Melatonin

What Kind of Drug Is It?

Melatonin is a dietary supplement sold without a prescription at U.S. health stores or through Web sites. It is sold primarily as a sleep aid because it induces sleep. Researchers have studied melatonin's potential benefits for certain conditions, such as insomnia (difficulty sleeping); jet lag; and even cancer (the uncontrolled, abnormal growth of cells that can lead to serious illness and death).

However, taking melatonin supplements has not been proven by scientific studies to be effective for any condition. Much more research needs to be done to prove the positive claims of melatonin use. Also, because it is considered a dietary supplement, it is not regulated by the U.S. Food and Drug Administration (FDA). This means that the supplements are not produced under the strict guidelines of the FDA, so their side effects and long-term effects are not clearly known.

Melatonin is a hormone—a substance created by the body to control certain bodily functions. It is found naturally in humans and other animals. It is secreted by the pineal (PY-nee-uhl) gland, which is located in the middle of the brain. Melatonin helps to regulate when animals, including humans, fall asleep and when they wake up. This sleep/wake cycle is known as the circadian rhythm (sir-KAY-dee-in RIH-thum), the twenty-four-hour sleep/wake cycle in humans and other animals. Some people believe that taking melatonin supplements can help alleviate problems that can occur when this cycle is disrupted.

Official Drug Name: Melatonin, 5-methoxy-N-acetyltryptamine

Also Known As: Mel, Melliquid, mellow tonin, MLT, somniset

Drug Classifications: Not scheduled

Overview

Sleeping is a part of life. It allows the body to rest and repair itself after physical activity. Ruth Winter, writing in The Anti-Aging Hormones: That Can Help You Beat the Clock, stated that "most people need at least seven and a half hours [of sleep] to function adequately and be fully alert the next day, but some may need as little as five while others need nine to ten hours." Lack of sleep can cause a host of problems such as fatigue and poor mood. Thus, it is important to have a normal sleep/wake cycle for good health.

Melatonin plays an active role in maintaining a regular schedule for sleeping and waking. It induces sleep when it is secreted into the bloodstream by the pineal gland, a pea-sized gland that is part of the endocrine system. Darkness stimulates its secretion, while light, both natural and artificial, inhibits it.

The Dracula of Hormones

Melatonin has been called the "Dracula of hormones" because, like the vampire Dracula, it only comes out at night. Usually around 9 p.m., after daylight fades away and darkness arrives, the pineal gland begins releasing melatonin, causing sleepiness and initiating a decline in body temperature. The hormone is continually released throughout the night as the body sleeps until about 9 a.m. the next morning, when it is light again. Peak production occurs approximately between 2 a.m. and 4 a.m.

In the morning, when light hits the retina, messages are sent to the hypothalamus in the brain. In the hypothalamus, the messages find the suprachiasmatic (SOO-pruh-ky-uhz-MAH-tik) nucleus (SCN), prompting the SCN to send signals to the glands that control hormones, including the pineal gland. When the pineal gland receives a message from the SCN, it slows down the release of melatonin until darkness comes and it is time to sleep again. Daytime melatonin levels are so small they are usually undetectable. The decrease of melatonin in the morning signals the body temperature to rise, and the body feels awake and alert.

Discovering Melatonin

For centuries, the function of the pineal gland was unknown. This was partly due to the fact that melatonin is created in very small amounts, smaller than any other hormone, and is hard to detect. In the 1950s, Yale University dermatologist Dr. Aaron Lerner was conducting research on skin pigmentation, or color. Thinking the pineal gland may be involved in skin pigmentation, he began the process of trying to isolate a molecule from this gland that he believed may be responsible for lightening skin. In 1958, Lerner was finally successful in isolating a molecule from the pineal gland.

Because the molecule is chemically related to melanin (skin pigment) and serotonin, Lerner named his discovery melatonin. Though melatonin lightened the skin of frogs, it did not affect the color of the skin of humans. In the end, Lerner did not find a molecule that would help his research, but he did help answer the mystery of the pineal gland. He discovered a very powerful hormone that has helped researchers understand more about the human sleep/wake cycle.

After Lerner's discovery, other scientists began testing melatonin to see what benefits it may have. They found that injecting synthetic (human-made) melatonin into people could cause a tranquilizing effect and induce sleep. From there, more studies were done, and eventually melatonin was made into a dietary supplement that could be self-administered.

The Melatonin Craze

In the mid-1990s, when melatonin supplements became available without a prescription, a frenzy over the possible benefits of taking these supplements occurred. Some called it a "miracle" or "wonder" drug. Many praised it as an immune-booster, a youth serum, a cancer-fighter, and a cure for insomnia.

Various books were written about the wonders of melatonin. The craze eventually died down, and, as of the early twenty-first century, research has not been able to prove or disprove the benefits of melatonin. In 2000, University of Surrey's Josephine Arendt discussed the supplement. As quoted by Elizabeth Cohen in "Study Bolsters Melatonin Sleep Claims" on CNN.com, Arendt stated that "the hype and claims of the so-called miraculous powers of melatonin several years ago did a great disservice to a scientific field of real importance."

Melatonin as a Supplement

In 1994 melatonin became available over the counter as a dietary supplement. Manufacturers claimed melatonin could bring on sleep, ease jet lag, and more. Studies have been conducted and books written on the potential benefits of melatonin, but no one has been able to prove or disprove these claims. Most research suggests that melatonin can help regulate the sleep/wake cycle for conditions such as insomnia and jet lag, as well as problems from shift work (people working at night and sleeping during the day). It has also been regarded as an antioxidant and an immune-booster. Some people believe it also combats aging.

What Is It Made Of?

Melatonin is a hormone found naturally in the human body, in other animals, in certain plants, and even in some foods. It is made from tryptophan (TRIP-tuh-fan), an essential amino acid. When tryptophan is ingested, the body turns it into serotonin that is then made into melatonin. The pineal gland is the primary location for melatonin production but the retina and intestines make small amounts as well.

Melatonin supplements are either synthetic (human-made) or natural (contain animal products). They are chemically identical to the melatonin that is produced by the human body. Some people think that using the natural melatonin, typically made from the pineal glands of animals such as sheep, run a greater risk of being contaminated by a virus. Therefore, the synthetic version is the most recommended and most popular form of melatonin. However, since the FDA does not regulate it, one can never be sure of the effectiveness, purity, or safety of the supplement.

The Trouble with L-tryptophan

Tryptophan is an essential amino acid from which melatonin is made in the body. It was once available as a dietary supplement, known as L-tryptophan. Much like melatonin, it was marketed as a sleep aid. However, in 1989, a batch of L-tryptophan pills (all made in Japan) was contaminated and caused 1,500 people to contract the disease eosinophilia-myalgia syndrome (EMS; pronounced ee-oh-sin-oh-FIHlee-uh my-AL-jee-uh). EMS causes weakness, severe muscle and joint pain, headaches, fever, and shortness of breath. More than thirty people died from the disease in the United States. The FDA banned L-tryptophan, and from that point on Americans had to get tryptophan from food sources.

Some foods that contain tryptophan include the following:

• Almonds
• Bananas
• Chicken
• Cottage Cheese
• Eggs
• Ice Cream
• Milk
• Peanuts
• Shrimp
• Soy Nuts
• Tofu
• Tuna
• Turkey
• Yogurt

As a supplement, melatonin consists of much higher amounts of the hormone than are naturally secreted at any one time in the body. A single dose is usually 500 micrograms to 5 milligrams per dose, more than 10 times higher than what is normal in the human body.

Studies have not shown the high doses cause greater benefit or greater risk to the body. However, a doctor should be consulted before taking any supplement.

Age Factors

Before reaching puberty, children create the largest amounts of melatonin, with the highest levels between the ages of four and seven. At puberty, melatonin production begins to slow down and gradually decreases to an average of about 30 micrograms per day. Some researchers suggest that the decrease in the level of melatonin at puberty may be related to the fact that the child is maturing sexually.

Research findings have been inconsistent about whether or not melatonin continues to diminish with age. A number of scientists believe that melatonin production decreases as the body ages, which might explain why elderly people have greater sleep problems. However, a study by Dr. J. B. Fourtillan, published in the January 2001 issue of American Journal of Physiology, indicated that the levels of melatonin did not differ between a group of 34 healthy adults over age 65 and a group of 101 healthy adults under age 30.

How Is It Taken?

Melatonin is sold over the counter as a dietary supplement. It is available in pill form (tablets or capsules), as a cream or tea, or as a lozenge that can be dissolved under the tongue. Time-release capsules are also sold. Such capsules release the melatonin slowly over time after the dose is ingested. Manufacturers provide a range of doses. A person should consult a physician about the proper dose and how long to take the supplement as results can vary for each individual. Typical doses fall in the range of 0.1 milligram to 10 milligrams. However, a noticeable difference in effectiveness usually is not seen in doses over 5 milligrams. A person normally takes melatonin only a few days at a time.

The time of day that the supplement is taken also plays an important role in melatonin's effectiveness. Usually, melatonin is taken right before bedtime. Taking melatonin during the day has minimal effect other than drowsiness. In the treatment of jet lag, it is recommended that melatonin be taken on the day of travel and then for a few days after arrival at the destination.

Are There Any Medical Reasons for Taking This Substance?

Many studies suggest that taking melatonin may have positive effects on a number of human ailments, especially sleep-related conditions. However, such studies have not shown that taking melatonin supplements will result in healing or prevention of these ailments. More research needs to be completed in order to really know what melatonin supplements can do for the human body.

Helping the Blind

As reported by Elizabeth Cohen on CNN.com, a study on the blind was conducted by scientists at Oregon Health Sciences University. The blind tend to suffer sleep problems due to their inability to detect the daily light and dark cycles. The study revealed that the blind had more regular sleep cycles after taking melatonin. The scientists concluded that melatonin could help the sleep patterns of those who can see as well. However, one of the scientists, Dr. Al Lewy, pointed out the importance of knowing when, how, and why to take melatonin. "The concern I have," the doctor remarked, "is that people have been taking melatonin at the wrong time at the wrong dose for the wrong reasons."

Usage Trends

According to the Agency for Healthcare Research and Quality in "Melatonin for Treatment of Sleep Disorders," "Studies suggest that sleep disorders affect 50 to 70 million Americans, representing 20 percent of the population." Since naturally occurring melatonin induces sleep, many people take melatonin supplements to help combat these sleep disorders. Cohen claimed that in the year 2000 more than 20 million Americans took melatonin supplements to help regulate their sleep. In addition to taking melatonin for sleeprelated problems, people may also be taking melatonin for its supposed benefits for a number of other conditions.

Insomnia

Insomnia is a sleep disorder in which a person has difficulty falling or staying asleep. As reported in "Melatonin for Treatment of Sleep Disorders," insomnia affects 6 to 12 percent of adults. Medical treatment for insomnia can include taking sleep aids, like benzodiazepines, in order to help the patient fall asleep. (A separate entry on benzodiazepine is available in this encyclopedia.) Relaxation techniques are also used. Some researchers believe that melatonin supplements can be used in the treatment of insomnia as well. However, other researchers have not found melatonin to have much effect at all on those suffering from insomnia.

There is some promising news for those who suffer from a form of insomnia called delayed sleep phase syndrome (DSPS). People with this condition have a sleep/wake cycle that has them set to fall asleep much later in the night, like 4 a.m., and rise much later the following day, like noon. According to "Melatonin for Treatment of Sleep Disorders," when taking melatonin supplements, the time it takes to fall asleep "decreased greatly in people with delayed sleep phase syndrome." This finding was considered "clinically significant." However, the time it takes to fall asleep only "decreased marginally in patients with insomnia," which was considered "clinically insignificant."

Jet Lag

People need to adjust their watches to the local time when they travel through time zones. But humans also need their body clocks, or sleep/wake cycles, to adjust to the local time as well. Being out of

synch with the new time zone can result in feeling tired or awake or hungry at all the wrong times. An out-of-synch body clock, coupled with a lack of sleep during a flight that has crossed multiple time zones, can result in "jet lag." Symptoms of jet lag can include:

• Constipation or diarrhea
• Disorientation
• Dry cough, eyes, and skin
• Earache
• Fatigue
• Headache
• Impaired concentration, coordination, or vision
• Insomnia
• Irritability
• Loss of appetite
• Low mood
• Memory loss
• Nausea
• Sore throat
• Swollen feet

Melatonin supplements are thought to help reduce jet lag by helping the body clock more rapidly adjust to the new time zone.

Shift Work

A large number of people work during the hours that most people sleep. Having to be awake and alert during the time when the body normally should be sleeping can cause problems in a person's sleep/wake cycle. Melanie Johns Cupp in American Family Physician pointed out that in a "trial involving 27 shift workers, melatonin was found capable of 'resetting' sleep patterns to match the change in schedule in approximately one half of the patients tested."

Seasonal Affective Disorder (SAD)

Seasonal affective disorder, or SAD, is a mood disorder that causes depression in the winter months when the days are shorter and less light is available. Symptoms include low mood, irritability, fatigue, weight gain, and cravings for carbohydrates—like pasta, potatoes, or bread. Some researchers suggest that SAD is caused by elevated melatonin levels at the wrong times (i.e., not at bedtime) and that taking melatonin supplements may help regulate its production. Other studies have found melatonin does not help curb the symptoms of SAD and may actually make the symptoms worse. Light therapy (going outside in natural light or looking at artificial light) is another form of treatment for SAD sufferers.

Melatonin and Jet Lag

To help combat jet lag, according to Health Services at Columbia: Go Ask Alice!, it is suggested that a person take melatonin at the start of and during a trip at specific times in order to achieve the best results. If traveling east, a person, on the day of travel, should take one dose of melatonin between 6 and 7 p.m. of his or her normal time zone. At the destination, the person should take one dose of melatonin during the first five days at bedtime (between 9 and 10 p.m.) of the local time.

When traveling west, a person should take one dose of melatonin at the local bedtime after arriving at the destination, and continue to do so for the next four days. Melatonin has not been proven to help when traveling less than five time zones to the west.

Cancer

Researchers have studied a number of ways that melatonin may be helpful in fighting cancer. Some evidence suggests that melatonin may help regulate other hormones. Therefore, it may be helpful with cancers that are triggered by hormones like estrogen, such as breast cancer, or testosterone, such as prostate

cancer. Melatonin has also been described as an immune-booster and antioxidant. Having a stronger immune system and a greater ability to fight off cancer-causing free radicals can aid in fighting cancer.

According to the University of Maryland Medical Center, other conditions thought to be improved by melatonin (although with limited or no research support), include: 1) osteoporosis—fragile bones; 2) menopause—a period in a woman's life in which menstruation ends; 3) eating disorders; 4) epilepsy—a disorder causing seizures; 5) heart disease; 6) inflammatory diseases; 7) attention-deficit/hyperactivity disorder (ADHD); and 8) sunburn. Others claim that melatonin can improve life span, aid a person trying to stop smoking, and help with benzodiazepine withdrawal.

Effects on the Body

Because research has not been able to prove or disprove the benefits of supplemental melatonin, it is difficult to pinpoint all of the effects it has on the body. If taken at the proper time, usually bedtime, melatonin has been shown to help regulate sleep. However, using too much melatonin or not using it according to directions could hinder instead of help the body's sleep/wake cycle.

Though found naturally in the human body, melatonin, if taken as a supplement, can have certain side effects. These include sleepiness, headache and dizziness, nausea, stomach cramps, irritability, and depression. Users claim it causes more intense dreams, even nightmares. Melatonin has also been found to prevent ovulation. Some women have even used it to avoid getting pregnant. Overall, no serious side effects have been reported, and no long-term effects, negative or positive, have been proven.

The Fountain of Youth?

Some researchers believe that melatonin holds the key to a longer life. Walter Pierpaoli, William Regelson, and Carol Colman reported in their book The Melatonin Miracle: Nature's Age-Reversing, Disease-Fighting, Sex-Enhancing Hormone, that "melatonin is a potent age-reversing compound." They added that "we are confident that melatonin's primary benefit is in its ability to prevent disease by preventing the downward spiral that leads to illness." Their beliefs stem from research with mice, including studies that revealed mice that had improved health and longer lives as a result of taking melatonin. They also cited studies that showed older mice live longer when given pineal glands from younger mice and that the younger mice with the older pineal glands die at an earlier age. However, no studies on humans have been done that conclude that melatonin helps diminish the aging process.

Reactions with Other Drugs or Substances

Melatonin is not recommended for users who are taking antidepressants, corticosteroids (steroids used to counteract inflammation), blood pressure medication, or drugs that suppress the immune system, as it may reduce the other medicine's effects. Taking melatonin along with other sleep aids should be avoided although melatonin may be helpful in getting through withdrawal from the highly addictive benzodiazepines. Withdrawal is the process of gradually cutting back on the amount of a drug being taken until it can be stopped entirely.

Melatonin has also been suggested as an aid in quitting smoking. In addition, certain drugs and substances have been found to lower the level of melatonin in the body. These include alcohol, caffeine, tobacco, some high blood pressure medications including beta-blockers, and anti-inflammatories such as ibuprofen. Amphetamines and cocaine may raise the level of melatonin in the body.

Treatment for Habitual Users

There is no treatment available for habitual users of melatonin. This supplement has not been proven to be an addictive substance, nor have any studies been conducted on whether or not a person can build up a tolerance to it or suffer any withdrawal symptoms when stopping its use. Tolerance is a condition in which higher and higher doses of a drug are needed to produce the original effect.

Consequences

Hormones are very powerful. They control the functions of many parts of the body naturally. Even though melatonin is considered a dietary supplement and is available without a prescription, it is important to consult with a physician before taking any hormones. A press release by Robert Sanders in UCBerkeleyNews notes that George E. Bentley, an assistant professor of integrative biology, has conducted research on melatonin and its effects in the brain. According to Bentley: "It really amazes me that melatonin is available in any pharmacy." He continued, "It is a powerful hormone, and yet people don't realize that it's as 'powerful' as any steroid. I'm sure that many people who take it wouldn't take steroids so glibly." Bentley noted that melatonin could have many unknown effects, but few data are available about how "it interacts with other hormone systems." (A separate entry on steroids is available in this encyclopedia.) Research has shown some benefits in taking melatonin as a supplement, primarily for sleep disorders, but its long-term effects are unknown. Therefore, people who take melatonin do not know what it may do to their bodies over time.

Melatonin is not recommended for some people. Healthy children produce large amounts of melatonin, so they should not take melatonin as a supplement. Nor is it recommended for women who are trying to become pregnant because melatonin can inhibit ovulation. Also, since the effects of melatonin on babies are not known, melatonin should not be used by pregnant or nursing mothers. People with certain immune-system conditions, like the disease leukemia, should not take melatonin either.

Because melatonin is a dietary supplement, it is not regulated by the FDA. Since the manufacturers do not have to follow strict guidelines, they can be more relaxed about ensuring a high quality product. This puts the user at risk of ingesting substances not listed on the bottle label or taking an amount of melatonin that is not reflected accurately on the label.

The Law

Melatonin is neither an illegal drug nor is it monitored by the U.S. government. It is illegal to use it without a prescription in other countries. Under the U.S. Dietary Supplement Health and Education Act (DSHEA) of 1994, it is legal to sell melatonin as a dietary supplement in the United States. According to this Act, a dietary supplement:

• is a product (other than tobacco) that is intended to supplement the diet that bears or contains one or more of the following dietary ingredients: a vitamin, a mineral, an herb or other botanical, an amino acid, a dietary substance for use by people to supplement their diet by increasing the total daily intake, or a concentrate, metabolite, constituent, extract, or combinations of these ingredients.
• is intended for ingestion in pill, capsule, tablet, or liquid form.
• is not represented for use as a conventional food or as the sole item of a meal or diet.
• is labeled as a "dietary supplement."
• includes products such as an approved new drug, certified antibiotic, or licensed biologic that was marketed as a dietary supplement or food before approval, certification, or license (unless the Secretary of Health and Human Services waives this provision).

For More Information

Books

Bock, Steven J., and Michael Boyette. Stay Young the Melatonin Way. New York: Plume, 1995.

Pierpaoli, Walter, William Regelson, and Carol Colman. The Melatonin Miracle: Nature's Age-Reversing, Disease-Fighting, Sex-Enhancing Hormone. New York: Simon & Schuster, 1995.

Reiter, Russel J., and Jo Robinson. Melatonin: Your Body's Natural Wonder Drug. New York: Bantam Books, 1995.

Sahelian, Ray. Melatonin: Nature's Sleeping Pill. Marina Del Rey, CA: Be Happier Press, 1995.

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.

Winter, Ruth. The Anti-Aging Hormones: That Can Help You Beat the Clock. New York: Three Rivers Press, 1997.

Periodicals

Cupp, Melanie Johns. "Melatonin." American Family Physician (October 1, 1997).

Fourtillan, J. B., and others. "Melatonin Secretion Occurs at a Constant Rate in Both Young and Older Men and Women." American Journal of Physiology: Endocrinology and Metabolism (January, 2001): pp. E11-22.

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

"What about Melatonin?" Nursing (May, 2001).

Web Sites

Buscemi, N., B. Vandermeer, R. Pandya, et al. "Melatonin for Treatment of Sleep Disorders" (November, 2004). Agency for Healthcare Research and Quality.http://www.ahrq.gov/clinic/epcsums/melatsum.htm (accessed July 26, 2005).

Cohen, Elizabeth. "Study Bolsters Melatonin Sleep Claims." CNN.com, October 12, 2000. http://archives.cnn.com/2000/HEALTH/alternative/10/12/melatonin.clock/ (accessed July 26, 2005).

"Dietary Supplement Health and Education Act of 1994" (December 1, 1995). U.S. Food and Drug Administration: Center for Food Safety and Applied Nutrition.http://www.cfsan.fda.gov/~dms/dietsupp.html (accessed July 26, 2005).

"Melatonin." Drug Digest.http://www.drugdigest.org/DD/DVH/HerbsWho/0,3923,4060|Melatonin,00.html (accessed July 26, 2005).

"Melatonin." familydoctor.org.http://familydoctor.org/258.xml?printxml (accessed July 26, 2005).

"Melatonin." University of Maryland Medical Center.http://www.umm.edu/altmed/ConsSupplements/Melatonincs.html (accessed July 26, 2005).

"Melatonin: The Basic Facts." National Sleep Foundation. http://www.sleepfoundation.org/sleeplibrary/index.php?secid=&id=60 (accessed July 26, 2005).

"Melatonin—Jet Lag?" (September 27, 1996). Health Services at Columbia: Go Ask Alice!http://www.goaskalice.columbia.edu/0970.html (accessed July 26, 2005).

Sanders, Robert. "Popular Supplement Melatonin Found to Have Broader Effects in Brain Than Once Thought." UCBerkeleyNews, February 7, 2005. http://www.berkeley.edu/news/media/releases/2005/02/07_melatoninfin.shtml (accessed July 26, 2005).

See also: Benzodiazepine; Herbal Drugs