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An Executive Review: Melatonin, the Smart Hormone

Roger F. Peters [RFD, BA, BSc, Hon, MSc, Phd, DACPCP, FEAPAA. Director of Clinical Services, HEAS Pty Ltd].

1.0 Introduction

2.0 Melatonin Production in Man

3.0 Melatonin and Jet Lag

4.0 The Melatonin Miracle
4.1 Does Melatonin Improve or Impair Mental Performance?
4.2 Melatonin for seasonal Affective Disorder, (SAD) and Depression
4.3 Melatonin Extends Lifespan
4.4 Melatonin: Anti-Stress Hormone
4.5 Melatonin for Cancer Treatment
4.6 Melatonin in Alzheimer's Disease

5.0 Dosage

6.0 Precautions

7.0 Sources


1.0 Introduction

The pineal gland, until recently, has been referred to as "the mystery gland", since it's functions were largely unknown. The pineal is now recognised 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. Melatonin levels peak at about 2 a.m. in normal, health young people and about 3 a.m. in elderly people. This explains, given the affects of sleepiness why high risk time in workplaces may occur most frequently between 2-4. What is interesting of course is that the circadian rhythm of Melatonin is travelled. This causes the frequently referred to "jet lag" phenomenon. In the case of a global sports competition that is played on a weekly basis it is clear that travelling to the UK from Australia and return may have the same psychophysiological affects on players as it does on travellers and certainly cabin crew. This affect is described in a review by the author and others, separate from this paper.


2.0 Melatonin Production in Man

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.


3.0 Melatonin and 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 characterised 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 find even more difficulty adjusting to time changes than younger people. Circadian disturbances can easily result from conditions other than jet travel. These 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 condition), or by staying up all night. Whatever its causes, jet-lag and artificial jet-lag syndromes are seriously debilitation to cognitive functions. Melatonin taken in the evening (in the new time zone!) will rapidly reset travelled biological clocks and almost totally alleviate (or prevent) the symptoms of jet-lag. The ability of Melatonin to alleviate jet-lag was first demonstrated in a study of 17 subjects flying from San Francisco to London (eight time zones away). Eight subjects took 5mg of Melatonin, while nine subjects look a placebo. Those who took Melatonin had almost no symptoms of jet-lag (Arendt, et al.,1986). Six out of nine placebo subjects scored about 50 on the jet lag scale, and all of the Melatonin subjects scored below 17.


4.0 The Melatonin Miracle

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 travelling). Melatonin is now being used with people without any noticeable symptoms of circadian disturbance to enhance their circadian rhythms. Regular users 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). It has been recommended that Melatonin should be taken at night (preferably before midnight) before going to bed. However, that's when the pineal gland naturally releases Melatonin. In cases of nocturnal wakening, i.e., about 2-3 am it may be that taking Melatonin may reverse the affects caused by the early on set of adrenaline and 17 hydroxycorticosteriod (cortisol) two hormones most related to the so called "stress: response. Some evidence suggests that 3mg of Melatonin at that time allows for a further three hours of sleep, waking at a normal time of between 5.30 and 7.00. Taking Melatonin at night (or before your normal bedtime if you are a shift worker) helps restore and maintain normal circadian metabolic rhythms.

4.1 Does Melatonin Improve or Impair Mental Performance?

There have been a number of studies that supposedly report the adverse affects 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 [Meville, 1986]. However, it should be noted 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! However, it is important to remember in circadian enhancers like Melatonin, the timing is critical. When taken in opposition to the body's natural circadian rhythm it can cause cognitive deficit just like jet-lag. When taken in synchronisation with the body's natural circadian rhythms, Melatonin enhances mental performance. In the studies above by administering 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 organisation of memory processes [Sandyk, 1991], so these results were not surprisingly adverse. Melatonin, by correcting circadian rhythms should, theoretically, improve mental performance, One study, Ovanesov (1990), administered Melatonin to rats at night. This study confirmed that next-day measures of learning ability improved. Melatonin, when taken before sleep, will decrease sleep disturbances of any kind, and will, therefore, improve mental function during the following day.

4.2 Melatonin for seasonal Affective Disorder, (SAD) and Depression

Notable features of depression and SAD are diminished by night time release of Melatonin and abnormal sensitivity to Melatonin suppression by light [Brown, 1989]. This led researchers and clinicians to try Melatonin as an experimental treatment for depression, with exceptional results. This is discussed in the book Melatonin Miracle by Pierpalol (1996). These results should not be of surprise, given the close relationship Melatonin has pharmacologically with serotonin, believed of course to be a major factor in depression.

4.3 Melatonin Extends Lifespan

Melatonin has also been shown to improve immunity and extend lifespan in rodents [Regelson & amp; Pierpaoli, 1987; Pierpaoli, 1990]. Meastroni [1988] gave Melatonin to middle-aged mice each evening. The treated mice became more healthy (better posture, increased activity levels, and thinker, more lustrous fur) and lived an average of 20% longer than control mice. Melatonin secretion naturally drops off will age. This decrease is so reliable that blood Melatonin Levels have been proposed as a measurement of biological age [Nair, 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 form age-induced "jet-lag" Restoration of normal sleep-wake cycles in many elderly patients with supplemental Melatonin before bedtime has dramatically improved their quality of life.

4.4 Melatonin: Anti-Stress Hormone

Night time 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 Meastroni, 1987].

4.5 Melatonin for Cancer Treatment

Melatonin also appears to inhibit tumour growth, In the United Kingdom, a study was carried out on 14 cancer patients with cancers of different types. The researchers concluded "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-tumour treatments" [Lissioni, 1989].

4.6 Melatonin in Alzheimer's Disease

More recent studies have found reduced levels of Melatonin in the cerebrospinal fluid of patient's 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.

5.0 Dosage

The appropriate dose can vary enormously from person to person. Dr Pierpaoli, a leading Melatonin researcher, successfully used dosages ranging from 0.1 to 200mg. That's a 2000-fold difference between the lowest dose and the highest! Others including the author suggest 3 mg at 11pm, then adjust the dose in relation to the response. If patients slept well, but were drowsy in the morning, reduce the dose by half.

6.0 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 difference in size and timing of the resulting Melatonin pulse. A good illustration of this affect 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 cuing 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 5mg and 10mg of Melatonin administered at bedtime (10 - 10:30pm), Dr Tzischinsky tried a third regimen of only 5mg at 8:00pm for three weeks. This approach resulted in a successful resolution of the man's sleep disturbances. In 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 drugs.

7.0 Sources

Melatonin is a non-prescription substance and can not be purchased in Australia. Despite claims that strict controlled pharmacological studies need to be carried out, it is the view of the author that this is more about the impact Melatonin use may have on the synthetic prescribed industry in Australia. Paradoxically the Australian Federal Government will allow however, purchase overseas and importation for personal use. The average is US$9.00 for 60 3mg tablets. The research in this executive review clearly indicates that Melatonin can be used as a safe substitute without side effects, in the treatment of many common problems, including sleep disorders, depression and anxiety. It's use in the reduction of the adverse affects caused by international travel is undeniable and the subject of a further report in HEAS Research and Development Training Services.


References

Arendt J, Aldhouse M, and Marks V. (1986) Alleviation of Jet Lag by Melatonin: Preliminary results of controlled double-blind trial. British Medical Journal 292: 1170.

Belokrylov GA, Morozov VG, Khavinson VH, (1976). The action of low molecular extracts from heterological thymus, pineal and hypothalamus on the immune response in mice. Bulletin of Experimental Biological Medicine, 81: 202-4.

Brown GM (1989). Psychoneuroendocrinology of depression. Journal of Psychiatry University of Ottawa 14 (2): 344-8; Jun.

Souetre E, Salvati E, Krebs B, Belugou JL and Darcourt G (1989). Abnormal Melatonin Response to 5-Methoxypsoralen in Dementia. American Journal of Psychiatry 146(8): 1037-40, Aug.

Tohgi H, Abe T, Takahashi S, Kimura M, Takahashi J and Kikuchi T (1992). Concentrations of Serotonin and it's Related Substances in the Cerebrospinal Fluid Inpatients with Alzheimer Type Dementia. Neuroscience Letters (Ireland) 141(1): 9-12 1992.

Tzischinsky O, Pal I, Epstein R, Dagan Y and Lavie P (1992). The Importance of Timing in Melatonin Administration in a Blind Man. Journal of Pineal Research (Denmark) 12(3): 105-8

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