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Low melatonin doses probed

Very small doses of a human hormone have been found to induce sleep when given during the day, MIT researchers reported at a meeting of the Society for Neuroscience on Friday, Nov. 12. These doses raise blood levels of the hormone to the range normally found at nighttime, when people usually are sleeping.

The findings also suggest that the hormone, melatonin, may be an effective sedative with few side effects because it works by activating the body's normal sleep-inducing mechanisms. Conventional sedatives, a class of drugs known as benzodiazepines, often produce side effects because they over stimulate a particular receptor in brain cells. They also can be addictive.

The MIT work is the first to show that, even at levels no higher than normal night concentrations, melatonin can induce daytime sleep. The research also provides a strong indication that melatonin may be partly responsible for normal sleep.

Melatonin is secreted by the pineal gland, normally at night, beginning around 9pm. Blood levels of the substance rise tenfold, peaking between 2 and 4am, and return to low day levels by the time people awaken. It has been known for some time that very large doses of melatonin-doses that increase melatonin levels to several hundred times the normal night concentrations-can cause drowsiness and sleep.

However, at such concentrations, melatonin is acting as a drug, said Professor Richard J. Wurtman, MD, the principal researcher for the MIT study and one of the authors of the paper. The significance of the MIT work is the finding that low doses, which produce normal nighttime blood melatonin levels, are effective at inducing sleep, he said. Dr. Wurtman, a professor of neuropharmacology and a member of the Department of Brain and Cognitive Sciences, is director of the MIT Clinical Research Center, where the latest work was done.

The other members of the research team also are or were associated with the center and the department. They are Dr. Andrew B. Dollins, first author of the report presented at the meeting in Washington, Irina V. Zhdanova, Harry J. Lynch and Mae H. Deng. Dr. Dollins is now with the Department of Defense's Polygraph Institute at Fort McClellan, AL.

The research involved 20 male volunteers. They were tested during each of five sessions, separated by at least five days.

At 11:45am, the volunteers took capsules of melatonin or a placebo. The melatonin was given in doses of 0.1mg, 0.3mg, 1.0mg, or 10mg. Neither the investigators nor the volunteers knew whether a volunteer received melatonin or a placebo at a given session.

At each session, the volunteers completed questionnaires and performance tasks to measure changes in mood, sleepiness and alertness during testing. At 1:30pm, volunteers participated in a sleep test. They were asked to relax with eyes closed while reclining in a quiet, darkened room. In each hand, they held a squeeze switch, which they were told to keep closed. If they grew sleepy and fell asleep, their hands would relax and the switches would be released. The opening and closing of the switches indicated sleep.

Blood tests done on the volunteers indicated that peak melatonin levels following the 0.1mg and 0.3mg treatments were comparable to the normal night levels of the hormone. Levels following the 1.0 and 10 mg treatments were greater than normal night levels.

All melatonin levels significantly increased sleep duration and led to reports from the volunteers of feeling sleepy following the sleep tests. The volunteers who received melatonin felt sleepy and fell asleep faster than those who received the placebo treatment.

Melatonin has been referred to as a physiological "zeitgeber," or time giver, Dr. Wurtman said.

"A number of our body's circadian (daily) rhythms such as temperature regulation and behavior have been shown to be affected by melatonin levels," Dr. Wurtman said. "For example, we have found high levels of melatonin well into the morning in people suffering from Seasonal Affective Disorder, a form of depression that occurs during winter months when exposure to bright light is diminished. It has also been shown that suppressing melatonin secretion by exposure to bright light has been useful in changing the sleep-wake patterns of night-shift workers, astronauts and people suffering from jet-lag.

"Our current research suggests an additional important role for melatonin. It acts directly on brain centers to bring about sleep." Dr. Wurtman continued. "The fact that we observed sedative-like effects following a single administration of melatonin suggests that its hypnotic properties are independent of melatonin's role as a circadian `zeitgeber.'

"We want to do more studies, looking at whether women will have the same reaction to low doses of melatonin, whether its effectiveness is influenced by the time of day it is administered, whether there are side effects following repeated doses, and whether there are differences between normal sleep and sleep induced by doses of melatonin."

The work was supported in part by grants to the Clinical Research Center from the Air Force, the National Aeronautics and Space Administration, the Center for Brain Sciences and Metabolism Charitable Trust and the National Institutes of Health.

A version of this article appeared in the November 17, 1993 issue of MIT Tech Talk (Volume 38, Number 14).

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