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Melatonin: A Chemical Slumber Switch
Author: Victoria L. Contie Affiliations: NCRR Reporter July/August 1994Copyright © 1994, David Dodell, D.M.D. When a cup of warm milk or a relaxing bath doesn't do the trick, millions of Americans turn to their medicine cabinet for help in falling asleep. But medicinal assistance comes at a price: common sleep-producing drugs like barbiturates, benzodiazepines, and antihistamines can be addictive, induce tolerance, or cause hangovers. Now scientists at the Massachusetts Institute of Technology (MIT) in Boston report that a tiny dose of a natural hormone, administered orally, rapidly induces fatigue and sleepines in healthy subjects. Dr. Richard J. Wurtman and his associates say that this brain hormone, melatonin, is a promising candidate for safe and effective treatment of insomnia, although further evaluation is still needed.National surveys indicate that each year one in three Americans has trouble falling asleep, and sleep-inducing, or hypnotic, drugs are among the most widely prescribed medicines. Dr. Wurtman, professor of neuroscience and director of MIT's General Clinical Research Centcr (GCRC), has been exploring the hypnotic potential of melatonin since the mid-1980's, but his interest in this substance goes back even farther. Working with Dr. Julius Axelrod at the National Institute of Mental Health in 1963, Dr. Wurtman and coworkers were the first to recognize that melatonin is a hormone. Back then melatonin was known only to affect the reproductive glands of animals. Scientists have since uncovered a fascinating, but still poorly understood, relationship between melatonin, environmental lighting, and the regulation of the body's biological clock.
Researchers now know that melatonin, secreted by the tiny pinecone-shaped pineal gland near the center of the brain, is generally produced briskly in darkness and sluggishly in light. By the mid-1970's Dr. Wurtman and other researchers discovered that melatonin levels in human adults ebb and flow each day, falling as low as 10 picograms per milliliter during the day and increasing about tenfold at night. "We showed that the rhythm is not really caused by light and darkness, since the cycle persists even when subjects are in constant darkness, but it's normally locked into place by light and darkness," says Dr. Wurtman. "The relationship between melatonin and sleep became an obvious possibility to explore," he says.
Ten years ago, in a trial at MIT's GCRC, Dr. Wurtman and his colleagues administered megadoses (240 mg in three doses of 80 mg, given an hour apart) of melatonin to healthy subjects and noted a rapid induction of sleep compared to volunteers who took placebos. But the hormone pills raised blood levels to 1,000 to 10,000 times their normal values. "The megadoses made people sleepy, but they also gave people a hangover and made them dysphoric and nasty," says Dr. Wurtman.
In their most recent study, designed to measure the effects of smaller doses of the hormone, the MIT researchers administered melatonin or placebo capsules to 20 healthy male volunteers at midday. For the next 6 hours the volunteers participated in a battery of tests to measure their physiological status, mood, sleepiness, and ability to perform tasks. Each volunteer was tested on five separate occasions, each time with a different dose of the hormone (0, 0.1, 0.3, 1, or 10 mg). Forty-five minutes after taking the pills, volunteers were asked to close their eyes and squeeze a bar in each hand while relaxing in a quiet, dark room for half an hour. All doses of the hormone significantly shortened the time to sleep onset, as measured when a subject loosened his grip on the bar. A 0.3-mg dose of melatonin put volunteers to sleep about 9 minutes sooner, and a 1-mg dose about 11 minutes sooner, than did placebo. The 0.3-mg dose raised participants' melatonin levels to about 100 picograms per milliliter of blood, which is the normal nighttime concentration of the hormone. "This suggests that the natural rise in melatonin each evening induces sleep," Dr. Wurtman says.
All doses of melatonin significantly increased sleep duration and volunteers' self-reported feelings of fatigue and sleepiness during the course of the test. In addition, melatonin significantly reduced participants' body temperature and their performance on a vigilance test. The Boston researchers note that melatonin's hypnotic effects are similar to those produced by benzodiazepine sleeping pills like Halcion. "Repeated use of benzodiazepines, however, can lead to habituation or tolerance," Dr. Wurtman says. "I'm optimistic that we won't see those effects with melatonin, since blood levels normally go from 10 to 100 picograms per milliliter every day and this rise doesn't induce tolerance. All we have to do is raise blood levels to their normal nighttime range to produce sleep." He adds that larger clinical trials are needed to confirm melatonin's hypnotic effects and safety.
Melatonin tablets can be purchased in some health food stores, but Dr. Wurtman advises against their use. "These pills are being sold without certification by the Food and Drug Administration, and this worries me terribly," he says, noting that melatonin is chemically similar to the amino acid tryptophan. Several years ago dozens of people died after ingesting impure L-tryptophan tablets purchased by mail order or at health food stores (see NCRR's Research Resources Reporter, August 1990, p. 1). "We've purchased melatonin from some health food stores and checked the purity. These tablets are not pure. People should not take melatonin for the time being except under controlled research conditions," Dr. Wurtman warns.
In a more recent study, which has been submitted for publication, Dr. Wurtman and his associate Dr. Irina Zhdanova discovered that melatonin's hypnotic effects are enhanced when the pills are given in the evening, closer to the subjects' regular bedtime. Moreover, the sleep-inducing effect of melatonin is readily demonstrable using electroencephalograms (EEG)- rather than the squeeze-bar technique- to measure sleep onset. The squeeze method was simple and "surprisingly good," says Dr. Wurtman, but it did have its drawbacks. For instance one volunteer, after Iying in the darkened room for several minutes, maintained a strong grip on the bar even as he snored loudly. EEG, a more accurate indicator of mental arousal, has since confirmed that low doses of melatonin do indeed induce true, stage 2 sleep more rapidly than does placebo, says Dr. Wurtman. "People have been looking for a sleep hormone for years," he says. "Maybe this is it."
-Victoria L. Contie
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