al. Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates. Biochem Mol Biol Int 1995 Mar;35(3):627-634. 31 Dubbels R, Reiter RJ, et al. Melatonin in edible plants identified by radioimmunoassay and by high performance liquid chromatography-mass spectrometry. J Pineal Res 1995 Jan;18(1):28-31. 32 Hattori A, Migitaka H, et al. Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates. Biochem Mol Biol Int 1995 Mar;35(3):627-634. 33 Massion AO, Teas J, et al. Meditation, melatonin and breast/prostate cancer: hypothesis and preliminary data. Med Hypotheses 1995 Jan;44(1):39-46. 34 Reiter RJ, Robinson J. Drugs That Deplete Melatonin. In: Melatonin: Your Bodys Natural Wonder Drug. New York, NY: Bantam Books, 1995 p. 188.
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35 Ekman AC, Leppaluoto J, et al. Ethanol inhibits melatonin secretion in healthy volunteers in a dose-dependent randomized double blind crossover study. J Clin Endocrinol Metab 1993 Sep;77(3):780-783. 36 Touitou Y, Fevre-Montange M, et al. Age- and sex-associated modification of plasma melatonin concentrations in man. Relationship to pathology, malignant or not, and autopsy findings. Acta Endocrinol (Copenh) 1985 Jan;108(1):135-144.

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