he human biological clock has fascinated and vexed scientists for decades. It has long been known that many functions of the body operate on a circadian, or daily, rhythm. Yet the mechanism that sets and maintains this rhythm is not known. External cues, such as cycles of light and darkness defined by day and night, play an important role in controlling the circadian rhythm in humans, but they are not the whole story. For example, healthy volunteers who have spent extended periods living in comfortable quarters underground in the total absence of time cues have a biological clock that works on a 25-hour cycle, on average. Aboveground, external cues (often called by the German term Zeitgeber, which translates as "time giver") allow the body to synchronize its internal clock with the 24-hour day.

Circadian rhythms are characterized by daily fluctuations in the levels of certain hormones, which in turn regulate sleep patterns and energy levels. Most notable among such hormones is melatonin, which is secreted by the pineal gland situated in the very center of the brain. The pineal gland produces at least two important compounds: the neurotransmitter serotonin, which plays an important role in regulating mood, and the sleep-inducing hormone melatonin.

Nighttime Melatonin Induces Sleep

Biochemically, serotonin is a precursor to melatonin, and the conversion is closely correlated with circadian patterns. Serotonin is produced predominantly during the day, whereas melatonin is produced mainly at night (illustrating, by the way, that the relationship between a compound and its precursor is often complex and counterintuitive). Interestingly, a darker nighttime environment triggers the synthesis of greater amounts of melatonin, as do longer nights (such as during winter). Clearly, the synthesis of these two compounds is delicately regulated, and slight variations in their production or release can have a profound impact on one's mood, energy, and sleep.

Researchers believe that the production of melatonin is triggered by dark-sensitive cues. During the day, through a complex mechanism, light cues are sent from the eye to the hypothalamus (a part of the brain that communicates with the pineal gland), which regulates the conversion of serotonin to melatonin. The light cues inhibit the synthesis of melatonin. Periods of darkness, however, do the opposite. Thus, melatonin is produced mainly at night, and it plays an important role in inducing the body to sleep. Indeed, elevated levels of melatonin in the blood correlate with enhanced sleep, and research has shown that supplementation with melatonin can be an effective sleep-inducing aid.

Melatonin Levels Decline with Age

Melatonin has been used to regulate sleep patterns in a variety of situations, including sleep disruption caused by jet lag and night-shift work. Another "situation" is age: melatonin production generally decreases with age, and this is thought to explain why older individuals are particularly susceptible to insomnia and other sleep disturbances.

Researchers at MIT recently studied the effects of melatonin supplementation on age-related insomnia.¹ They enrolled men and women over the age of 50 who experienced chronic insomnia, as defined by one of the following criteria: two or more nighttime awakenings; taking longer than 30 minutes to fall asleep (sleep latency); or total nighttime sleep of less than 6 hours. Aside from their insomnia, the patients were not necessarily healthy, but certain types of conditions were grounds for exclusion from the study, including: major psychiatric disorders; a wide variety of chronic diseases if they were in an acute or unstable phase; certain other sleep disorders; more than moderate alcohol consumption; and the use of medications that might interfere with the test results.

The patients were tested to ensure that their sleep efficiency (the percentage of time spent asleep during their total time in bed) was below 85%. For example, if a patient was in bed for 8 hours, he or she had to be asleep for less than 6 hours and 48 minutes (85% of the time) in order to qualify as an insomniac for this study. Importantly, an equal number of normal sleepers (with a sleep efficiency of 90% or more) over the age of 50 also participated in the study.

The study lasted for 9 weeks. An initial 1-week washout period (a period during which no medications or supplements related to the study are taken) was followed by a 1-week treatment period; alternating washout and treatment periods ensued for the remainder of the trial. One of three doses of melatonin - 100 micrograms, 300 micrograms, or 3 milligrams (3000 micrograms) - or a placebo was administered orally 30 minutes before bedtime to both the insomniacs and the control subjects. All the subjects slept in complete darkness, and the researchers carefully monitored their sleep habits, including total sleep time, time in bed (sleep period), sleep efficiency, sleep latency, and time before reaching the REM (rapid eye movement) phase of sleep - the most pronounced dreaming phase.

Very Little Melatonin Is Required for Sound Sleep

An important aspect of the MIT study was to ascertain the melatonin dosage most beneficial in promoting sleep. Although the treatments had essentially no effect on those with normal sleep patterns, all three doses of melatonin (100 mcg, 300 mcg, and 3 mg) improved sleep efficiency in the insomniacs significantly, but not in a dose-dependent manner: the efficiencies achieved were 84%, 88%, and 84%, respectively (vs. 78% with placebo). Thus, the intermediate 300-mcg dose (a physiological dose, meaning that it fell within normal physiological limits) apparently worked best in this study.

The 10-times-higher dose of 3 mg (a pharmacological dose, meaning that it exceeded normal physiological limits) not only did not offer any additional benefit, it had one potential disadvantage: it caused melatonin levels to remain elevated throughout much of the following day, which could induce lethargy at a time when one should be bright-eyed and bushy-tailed. The physiological doses did not have this effect.

Does Melatonin Delay Aging? Recent research suggests that melatonin, which has antioxidant properties, may slow down the aging process, perhaps because it protects certain parts of the brain from oxidative damage caused by free radicals.1 Because melatonin production typically decreases with age, and because nervous tissue is particularly susceptible to oxidative damage, it follows that brain aging may be accelerated in individuals with low melatonin levels. Some animal studies support this theory. For example, mice fed with melatonin in their nighttime drinking water lived an average of 18% longer (28.1 months) than those that did not receive melatonin (23.8 months). More recently, researchers have used the fruit fly Drosophila melanogaster to investigate the effect of melatonin on lifespan. With melatonin, the flies' maximum lifespan increased from 61.2 days (in the control specimens) to 81.5 days, an increase of 33.2%; the average increase in lifespan in these tiny critters was 13.5%.2 Does melatonin also slow down aging in humans? We don't know yet. Although the animal results are tantalizing, we must remember that it's a long way from fruit flies and mice to humans. Nonetheless, there are similarities in the biochemical and biological mechanisms of the aging processes between the animals and humans, and these early results might be pointing to an important antiaging mechanism that we need to study more thoroughly. References Oxenkrug G, Requintina P, Bachurin S. antioxidant and antiaging activity of N-acetylserotonin and melatonin in the in vivo models. Ann NY Acad Sci 2001 Jun;939;190-9. Bonilla E, Medina-Leendertz S, Diaz S. Extension of life span and stress resistance of Drosophila melanogaster by long-term supplementation with melatonin. Exp Gerontol 2002;37:629-38.

Melatonin Works Best in the Middle of the Night

Furthermore, the pharmacological dose (but not the smaller physiological doses) caused a drop in the subjects' core body temperature by about 0.3°C (0.5°F) more than the usual nighttime drop of about 0.5°C (0.9°F). This does no harm, but the results confirm one thing: contrary to some prior belief, lowering the core body temperature below the nighttime norm is not a prerequisite for melatonin to promote better sleep.

The time required to enter the REM sleep phase decreased from 99 minutes (with placebo) to 54 minutes (with 300 mcg of melatonin), on average; this effect was not judged to be statistically significant, however, owing to the large variation among the patients in this measure. Nonetheless, it serves as a reminder of the fact that when REM sleep is disrupted or shortened, sleep tends to be less restful.

Interestingly, melatonin had no effect on sleep latency (the time required to fall asleep) in this study, although other reports suggest that melatonin does improve it. Values for sleep latency remained constant following administration of placebo (11 minutes) or any of the three doses of melatonin (10 minutes in each case). Thus, melatonin did not act immediately, but required a bit of time before it "kicked in." In fact, the greatest impact was observed during the middle third of sleep, when sleep efficiency increased from around 70% to over 90%. Improvement was also noted during the last third of sleep, but not during the first third.

Prescription Sleeping Pills Have Some Serious Downside

Getting enough sleep is a problem for most Americans (see the sidebar "Make Sleep a Priority"). Indeed, hundreds of millions of dollars are spent each year in pursuit of a restful night's sleep. Two popular drugs for combating insomnia are triazolam (Halcion^®) and zolpidem tartrate (Ambien^®). Both work by depressing neural activity in the central nervous system to cause drowsiness and mild sedation. However, they can have serious side effects as well, and they may encourage hallucinations and altered or abnormal behavior in some individuals.

Make Sleep a Priority Most sleep experts recommend that adults get about 8 hours of sleep (but not more, which can become counterproductive) if they want to wake up the next morning feeling refreshed, invigorated, and ready for a new day. The National Sleep Foundation reports, however, that most Americans get just under 7 hours of sleep per night during the week, and around 7 1/2 hours on weekend nights. The study claims that 35% of respondents report one or more symptoms of insomnia every night or almost every night, while only 21% rarely or never have trouble sleeping. Among the many symptoms that plague the insomniacs are: "Woke up feeling unrefreshed" (40%) "Awake a lot during the night" (36%) "Difficulty falling asleep" (25%) "Woke up too early and could not get back to sleep" (24%) Sleep deprivation takes its toll in a variety of ways. Those who suffer from insomnia or who don't make adequate sleep the priority it should be may exhibit a high level of irritability in addition to feeling chronically tired, and their work performance may suffer noticeably. In addition, people with chronic illnesses are more prone to have insomnia, which significantly worsens their quality of life. The message here is clear: Make sleep a priority.

Common side effects of these drugs include: loss of coordination, unsteady gait, dizziness, lightheadedness, and slurred speech (triazolam); and diarrhea, general pain or discomfort, memory problems, bizarre or unusually vivid dreams, nausea, and vomiting (zolpidem tartrate). Not exactly the kind of calm, soothing sleep medications you might be looking for, are they?

Melatonin, the Natural Sleep Enhancer

Because sleep deprivation can be a serious individual and societal problem, it makes good sense to stack the sleep cards in your favor. Making changes in your daily behavior, as suggested in the sidebar "Make Sleep a Priority," is one approach you can employ. Another is to use a natural, safe sleep aid, such as melatonin, which helps you fine-tune your circadian rhythm and sleep patterns so you can feel rested and energetic all the next day.

Reference

1. Zhdanova IV, Wurtman RJ, Regan MM, et al. Melatonin treatment for age-related insomnia. J Clin Endocrin Metab 2001;86:4727-30.

Dr. Jensen is a cell biologist who has conducted research in England, Germany, and the United States. He has taught college courses in biology and nutrition and has written extensively on medical and scientific topics.