Like a certain fictional Transylvanian count,melatonin only comes out at night. While Dracula actively seeks blood, however, melatonin silently
enters the bloodstream, where it engages in a myriad of vital body processes. One of these involves setting the body's internal daily rhythms, which
includes regulating the onset of sleep. Melatonin may also be a useful therapy in treating the apathy common in jet lag, an adjunctive preventive
for cancer, a possible treatment for certain forms of depression and an anti-aging substance.
This hormone is secreted from the pineal gland, a small pine-shaped gland attached to a stalk on the back wall of the brain's third ventricle. In
species such as fish, frogs and lizards the gland is a light-sensitive organ that functions as a "third eye." As such it plays a central role in
modulating the animal's sex life by inhibiting the flow of sex hormones. This function has led some people to erroneously suggest that melatonin
may likewise depress sex hormones in humans.
In lower species melatonin appears to lighten skin. While researching this function in 1958, Yale University dermatologist Aaron Lerner analyzed
thousands of beef pineal glands to find the substance that produced the skin lightening effect in amphibians. He eventually isolated a substance he
dubbed "melatonin" because of its ability to stimulate amphibian pigment cells called melanophores.
Over the years research has further elucidated melatonin's function in the body. The pineal gland appears to receive nerve signals from the sympathetic
nervous system. When this happens, the gland transduces, or converts, such signals into the hormonal product, melatonin. Of special significance is
the fact that two brain neurotransmitters, norepinephrine and serotonin, are intimately involved in melatonin release.
Melatonin is synthesized in the pineal from serotonin, which is itself made in the brain from the essential amino acid tryptophan. As you consume
tryptophan in foods during the day, your body converts much of it into serotonin; however, the brain enzymes that convert serotonin into melatonin
are suppressed by light, which explains the preponderance of melatonin secretion that occurs at night. The night release of melatonin begins with the
"turning on" of sympathetic nerve tracts in the brain that secrete the neurotransmitter norepinephrine. Norepinephrine, in turn, stimulates cells in
the pineal gland to produce melatonin.
Role in Depression?
As discussed above, the brain chemicals norepinephrine and serotonin act as neurotransmitters, or conductors, of nerve signals in certain brain
regions. Both of these chemicals are also involved in mental depression, which can be caused by decreased levels of them. Such decreases are brought
on by either rapid breakdown or inadequate production of these neurotransmitters. Current medical treat men of depression centers on drugs called
antidepressants, which work by increasing the brain's content of the deficient neurotransmitters.
Since both norepinephrine and serotonin are involved in melatonin production, scientists investigated the role that melatonin may play in the onset
of various mental disorders. Studies show that people prone to depressive symptoms show aberrant melatonin rhythms, with melatonin production peaking
at dawn or midnight instead of the usual 2 a.m., while in those who suffer from the lethargy and fatigue that characterizes seasonal affective disorder,
melatonin rises and falls at unusually odd hours.
Other preliminary reports link increased levels of melatonin with the crazed behavioral symptoms known as mania. In contrast, low levels are frequently
observed in people who suffer from the loss of reality termed schizophrenia.
An interesting observation arose out of research that's been done on seasonal affective disorder, or SAD. The acronym is appropriate because people who
suffer from SAD experience certain symptoms with the onset of winter that include excessive sleeping, fatigue, appetite increase and carbohydrate craving.
Given those symptoms, you might expect such people to have decreased metabolic rates because most of the symptoms appear to conserve energy.
The fact is, however, that SAD patients show increased resting metabolic rates (which are lowered by the light therapy that's used to treat the disorder).
Researchers suggest that this phenomenon may be caused by increased melatonin. Here's how they think the mechanism may work.
Treating Jet Lag
The ability of melatonin to reset the body's chemical clock, or circadian - than rhythm, may be used to advantage in dealing with the fatigue seen in jet lag.
Jet lag is a set of symptoms characterized by fatigue, insomnia, irritability, poor concentration and a general disoriented feeling. The symptoms occur when
you fly across several time zones, particularly when heading eastward. The more time zones you cross, the greater the fatigue, which can last a week. Such
rapid travel throws your body's rhythms out of kilter. In effect you may physically be in Paris, but your body thinks you're still in Los Angeles.
Since melatonin appears to play an integral role in controlling the body's circadian rhythms, scientists have tested it as a "jet lag pill" to reset them.
In one such study 20 subjects ages 28 to 68 crossed 12 time zones during a 26-hour flight eastward from New Zealand to England and returned three weeks later
they were randomly selected to receive either five milligrams of melatonin or a placebo daily for three days before the flight and three days after. For the
return flight the subjects switched groups. The researchers used various tests to measure feelings of fatigue.
The subjects taking melatonin reported fewer jet lag symptoms and established normal sleep patterns more rapidly. According to Roger Short, Ph.D., a
physiologist from Monash University in Melbourne, Australia, who has studied the relationship between melatonin and jet lag, travelers arriving in a new time
zone should take melatonin two nights in a row when they arrive. This replaces the melatonin that would normally be made at that time and thus resynchronizes
the body rhythm.
According to Alfred Lewy, Ph.D., of the Oregon Health Sciences University, the best dose of melatonin to prevent jet lag is far less than most people use to
induce sleep. He suggests less than one milligram. The trick is knowing the best time to take it.
For example, let's say you're traveling from Los Angeles to New York, a three-hour time difference. According to Lewy, you should take your first dose of
melatonin at 2 p.m. the day before you leave Los Angeles. Take it again at 2 p.m. on the day you travel and at 5 p.m. when you get to New York,
corresponding to 2 p.m. in Los Angeles. Using this techniques resets your body clock from Pacific to East Coast time. A good dose is one-half milligram.
Perhaps the best way to take melatonin as a treatment for jet lag is to combine it with sunlight, which also helps to reset your natural body clock. Thus,
if you arrive at your destination during the day, take a walk rather than succumbing to the urge for a nap. Other studies show that exercise appears to aid
in rapidly resetting natural rhythms.
The Stuff Dreams are Made of ...
Indian yogis have a novel way of taking supplemental melatonin. In a procedure called "amaroli," they drink their early morning urine, rich in melatonin.
This leads to slower brain wave activity and heightened visual ability. It convinces the body that it's had more sleep and reduces the pain associated with
sitting absolutely still for two hours.
The amino acid tryptophan was a popular sleep aid until it was removed from sale by the Food and Drug Administration a few years ago. At that time a contaminant
discovered in some batches of tryptophan imported from Japan caused an outbreak of a disease called eosinophilia-myalgia. While tryptophan itself was never the
actual cause of the outbreak, the government still refuses to lift the ban on its sale.
Tryptophan's sleep-inducing action was thought to be related to its conversion to serotonin in the brain. Since melatonin is a serotonin product, produced
mostly during sleep, scientists investigated whether it might be useful as a sleep aid.
Insomnia is a common malady in people over age 50, just when melatonin production starts to decrease. This was confirmed by Peretz Lavie, a researcher at the
Technion Israel Institute of Technology, who measured melatonin output in adults between the ages of 68 and 80. All of them produced lowered amounts of melatonin,
but those who had the worse cases of insomnia also had the lowest melatonin release.
Lavie then gave the insomniacs two-to-five-milligram doses of melatonin a few hours before bedtime. Others received placebo pills. The melatonin group fell
asleep twice as fast and slept more soundly. The only side effect was slight residual fatigue in the morning.
In another study a dose of five milligrams of melatonin taken daily for a month proved effective to treat delayed sleep phase syndrome. Significantly, this
study showed no next day hangover, as is common with many prescription sleeping pills that interfere with a portion of sleep called the REM phase, which is
where dreams occur. Only one subject reported a side effect-a headache. The study also noted that while oral melatonin reaches peak blood concentrations in one
hour, the sleep onset effect occurs in three to four hours.
A more recent study, conducted by Richard J. Wurtman, Ph.D., professor of neuroscience at the Massachusetts Institute of Technology, found that melatonin works
equally well for younger people in promoting more rapid sleep onset. Twenty young male subjects were given various doses of either melatonin or a placebo and
then placed in a dark room at midday and told to close their eyes for 30 minutes. The placebo group took 25 minutes to fall asleep, compared to five to six minutes
for the melatonin group. Those on melatonin also tended to sleep twice as long compared to their placebo-using peers.
Another possible use of melatonin is as a sleep aid for night shift workers, who often experience a type of jet lag effect due to disordered circadian rhythms.
One study, however, showed that people working the night shift naturally adapt to this rhythm through an increased melatonin output.
A side effect frequently reported by melatonin users is more vivid dreams. This may relate to melatonin's chemical structure. Melatonin is a tryptamine, which
can have hallucinogenic properties. Some researchers believe that natural forms of these chemicals in the brain are what produce dreams. In this sense melatonin
may be the stuff dreams are made of.
Increases Immune Power and Prevents Cancer
Studies show that melatonin may work in concert with the thymus gland to increase production of helper T-cell antibodies that protect against various diseases,
including cancer. Breast tumor cells rich in estrogen receptors seem to be especially responsive to melatonin. Women who have such estrogen receptor-rich cancer
cells are usually also low in melatonin production.
When researchers at Tulane University School of Medicine in New Orleans added melatonin to human breast cancer cells grown in a laboratory, the estrogen receptive
cells grew only one-fourth to one-half as fast as untreated cells. Melatonin didn't affect cancerous cells lacking estrogen receptors. According to Steven Hill,
M.D., who conducted the experiments, melatonin decreases estrogen cell receptors.
Melatonin also boosts the cancer-fighting effect of the estrogen-blocking drug Nolvadex (tamoxifen citrate). This is advantageous because large doses of Nolvadex
are associated with tumors in the uterus and liver. Combining melatonin with Nolvadex may decrease the dose of Nolvadex needed to arrest the cancer's progress while
mitigating the side effects of the drug.
Other studies show that melatonin inhibits the growth of a deadly skin cancer called melanoma in animals, but the research hasn't yet been done to determine
whether it duplicates this in humans. Men with prostate cancer also show decreased melatonin levels.
Melatonin and Hormones
An often voiced criticism of melatonin involves its antigonadotropic effect; that is, its ability to interfere with the release of sex hormones, including testosterone.
One study reported a case of decreased testosterone in a 21-year-old man. This person had an enlarged pineal gland that was much more active than normal, however. His
daytime melatonin output was 15 to 20 times higher than normal, while his night production was four to five times higher.
The researchers noted that "the administration of melatonin to adults for several weeks has little effect on reproductive or endocrine function." Other studies also
confirmed this finding. For example, a study of six men who took oral doses of two milligrams of melatonin for two months showed no changes in any hormones,
including luteinizing hormone, or LH, and testosterone.
Even short-term high doses of melatonin appear to have little effect on hormonal release. In a study where 25 subjects took 50 milligrams of melatonin for one
week, no changes were found in the output of any hormones.
Taken in high doses, melatonin does potentiate the effects of testosterone in the reverse feedback loop that inhibits the pituitary gland release of LH. This,
in turn, turns off testosterone production in the body. Even so, the effect only occurs with high doses of melatonin. In women, the effect of melatonin in reducing
hormone output is accelerated by a low-calorie diet.
Doses of 10 milligrams of melatonin have a mild effect on growth hormone stimulation because they inhibit somatostatin release, which inhibits growth hormone release.
Stimulating growth hormone release through various mechanisms, on the other hand, appears to inhibit melatonin release.
Regarding the effects of melatonin on exercise, a few studies show that intense exercise in the afternoon increases melatonin production at night and into the day.
Some researchers theorize that this may cause a cessation of menstrual function. Another study found that melatonin release was dramatically blunted in late-night male
exercisers, possibly due to increased rapid breakdown in the liver. Since one sleep-producing effect of melatonin is that it lowers the core temperature of the body,
one can speculate that the temperature-raising effects of night exercise may decrease both sleep onset and melatonin release.
The stress of high-intensity exercise causes a post exercise decrease in luteinizing hormone from the pituitary gland. This hormone, in turn, controls testosterone
synthesis in the body. Studies show that melatonin levels do not fall after exercise, however, which indicates that it has no effect on the lowered LH and subsequent
A recent study involving rats found that not only did adding melatonin to the animals drinking water increase their life spans, but it may also be the reason the male
rats that got the melatonin showed testosterone levels three times higher than the control animals. This suggests that melatonin may delay the usual drop in testosterone
production common with aging.
A few naysayers point out that since melatonin is a hormone, taking it could be dangerous. This assumption is not backed by studies, however. If anything, melatonin
is extremely nontoxic. Rats given the human equivalent of 50,000 milligrams suffered no ill effects. In a human study where subjects took 6,000 milligrams of melatonin
a night for one month, the only side effects noted were upset stomachs and-as expected-daytime grogginess.
Although the optimal dose for sleep promotion hasn't yet been established, in their book, The Melatonin Miracle (Simon and Schuster, 1995), researchers Walter Pierpaoli
and William Regelson suggest the following:
Age / Dose
40-44 / 0.5-1 milligram
45-54 / 1-2 milligrams
53-64 / 2-2.5 milligrams
65-74 / 2.5-5 milligrams
75+ / 3.5-5 milligrams
Supplemental melatonin usually comes in pills ranging from one-half to five milligrams. These pills are either sublingual or regular, with the former having a more
rapid action. For best results take sublingual tablets at least one hour before bed, or regular tablets two hours before bed.
Since melatonin is metabolized in about two hours, some people may find themselves waking up in the middle of the night. In this case, either consider the newer time-released
forms of melatonin, or simply take another dose.
Finally, some intriguing new research points to a few anti-aging effects of melatonin. A 1987 Swiss study found that when melatonin was added to the drinking water
of mice during the night, the animals' aging slowed and their lives were prolonged by 20 percent, or six months longer than average. Another study found that melatonin
decreased cholesterol levels in rats that had genetically elevated levels.
A study recently reported in the journal Lancet found that heart patients may not produce enough melatonin. This is significant because melatonin dampens the excessive
secretion of norepinephrine, a substance that constricts blood vessels and adds stress to the heart.
This may be related to the finding of Russell. Reiter, M.D., professor of neuroendocrinology at the University of Texas Health Sciences Center, who discovered that
melatonin is the most efficient free-radical scavenger yet found. Rats pretreated with melatonin sustained 41 to 99 percent less DNA cellular damage resulting from
free-radical attack. Free radicals are by-products of metabolism implicated in diseases ranging from cancer to heart disease to aging. Reiter notes that we become more
susceptible to such diseases with aging-just when melatonin production slows down.
Unlike vitamin E, which functions best in the fatty portions of cells, and vitamin C, which works best in a watery medium, melatonin can enter all parts of the cells
and is especially effective at getting into the brain and preventing dangerous free-radical reactions that may cause brain degeneration. It also stimulates production
of the brain's primary antioxidant, glutathione peroxidase. And unlike other antioxidants, melatonin is stable, never turning into a peroxidant.
Reiter also says that Alzheimer's disease patients have lowered melatonin levels coupled with increased free-radical production that may play a role in the destruction
of nerve cells characteristic of the disease. While all the evidence isn't yet in, Reiter speculates that "melatonin could delay aging-and the onset of the major diseases
that accompany it."