In recent years, melatonin has been touted in the media as a "hot sleeping pill, natural and cheap" and as the drug that "may help ease insomnia, combat jet lag...and extend life" (Cowley, 1995). At a 1996 National Institutes of Health workshop on melatonin and sleep, chronobiology experts-worried by the public's growing fervor for melatonin-called for controlled clinical trials to determine its efficacy and long-term safety (Lamberg, 1996).
Finally, those trials are being conducted. Across the United States, some 30 medical centers are studying melatonin as a potential treatment for sleep disturbances associated with Alzheimer's disease (AD). In Israel, researchers published their study of melatonin's efficacy in the long-term treatment of delayed sleep phase syndrome (Dagan et al., 1998).
Melatonin, a naturally occurring hormone secreted by the pineal gland, is thought to affect circadian rhythmicity. Secreted only in the dark, it provides a time-of-day cue to diurnal and nocturnal species. For some animals and birds, it also provides a time-of-year signal for migration, hibernation and estrus cycles. Melatonin's secretion is one of hundreds of circadian rhythms in bodily functions controlled by the suprachiasmatic nuclei (SCN) of the hypothalamus, which comprise the body's master clock. Melatonin receptors have been found in the SCN, which is itself entrained by daylight signals received through the eyes (Lamberg, 1996).
Melatonin also occurs naturally in such foods as rice and bananas. Consequently, it can be sold as a dietary supplement in the United States without premarket approval from the U.S. Food and Drug Administration. Clinical studies of melatonin have been few, but gradually more are being funded.
Melatonin for Sleep Problems
The National Institute on Aging, for example, is funding the Alzheimer's Disease Cooperative Study of melatonin for sleep problems in AD patients. Sleep disruption, nightly restlessness and other circadian disturbances are seen frequently in patients with AD.
"When Alzheimer's disease patients have difficulty sleeping, [and] stay up for hours at night and wander, they wear out the caregivers," said Mary Pay, R.N., C.N.P., with the Alzheimer's Research Center, University of California San Diego. Because of the AD patient's sleeping difficulties, many families finally decide to place their loved ones in nursing homes.
Prior research indicates that melatonin decreases with advanced age. In one recent study, Liu et al. (1999) sought to determine whether melatonin production was affected in AD. Ventricular postmortem cerebrospinal fluid (CFS) was collected from 85 clinically and neuropathologically well-defined AD patients and from 82 age-matched control subjects who did not have primary neurological or psychiatric disease. The investigators found the CSF melatonin levels in AD patients were only one-fifth of those in control subjects. They concluded: "Whether supplementation of melatonin may indeed improve behavioral disturbances in AD patients should be investigated."
Such an investigation is being carried out by the Alzheimer's Disease Cooperative Study. Nationwide, centers are enrolling 150 individuals with a sleep disturbance associated with AD in the randomized, placebo-controlled, double-blind study.
Physicians can refer their patients, or families can self-refer to the medical centers participating in the melatonin protocol, said Pay. The University of California, San Diego is one such center. (A list of the participating centers throughout the United States, contact people and phone numbers is available at<http://galen.ucsd.edu/adcs/adcs_new.html>.) Individuals are eligible to participate if they have a diagnosis of probable AD, have sleep disturbance associated with AD, are in stable health (do not have any medical condition that would put them at risk in the study or interfere with the results of the study) and are at least 55 years of age.
"Once they contact us, we conduct the screening evaluation. They must also be living at home with a responsible caregiver, usually a spouse, who is able to observe the AD patient's nighttime behavior on a daily basis," Pay said.
Patients who meet the eligibility requirements and decide to participate in the study are randomly assigned to receive 3 mg of melatonin, 10 mg of melatonin or placebo. During the study period, they wear an actigraph, a microcomputer that is attached to the wrist and differentiates between sleep and waking based on the amount of movement in the limb. They also visit the medical center site every other week for 10 weeks to evaluate sleep patterns and vital signs.
Delayed Sleep Phase Syndrome
While enrollment is still going on for the Alzheimer's Disease Cooperative Study, another study evaluating the role of melatonin in long-term treatment of delayed sleep phase syndrome (DSPS) was published in Chronobiology International (Dagan et al., 1998). Delayed sleep phase syndrome involves a mismatch between the usual daily schedule required by each individual's environment and their circadian sleep/wake pattern. Individuals suffering from DSPS, despite having completely normal sleep architecture and sleep duration, experience great difficulty falling asleep before 1 a.m. or 2 a.m., if not later, as well as rising at acceptable hours of the morning.
"Delayed sleep phase syndrome usually first appears in childhood or early adolescence, interferes with the child's adjustment to school demands and causes attention and learning disorders due to sleepiness. Many times the child has ongoing conflicts with his or her environment [e.g., parents and teachers], leading to dropping out from school or all kinds of behavior disorders," said Yaron Dagan, M.D., Ph.D., principal investigator of the study and director of the Institute for Fatigue and Sleep Medicine at Chaim Sheba Medical Center in Israel. "We even found a high prevalence of personality disorders among DSPS patients compared to normal controls [Dagan,1996]. The disorder does not disappear and later in life causes functional troubles for the patient."
In the study, Dagan and colleagues examined the efficacy of melatonin treatment in a relatively large population of DSPS subjects through the use of subjective reports. They studied 61 people (37 men and 24 women) who had been diagnosed as having DSPS by means of both clinical assessment and actigraphy at the sleep clinic. According to actigraphic measures, the patients' mean length of sleep was eight hours and 21 minutes (SD=47.04 minutes). The mean pretreatment falling asleep and waking times were 3:09 a.m. (SD=86.22 minutes) and 11:31 a.m. (SD=98.58 minutes), respectively. They were treated with a six-week course of 5 mg of oral melatonin taken daily at 10 p.m., five hours before estimated mean pretreatment sleep onset time. Between one year and 18 months after the treatment ended, patients were sent a survey questionnaire. The survey included such questions as: Did the melatonin treatment resolve your sleep schedule problem? How long did it take for the melatonin to take effect? Did you experience any side effects during the melatonin treatment?
Of the 61 subjects who answered the questionnaire, 59 (96.7%) reported that the treatment improved their condition, while only two (3.3%) reported that the treatment had not helped them at all. Furthermore, 31 (50.8%) of the subjects reported that the change took place within less than one week, 17 (27.9%) within one to two weeks, nine (14.8%) within two to four weeks and two (3.3%) after a month. Side effects were minimal. Thirty-five of the subjects (57.4%) reported no side effects, 21 (34.4%) reported slight fatigue, and five (8.2%) experienced headaches or nausea. None of the women reported menstrual changes. Of the 59 subjects who found the treatment helpful, 54 (91.5%) reported a relapse to their pretreatment sleeping patterns within one year of stopping the melatonin. Only 17 (28.8%) reported that the relapse occurred within one week.
Dagan and colleagues wrote:
The finding that melatonin is effective in changing the sleep-wake patterns of DSPS patients is important and supports prior laboratory studies carried out on relatively small numbers of patients by other investigators. However, the finding that the new sleep patterns are not permanently retained suggests that external administration of melatonin does not cause a fundamental and permanent change in sleep regulation. Thus, DSPS patients may need to take melatonin regularly, in much the same way that diabetic patients take insulin or hypothyroidic patients receive thyroid hormone replacement treatment. This suggestion seems reasonable in light of past findings, which are substantiated in the present study, regarding melatonin's relative absence of side effects.
In an interview with Psychiatric Times, Dagan said he has experience with more than 600 patients (ages 13 to 56) who have sleep/wake schedule disorders, and most of them were treated successfully with melatonin.
"We found melatonin to be a very good treatment for these patients. In Israel, [melatonin] is a pharmaceutical substance that needs a physician's prescription and is prepared in pharmacies. The usual dosage...is 5 mg taken daily at a fixed time [usually 10 p.m. to 11 p.m.]. Melatonin treatment is well established in our treatment protocol," he said. "It has to be emphasized, however, that this treatment is only effective for biological rhythm disorders [sleep/wake schedule disturbances and jet lag], but it is not a miracle sleeping pill for psychophysiological insomnia." Dagan added that he has not confronted any major side effect.
In addition to exploring the use of melatonin for sleep/wake schedule disorders, Dagan and colleagues are studying melatonin and selective serotonin reuptake inhibitor treatment, melatonin and haloperidol (Haldol), melatonin treatment for hemodialysis patients, and melatonin administration for patients hospitalized in intensive care units.
Cowley G (1995), Melatonin. Newsweek. Aug. 7.
Dagan Y, Sela H, Omer H et al. (1996), High prevalence of personality disorders among circadian rhythm sleep disorders (CRSD) patients. J Psychosom Res 41(4):357-363.
Dagan Y, Yovel I, Hallis D et al. (1998), Evaluating the role of melatonin in the long-term treatment of delayed sleep phase syndrome (DSPS). Chronobiol Int 15(2):181-190.
Lamberg L (1996), Melatonin potentially useful but safety, efficacy remain uncertain. JAMA 276(13):1011-1013.
Liu RY, Zhou JN, van Heerikhuize J et al. (1999), Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer's disease and apolipoprotein E-epsilon 4/4 genotype. J Clin Endocrinol Metab 84(1):323-327.