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