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Low Doses of Melatonin Promote Sleep Onset and Maintenance in Older People—An Update

US Neurology, 2014;10(2):117–9 DOI:


Plasma melatonin levels in young adults are about 10-fold higher during the night than during daylight hours, and these high levels promote both the onset of sleep at bedtime and the speedy resumption of sleep after premature nocturnal awakenings. With aging, melatonin’s nocturnal secretion from the pineal gland declines, as do plasma melatonin levels, total sleep time, and sleep efficiency. A very small dose (0.3 mg) of melatonin is usually sufficient to restore nighttime plasma melatonin levels to those characteristic of young people, and to accelerate the resumption of sleep after premature awakenings. The much larger doses that are marketed can produce side effects that are not observed when the melatonin in the plasma derives solely from its secretion by the pineal. Very high doses may also desensitize melatonin’s receptors in the brain, subsequently diminishing melatonin’s efficacy in promoting sleep. This article updates an earlier summary (Richard J Wurtman, Use of melatonin to promote sleep in older people, US Neurology, 2012;8(1):10–1) of melatonin’s utility in promoting sleep among older people.
Keywords: Melatonin, sleep, insomnia, desensitization, melatonin receptors, FDA
Disclosure: Richard J Wurtman, MD, has been a short-term consultant to several companies that required advice as to the correct melatonin dose to put in their products: Dreamerz, Healthy Directions, and Nature’s Bounty, but no longer has formal relations with any of them. Similarly, Massachusetts Institute of Technology (MIT) formerly owned US patents on his discoveries relating melatonin dose to sleep; however, these patents have all expired. All of his melatonin research has been fully and exclusively supported by the US National Institutes of Health. No funding was received for the publication of this article.
Received: September 02, 2014 Accepted: September 18, 2014
Correspondence: Richard J Wurtman, MD, Massachusetts Institute of Technology, 77 Mass Ave, 46-5009, Cambridge, MA 02139 US. E:

Many older people purchase the hormone melatonin and consume it orally, each evening, to promote the onset of sleep at bedtime and, particularly, the resumption of sleep after premature nocturnal awakenings. This need for exogenous melatonin to supplement that secreted from the aging pineal arises from the gland’s progressive, agerelated calcification, which decreases the number of active pineal cells, causing parallel reductions in melatonin’s synthesis and secretion.1–3 Inyounger people, plasma melatonin levels generally are about 8-10 pcg/ml during the daytime hours when little melatonin is secreted, quickly rise to 100–200 pcg/ml with the onset of darkness, and remain at around that level until daybreak. With aging, plasma melatonin levels may be slightly lower during the daylight hours, however, nighttime levels are markedly reduced, usually rising only to 20–50 pcg/ml.4 A single bedtime dose of 0.2–0.5 mg of melatonin will restore nighttime levels to those of younger people for several hours;4,5 however, this dosage is not stocked in most pharmacies, so patients usually have little choice but to take the much higher doses (e.g. 3–10 mg) that are available. As discussed below, the very high doses may actually exacerbate insomnia in some people, by desensitizing the melatonin receptors on the brain neurons that mediate the hormone’s sleep-promoting effects. Moreover such doses may also produce side effects (hypothermia,4 hyperprolactinemia,6 morning grogginess5), which rarely, if ever, occur with endogenous melatonin secretion. Even with access to low melatonin dosages, it is still difficult, using melatonin supplements, for older people to reproduce the normal ‘square-wave’ pattern of plasma melatonin levels observed in younger people, i.e. the sudden, 10-fold-or-greater rise around 9–11 PM and the similar fall around daybreak. Doses that are high enough to produce satisfactory elevations in nocturnal plasma levels throughout the night usually cause plasma levels initially to peak well beyond their normal range, thus risking desensitization of the melatonin receptors. Some possible strategies for obviating this problem were described previously (Richard J Wurtman, Use of melatonin to promote sleep in older people, US Neurology, 2012;8(1):10–1) and additional ones are discussed below.

Regulatory Considerations in the Availability of Oral Melatonin
Although large numbers of older Americans purchase the hormone melatonin and take it nightly to promote and sustain sleep, the US Food and Drug Administration (FDA) does not require that consumers be provided with guidelines concerning its proper dosage, nor information about its generally minor side effects, as would be obligatory for hypnotic drugs or for other hormones, such estrogens or thyroxine.

This is because, from a regulatory standpoint, orally-administeredmelatonin is classified not as a drug or hormone but as a ‘dietary supplement’—even though no food has ben compellingly shown to contain more than trace amounts of authentic melatonin, nor has consumption of any food been shown by gas-chromatography-massspectroscopy to elevate plasma melatonin levels. And, by virtue of the Dietary Supplement Health and Education Act of 1994, dietary supplements are regulated as though they are foods, (which do not require prior FDA approval) rather than as drugs, so long as their marketers make only ‘structure or function claims’ relating to effects on normal people, and do not promote the supplements for treating disease states. Supplements are not subject to the safety and efficacy testing requirements imposed on drugs, and the FDA may take action against their sale only after they have been shown to be unsafe (which, fortunately, has not been the case for melatonin).

Recently the first official regulatory body—the European Food Safety Authority (EFSA)—evaluated the available evidence that melatonin can reduce the time it takes for normal sleepers and patients with insomnia to fall asleep.7 It concluded that the evidence from all three of the statistically valid meta-analyses that have been published8–10 affirms ‘… a cause and effect relationship … between the consumption of melatonin and [a] reduction of sleep onset latency …,’ and that ‘… 1 mg of melatonin should be consumed close to bedtime …’7 (Individual publications demonstrated that a lower dose—0.3–0.5 mg—was as effective as 1.0 mg, however, too few such articles existed to enable a meta-analysis10). This recommendation can also help American physicians in dealing with patients’ questions about melatonin’s safety, and about which of the doses currently marketed is best for them. However, as described below, most Americans have little or no access to the low doses of melatonin recommended in the EFSA report and the meta-analyses because, due to absent FDA regulation, most stores stock melatonin only in doses as much as three to 30 times greater.

Melatonin, Melatonin Receptors, and Sleep
Melatonin, a derivative of the circulating amino acid tryptophan, was discovered by Aaron Lerner in 1958, based on its ability to lighten the skin color of amphibians, in vitro. We then showed, in 1963, that melatonin functions as a hormone in mammals,1 which the pineal gland produces and sectretes when the animals are exposed to darkness.1,11 In 1975 our laboratory further showed that blood melatonin levels in humans are also about tenfold higher during the hours of darkness than in daytime.11 This finding was interpreted as suggesting that the hormone might have something to do with sleep in humans and other diurnally active animals. Lerner had, in fact, described feeling ‘relaxed’ after selfadministering a very large dose of melatonin (200 mg i.v.); however, thehormone’s possible relationship to sleep was not systematically explored until the 1990s, when it was found that giving single melatonin doses to normal young subjects during the daytime caused dose-related, parallel increases in sleepiness, sleep, and plasma melatonin levels.5 Peak effects were observed after surprisingly low doses ( 0.3–1.0 mg), which elevated plasma melatonin to the same levels (100–200 pcg/ml) as those normally occurring in young people at nighttime.5

  1. Wurtman RJ, Melatonin. In: Coates P, Blackman M, Cragg G, et al., (eds), Encyclopedia of Dietary Supplements, Marcel Dekker, Inc., NYC, 2005;457–66.
  2. Iguchi H, Kato KL, Ibayashi H, Age-dependent reduction in serum melatonin concentrations in healthy human subjects, J Clin Endocrinol Metab, 1982;55:27–9.
  3. Baskett JJ, Wood PC, Broad, B, et al., Melatonin in older people with age-matched sleep maintenance problems: A comparison with age-matched normal sleepers, Sleep, 2001;24:418–24.
  4. Zhdanova IV, Wurtman RJ, Regan MW, et al., Melatonin treatment for age-related insomnia, J Clin Endocrin Metab, 2001;86:4727–30.
  5. Dollins AB, Zhdanova IV, Wurtman RJ, et al., Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance, Proc Natl Acad Sci, 1994;91:1824–8.
  6. Waldhauser F, Lieberman HR, Lynch HJ, et al., A pharmacological dose of melatonin increases PRL levels in males without altering those of GH. LH. FSH, TSH, testosterone, or cortisol, Neuroendocrinol, 1987;46:125–30.
  7. European Food Safety Authority. Scientific Opinion on the substantiation of a health claim related to melatonin and reduction of sleep onset latency (ID 1698, 1790, 4080) pursuant to Article 13(1) of Regulation (EC) No 1924/2006, EFSA Journal, 2011;9:2241.
  8. Buscemi N, Vandermeer B, Pandaya R, et al., Melatonin for treatment of sleep disorders. Summary, evidence report/ technology assessment No. 108. (Prepared by the University of Alberta evidence-based practice center under contract No. 290- 02-0023) AHRQ Publication No. 05-E002-1. Agency for Healthcare Research and Quality, Rockville., 2004.
  9. Buscemi N, Vandermeer B, Hooten N, et al., The efficacy and safety of exogenous melatonin for primary sleep disorders: a meta-analysis, J Gen Int Med, 2005;20:1151–8.
  10. Brzezinski A, Vangel MG, Wurtman RJ, et al., Effects of exogenous melatonin on sleep: a meta-analysis, Sleep Med Rev, 2005;9:41–50
  11. Lynch HJ, Wurtman RJ, Moskowitz MA, et al., Daily rhythm in human urinary melatonin, Science, 1975;187:169–71.
  12. Gerdin MJ, Masana MI, Rivera-Bermudez MA, Melatonin desensitizes endogenous MT2 melatonin receptors in the rat suprachiasmatic nucleus: relevance for defining the periods of sensitivity of the mammalian circadian clock to melatonin, FASEB J, 2004;18:1646–56.
  13. Dubocovich M, Melatonin receptors: Role in sleep and circadian rhythm regulation, Sleep Med, 2007;8(Suppl. 3):34–42.
  14. Gerdin MJ, Masana MI, Dubocovich ML, Melatonin-mediated regulation of human MI1 melatonin receptors expressed in mammalian cells. Biochem, Pharmacol, 2004;67:2023–30.
  15. Witt-Enderby PA, Bennett, J, Jarzynka, MJ, et al., Melatonin receptors and their regulation. Biochemical and structural mechanisms, Life Sci, 2003;72:2183–98.
  16. Garfinkel D, Laduron M, Nof D, et al., Improvement of sleep quality in elderly people by controlled-release melatonin, Lancet, 1995;346:541–4 .
  17. Haimov I, Lavie P, Laudon M, et al., Melatonin replacement therapy of elderly insomniacs, Sleep, 1995;18:598–603.
  18. Zhdanova IV, Wurtman, RJ, Balcioglu A, et al., Endogenous melatonin levels and the fate of exogenous melatonin: age effects, J Gerontol, 1998;53A:B293–8.
Keywords: Melatonin, sleep, insomnia, desensitization, melatonin receptors, FDA