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                                 Melatonin
                 from 'Smart Drugs II: The Next Generation'
         by Ward Dean M.D., John Morgenthaler and Steven Wm. Fowkes

           Conversion to the electronic form by Swedish Infomania
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The pineal gland, until recently, has been referred to as mystery gland,
since its functions were largely unknown. The pineal is now recognized as a
key element in the maintenance of the body's endocrine regulation (hormone
balance), immune system integrity, and circadian rhythm (daily metabolic
balance). Melatonin is the principal hormone produced by the pineal gland.
Melatonin is under investigation as a treatment for a number of conditions,
including jet-lag, seasonal affective disorder (SAD), depression, and
cancer. Pineal polypeptide extract (which contains a broad spectrum of
other, protein-based pineal hormones) has been shown to inhibit the
development of atherosclerosis [Tasca, et al., 1974], reduce blood
triglyceride levels [Ostroumova and Vasiljeve,1976], improve cellular
immunity [Belokrylov, et al.,1976; Dilman,1977], and increase lifespan in
animals [Dilman, et al.,1979]. The pineal gland functions as a biological
clock by secreting melatonin (along with many other neuropeptides) at
night. As you can see from the following illustration, melatonin levels
peak at about 2 a.m. in normal, healthy young people and about 3 a.m. in
elderly people. The maximum amount of melatonin released in the bloodstream
of the elderly is only half of that in young adults.

Melatonin levels are low during the day. At sunset, the cessation of light
triggers neural signals which stimulate the pineal gland to begin releasing
melatonin. This rise continues for hours, eventually peaking around 2 a.m.
(3 a.m. for the elderly) after which it steadily declines to minimal levels
by morning. The delay in timing and decrease in intensity of the melatonin
pulse is a manifestation of the aging process.

The melatonin pulse regulates many neuroendocrine functions. When the
timing or intensity of the melatonin peak is disrupted (as in aging,
stress, jet-lag, or artificial jet-lag syndromes), many physiological and
mental functions are adversely affected. The ability to think clearly,
remember key facts, and make sound decisions can be profoundly hampered by
these upsets in the biological clock.

Melatonin for Jet-Lag

Jet-lag is a condition caused by desynchronization of the biological clock.
It is usually caused by drastically changing your sleep-wake cycle, as when
crossing several time zones during east-west travel, or when performing
shift work. Jet-lag is characterized by fatigue, early awakening or
insomnia, headache, fuzzy thinking, irritability, constipation, and reduced
immunity. The symptoms are generally worse when flying in an easterly
direction, and it may take as long as one day for each time zone crossed in
order to fully recover. Older people have an even tougher time adjusting to
these changes than younger people.

Circadian disturbances can easily result from conditions other than jet
travel. We call these "artificial jet-lag syndromes" because jet-lag is
universally understood. Artificial jet-lag can be induced by working night
shifts, working rotating shifts (like physician-interns, management
trainees for 24-hour businesses, and soldiers under battle-alert
conditions), or by staying up all night. Whatever its causes, jet-lag and
artificial jet-lag syndromes are seriously debilitating to cognitive
function. Melatonin taken in the evening (in the new time zone!) will
rapidly reset your biological clock and almost totally alleviate (or
prevent) the symptoms of jet-lag. The ability of melatonin to alleviate
jet-lag was demonstrated in a study of 17 subjects flying from San
Francisco to London (eight time zones away). Eight subjects took 5 mg of
melatonin, while nine subjects took a placebo. Those who took melatonin had
almost no symptoms of jet-lag (see illustration below) [Arendt, et
al.,1986). Six out of nine placebo subjects scored above 50 on the jet lag
scale, and all of the melatonin subjects scored below 17.

Most people sleep well with melatonin, and wake up the next day refreshed
with no symptoms of jet-lag [Claustrat, 1992) (although they may still have
some Fatigue from the wear and tear of traveling).

Many melatonin fans without any noticeable symptoms of circadian
disturbance are now using melatonin to enhance their circadian rhythms.
They report that it helps them get to sleep and helps them sleep more
soundly. It also makes them more alert the next day and even lessens
mid-afternoon tiredness (and naps).

In all cases, melatonin should be taken at night (preferably before
midnight) before going to bed. That's when your pineal gland naturally
releases melatonin. Taking melatonin at night (or before your normal
bedtime if you are a shift worker) helps restore and maintain normal
circadian metabolic rhythms. See the Precautions section in this chapter.

Does Melatonin Improve or Impair Mental Performance?

We were initially surprised to find a number of studies which reported on
adverse effects of melatonin on performance and alertness. One study
[Lieberman, 1984] reported that melatonin users were less alert, more
sleepy, and demonstrated slowed "choice-reaction time." Other studies also
indicated that melatonin impaired memory and performance [Neville, 1986).
We found, however, that in all of these studies, melatonin was given to
subjects in the daytime, before the performance tests, just the opposite
of what they should have been doing!

With circadian enhancers like melatonin, the timing is critical. When taken
in opposition to the body's natural circadian rhythm, they cause cognitive
deficit just like jet-lag does. But when taken in synchronization with the
body's natural circadian rhythms, they enhance mental performance. By
giving melatonin in the daytime, before the cognitive tests, the
researchers were causing the test subjects to suffer from artificial
jet-lag and then measuring the resulting cognitive impairment. Disruption
of circadian rhythms produces amnesia by interfering with the circadian
organization of memory processes [Sandyk,1991]. Melatonin, by correcting
circadian rhythms should, theoretically, improve mental performance. We
could only find one study in which melatonin was given to rats at night.
This study confirmed that next-day measures of learning ability improved
[Ovanesov,1990).

We believe that melatonin, when taken before sleep, will decrease sleep
disturbances of any kind, and will, therefore, improve mental function
during the following day.

Melatonin for SAD and Depression

Two particularly notable features of depression and SAD are diminished
nighttime release of melatonin and abnormal sensitivity to melatonin
suppression by light [Brown, 1989). This has led researchers and clinicians
to try melatonin as an experimental treatment for depression, with
gratifying results.

Melatonin Extends Lifespan

Melatonin has also been shown to improve immunity and extend lifespan in
rodents [Regelson & Pierpaoli, 1987; Pierpaoli, et al.,1990). Dr. Maestroni
[1988] gave melatonin to middle-aged mice each evening. The treated mice
became more healthy (better posture, increased activity levels, and
thicker, more lustrous fur) and lived an average of 20% longer than control
mice.

Melatonin secretion naturally drops off with age (see the following graph).
This decrease is so reliable that blood melatonin levels have been proposed
as a measurement of biological age [Nair, et al.,1986]. This age-related
reduction in melatonin levels may partially account for the reason many
older people have difficulty sleeping at night, and for why they are so
fatigued during the day. We believe they may be suffering from age-induced
"jet-lag." Restoration of normal sleep-wake cycles in many of my [WD)
elderly patients with supplemental melatonin before bedtime has
dramatically improved their quality of life.

Melatonin: Anti-Stress Hormone

Nighttime administration of melatonin can also counteract the
immune-suppressing effects of acute anxiety stress in mice. Measures used
to confirm this were: thymus weight, antibody production, and ability to
fight off a lethal viral infection [Pierpaoli and Maestroni,1987).

Melatonin for Cancer Treatment

Melatonin also appears to inhibit tumor growth. In the United Kingdom, a
study was carried out on 14 cancer patients with cancers of different
types. The researchers concluded that "this study would suggest that
melatonin may be of value in untreatable metastatic cancer patients,
particularly in improving their quality of life. Moreover, based on its
effects on the immune system, melatonin could be tested in association with
other anti-tumor treatments" [Lissoni,1989).

Melatonin in Alzheimer's Disease

Very recent studies have found reduced levels of melatonin in the
cerebrospinal fluid of patients with Alzheimer's disease compared to
age-matched control subjects [Tohgi,1992; Skene, 1990]. Since circadian
rhythms are disrupted in Alzheimer's disease, it is interesting to
speculate whether restoration of melatonin to normal levels in these
patients would alleviate other symptoms as well.

Melatonin and Exposure to Electromagnetic Fields

Sunlight is the primary environmental influence that regulates the internal
clock and the associated late-night melatonin pulse. There is some evidence
that the earth's magnetic field may also be an environmental signal
affecting circadian rhythms in humans. When shielded from the earth's
ambient magnetic field, human circadian rhythms can become disrupted
[Tohgi, 1992).

Exposure to electromagnetic fields from appliances and from powerlines may
be even more significant than we think. There are reports of altered neural
function from exposure to ELF (extremely low frequency) fields, as found
near high-voltage powerlines, including suppressed melatonin levels
[Lovely, 1988]. Supplemental melatonin may help to overcome the negative
health consequences of these fields.

Dosage

The appropriate dose can vary enormously from person to person. Dr.
Pierpaoli, a leading melatonin researcher, has successfully used dosages
ranging from 0.1 to 200 mg. That's a 2000-fold difference between the
lowest dose and the highest! Several intelligent melatonin users we know
started by taking 3 mg at 11 p.m., and then adjusted the dose from there.
If they found that they slept well but were drowsy in the morning, they cut
the dose in half. If they found the dose had little or no sleep-inducing
effect, they increased the dose by 3 mg each night until they got the
desired effect. We have received reports from one person who gets good
results from less than one milligram, and several from people who use in
the vicinity of 20 mg. Most people get good results with doses between 3
and 10 mg.

Precautions

Timing may be crucial for the most effective use of melatonin. Individual
differences in the absorption and metabolism of melatonin may account for
the differences in size and timing of the resulting melatonin pulse. A good
illustration of this effect is found in the experiences of Dr. Tzischinsky
[1992] of the medical university in Haifa, Israel. Dr. Tzischinsky treated
an 18-year-old blind man suffering from chronic sleep disturbances.
Presumably, the young man's blindness prevented sunlight from cueing his
circadian rhythm. He suffered from daytime fatigue, often falling asleep
during the day, but was awake at night. After two unsuccessful treatment
regimens with 5 mg and 10 mg melatonin administered at bedtime (10-10:30
p.m.), Dr. Tzischinsky tried a third regimen of only 5 mg administered at 8
p.m. for three weeks. This approach resulted in a successful resolution of
the man's sleep disturbances.

This observation (and others like it) demonstrate the importance of not
only adjusting the dosage but also the time of the dose. Melatonin seems to
be much more critical in this regard than other smart drugs. One melatonin
user reports that he gave himself terrible jet-lag by absent-mindedly
taking melatonin at 3 a.m. after staying up late. He recovered from this
error, resetting his circadian rhythm back to normal with melatonin at 10
p.m. the following evening, but not before he had to spend an entire day in
jet-lag hell for his mistake.

Sources

Melatonin is a non-prescription substance and can often be found where
supplements are sold. For information about mail-order sources for
melatonin you can send in the tearout card at the front of this book and
ask for the product sources list. (See also Appendix A).

References

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Belokrylov GA, Morozov VG, Khavinson VH, et al. The action of low molecular
  extracts from heterological thymus, pineal and hypothalamus on the immune
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Brown GM. Psychoneuroendocrinology of depression. Psychiatr J Univ Ott
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Claustrat B, Brun J, David M, Sassolas G and Chazot G. Melatonin and
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Dilman VM, Anisimov VN, and Ostroumova MN. Increase in lifespan of rats
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Dilman VM. Improvement of cell-mediated immunity after pineal gland extract
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Lissoni P Barni S, Crispino S, Tancini G and Fraschini F Endocrine and
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Lovely RH. Recent studies in the behavioral toxicology of ELF electric and
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Maurizi CP The therapeutic potential for tryptophan and melatonin: possible
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Nair NPV Hariharasubramanian N, Pilapil C, Issac I, and Thavundayil JX.
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Ostroumova MN and Vasiljeve IA. Effect or polypeptide pineal extract on
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