Melatonin Is Right on Time

Restoring the sleep/wake cycle (a common casualty of aging) 
may also help Alzheimer’s patients 
By Dr. Edward R. Rosick

I enjoy traveling (when I can find the time for it!), especially to far-flung regions of the world. Half a century ago, when jet aircraft made travel between countries and continents effortless and fairly comfortable (once you were on the plane)—and very fast—it brought a new malady to the human condition: jet lag. The disruption of one’s normal sleep/wake cycle and the accompanying persistent feelings of physical and mental fatigue could make one almost long for the bygone era of a slow, week-long ocean cruise.

But why should flying to distant places—or, more specifically, to places of distant longitudes (widely differing time zones)—have anything to do with how you feel or think?* The answer lies in the daily rhythms of your body and mind, including those of temperature, blood pressure, hormone production, and sleep.


*Flying to distant latitudes (north or south) does not produce jet lag, but it may cause temporary fatigue from all the hassle involved in air travel, especially in the age of terrorism.


Circadian Rhythms and the Biological Clock

Although most people tend to think that manifestations of body function such as temperature and blood pressure are constant throughout the day, the fact is that many functions change in cyclic patterns—especially those that are affected by hormones, such as cortisol (we’ll meet another such hormone in a moment). These daily fluctuations, or circadian rhythms (from Latin: “about one day”), are fundamental to all organisms, from bacteria to human beings. Circadian rhythms help coordinate and synchronize our internal body functions, as well as our interactions with the external world.

Scientists are still learning about how the body maintains this synchronicity with its environment. Let’s look at some of what they’ve found.

Deep within the brain, in the anterior hypothalamus, lies the suprachiasmatic nucleus(SCN), a dual cluster of thousands of nerve cells. This is the body’s circadian pacemaker, popularly known as the biological clock, which is powered, in a sense, by light. The SCN receives signals from the outside world via the retina of the eye (the back inside lining of the eyeball, analogous to the film in a camera). When light strikes the retina, bioelectric signals are generated and sent to the SCN via a neural pathway called the retinohypothalamic tract. Signals are also sent, of course (via the optic nerve), to the visual cortex, where the sensation of vision is produced.

Melatonin—The Biological Clock’s Hour Hand

The signals that reach the SCN are processed and forwarded to a small number of other hypothalamic nuclei and to the destination of primary importance, the pineal gland. This is an endocrine gland whose pea size proves that, at least in terms of physiological importance, size doesn’t matter. What makes the pineal gland so important is the hormone it secretes: melatonin. This compound is the end product of a biosynthetic pathway that begins with the nutrient amino acid tryptophan.

Through a series of enzyme-catalyzed reactions, tryptophan is partially converted to 5-hydroxytryptophan (5-HTP), which is partially converted to serotonin, which is partially converted to melatonin. (How “partial” each of these conversions is depends on many factors governed by prevailing chemical conditions in different parts of the body.)

Lights Out = Melatonin On

The relationship between light and melatonin is inverse. When the SCN is stimulated by daylight signals from the retina, it instructs the pineal gland to suppress melatonin production (though not entirely). Then, when daylight fades in the evening, the SCN’s lack of stimulation is signaled to the pineal gland, and melatonin secretion is increased many times over, creating a physiological condition of “biological night” in the person. The circadian rhythm of melatonin secretion is so tied to the day/night cycle that the daily duration of the secretion (at high levels) is shorter during the summer, when the nights are short, and longer during the winter, when the nights are long.

By directly controlling the pineal gland’s melatonin secretion, the SCN indirectly controls many of the body’s circadian rhythms, including those affected by jet lag. Consequently, many physicians recommend supplemental melatonin for relieving the symptoms of this condition. Studies have shown that melatonin is effective in phase-shifting human circadian rhythms either forward or backward, giving long-distance travelers welcome relief from both the physical and psychological effects of jet lag.

Melatonin Is Good for Insomnia

Melatonin has also been used successfully for treating insomnia. In a newly published meta-analysis on the effects of supplemental melatonin on sleep, the authors analyzed the data from 17 previously published studies and concluded that melatonin can significantly decrease sleep latency (the time it takes to fall asleep) and increase sleep efficiency and sleep duration.1

The fact that melatonin can be used for treating insomnia is especially relevant to the elderly. As people grow older, sleep problems, including difficulty in falling asleep and staying asleep, become common. This is probably because a general disruption of circadian rhythms associated with declining melatonin production is characteristic of the aging process. With melatonin levels declining as we age, it makes sense to think that melatonin supplements (taken in the evening, of course) may be able to help us achieve a good night’s sleep.

Melatonin Deficiency May Cause Sundowning

The benefits of melatonin supplementation are not limited to normal aging, however. Surprisingly, there is evidence that melatonin may also be able to help relieve some of the symptoms of an emerging twenty-first-century epidemic: Alzheimer’s disease (AD). First described clinically in 1906, AD is the most common cause of dementia in those aged 65 or older. With the rapidly aging population in the United States (it’s estimated that 30% of the population will be 65 or older by the year 2050), projections are that 14 million people will develop this devastating disease during the next four decades.2,3

Disruption of the sleep/wake cycle is highly characteristic of AD, and a commonly observed problem in AD patients is a phenomenon called sundowning. This is a worsening, during the evening hours, of a constellation of cognitive and behavioral symptoms associated with the disease. Although there is no clear answer as to why this occurs, many researchers are coming to believe that declining melatonin levels may play a significant role. A recent review by scientists at the Netherlands Institute for Brain Research in Amsterdam explains how declining melatonin production in the aged can not only affect their circadian rhythms but also play a role in the development and characteristics of Alzheimer’s disease itself.4

Melatonin May Help Alleviate Alzheimer’s Disease

The authors cite research showing that aging is characterized by a progressive deterioration of circadian rhythms, due at least in part to degenerative changes in the SCN and the pineal gland, which result in diminished melatonin production. They go on to cite studies showing that, in AD patients, the biological clock (SCN) is severely impaired, and the resultant degree of impairment of melatonin secretion is related to the severity of the mental impairment caused by the disease. They state, “AD patients with disturbed sleep-wake cycle possess melatonin secretion rhythm disorders, and the disappearance of daily melatonin rhythm in AD patients is consistent with clinical circadian rhythm disorders, such as delirium, agitation, and sleep-wake disturbance.”

When the sun goes down, melatonin levels go up.

While it’s common in mainstream medical practice to use sedatives such as benzodiazepines, and antipsychotics such as haloperidol, to try to ameliorate the sundowning and sleep disturbances so commonly seen in Alzheimer’s patients, these drugs do little or nothing to help, and in some cases they may even exacerbate the problems. This makes the use of melatonin supplementation seem all the more attractive by comparison, especially since it’s designed to rectify the very deficiency that caused the problem in the first place. The Dutch authors go on to state,

In AD patients, melatonin [supplementation] has been suggested to improve circadian rhythmicity, decreasing agitated behavior, confusion, and ‘sundowning’ in uncontrolled studies. Melatonin has also been suggested to have beneficial effects on memory in AD, possibly through protection against oxidative stress and neuroprotective capabilities. However … it should be noted that a few randomized, placebo-controlled trials of melatonin administration to AD patients did not find improved sleep-wake pattern. If there are beneficial effects of melatonin in AD, it may relate both to the indole’s [melatonin’s] ability to synchronize circadian rhythms and to the antioxidant action of melatonin.

Melatonin Is an Antioxidant and Neuroprotector

Oxidative damage to the brain caused by free radicals is thought to play a significant role in the cognitive impairments characteristic of Alzheimer’s, a disease in which free radicals are produced in much greater amounts then normal. These excess free radicals are known to cause significant damage to the brain, including the actual death of many neurons. A review paper in 2000 reported that, in the autopsied brains of Alzheimer’s patients, there were many hallmark pathological changes caused by free radical activity, including oxidative damage to DNA, proteins, and lipids.5

Melatonin has significant antioxidant and neuroprotective properties, and it is believed that they may be important with regard to its role in aging and Alzheimer’s disease. Thus it is intriguing to note that the precursor molecule 5-HTP (which can be taken as a supplement for the purpose of boosting serotonin levels) has recently been found to have a much higher antioxidant activity than melatonin.6



Melatonin May Be Good for Your Gut Too

Surprisingly, melatonin is found in large quantities in the gastrointestinal tract, but its role there is largely unknown. A recent article by researchers at the Jagiellonian University College of Medicine in Kraków, Poland, reviewed studies suggesting that melatonin may provide a protective effect against gastritis and pancreatitis (inflammation of the stomach and pancreas, respectively).1

The authors cite research showing that melatonin is widely circulated throughout the body, and its concentration in the GI tract may be 400 times higher than in the pineal gland. In fact, since melatonin levels in the gut remain the same even after removal of the pineal gland, the authors postulate that this hormone is actually being produced somewhere in the GI tract.

So what is a hormone that’s generally associated with the brain and circadian rhythms doing in the gut? The authors present evidence that melatonin provides protection to the gastric mucosa, aids in healing of chronic gastric ulcers, and provides protection against pancreatitis via antioxidant and anti-inflammatory effects.

Although it’s too early to be abandoning traditional medications for digestive problems, it may someday be common to take a melatonin supplement for both your brain and your belly.

  1. Jaworek J, Brzozowski T, Konturek SJ. Melatonin as an organoprotector in the stomach and the pancreas. J Pineal Res 2004 Oct 5 (online pub date).


That sounds exciting, but there is a catch: this comparison was made in vitro (in laboratory experiments with chemicals), not in vivo (in living organisms). The chemical conditions in antioxidant studies can make a huge difference in the outcome, so only realistic in vivo studies can shed meaningful light on the question of whether 5-HTP is really the more potent antioxidant—or whether it has any appreciable antioxidant activity at all in vivo.

Melatonin—Good for Restful Sleep and More

The vital role that melatonin plays in maintaining optimal human health is still emerging, and it’s likely that many new discoveries concerning this powerful and versatile hormone are yet to come. It seems clear by now, however, that, besides being a safe, natural supplement for restoring the sleep/wake cycle and relieving jet lag after long-distance travel, melatonin may be an effective way to ameliorate some of the deleterious effects of aging, and even of Alzheimer’s disease.


  1. Brzezinski A, Vangel MG, Wurtman RJ, et al. Effects of exogenous melatonin on sleep: a meta-analysis. Sleep Med Rev 2005;9(1):41-50.
  2. Grundman M, Thal L. Treatment of Alzheimer’s disease. Neurol Clin2000;18(4):807-28.
  3. Mayeux R, Sang M. Treatment of Alzheimer’s disease. New Engl J Med1999;341:1670-9.
  4. Wu YH, Swaab DF. The human pineal gland and melatonin in aging and Alzheimer’s disease. J Pineal Res 2004 Dec 21 (online pub date).
  5. Christen Y. Oxidative stress and Alzheimer’s disease. Am J Clin Nutr2000;71(2):621-9.
  6. Keithahn C, Lerchi A. 5-Hydroxytryptophan is a more potent in vitro hydroxyl radical scavenger than melatonin or vitamin C. J Pineal Res 2005;38:62-6.


Dr. Rosick is an attending physician and clinical assistant professor of medicine at Pennsylvania State University, where he specializes in preventive and alternative medicine. He also holds a master’s degree in healthcare administration.