Physiology and available preparations of melatonin

Author:
Richard Wurtman, MD
Section Editor:
David S Cooper, MD
Deputy Editor:
Kathryn A Martin, MD
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Dec 2017. | This topic last updated: Apr 17, 2017.

INTRODUCTION — Melatonin is a hormone produced in the pineal gland from the amino

acid tryptophan and secreted into the blood and cerebrospinal fluid. It conveys signals to
distant organs, principally the brain, and affects the synthesis of second messengers and,
ultimately, sleep and circadian rhythms.

The physiology of melatonin and an overview of its clinical uses are reviewed here.
Additional information on clinical uses of melatonin are found separately. (See "Treatment
of insomnia in adults", section on 'Melatonin agonists' and "Jet lag" and "Complementary
and alternative therapies for cancer", section on 'Melatonin'.)

OVERVIEW — The human pineal gland is an important structure that transmits signals to

the brain and other organs by secreting its unique hormone, melatonin. However, this
concept is only a few decades old. In 1975, it was discovered that melatonin production in
humans, like that in all other mammals studied, exhibits a pronounced circadian rhythm
such that nocturnal plasma melatonin concentrations are at least 10-fold higher than
daytime concentrations [1,2]. In humans, nocturnal serum concentrations of melatonin
decline across puberty [3], but no reproductive effects of exogenous melatonin have been
clearly demonstrated [4].

Much pineal research has concerned the human brain's responses to melatonin rhythms.
The most compelling evidence supports two roles for melatonin in humans: the
involvement of nocturnal melatonin secretion in initiating and maintaining sleep, and
control by the day/night melatonin rhythm of the timing of other 24-hour rhythms.
Melatonin's effect on sleep underlies most of its current use as a drug and the
development of melatonin analogs as new drugs [5,6]. (See 'Circadian rhythm' below
and 'Melatonin agonists' below.)

MELATONIN PHYSIOLOGY

Synthesis and metabolism — Almost all of the melatonin formed in mammals is

synthesized within the pineal gland from the essential amino acid tryptophan (figure 1) [7].
Plasma melatonin and its circadian rhythm largely or completely disappear among
pinealectomized animals [8] or human subjects post-pinealectomy [9]. Tryptophan is first
5-hydroxylated by the enzyme tryptophan hydroxylase and then decarboxylated by the
enzyme aromatic L-amino acid decarboxylase to form 5-hydroxytryptamine, or serotonin
(figure 1) [7].

During daylight hours, the serotonin in pinealocytes tends to be stored and unavailable to
monoamine oxidase and the melatonin-forming enzymes that would otherwise act on it.
With the onset of darkness, postganglionic sympathetic outflow to the pineal increases,
and the consequent release of norepinephrine onto pinealocytes causes stored serotonin
to become accessible for intracellular metabolism. At the same time, the norepinephrine
activates the enzymes that convert serotonin to melatonin, especially serotonin-N-
acetyltransferase (SNAT) [10], but also hydroxyindole-O-methyltransferase (HIOMT)
[11,12]. Consequently, pineal melatonin levels rise many-fold [13]. Pineal levels of the
corresponding deaminated and O-methylated metabolite of serotonin, 5-
methoxytryptophol, also rise [14], even though formation of this compound is independent
of SNAT. This suggests that the daily rhythm in pineal SNAT activity is not the cause of the
rhythm in melatonin synthesis, as has sometimes been proposed.

Melatonin then diffuses out of the pineal gland and into the blood stream and
cerebrospinal fluid [15], rapidly raising its plasma concentrations from approximately 2 to
10 pg/mL (8.61 to 43.05 pmol/L) to 100 to 200 pg/mL (430 to 861 pmol/L) [1]. Melatonin is
highly lipid soluble because both of the ionizable groups in serotonin, the hydroxyl and the
amine, have been blocked by its O-methylation and N-acetylation. Thus, it diffuses freely
across cell membranes, including those of the blood-brain barrier [16], and travels in the
blood largely bound to albumin [17].

Most of the melatonin in the circulation is inactivated in the liver, where it is first oxidized to
6-OH-melatonin by a P450-dependent microsomal oxidase and then largely conjugated to
sulfate or glucuronide before being excreted into the urine or feces [18]. Approximately 2
to 3 percent of the circulating melatonin is excreted unchanged into the urine or the saliva,
enabling measurements of urinary or salivary melatonin to be used as rough estimates of
plasma melatonin concentrations. Salivary melatonin levels apparently correspond to
those of the 25 to 30 percent of blood melatonin that is not bound to albumin. Salivary
melatonin measurements are not widely used.

Studies using radioactively labeled melatonin have identified three probable melatonin
receptors, two of which have been cloned using human sources [19]. These
macromolecules are concentrated, respectively, within the suprachiasmatic nucleus (SCN)
of the hypothalamus, the pars tuberalis of the pituitary, and cardiac blood vessels (MT1);
the retina and hippocampus (MT2); and in kidney, brain, and various peripheral organs
(MT3). Their affinities for melatonin are enhanced in the presence of several G-proteins.

The MT1 receptors in the SCN allow melatonin to inhibit the firing of SCN neurons during
the nighttime, an action that might contribute to melatonin's sleep-promoting effects. The
SCN's MT2 receptors apparently mediate melatonin's effects on the SCN's own circadian
rhythms.
Melatonin's MT1 and MT2 receptors are highly susceptible to "desensitization," their
activity decreasing markedly after exposure to supranormal concentrations of the hormone
[20,21]. This is relevant to the prolonged use of high melatonin doses to promote sleep,
particularly among older adults with insomnia who might inadvertently purchase
excessively large doses of the hormone.

Circadian rhythm — In all mammals examined thus far, melatonin secretion manifests a
similar circadian rhythm, with plasma and urine concentrations low during daylight,
ascending after the onset of darkness, peaking in the middle of the night between 11 PM
and 3 AM, and then falling sharply before the time of light onset [1]. It should be noted that
high nocturnal plasma melatonin concentrations are characteristic of both diurnally active
species (like humans), in which the high levels promote sleep onset and maintenance, and
nocturnally active ones (like rats), in which melatonin has no obvious relationship to sleep.

While this rhythm normally is tightly entrained to the environmental light cycle, it does
persist when people are placed for a few days in a dark room [22] and, as described
above, does not immediately phase shift when the light schedule is altered [2], indicating
that it is not simply generated by the light-dark cycle but also by cyclic endogenous
signals, probably arising in the SCN. Signals originating in the retina or the SCN reach the
pineal via a retinohypothalamic tract, the superior cervical ganglia, and postganglionic
sympathetic fibers that re-enter the cranial cavity [23,24]. In contrast, light has no known
direct effects on pineal melatonin synthesis in humans and other mammals.

The ability of exogenous melatonin to synchronize and to shift the phases of various
human circadian rhythms is generally accepted. In studies of healthy volunteers, 0.5 mg of
pure melatonin [25] or 0.05 mg of melatonin in corn oil (which causes earlier peaks in, and
the more rapid disappearance of, elevated plasma melatonin concentrations) was able to
advance the onset of nocturnal melatonin secretion when administered at 5 PM, and larger
doses caused greater phase advances [26]. In addition, melatonin was able to shift the
core body temperature rhythm; however, a statistically significant effect was found only
with doses ≥0.5 mg. These doses increased plasma melatonin concentrations well above
the upper limits of normal (>1327 pg/mL [5712 pmol/L]) [26], suggesting that this may not
be a physiologic effect.

Potential role in cyclic disorders — Besides its iconic circadian rhythm, plasma

melatonin concentrations have a seasonal (or circannual) rhythm, with higher levels in
the fall/winter, when nights are longer, and lower levels in the spring and summer [27-29].
This has led some to propose that the annual rhythms in peak melatonin levels, or in their
duration each night, may play a role in the pathophysiology of neurobehavioral diseases
like multiple sclerosis (MS) and seasonal affective disorder (SAD), For example, the
frequency of relapses in MS is significantly lower in fall and winter, when melatonin levels
are highest [29-31], and SAD, also termed "winter blues," is identified in patients by its
annual presentation in fall and winter [32].
Plasma concentrations — Plasma melatonin concentration reflects:

●The amount secreted by the pineal gland (and, conceivably, the other organs
described above)

●The influx of melatonin into tissues when its plasma concentrations are high and
efflux from them when plasma concentrations are low

●Its destruction in the liver

●Its secretion into such body fluids as urine and saliva

Although it has been claimed that certain foods contain melatonin (wine, tomatoes), there
is no evidence using specific assay techniques that food is a source of melatonin or that
food sources increase plasma melatonin concentrations.

Usually, the principal factor affecting plasma melatonin concentration is its rate of
secretion, which varies with the circadian rhythm and with age. Diet does not affect
melatonin concentrations. (See 'Circadian rhythm' above and 'Age' below.)

Age — Melatonin secretion by the human pineal varies markedly with age. Melatonin
secretion starts during the third or fourth months of life, coincident with the consolidation of
sleeping at nighttime [33]. It then increases rapidly, causing nocturnal melatonin
concentrations to peak at ages one to three years, then declines slightly to a plateau that
persists throughout early adulthood (figure 2).

Nocturnal melatonin secretion then starts a marked continuing decline in most people, with
peak nocturnal concentrations in 70 year olds being only a quarter or less of what they are
in young adults (figure 2) [3,34]. This decline may reflect the progressive, age-related
calcification of the pineal gland and its resulting loss of secretory tissue. Obviously, one
strategy in using supplemental melatonin is to administer it to older adults with age-
associated insomnia in doses just sufficient to compensate for this age-related decline.

Effects of drugs or light — Nocturnal melatonin concentrations can also be affected by

drugs that interfere with the transmission of neurotransmitter signals to pineal cells
(like propranolol, a beta-blocking agent [35]) or those that inhibit melatonin's metabolism
(like 8-methoxypsoralen [36]) and by a few drugs that lack clear links to melatonin's
synthesis or metabolism (eg, caffeine [37], ethanol [38,39]).

Nocturnal melatonin secretion is also suppressed by a relatively dim 100 to 200 lux when
pupils are dilated [22,40,41]. The most potent wavelength for suppressing melatonin
secretion appears to be 446 to 477 nm, which differs from the peak absorbances of the
photopigments for vision [42].

Prolonged use of portable light-emitting devices (laptops, tablets, smartphones) before

bedtime can have a negative impact on melatonin secretion, circadian rhythms, and sleep.
One study compared the effects of reading an electronic book illuminated by a light-
emitting device (LE-ebook) versus a printed book (by reflected light) for four hours prior to
bedtime for five consecutive nights [43]. Subjects in the LE-ebook group had suppressed
melatonin concentrations in the early part of the night, a delayed endogenous circadian
melatonin phase, felt less sleepy before bed, took longer to fall asleep, and reported
feeling sleepier the following morning. These observations suggest that evening use of
light-emitting devices may contribute to phase delays in the circadian clock and difficulty
initiating sleep.

Patients with nocturnal hypertension — While sleeping at night, the blood pressure

normally falls by approximately 15 percent from daytime values. Patients in whom this
reduction does not occur are considered to have nocturnal hypertension, which has been
associated with an excess risk of cardiovascular disease. (See "Ambulatory and home
blood pressure monitoring and white coat hypertension in adults", section on 'Nocturnal
blood pressure and nondippers'.)

Two observations suggest that melatonin plays a role in nocturnal blood pressure
regulation:

●The normal nighttime surge in serum melatonin concentration may be blunted in

patients with nocturnal hypertension [44].

●Melatonin administration appears to lower blood pressure, particularly at night [45-

48].

Although exogenous melatonin may have a modest effect on nocturnal blood pressure, we
do not currently recommend its use for this indication, since there are no data showing
improved outcomes.

MELATONIN PREPARATIONS

Regulatory issues — Melatonin products are regulated differently in many countries [49]:

●In the United States, melatonin falls under the US Food and Drug Administration
(FDA)'s Dietary Health and Education Act as a "dietary supplement." It can be
purchased in any dose without a prescription.

●In the European Union, melatonin has been evaluated by an official regulatory
agency, the European Food Safety Authority (EFSA), for use in reducing sleep
latency, the time it takes for normal sleepers or people with insomnia to fall asleep (at
bedtime or after a nocturnal awakening) [50]. Based on the evidence provided in all
three of the statistically valid published meta-analyses [51-53], the agency concluded
that there exists "a cause and effect relationship between the consumption of
melatonin and a reduction of sleep onset latency" and that "in order to obtain the
claimed effect, 1 mg of melatonin should be consumed close to bedtime" [50].
 ●In Canada, melatonin is included in the Natural Health Products Directorate of
Health Canada and is available for sale, once preparations meet the licensing,
manufacturing, labeling, and safety standards.

●In Australia, melatonin is an unregistered product under the Therapeutic Goods

Administration. With a prescription, it can be imported for use under the Personal
Import Scheme.

Of note is that in situations where the sale of melatonin is not regulated, very high doses
can be sold, and preparations may contain additives that have their own pharmacologic
actions and potential side effects. Occasional claims to the contrary notwithstanding,
apparently all of the melatonin sold in the United States is of synthetic origin.

Over the counter

Dosing — As noted above, in the United States, melatonin is considered a "dietary

supplement" and can therefore be purchased in any dose without a prescription.
Exogenous melatonin administration appears to have two effects like those occurring
physiologically with nocturnal melatonin secretion: the promotion of sleep onset and
maintenance [51-71] and the phase shifting of circadian rhythms, including the rhythm in
melatonin itself [25]. Both have been shown to be produced by physiologic doses (ie, 0.1
to 0.3 mg for sleep and 0.3 to 0.5 mg for phase shifting, doses which raise daytime plasma
melatonin levels into the normal nocturnal range observed in young adults). We therefore
suggest the use of lower, more physiologic doses of melatonin, particularly in older adults
(figure 3) [72]. When preparations providing 0.3 to 0.5 mg are unavailable, the user can
purchase 1.0 mg pills and cut them in half.

Although melatonin is relatively nontoxic, some marketed doses (1 to 10 mg) can elevate
plasma concentrations to 3 to 60 times their normal peak values (figure 3) [54].
Supraphysiologic concentrations of melatonin produce numerous biological effects,
including daytime sleepiness, impaired mental and physical performance [73], hypothermia
[26], and hyperprolactinemia [74]. These effects are not observed with physiologic
concentrations of melatonin.

Bioavailability — There is considerable person-to-person variability in the bioavailability

of melatonin. In one study using 0.5 mg oral doses, peak plasma melatonin concentrations
among subjects varied over a greater than 10-fold range [75]. Melatonin's bioavailability
was relatively poor (10 to 56 percent), which the authors attributed to person-to-person
differences in first-pass hepatic extraction. Perhaps reflecting such differences in hepatic
function, older adult subjects in another study given a 0.3 mg oral dose of melatonin were
found to exhibit considerably greater increments in plasma melatonin concentrations, with
correspondingly greater variability, than young adults receiving that dose [76].

These findings all suggest that, while a 0.3 mg dose given to young subjects during the
daytime or to older adult insomniacs at night can, on average, produce normal nocturnal
plasma melatonin concentrations, some individuals may need slightly more or significantly
less melatonin to attain this effect on sleep.

Prolonged-release formulation — A prolonged-release (PR) prescription preparation of

melatonin (melatonin PR 2 mg) is available in some countries but not the United States. In
clinical trials in patients ages ≥55 years with primary insomnia, this preparation was
associated with improvements in sleep quality and latency, morning alertness, and health-
related quality of life [77,78].

Melatonin agonists — A synthetic melatonin agonist, ramelteon, thought to activate MT1

and MT2 melatonin receptors selectively, is available in the United States for the treatment
of chronic insomnia but not in the European Union, where it was denied approval. No data
are available that directly compare the efficacies and toxicities of this compound with those
of the much lower recommended dose (0.3 mg) of melatonin. The clinical use of melatonin
agonists for the treatment of insomnia is discussed separately. (See "Treatment of
insomnia in adults", section on 'Melatonin agonists'.)

Tasimelteon is a second melatonin agonist that has been used for the treatment of
insomnia and circadian rhythm sleep disorders, including non-24-hour sleep-wake disorder
[6].

Adverse effects — Despite the fact that melatonin is an unregulated drug in many

countries and is often used in excessive doses, there does not appear to be a major
pattern of side effects. One report described a search for reports of adverse effects with
melatonin over 35 years [79]. Of the nine studies reporting adverse effects, pharmacologic
doses were used (1 to 36 mg), and the number of patients was not included. However,
headache, confusion, and fragmented sleep were among the side effects reported.
Dizziness, somnolence, nausea, and headache have been reported with the melatonin
agonist ramelteon. (See 'Melatonin agonists' above.)

CLINICAL USES — The clinical uses of melatonin include treatment of age-associated

insomnia, jet lag, and shift work. These, as well as other potential uses of melatonin, are
reviewed separately. (See "Treatment of insomnia in adults", section on 'Melatonin
agonists' and "Jet lag" and "Complementary and alternative therapies for cancer", section
on 'Melatonin'.)

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SUMMARY AND RECOMMENDATIONS

●Melatonin production in humans has a pronounced circadian rhythm; nocturnal

plasma melatonin concentrations are at least 10-fold higher than daytime
concentrations. (See 'Synthesis and metabolism' above.)

●The nocturnal rise in melatonin secretion plays an important role in the initiation and
maintenance of sleep. The normal day/night melatonin rhythm regulates the timing of
other 24-hour rhythms. (See 'Melatonin physiology' above.)

●Nocturnal melatonin plasma concentrations decline with age; many older adult
individuals develop age-associated insomnia (eg, waking up during the night,
diminished sleep efficiency). Physiologic doses of melatonin may be beneficial for
these individuals. (See 'Age' above.)

●Exposure to light suppresses the normal nocturnal rise in plasma melatonin

concentrations. (See 'Effects of drugs or light' above.)

●Melatonin is available in some countries, including the United States, as an over-

the-counter preparation. We suggest the use of low, physiologic doses (0.1 to 0.5 mg)
for insomnia or jet lag (Grade 2B). High-dose preparations raise plasma melatonin
concentrations to a supraphysiologic level and alter normal day/night melatonin
rhythms. (See 'Dosing' above.)

●Melatonin agonists are also now available for the management of insomnia and
circadian rhythm sleep disorders. (See 'Melatonin agonists' above.)

●Recommendations for melatonin use for insomnia and jet lag are found separately.
(See "Treatment of insomnia in adults", section on 'Melatonin agonists' and "Jet lag".)