Cognitive Health, Dietary Supplements, and Sleep: Melatonin

In an ideal world, everyone would get a good night’s sleep. Infants need 16 hours of sleep per day; for adults, seven to eight hours appears to be the best amount. Unfortunately, many have trouble getting the sleep they need, for various reasons.

The National Institute of Neurological Disorders and Stroke estimates that at least 40 million Americans suffer from chronic, long-term sleep disorders each year, and an additional 20 million experience occasional sleeping problems. A sleep disorder exists whenever a lower than desired amount of sleep results in impaired awake functioning or excessive sleepiness.(1) The International Classification of Sleep Disorders documents 81 official sleep disorders. “Primary” disorders include insomnia, sleep apnea, restless leg syndrome, sleepwalking, narcolepsy, time zone change (jet lag), and night shift work. “Secondary” disorders are secondary to illness, mental disorders, or are caused by drugs.(2)

Why sleep? Our bodies perform repair-and-refresh activities during sleep. Our nights repeatedly cycle through five sleep phases: stages 1, 2, 3, 4, and rapid eye movement (REM). Each cycle takes 1.5 to 2.0 hours. Stages 1 and 2 are progressively light-to-moderate sleep. Stages 3 and 4 represent deep sleep. REM sleep is about 20% of total sleep. Almost all dreams occur during REM sleep. During REM, heart rate and blood pressure rise, and the pons, thalamus, and cerebral cortex regions of the brain become active, while at the same time nerve signals suppress motor activity so that someone dreaming of fighting or running is not vigorously thrashing about in bed. For some people, this suppression function is compromised-which can be very inconvenient if sharing a bed with another!

In the dietary supplements sphere, consumers struggling to get more sleep often turn to melatonin, a hormone produced by the brain’s pineal gland that triggers evening drowsiness. While those craving sleep may desire a higher supplement dose, research is still exploring what is the ideal dose for optimum sleep.

Melatonin’s Role in Sleep

Under normal circumstances, there is little to no melatonin production or circulating melatonin in the body during daylight hours. The dim light of dusk and early evening triggers the production and blood circulation of melatonin. (See figure.) Melatonin functions by binding to melatonin receptors MT1 and MT2 in the supra-chiasmatic nucleus of the brain. When activated, MT1 and MT2 suppress the anti-sleep alerting signal. As a consequence, lowered body temperature and drowsiness set in, followed by sleep.

The hypothesized mechanism for melatonin is supported by evidence for the FDA-approved drug Rozerem. Rozerem binds to the same MT1 and MT2 receptors in the brain, and unlike most sleep-aid drugs does not result in next-morning mental impairment or rebound insomnia when use is stopped.

Supplementing with melatonin has repeatedly proven to raise blood concentration of melatonin, helping to initiate a pre-sleep stage. It’s usually advised to take a melatonin product an hour before intending to go to sleep.

Why supplement? Some people are low or delayed producers of melatonin, or produce melatonin but have a reduced sensitivity to it. For example, it is well known that production of melatonin decreases with age and that older people have more difficulty falling asleep and sleeping through the night without interruption.

One clinical evaluation confirmed that the nighttime plasma melatonin peak reached in 60-year-old subjects was lower compared to 30-year-old subjects. However, older subjects achieved a 50% higher plasma peak when dosed with the same 0.3-mg melatonin amount given to the younger subjects.(5) This finding supports the idea that age-related insomnia involves lessened melatonin production rather than loss of receptor sensitivity.

Human Evidence

Human trials have shown that melatonin can be effective in aiding sleep. In 2005, Amnon Brzezinski, MD, published a meta-analysis of 17 clinical trials on melatonin supplementation. Dosing ranged from as low as 0.1 mg to as high as 80 mg. Nine trials tested the improvement in time it took to fall asleep and reported a statistically significant average improvement of 7.5 minutes compared to placebo. Three studies had an average improvement exceeding 20 minutes.(7)

Seven of the studies Brzezinski cites also reported on sleep efficiency. Sleep efficiency is defined as time asleep compared to time in bed. The studies reported a modest but statistically significant improvement of 2.2% in sleep efficiency with supplementation. Eight studies reported on total sleep duration and found a statistically significant average increase in sleep duration of 12.8 minutes with melatonin. Subjects experienced fewer sleep interruptions and reported improved sleep quality.(7)

Other studies show that melatonin taken the night before also resulted in improved morning alertness and quality of life the next day.(8,9,12) This is the opposite of the consequences of most sleep drugs, which are known to interfere with cognition and result in morning fatigue the next day. Furthermore, discontinuing melatonin supplementation did not result in any rebound insomnia or withdrawal effects typically seen when drug sleep-aid products are discontinued.(9)

Thus, the meta-analysis and subsequent clinical trials support the hypothesis that melatonin decreases sleep onset latency, increases sleep efficiency, increases REM sleep, increases total sleep duration, and improves next-day alertness and mental functions.

Safety Issues

Dietary supplement companies rejoice when there is a lengthy government-published document declaring an ingredient “safe.” In 2004, the Agency for Healthcare Research and Quality of the U.S. Department of Health and Human Services concluded that melatonin “…is a relatively safe substance when used in the short term, over a period of days or weeks, and is safe at relatively high doses and in various formulations.”(13)

FDA, however, revisited the safety question in 2011 in the context of a Warning Letter. Briefly, based on several published clinical trials, there were concerns that melatonin may raise postprandial blood glucose, lower insulin sensitivity, and lower blood pressure, with preliminary evidence suggesting changes in reproductive hormones and epileptic seizure risk. Some of these changes were said to have been seen with doses as low as 1.0 mg/day.(14)

How Much Melatonin Is Too Much?

So, what is considered an ideal supplement dose? Opinions vary as research develops. However, some sleep researchers have speculated that a higher dose may actually be counterproductive and that a prolonged elevation of melatonin in circulation may interfere with normal sleep patterns.

Some of the more interesting aspects of exactly how melatonin functions were discovered by the research group headed by Richard J. Wurtman, MD, professor of neuroscience at the Massachusetts Institute of Technology. Based on his group’s work conducted at MIT between 1990 and 2001,(3–6) Dr. Wurtman’s reply to a query about the ideal melatonin dose was “…just enough oral melatonin to raise nighttime blood levels to 100–200 picograms (pg)/ml.” In Dr. Wurtman’s opinion, the dose of supplemental melatonin most people require to attain this blood plasma range is about 0.3 mg.

Other clinical trials have reported improved REM sleep with melatonin doses in the range of 0.3 to 3.0 mg.(8-12) Studies that tested more than one dosage level did not find any improvement over what was seen with 0.3 mg.(4,10)

In a study of middle-aged people with insomnia, supplemental melatonin doses of 0.1, 0.3, or 3.0 mg taken in the evening all resulted in improved sleep efficiency. However, the 0.3-mg dose trended better than both the higher and lower doses. The largest dose also led to a greater body temperature decrease compared to the other groups.(6)

However, another study examining the effects of different doses of supplemental melatonin on nighttime plasma melatonin levels determined that a 0.3-mg dose may still result in above-normal plasma peak levels. The study found that a placebo dose resulted in a nighttime plasma melatonin peak of 50 pg/ml. By contrast, a 0.1-mg dose of supplemental melatonin resulted in a peak of 84 pg/ml; a 0.3-mg dose, in a peak of 220 pg/ml; and a 3.0-mg dose, in a peak of 1,370 pg/ml. In this study, the last two plasma peak levels-including the one achieved by the 0.3-mg dose-were considered above the normal peak range. (The highest dose of 3.0 mg also resulted in an elevation that lasted into the following morning, while the two lower doses resulted in morning blood levels similar to placebo.)

While more research is needed to determine an ideal dose, Dr. Wurtman tells Nutritional Outlook, “A pharmacologic dose of melatonin is any dose that raises plasma melatonin levels beyond their normal range. Such doses also produce side effects that hormonal melatonin-the melatonin secreted from the pineal gland-doesn’t produce; for example, significant hypothermia, elevated blood levels of the hormone prolactin, and desensitization of the brain’s melatonin receptors.”

Regarding higher doses, he added, “It is conceivable, of course, that pharmacologic doses could have some utility-e.g., in treating a disease.” However, he said, this would have to be tested in a controlled study.

References

1. “Brain Basics: Understanding Sleep.” National Institute of Neurological Disorders and Stroke. www.ninds.nih.gov/disorders/brain_basics/understanding_sleep.htm

2. American Academy of Sleep Medicine. International Classification of Sleep Disorders: Diagnostic and Coding Manual, 2nd ed., Westchester, IL: American Academy of Sleep Medicine, 2005.

3. Zhdanova IV, Wurtman RJ, et al. ”Sleep-inducing effects of low doses of melatonin ingested in the evening.” Clin Pharm Therap, vol. 57, no. 5 (May 1995): 552-558.

4. Zhdanova IV, Wurtman RJ, et al. ”Effects of low oral doses of melatonin, given 2-4 hours before habitual bedtime, on sleep in normal young humans.” Sleep, vol. 19, no. 5 (June 1996): 423-431.

5. Zhdanova I, Wurtman RJ et al. ”Endogenous melatonin levels and the fate of exogenous melatonin: age effects.” J Gerontol A Biol Sci Med Sci., vol. 53, no. 4 (July 1998): B293-298.

6. Zhdanova IV, Wurtman RJ, et al. ”Melatonin treatment for age-related insomnia.” J Clin Endocrin Metab, vol. 86, no. 10 (October 2001): 4727-4730.

7. Brzezinski A, Vangel MG, et al. ”Effects of exogenous melatonin on sleep: a meta-analysis.” Sleep Med Rev, vol. 9, no. 1 (February 2005): 41-50.

8. Wade AG, Ford I, et al. ”Efficacy of prolonged release melatonin in insomnia patients aged 55-80 years: quality of sleep and next-day alertness outcomes.” Curr Med Res Opin, vol. 23, no. 10 (October 2007): 2597-2605.

9. Lemoine P, Nir T, Laudon M, Zisapel N. “Prolonged-release melatonin improves sleep quality and morning alertness in insomnia patients aged 55 years and older and has no withdrawal effects.” J Sleep Res, vol. 16, no. 4 (December 2007): 372-380.

10. Mundey K. et al. “Phase-dependent treatment of delayed sleep phase syndrome with melatonin.” Sleep, vol. 28, no. 10 (October 2005): 1271-1278.

11. Rajaratnam S, et al. “Melatonin advances in circadian timing of EEG sleep and directly facilitates sleep with altering its duration in extended sleep opportunities in humans.” J Physiol, vol. 561 (Pt. 1) (November 2004): 339-351.

12. Kunz D, et al. “Melatonin in patients with reduced REM sleep duration: two randomized controlled trials.” J Clin Endocrinol Metab, vol. 89, no. 1 (January 2004): 128-134.

13. Buscemi N, Vandermeer B, et al. ”Melatonin for treatment of sleep disorders.” Evidence Report/Technology Assessment No. 108. AHRQ Publication No. 05-E002-2. Rockville, MD. November 2004.

14. Food & Drug Administration Warning Letter to HBB, LLC dba Baked World 7/28/11. www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm266129.htm.

15. Härtter S, Grözinger M, Weigmann H, Röschke J, Hiemke C. “Increased bioavailability of oral melatonin after fluvoxamine coadministration.” Clin Pharmacol Ther, vol. 67, no. 1 (January 2000): 1-6.