MELATONIN

OFFICIAL NAMES: Melatonin, 5-methoxy-N-acetyltrypt-amine

STREET NAMES: Melliquid, mellow tonin, somniset

DRUG CLASSIFICATIONS: Not scheduled

OVERVIEW

Melatonin is a natural hormone produced by many animals. In humans, it is produced in several parts of the body, including the pineal gland, which is a small organ located at the base of the brain. Historically, the pineal gland was thought to have some sort of metaphysical function. It was often called the "third eye" and was said to be "the seat of the soul" by Descartes. It is now known to be involved in the neuroendocrine system, which involves the interaction of the nervous and endocrine systems (organs that produce hormones). This interaction results in the regulation of essential body functions. The neuroendocrine system is responsible for the fight or flight response, as well as many other processes that keep people alive and healthy. Melatonin is thought to be important in maintaining certain essential physiological functions such as sleep.

There are many nerve fibers in the pineal gland. Some of these fibers release noradrenalin, a chemical messenger produced by the nervous system. Noradrenalin stimulates certain cells in the pineal gland, called pinealocytes, to produce and release melatonin.

Some parts of the brain, like the cerebral cortex, are much more highly evolved in humans than in other animals. The pineal gland, however, is a very basic organ that first evolved in primitive species. It is found in lampreys, fish, amphibians, and reptiles, as well as in mammals. The hormone melatonin has also been found in insects and plants.

Researchers first hypothesized the existence of melatonin almost 100 years ago. Back in 1917, scientists noticed that an unknown substance from the pineal gland affected melanophores, a kind of pigment cell found in frog skin. More than 40 years later, a dermatologist, Dr. Aaron Lerner, finally isolated this substance from the pineal gland and named it melatonin.

Over the next few decades, researchers learned that melatonin had many other effects in addition to influencing pigmentation in amphibians. Most current research has studied its influence on promoting sleep. Other studies have linked this hormone to other processes such as reducing jet lag, boosting the immune system, and fighting cancer.

Scientists have learned that the retina of the eye and parts of the gastrointestinal tract also produce melatonin. It is not known if the function of melatonin produced by these parts of the body differs from that made by the pineal gland.

The production of melatonin varies over the course of a day. Darkness stimulates the pineal gland to produce melatonin, while the presence of light inhibits the release of this hormone. Melatonin levels are so low during the daytime that they are almost immeasurable. The amount of melatonin starts to increase around 9 p.m. or 10 p.m. Levels continue to increase during the early part of the night and peak at about 2 a.m. to 4 a.m. and thereafter start to decrease through the rest of the morning.

While everyone follows this general pattern of diurnal melatonin secretion, each individual has his or her own unique pattern. Melatonin peaks and valleys can occur at different times in different people and may explain why some individuals are "morning" people, while others are "night owls."

This circadian rhythm of melatonin production is not limited to humans and animals. Certain types of alga show a daily variability in their synthesis of melatonin. Darkness stimulates melatonin production by these one-celled creatures.

The presence of light influences the pattern of melatonin release. In some people, melatonin is secreted for a shorter period during the shorter nights of summer. But in winter, melatonin release lasts longer during the prolonged darkness in these susceptible individuals. Some scientists hypothesize that this variation in melatonin production may be responsible for seasonal affective disorder (SAD). SAD is a form of depression that occurs during the winter. It is frequently successfully treated by exposure to artificial light.

Artificial light, like natural light, influences the synthesis of melatonin by the pineal gland. Exposure to light during the night will inhibit melatonin production. Research results show that women who work night shifts have an increased risk of getting breast cancer; scientists are investigating whether this alteration in melatonin production may be linked to the development of cancer.

Melatonin secretion also varies over the course of a lifetime. Newborn babies produce very little of this hormone, but after the first few months of life the pineal gland increases its production of melatonin. Very small babies produce a relatively constant amount of melatonin throughout the day and night. They do not have any diurnal variation in the production or release of melatonin. It is not until infants are between nine and 12 weeks old that the pineal gland starts to shift towards a nocturnal production of this hormone. Highest levels occur in children who are about four to seven years old. Older children and adults produce smaller amounts, as production gradually decreases during puberty. The typical adult male produces about 30 micrograms of melatonin during a typical day.

Because melatonin production goes down during puberty, some researchers suspect that the decreasing levels of this hormone are somehow linked to sexual maturation. Melatonin also influences the levels of certain reproductive hormones such as prolactin and luteinizing hormone. Due to these effects, many experts recommend that children, teenagers, pregnant women, and breastfeeding mothers do not take melatonin.

Researchers used to think that older adults produced very little melatonin. Since the elderly tend to have more problems with insomnia and other sleeping disorders, scientists hypothesized that these lower levels of melatonin were the cause of sleeping problems in this population.

However, a study published in the January 2001 issue of the American Journal of Physiology showed that melatonin levels are just as high in older adults as they are in younger individuals. Dr. J. B. Fourtillan measured melatonin levels in 34 healthy adults who were over 65 years of age and in 101 healthy adults who were under 30 years of age. The levels of this hormone did not differ between the two age groups.

Researchers still need to learn a lot about what melatonin does and how it can be safely used. Scientists have not completed enough studies to know exactly what functions melatonin carries out in the human body. Similarly, physicians do not understand at what time during the day or night melatonin should be taken or what dose is most effective. Nor do physicians know enough about the long-term effects of taking melatonin since it has only became popular in the 1990s.

In spite of this lack of information, several popular books came out during the 1990s advocating the supposed usefulness of melatonin as a treatment for everything from insomnia to jet lag to aging. Consumer interest in melatonin increased dramatically. It is estimated that millions of Americans take melatonin supplements as a "natural" remedy.

Although melatonin is a hormone and a drug, it is not regulated by the Food and Drug Administration (FDA). That is because melatonin is naturally found in certain foods. However, the amount of melatonin in over-the-counter medications is a great deal higher than what is found in food, or is produced by the human body. A typical supplement may contain anywhere from 500 micrograms to 5 mg. A supplement containing 500 micrograms will produce blood concentrations similar to those normally found in the human body. Doses of 1–5 mg will result in blood levels anywhere from 10 to 100 times higher than normal.

Melatonin can have different effects depending on when it is taken. If taken slightly before bedtime, it may be useful in adjusting a person's sleep schedule following a long flight. Taken during the day, however, it will not change the sleeping pattern; it will just make the person sleepy. Similarly, some cancer research suggests that melatonin may be helpful as a cancer therapy if given at the correct time of day. If it is given at the wrong time, it may end up having no effect or may actually increase the risk of developing cancer.

Because melatonin is not regulated by the FDA, commercially available preparations are not subject to the same scrutiny as medications under the direction of this federal agency. Melatonin supplements do not have to be extensively tested in animals and humans before being sold in over-the-counter preparations. Manufacturers do not have to maintain high production standards, nor do they have to be as concerned with instituting FDA-required safety checks. Manufacturers are, however, limited by law in one way: They cannot claim that their product will cure or treat anything. They can only make general statements. While they can say that melatonin helps people sleep, they cannot say that it treats insomnia.

CHEMICAL/ORGANIC COMPOSITION

Melatonin is made from tryptophan, a type of amino acid. Pinealocytes absorb tryptophan from the blood. Through a series of chemical reactions, the pinealocytes then convert the amino acid into melatonin.

Melatonin is a relatively simple type of chemical compound. It is rapidly absorbed and will reach its peak concentration within about an hour after it is swallowed. Melatonin is fat soluable, which means it is able to enter all the cells of the body, including brain cells. So melatonin can easily leave the bloodstream and enter brain cells. But melatonin does not remain in the bloodstream for very long as it is quickly broken down by the liver. It takes about 30 to 40 minutes for the liver to remove one half of the melatonin that is present in the blood.

Many over-the-counter drugs contain melatonin. Some of these products are made from animal sources. However, most commercially available melatonin is synthetic.

Since melatonin is naturally found in some foods, it is legal to sell it as a dietary supplement in the United States under the U.S. Dietary Supplement Health and Education Act (DSHEA) of 1994. Dietary supplements like multivitamins are not as carefully regulated by the federal government as are prescription medications. However, the amount of melatonin in food is very low. A person would have to eat 120 bananas or 30 large bowls of rice to get the same amount of melatonin that is contained in a 3-mg capsule. The amount of melatonin contained in dietary supplements is much, much higher than that produced by the pineal gland or obtained through food.

Since commercially available drugs containing melatonin are not regulated, they are not held to the same high standards of purity and efficacy as are other medications. Melatonin, being a hormone, is just as potentially dangerous as other naturally occurring substances such as estrogens and androgens.

Drugs that are not regulated by the FDA are more likely to be contaminated with impurities. They may also be inaccurately labeled and not contain the amount of melatonin listed on the label. According to the National Sleep Foundation, a batch of melatonin was examined and found to contain much more of the hormone than was listed on the label. According to another study, one third of the medications that supposedly contained melatonin did not contain any melatonin, while an additional 40% contained much less than was stated on the label.

While many commercially available preparations contain only melatonin, many others contain a combination of this hormone with other active ingredients. Some of these other ingredients may be vitamins such as pyridoxine, while others are natural remedies such as kava root and valerian. It is even available combined with acetaminophen, a common over-the-counter pain reliever. Frequently, the long-term effects and safety of these other ingredients are not known. Even less is known about any possible interactions between these substances and melatonin, because melatonin has been available and used commercially for only a short period of time. Many experts have suggested that it would be preferable to test melatonin in controlled studies to determine if it is effective and safe before it was released on the market and used by millions of people.

INGESTION METHODS

Melatonin is usually taken orally. It is available in pills, capsules, and liquids. It also can be absorbed from under the tongue. It is sometimes injected when it is used as a treatment for cancer.

Most commercial preparations contain much higher doses than the 30 micrograms typically produced by an average adult male. While researchers do not know what dose may be optimal for therapeutic use, several studies indicate that between 0.5 to 5.0 mg is sufficient for treating jet lag. Some studies suggest that time-release forms, however, may be ineffective.

The natural production of melatonin by the pineal gland varies during the course of a day. Melatonin levels are very low during the daylight hours and increase when it is dark. The time a person swallows an over-the-counter formulation of melatonin is just as important as the amount ingested. Taking melatonin during the middle of the day may not help people to sleep better at night and, instead, may make them tired and decrease their alertness.

Slow-release capsules are also available. However, the results of a review of 10 studies that investigated the effectiveness of melatonin for treating jet lag indicated that time-release capsules are not effective for treating jet lag.

THERAPEUTIC USE

Melatonin may be an effective treatment for several conditions. Studies suggest that it may be helpful in treating sleep disorders, jet lag, and even cancer. However, research on this topic is still very limited and experts have warned consumers that very little is known about the effectiveness or long-term safety of taking melatonin supplements.

Sleep disorders

While the popular press has publicized the usefulness of melatonin as a natural sleeping aid, the results of studies are often contradictory. Some studies suggest that melatonin is helpful in treating insomnia, while others have shown that it is absolutely useless.

Researchers still have not investigated melatonin's effectiveness in treating insomnia in most age groups. As of 2000, only three studies had investigated the usefulness of melatonin in treating insomnia in people younger than 65 years of age.

While the effectiveness of melatonin in treating sleep disorders in most people remains unclear, research shows that it can be helpful for certain individuals. For example, many blind people have sleep disorders, and melatonin has been shown to help promote sleep in this population. Studies have also shown that it is helpful in treating sleep disorders in disabled children.

Jet lag/shift work

People and animals follow a natural circadian rhythm. Humans and many animals tend to be diurnal. They get up in the morning, are active during the day, and sleep at night. Disruptions in this natural cycle can be difficult. With the advent of air travel, people could travel halfway around the world, passing through several time zones. Their circadian rhythm can be very disrupted by the time differences. Besides having difficulties sleeping at the appropriate time, people with jet lag may also experience constipation and other digestive difficulties.

Shift workers have a similar difficulty in trying to stay awake at a time when they would normally be asleep. Nurses working an evening shift may start to get sleepy while they are still at work, while those on the morning shift may have a great deal of difficulty getting up well before dawn.

Melatonin may be helpful for both shift workers and air travelers trying to adjust to the local time. According to a paper published in 2002, nine out of 10 studies that investigated the effectiveness of melatonin in treating jet lag demonstrated that melatonin did help ease this condition. Individuals who had traveled across five or more time zones and then took melatonin close to the time they wanted to fall asleep were more easily able to make the adjustment to local time. Doses between 0.5 mg and 5 mg were effective, although the larger dose helped a bit more in promoting sleep. Larger doses did not provide any additional benefits. Reviewers suggested that melatonin was more effective when crossing more time zones and for eastbound travelers. The study review also indicated that time-release preparations or

taking any form of melatonin earlier in the day was ineffective. Not only was it not helpful, but taking melatonin during the middle of day just made people sleepy and delayed their adjustment to the local time.

While more research is needed, a few studies indicate that melatonin can help people adjust to working the night shift. It can also help people readjust back to sleeping during the night and staying awake during the day when they discontinue working the night shift. In one study of 32 night workers published in 2002, those taking 0.5–3.0 mg of melatonin during the afternoon helped them sleep during the day before leaving for work.

In addition to questions concerning the effectiveness of melatonin for any condition, researchers still do not know enough about the long-term consequences of taking melatonin on a regular basis. Many experts caution that until melatonin has been proven to be safe and not cause serious side effects, using it as a therapeutic agent is too risky.

Cancer

In the 1970s, researchers noticed that the amount of melatonin found in the blood of certain cancer patients was lower than in healthy individuals. Soon afterwards, other studies showed that the nighttime increase in melatonin, which occurs naturally in most humans, was markedly decreased in some cancer patients.

Experts are not sure how melatonin influences the development of cancer. A recent study published in 1999 in Cancer Research suggests that melatonin may help to starve cancer cells. Tumors use a type of fat called linoleic acid as a food source. Melatonin prevented the tumor cells in rats from being able to metabolize linoleic, but only when it was given to rats during the late afternoon. When it was given to the rats earlier in the day it did not have any effect.

Most of the research investigating the effectiveness of melatonin in treating cancer have been conducted in rats and mice, or in test tube samples of human cells. However, there have been several clinical trials that show that melatonin may be helpful as a therapy for different types of cancer. Again, timing of the dose is very important. Several other studies have shown that melatonin is not effective, or even promotes tumor growth, depending on when during the day it is given.

Other conditions

While melatonin is not currently being used to treat these conditions, research is currently underway investigating its role in preventing Alzheimer's disease. A study published in Biochemistry in 2001 showed that melatonin can inhibit the development of amyloid beta, a toxic substance that has been linked to the development of Alzheimer's. Other studies suggest that melatonin may be helpful in reducing the side effects caused by medications that are used to treat schizophrenia.

USAGE TRENDS

No one knows the exact number of people who use melatonin. According to a CNN report, 20 million Americans have taken melatonin to treat jet lag or sleeping disorders. It is legal and therefore easy to buy this hormone in over-the-counter medication in the United States. Several other countries have had a different attitude towards such widespread use of a potentially dangerous hormone; several European countries and Canada restrict the sale of melatonin.

Scope and severity

While it is estimated that millions of Americans have taken melatonin, the scope and severity of its use in the United States is unknown. Regardless, the use of this hormone is probably much higher in the United States where it is legal than in Canada or Europe where it is not.

Age, ethnic, and gender trends

Since the elderly tend to have more problems with insomnia than do younger individuals, it is thought that this age group is more likely to use melatonin. However, there is no proof that this is true. Research studies investigating which groups use melatonin are needed before it is possible to definitively state who is more likely to use this hormone.

MENTAL EFFECTS

Very little is known about what types of long-term psychological effects can be caused by the use of melatonin.

It is clear, however, that melatonin has short-term mental effects. It definitely can cause drowsiness when taken during the day. Melatonin taken at night, however, will not cause daytime sleepiness. People who take melatonin are also less likely to respond correctly to visual and auditory signals. They are more likely to make mistakes and their reaction time decreases when they take this hormone. Several studies have shown that taking melatonin inhibits a person's ability to concentrate and can cause confusion. People should therefore not take it when they need to stay alert, such as when they will be driving a car. The effects begin within approximately an hour of taking melatonin and last for about two hours.

Some experts are concerned that melatonin may worsen depression and recommend that people who have a mental illness not take this hormone.

Paradoxically, when taken with other drugs, melatonin may have very different mental effects. It tends to stimulate some of the biochemical effects caused by methamphetamines; it can end up aggravating insomnia, instead of causing sleepiness, when taken with these drugs. Taking melatonin with benzodiazepines has been reported to cause anxiety.

PHYSIOLOGICAL EFFECTS

Melatonin causes general effects that are felt throughout the body and specific effects on certain organs. Melatonin reduces body temperature so people may feel slightly cooler after they take a supplement containing this substance in addition to becoming sleepy. Melatonin produced by the pineal gland also has this effect. However, there is a slight variation in the ability of melatonin to reduce body temperature. Melatonin is not as effective at lowering body temperature during the luteal phase of the menstrual cycle, which is just before ovulation. Physicians and many women have long known that a woman's body temperature increases slightly just before ovulation.

Melatonin also causes vasoconstriction, which is the narrowing of the blood vessels.

Sleep/circadian sleep rhythms

The most well-known effect of melatonin is that it regulates the sleep cycle. Production of melatonin by the pineal gland increases with darkness. Increased melatonin levels, in turn, promote sleep.

Melatonin is not essential for sleep to occur. Many people take naps during the daylight hours and can stay awake into the early hours of the morning, although melatonin levels are very low at this time. Still, most people find it very difficult to stay awake all night and sleep during the day. Melatonin does, somehow, make sleeping easier. The abnormal production of melatonin has been linked to sleeping difficulties. Many blind people who do not have any perception of light also have an abnormal pattern of melatonin production. They may not have higher levels during the night or their highest levels of melatonin can actually occur during the day. These individuals tend to have sleeping disorders. They may have difficulty sleeping at night and take naps during the daytime. Exactly how melatonin is related to the maintenance of a normal sleep cycle is not yet understood.

Reproductive effects

Melatonin influences the level of other hormones in the body. It has been shown to have a particularly strong effect on prolactin and luteinizing hormone, both of which are major reproductive hormones. Some authorities caution that it may reduce the sexual drive in men.

The natural production of melatonin by the pineal gland peaks at the age of only four or five years of age. Since a decrease in its production occurs during sexual maturation, researchers warn that taking it during adolescence may have a detrimental effect on puberty.

Immune effects

Melatonin has been shown to boost certain parts of the immune system. It boosts the activity of natural killer cells, a type of immune cell. It also prevents apoptosis, a type of destruction of T-lymphocytes, which are other important immune cells found in the bloodstream. Melatonin also limits the effect of corticosteroids on the immune system. Corticosteroids are very potent drugs that are sometimes used to inhibit the immune system. Some people have autoimmune diseases in which their immune system attacks the cells of their own bodies. Physicians frequently prescribe corticosteroids for these individuals.

Harmful side effects

As there has been very little research studying the safety of taking melatonin, most experts caution people against using it, or to limit their intake of it. However, it is known that melatonin may be particularly dangerous for certain people. People should not take melatonin if they:

• Have not finished, or even started, puberty. The decreased production of melatonin by the pineal gland that occurs during late childhood and early adolescence may be linked to sexual maturation.
• Are breast-feeding. Melatonin affects the level of prolactin, a hormone that controls the production of breast milk.
• Are pregnant. Melatonin influences the levels of various sex hormones.
• Have a history of stroke or other cerebrovascular disease. Melatonin causes vasoconstriction, which, under certain circumstances, can be a risk factor for cerebrovascular disease.
• Have a history of liver disease. Melatonin is metabolized in the liver. Melatonin may remain within the body for a longer time and in larger amounts if the liver is not able to break down this hormone so that it can be excreted.
• Have an autoimmune disease. Melatonin has been shown to boost some processes of the immune system. People who have an autoimmune disease already have an overactive immune system, which is attacking their own body. Taking a substance such as melatonin, which further stimulates immune activity, may make their symptoms much more severe.
• Are depressed or have a neurological disorder. Although melatonin may be linked to the development of seasonal affective disorder (SAD), its exact role in emotional and neurological illnesses remains unclear.
• Take certain medications such as benzodiazepines, methamphetamines, dehydroepiandrosterone, magnesium, zinc, corticosteroids, and succinylcholine.

Melatonin can cause some adverse effects. People should contact their health care provider if they have difficulty sleeping or feel too sleepy, develop a headache, chills, or itching, feel confused, or have a fast pulse after taking melatonin. Individuals who will be undergoing surgery should tell the anesthesiologist that they have been taking melatonin.

Long-term health effects

No one knows what kind of effects may result after taking melatonin for a long period time. It has not been studied and its widespread use only started during the 1990s. Many experts strongly warn people not to take melatonin, or to at least limit their use to a short period of time such as for a few days after taking a long trip as a short-term treatment for jet lag. But some experts caution that withdrawal may occur after taking very high doses of melatonin.

REACTIONS WITH OTHER DRUGS OR SUBSTANCES

Much remains unknown about melatonin's interaction with many other drugs and substances. However, it is known that melatonin does interact with, and may limit the effectiveness of, benzodiazepines, methamphetamines, dehydroepiandrosterone, magnesium, zinc, corticosteroids, and succinylcholine. People who are being treated with these drugs should not take melatonin.

Interactions between drugs or substances and endogenous melatonin

Selective serotonin reuptake inhibitors (SSRIs) are a type of antidepressant that stimulates the pineal gland's ability to produce melatonin. Antipsychotic drugs also have this effect. Other medicines have the opposite effect. Certain types of medicines used to treat cardiovascular disease called beta blockers reduce the production of melatonin by the pineal gland. Nonsteroidal anti-inflammatories, which are used to treat pain and/or fever, benzodiazepines, and caffeine also inhibit the production of melatonin.

Interactions between drugs or substances and exogenous melatonin

Individuals who take melatonin supplements and benzodiazepines may feel very anxious and unsettled. Instead of causing sleepiness, melatonin can aggravate insomnia when taken with metamphetamines.

TREATMENT AND REHABILITATION

Currently, there are no treatment or rehabilitation options for people who use melatonin. It is not known if long-term users may have difficulty with sleeping or other side effects when they quit taking melatonin supplements. Discontinuing the use of melatonin after short-term use, such as for adjusting to jet lag, has not proved to be difficult or to cause any side effects.

Some experts, however, are concerned that abruptly discontinuing the use of melatonin after taking very high doses may result in withdrawal. Whether or not this is truly the case, or how it is best to deal with any symptoms of withdrawal, is not known.

PERSONAL AND SOCIAL CONSEQUENCES

The long-term personal and social consequences of routinely using melatonin are not known. It is known, however, that millions of people take over-the-counter melatonin preparations containing very large doses of melatonin relative to the amount produced by the human body or contained in foods. Even less is known about its interaction with other drugs or "natural remedies." Many experts are concerned that such large-scale use of a hormone may not be safe. Serious health implications of using melatonin may not be discovered until many people have placed themselves at risk.

Melatonin can cause unpleasant side effects, even when taken for a short period of time. The use of melatonin has been linked to sleepiness, confused thinking, rapid heartbeat, chills, headache, inability to sleep, and itching. People who experience these symptoms when using melatonin should contact their health care provider.

LEGAL CONSEQUENCES

It is legal to possess and use melatonin in the United States. However, it is illegal to use melatonin without a prescription in other countries.

RESOURCES

Books

Shneerson, John. Handbook of Sleep Medicine. Oxford, UK: Blackwell Science Inc., 2000.

Smokensky, Michael, and Lynne Lamberg. The Body Clock Guide to Better Health. New York: Henry Holt & Company, Inc.,2000.

Periodicals

Pray, W. Steven. "Consult Your Pharmacist—The Sleep-Wake Cycle and Jet Lag." U.S. Pharmacist 24 no. 3 (1999): 10.

"What About Melatonin?" Nursing (May 2001).

Other

"Melatonin." May 2002 (July 8, 2002). <http://www.familydoctor.org/handouts/258.html>.

"Proper Dose of Melatonin Curbs Insomnia in Older Adults." 2002 (July 8, 2002). <http://www.endo-society.org/pubrelations/pressReleases/melatonin.cfm>.

Organizations

National Sleep Foundation, 1522 K Street, NW, Suite 500, Washington, DC, USA, 20005, (202) 347-3471, (202) 347-3472, [email protected], <http://www.sleepfoundation.org>.

Sue Wallace