Melatonin Treatment for Age-Related Insomnia

Abstract & Commentary

Synopsis: In older people with insomnia, a 0.3-mg dose of melatonin improved sleep efficiency.

Source: Zhdanova IV, et al. J Clin Endocrinol Metab. 2001;86:4727-4730.

Melatonin is undeniably the best reflection of the central clock, but its role in human physiology and pathophysiology remains shrouded in conjecture. The present study was undertaken to discern its role in sleep patterns. Zhdanova and colleagues hypothesized that melatonin would improve sleep parameters in those with age-related sleep impairment. They noted that about 30% of people older than age 50 exhibit insomnia characterized by decreased total nocturnal sleep duration, frequent nocturnal awakenings with difficulty falling back asleep, and early morning awakening. These alterations lead to daytime sleepiness, attention and memory deficits, and mood changes. Other health consequences also are linked to insomnia, including cardiovascular disease. Since melatonin levels decline with aging, they reasoned that some individuals might develop insomnia due to a deficiency of melatonin secretion at night. To test the hypothesis, Zhdanova et al designed a clever and meticulous study. Men and women older than age 50 who were otherwise well and had no other known explanation for insomnia were recruited and studied for 9 weeks. Half of the subjects had age-related insomnia and half did not. Insomnia was documented by polysomnography and actigraphy prior to enrollment. Insomnia was defined as sleep latency > 30 minutes, 2 or more nocturnal awakenings, and/or total sleep duration of < 6 hours. In random order, each subject was given melatonin 0.1-mg, 0.3-mg, or 3-mg at bedtime for a week every other week. During the intervals, the subjects received placebo. At the end of each week, polysomnography was repeated and the nocturnal melatonin profile was characterized.

No significant increases in sleep efficiency were observed after subjects with normal sleep received any dose of melatonin. In contrast, the sleep of insomniacs was significantly improved by all 3 doses, with the 0.3-mg dose giving the greatest effect and the most physiological nocturnal melatonin profile. The 3-mg dose led to supraphysiological levels of melatonin that remained elevated throughout much of the next day. Normally, melatonin levels are absent during the day. The baseline nocturnal melatonin levels of insomniacs nor the levels acheived by melatonin administration did not differ from those free of sleep complaints. Zhdanova et al concluded that a 0.3-mg melatonin dose taken at bedtime restores sleep efficiency in insomniacs while having no effect on those with already good sleep patterns. They noted that sleep is controlled by multiple, redundant mechanisms. Those who enjoy good sleep patterns with aging despite the expected decline in nocturnal melatonin levels may have redundant mechanisms that allow them to compensate for an attenuation in circadian signaling.

Comment by Sarah L. Berga, MD

Melatonin is an intriguing hormone. It is made only in the pineal gland of humans from the amino acid trytophan. Serotonin is an intermediate product of this biosynthetic pathway. This observation led to the notion that the melatonin secretory pattern provided a marker of endogenous serotonin tone in psychiatric conditions. Generally, the pineal gland releases melatonin only at night. The pattern is entrained by the customary light-dark and rest-activity cycles of the individual. Unlike most hormones, the amount of melatonin released at night is extremely variable from person to person. No one knows why there is so much variability. Like most hormones, however, the amount secreted declines with age. The ramifications of this decline are open to speculation, but it is felt that attenuation of chronobiological signals is part of what underlies loss of adaptation in the elderly. Recently, 2 melatonin receptors were cloned. Most of them reside in the hypothalamic suprachiasmatic nucleus, our central clock. The predominant melatonin receptor gates arousal. The other receptor, which accounts for about 1% of the total, "sets" the clock. The second types are the ones we try to coax when we travel across time zones. The present study was predicated on the understanding that occupation of predominant melatonin receptors has soporific effects and might enhance sleep. Zhdanova et al did an elegant study and demonstrated convincingly that the nocturnal melatonin signal is particularly important for those with age-related insomnia. The best effect was seen with a dose that closely mimicked physiology. This finding is yet another example of an endocrine rule-of-thumb, ie, that the more physiological the pattern achieved by exogenous administration of a given hormone, the better the outcome. So far this seems to hold for almost all hormones. The only reason we don’t insist on mimicking physiology is that it is often cumbersome or costly or both.

Is this result clinically relevant? Yes. First, melatonin is sold over-the-health-food-counter and is a big seller. Second, a lot of people have age-related fragmentation of sleep. Assuming a safe source of melatonin is available (current products are not regulated in the United States), this is a great way to buttress the sleep patterns of midlife women whose sleep complaints are not resolved by HRT, stress reduction, and earplugs (in the case of snoring partners).

Dr. Berga is Professor and Director, Division of Reproductive, Endocrinology and Infertility, University of Pittsburgh.