It seems as though every time we turn around there is a new health fad, be it a drug, herb or diet. Within the past 10 years the drug melatonin has hit the market and seems to have made quite a splash with the public and the media. At a time when an estimated thirty to forty million Americans suffer from serious sleep disorders that interfere with their sleep quality and health, many are desperate for an easy solution (Sleep Foundation 1). The media claims that this ?wonder drug? melatonin is the answer to these sleep disorders and also can prevent several illnesses. But is melatonin really safe enough for the public to experiment with? How much is known about what it does and its side effects? These are many of the questions that scientists are currently trying to answer. Listening to claims from the media and consumers it is tough to get the real story about the research scientists are conducting on melatonin. Melatonin is an effective drug in aiding in sleep disorders.
Melatonin was discovered in 1963 by dermatologist Aaron Lerner at Yale University. Lerner found skin lightning properties from the aggregation of organelles containing pigment (melanin) in the skin cells of amphibians. These collections of organelles are called melanosomes.2 His findings were published in the Journal of American Chemistry Society in a paper on melatonin entitled ?Isolation of Melatonin, the Pineal Gland Factor that Lightens Melanocytes.?3
Melatonin is only one of the many hormones produced by our bodies. This specific hormone is produced in the pineal gland, a small pea sized gland located at the base of the brain. To a lesser extent, melatonin is also produced in the retina.4 The pineal gland begins its production and secretion of melatonin at dusk and ceases at dawn. The pineal gland is not solely responsible for the release of melatonin, it receives instructions from the hypothalamus telling it when to begin and cease. Part of the hypothalamus, called the Suprachiasmatic Nucleus (SCN), tracks the length of day. It is also responsible for the regulation of many chemicals that govern the complicated process of sleep, including melatonin. The SCN controls the sleep-wake cycle and release of melatonin to fit seasonal changes in the amount of daylight.5
Recently, melatonin has hit the market in the form of a pill and is sold in health stores throughout the country. It is sold as a sleeping aid in pill form that claims it cures and prevents sleep disorders and jet lag in some cases. It has also been called an anti-aging drug that may prevent hypertension, high cholesterol, migraine, and even cancer and AIDS. None of these claims have been proven, but this does not stop consumers from buying and using this drug.6 Melatonin use is not regulated by the government because it is found in some foods.7
Since Aaron Lerner?s discovery of melatonin there has been much research on what this hormone is responsible for. Since it was thought that melatonin was involved somewhere in sleep, researchers began a study administering a synthetic form of the hormone to subjects, taking note of the effect in had on different stages of sleep.
In the early 80?s, Dr. Richard Wurtman of the Massachusetts Institute of Technology?s Clinical Research Center began giving volunteers what now would be considered a megadose of melatonin (240 mg). He found that melatonin aided in sleep and later found that as little as a tenth of a milligram can hasten the onset of sleep regardless of the time of day.8 Wurtman is the named inventor on an MIT patent pending on a melatonin-based sleeping pill (the chemical itself can not be patented). He states there is ?no controversy? that melatonin, even in fractions of a milligram, can induce sleep and shift the sleep cycle.9
Attenburrow and associates conducted a double-blind, placebo controlled, cross-over experiment to determine the effect of melatonin on sleep. Fifteen subjects were given .3 mg, 1 mg of melatonin or a placebo. The subjects sleep was continually measured, including both non-REM and REM sleep, over a period of time. Subjects were then given the opposite substance they were administered in the first segment of the study. Research found that melatonin given out in a 1.0 mg dose significantly improved subjects sleep time (the amount of time it took to fall asleep) and their sleep efficiency (the amount of time spent sleeping compared to the amount of time they were in bed) compared to subjects administered the placebo. Both non-REM and REM sleep were prolonged by the melatonin.10
Over 58% of the blind population have sleep disorders. They have trouble maintaining body rhythms that are in sync with the outside world due to their inability to perceive light. After being given melatonin before bed, several blind subjects improved their sleep-wake cycle to match that of the outside world. It also helped those unable to fall asleep in the morning and in general, all subjects fell asleep faster.11
Ten years ago a study concerning the role of melatonin was done on rats. These animals were placed in total darkness and were given nightly doses of melatonin. The rats became locked into daily patterns of daily sleeping and nightly scurrying similar to the rise and fall of the sun. After this study, many researchers examined the possibility that melatonin had an effect on sleep cycles.12 In all species studied (even unicellular algae) there is a day and night rhythm.13 Without usual light cues, the body?s biological rhythms will continue, but will fall out of sync with the outside world. This is true of both rats and humans because both species maintain an internalized sleep cycle of 25 hours under these circumstances. If, for example, a human stayed in a cave with no way to determine what the sun was doing, their sleep rhythms will fall increasingly out of sync with the actual occurrence of day and night.14
Jenny Redman and colleagues at La Trobe University in Australia were among the first to demonstrate that administering melatonin to subjects can shift bio rhythms. They exposed rats to constant light conditions and measured their bio rhythms. These rhythms were found to be more in some cases and less than 24 hours in others. A rhythm more than twenty-four hours is referred to as a free-running bio rhythm. Redman injected melatonin daily into these rats and found that the injections caused a change from the free-running rhythm into a 24 hour rhythm.15
Chronobiologist Benita Middleton and colleagues from the University of Surrey in England wondered if subjects placed in low-light conditions but take melatonin supplements at night would have normal sleep-wake cycles. To answer this, Middleton placed ten male subjects in a dim lit suite for two weeks. Their heart rates, body temperature and other vital signs were monitored. Each took 10 mg of melatonin at eight PM each night. After the two weeks were up, eight of the ten maintained normal sleep-wake cycles. Two subjects had very fragmented sleep-wake patterns. Middleton commented, ?Their biological rhythms seemed to have been completely shot.? Middleton thought the timing of the doses may have been off since everyone?s biological clock is different- eight o? clock may not have been the correct time. Reviewing her research, Middleton found the two subjects that the melatonin did not work for had their highest body temperatures later in the day than the others. Usually, the lowest body temperature occurs during sleep and the highest in the middle of the day. The two subjects were receiving melatonin at different times in their metabolic cycles. Middleton repeated the experiment again, but with six subjects who received their melatonin when their temperature cycles corresponded with the two subjects in the first group. Two of these subjects? sleep pattern were upset. Between the two experiments, of the eight people receiving melatonin at a determined time, four had trouble sleeping.16
Also at the University of Surrey, Josephine Arendt researched the effect of daily melatonin on biological rhythms. She administered 2 mg of melatonin at five PM for one month to her subjects and another group was administered a placebo. Compared with the placebo, the melatonin produced an advance in evening tiredness. Alfred Lewy and co-workers at the Oregon Health and Science Center University in Portland showed that administering .5 mg of melatonin for 5 days will alter the body?s bio rhythms. When taken in the morning, the body?s rhythms are delayed and when taken in the early after noon or evening they are advanced. Bruno Cluastrat?s group from Hopital Neurologique in Lyon, France came to the same conclusions as Lewy. The time of day that melatonin is taken makes a difference. He feels that there may be a possibility that these findings could produce advances in finding treatments for those with bio rhythm problems.17
The reason for these phase shifts and resynchronizations is that they are a result of the melatonin interaction with the internal body clock (IBC), or as referred to before, the portion of the hypothalamus called the SCN. Steve Reppert and co-workers at Harvard Medical School came across melatonin receptors in human postmortem SCN tissue. Another group from the University of Illinois led by Martha Gillete found that adding melatonin to slices of rat SCN in a culture advanced the timing of neuronal activity rhythm, if the melatonin was given during a period of day to night transition.18
Dr. Alfred Lewy?s research suggests that melatonin can be used to reset the natural sleep-wake cycle. He states it can be used to relieve jet-lag symptoms. He does warn that melatonin must be administered at the right time of day. If melatonin is taken at the wrong time, jet-lag could worsen.19 In another study, people suffering from jetlag were given melatonin and a placebo. Melatonin was taken three days before the flight and four days after the flight. In the melatonin subjects, sleep quality was improved and the time needed to fall asleep was reduced. In other studies, there was a 50% reduction in jet-lag with only minimal side-effects. Researchers have also found that a brief nightly dose of 5 mg of melatonin can help airline workers adjust to new time zones. This finding also holds true for night shift workers. Night shift workers were given melatonin and claimed their day time sleep improved as well as their night time alertness. However, more tests and trials need to be conducted to determine the correct dosage.20
Walter Pierpaoli and William Regelson, two Italian immunologist?s, book ?The Melatonin Miracle? claim several controversial advantages to using melatonin. Regelson states he wrote the book because pharmaceutical companies will likely drag their feet on researching melatonin because natural chemicals are difficult to patent. The book claims that melatonin has anti-aging properties based on an experiment done on rats.21 The authors surgically switched the pineal glands from ten young and ten older mice. The young mice died in late middle age while the older mice lived a third longer than their life expectancy. Pierpaoli also put melatonin in the drinking water of mice and achieved the same results. The authors are strong believers that humans would have the same results as rats.22 However, Steven M. Reppert and David R. Weaver of Harvard Medical School found that Pierpaoli and Regelson?s experiment was seriously flawed. According to Reppert and Weaver, the mice used in the experiments had a genetic defect making them unable to produce melatonin due to a lack of necessary enzymes. Since melatonin was not involved anywhere in this experiment, it is ?absurd? to claim that it is responsible for the prolonged life span.23
Approximately three years ago, Russell Reiter and a colleague, Jo Robinson, began research on melatonin as an anti-aging drug at the University of Texas Health Science Center. The researchers claim melatonin is a free radical scavenger. Free radicals corrode our cell membranes and DNA and are thought to contribute the aging process. Free radical damage is known as oxidation. Chemicals that inhibit oxidation are known as antioxidants. Reiter and Robinson found that melatonin has anti-oxidant properties in rats.24 Wurtman feels that while this may be true, there is not enough scientific evidence to determine that melatonin promotes life longitivaty in mice and no evidence to show this could also be true for humans.25
Other claims from the media regarding melatonin include better sex drive and prevention for a myriad of diseases including AIDS, altziemers, heart diseases, and cancer.26 MIT?s Wurtman states melatonin may worsen conditions in AIDS if anything, not make them better.27 ?It has not been studied yet, but I think it would not be unexpected for high doses of melatonin to affect sex-drive? says Wurtman. He feels taking supplemental melatonin could decrease sex-drive because high levels of the hormone are thought to produce another hormone, prolactin, which decreases sex-drive in males.28 If this hormone does have any powers in the prevention of aging or chronic illness, it will take years or even decades to establish.29
Many people are using melatonin for a variety of reasons but don?t seem to be too concerned if there are side effects to using this drug. Sahelian, who monitors about six alternative-health discussion groups administered an informal survey to question melatonin use. She estimates that 80% of the recent postings regarding melatonin concern better sleep. In her survey results she found that 10% of the users said the hormone had no effect on them and 10% complained of nightmares, headaches, morning grogginess, mild-depression, and low sex-drive. The Food and Drug Administration has only received four complaints about the drug, two complained of disrupted sleep patterns, one of genital pain and the last of nausea. There is no way to determine if melatonin was the primary cause of these symptoms.30 High doses will cause a drowsy feeling and lower reaction time. It has also been recommended that children, teenagers, and pregnant or lactating women abstain from using thisdrug.31 There is no data on the long term-effects of taking melatonin, but the short term effects seem to be few and far between especially compared with over the counter and prescription sleeping aids.
Tim Roth of the Sleep Disorders and Research Center at the Henry Ford Hospital in Detroit feels that people should not experiment with melatonin purchased at health stores. To this point, research on melatonin has been mainly laboratory studies without much organized of definite research to prove without a shadow of a doubt that it does help people sleep or is safe to take for long periods of time. Dr. Robert Sack of the Oregon Health and Sciences University says ?We have people taking it in this sort of uncontrolled experiment. We are kind of nervous about that.? He also comments ?we are going at it backwards, people are taking it to figure out what it does.?32 Often in health stores, the melatonin level in the pill is not regulated. Some pills contain enough melatonin to raise the levels in blood more than ten times the normal level. Overall, not enough research has been done to determine the side effects of such high dosage.33
In August of 1997, the National Institutes of Health conference assembled sleep researchers and experts to establish what research must be done to determine the safety and efficiency of melatonin. It is not a scientifically proven safe or effective sleep aid and is even illegal in Canada and the European community.34 Experts at this convention deemed this melatonin revolution as ?scary? due to the lack of evidence, but the willingness to use the drug. In general, the opinion of the scientific community can be summed up with this statement from the European Pineal Society:
?Administration of melatonin is useful, when correctly time, in certain types of human circadian rhythm disorder leading to sleep problems. There is insufficient scientific evidence for any other therapeutic uses in humans as yet. There is no information on possible harmful long-term side effects. Melatonin may be dangerous if incorrectly timed, and should not be taken without medical supervision. We advise that this substance should be subjected to appropriate efficacy and safety evaluation in order to avoid potential problems.?35At this time, the medical jury is still ?out? on the effects of melatonin. Additional structural experiments must be conducted to determine both short term and long-term effects of melatonin on humans. Research has found many positive sides of melatonin and further investigations should be made to ensure the safety of it. Since there is a possibility we have a potential drug on our hands, it should definitely be tested, but not by those enticed by the media. Anytime hormone levels in the body get changed, there is always a possibility of disturbing the delicate balance of homeostasis which must be maintained to function properly. If people really want to be healthy, experimenting with drugs with unknown properties is out of the question.
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