Melatonina

HYPOTHESIS AND THEORY
published: 16 July 2019

doi: 10.3389/fendo.2019.00391
Melatonin: Countering Chaotic Time

Cues
Josephine Arendt*
Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
Last year melatonin was 60 years old, or at least its discovery was 60 years ago. The
molecule itself may well be almost as old as life itself. So it is time to take yet another
perspective on our understanding of its functions, effects and clinical uses. This is not
a formal review—there is already a multitude of systematic reviews, narrative reviews,
meta-analyses and even reviews of reviews. In view of the extraordinary variety of effects
attributed to melatonin in the last 25 years, it is more of an attempt to sort out some areas
where a consensus opinion exists, and where placebo controlled, randomized, clinical
trials have confirmed early observations on therapeutic uses. The current upsurge of
concern about the multiple health problems associated with disturbed circadian rhythms
has generated interest in related therapeutic interventions, of which melatonin is one.
The present text will consider the physiological role of endogenous melatonin, and the
mostly pharmacological effects of exogenous treatment, on the assumption that normal
circulating concentrations represent endogenous pineal production. It will concentrate
mainly on the most researched, and accepted area of therapeutic use and potential use
Edited by: of melatonin—its undoubted ability to realign circadian rhythms and sleep—since this is
James M. Olcese,
Florida State University, United States
the author’s bias. It will touch briefly upon some other systems with prominent rhythmic
Reviewed by:
attributes including certain cancers, the cardiovascular system, the entero-insular axis
Krystyna Skwarlo-Sonta, and metabolism together with the use of melatonin to assess circadian status. Many of
University of Warsaw, Poland the ills of the developed world relate to deranged rhythms—and everything is rhythmic
Hana Zemkova,
Institute of unless proved otherwise.
Physiology (ASCR), Czechia
Keywords: melatonin, circadian, seasonal, health, sleep, light, desynchrony
*Correspondence:
Josephine Arendt
arendtjo@gmail.com
BACKGROUND
Specialty section: The essential physiological role of the pineal hormone melatonin is to provide information on
This article was submitted to
photoperiod (day length) for the organization of seasonal physiology (1). It does not appear to
Cellular Endocrinology,
have an essential function in the circadian system but has clear modulatory effects. These functions
a section of the journal
Frontiers in Endocrinology depend primarily upon G-protein linked membrane receptors MT1 and MT2 (2, 3). It may also
be concerned with periodicities other than circadian and seasonal but as yet this is an emerging
Received: 15 March 2019
field (4–6). Its profile of secretion reflects the length of the scotoperiod (night). Even humans with
Accepted: 30 May 2019
Published: 16 July 2019 ubiquitious artificial light, can show this change in suitable conditions (7). It was originally called
a photo-neuroendocrine transducer molecule and subsequently, informally, a darkness hormone.
Citation:
Arendt J (2019) Melatonin: Countering
Most if not all vertebrate photoperiodic species depend on this signal to time seasonal breeding (1),
Chaotic Time Cues. but see (8).
Front. Endocrinol. 10:391. Melatonin is synthesized from tryptophan via 5-hydroxytryptophan and 5-hydroxytryptamine
doi: 10.3389/fendo.2019.00391 (serotonin). Then N-acetylation of serotonin by N-acetyl transferase (arylalkylamine N-acetyl
Frontiers in Endocrinology | www.frontiersin.org 1 July 2019 | Volume 10 | Article 391

Arendt Melatonin and Rhythms
transferase, AA-NAT) to N-acetylserotonin (NAT) and O- be found. This is curious in view of reported non-pineal
methylation by acetylserotonin O-methyltransferase (ASMT), melatonin synthesis, sometimes in very large amounts, and
[previously known as hydroxyindole-O-methyltransferase the highly lipophilic/amphipathic nature of the molecule which
(HIOMT)] to melatonin (N-acetyl-5-methoxytryptamine). penetrates all compartments rapidly (28, 29). Superior cervical
A major increase (7–150 fold) in the activity of AA-NAT at ganglionectomy (denervation of the pineal) also abolishes the
night is usually rate limiting in melatonin production. The rhythm (30). Retinal melatonin is of major interest [e.g., (31, 32)]
rhythm of production is endogenous, being generated by clock but beyond the scope of this text.
genes in the suprachiasmatic nuclei (SCN), the major central Non-pineal melatonin has been considered to act locally (29).
rhythm-generating system or “clock” in mammals (9, 10). The Local effects have been invoked with regard to metabolism,
rhythm, as for the circadian system in general, is synchronized immune function, gut function, inflammation, membrane
to 24 h primarily by the light-dark cycle acting via the retina and fluidity, mitochondrial function, apoptosis (both stimulation and
the retinohypothalamic projection to the SCN (9). inhibition), free radical scavenging, direct anti-oxidant activity,
Light of suitable intensity and spectral composition can influence on anti-oxidant enzymes, redox status, radioprotection,
phase shift and entrain circadian rhythms. Light also suppresses and others (33). Protective therapeutic effects are reported with
melatonin production at night (11). The amount of light required regard to many various systems but notably neural, oncological
for suppression varies from species to species, with time of night, and cardiovascular. Some of these effects are thought not to
with spectral composition and with previous light exposure. In require receptor signaling, although melatonin receptors are now
humans,∼2,000 lux full spectrum light (domestic light is around found widely distributed.
50 to 500 lux) is required for complete suppression at night. Very recently it has been demonstrated that in the mouse
However, much lower intensities will partially suppress and shift brain melatonin is exclusively synthesized in the mitochondrial
the rhythm (12, 13). A non-image forming photoreceptor system matrix. It is released to the cytoplasm, thereby activating a
of light sensitive retinal ganglion cells is implicated in these mitochondrial MT1 signal-transduction pathway which inhibits
effects, with a pivotal role of the photopigment melanopsin, stress-mediated cytochrome c release and caspase activation:
although in normal circumstances input from rods and cones these are preludes to cell death and inflammation. This is a
is also used (14, 15). In humans maximum suppression and new mechanism whereby locally synthesized melatonin protects
phase shifting for equal numbers of photons is given by blue against neurodegeneration. It is referred to as automitocrine
light (460–480 nm). signaling (34). Another recent addition to our understanding
In humans melatonin is metabolized, ∼70% to is the observation that a gut bacterium, Enterobacter aerogenes,
6-sulphatoxy melatonin (aMT6s), primarily within the liver, expresses an endogenous circadian clock that is responsive to
by 6-hydroxylation, followed by sulfate conjugation (with signals from the host’s circadian system, the hormone melatonin,
some species variaions). A number of minor metabolites and changes in temperature. This establishes a prospective link
are also formed, including the glucuronide conjugate. between melatonin as a peripheral circadian zeitgeber (time cue),
N1-acetyl-N2-formyl-5-methoxykynuramine and N1-acetyl- and the gut (35).
5-methoxy-kynuramine, were initially reported as brain Peripherally administered exogenous melatonin (sometimes
metabolites (1, 16) but have proved difficult to detect in plasma in very high pharmacological doses) can presumably access the
or urine except after administration of exogenous melatonin various structures involved in local effects even though the non-
(17). Exogenous oral fast release or intravenous melatonin has pineal endogenously synthesized melatonin does not apparently
a short metabolic half-life (20 to 60 min, depending on author get out. The gut is reported to contain several 100 fold more
and species), with a large hepatic first pass effect and a biphasic melatonin than the pineal gland, but does not contribute to the
elimination pattern (18). Slow release/prolonged release/surge circulating rhythm of melatonin. It is said to sustain the (very
sustained preparations are of course designed to extend the low) day time plasma levels (27). Although melatonin is present
time of high circulating melatonin [e.g., (19)]. It has low in some foodstuffs (36), in the authors experience it is hard to
bioavailability in general although transmucosal administration show an increase in plasma melatonin after a normal meal. This
increases bioavailability (20). A critical feature of exogenous area has been extensively reviewed by others and will also feature
melatonin with regard to its clinical uses is its very low toxicity in this volume.
and lack of addictive properties (21, 22). In principle the established role of melatonin in rhythmic
function is not necessarily incompatible with the use of high
Source of Endogenous Melatonin doses for ‘protective’ effects. Unless desensitization of the
The pineal gland is the source of the vast majority of circulating melatonin membrane receptors occurs as a result of continuous
melatonin in mammals [e.g., (23–25)]. Its synthesis and presence high circulating concentrations (37, 38) and compromises
has been described in a large number of other structures, functions responsive to low levels of melatonin such as sleep and
but they do not appear to contribute significantly to blood circadian phase.
levels in, for example, humans and rodents, except following
specific manipulations of synthesis such as provision of excess Melatonin Physiology
precursor (26, 27). Pinealectomy leads to loss of the rhythm Seasonal Rhythms
and usually undetectable amounts of circulating melatonin in A truly distinct physiological role for melatonin was initially
mammals although with high sensitivity assays traces may indicated by the fact that pinealectomy or ganglionectomy (which

abolished the rhythm of circulating melatonin) abolished the

ability of photoperiodic mammals to time seasonal physiology
according to the day length (with very rare exceptions) (39,
40). Melatonin secretion, long in long nights, short in short
nights provided the information, via photoneurotransduction, to
body physiology for the organization and timing of seasonally
rhythmic functions such as reproduction and coat growth.
Replacement of the endogenous melatonin signal by long or
short profiles of exogenous melatonin at the same plasma
concentration as the endogenous signal was equipotent with day
length for control of seasonal timing. The downstream events
have now been investigated in considerable detail [e.g., (41, 42)]
and melatonin treatment to shift the timing of seasonal breeding
in domestic species such as sheep, mink, and goats to maximize
profit is now commercialized (43).
FIGURE 1 | Desynchronized rhythms lead to lowered output of a
Humans have residual seasonality as evidenced by numerous
multi-oscillatory system. Simplified diagram of how melatonin might act
physiological variables. and particularly by the existence of endogenously to maintain coupling and synchronization of its target outputs
seasonal affective disorder and its treatment by suitable light and how desynchronized rhythms may lead to lowered production of
exposure (and on occasion by melatonin as a chronobiotic) (44, melatonin itself.
45). So for the therapeutic use of melatonin in humans it should
never be forgotten that this hormone has profound effects on
animal seasonal functions. The evidence for anti-gonadotrophic
maintaining the status quo (Figure 1). It could also be considered
effects of high amounts in humans is quite substantial (46–
with respect to any effects on other periodicities.
49), and an influence on pubertal development is possible but
Since melatonin is constantly referred to as the sleep hormone
not demonstrated. For example photoperiod, via melatonin
in the media, it is worth stating that it is not essential to sleep
profile, times puberty in sheep (50), melatonin inhibits LHRH
although we sleep better when in phase with rhythmic circulating
stimulation of LH in the neonatal rat pituitary (46, 51), and in a
melatonin and the rest of the circadian system (59). It is, to say
case report of successful treatment of delayed puberty in a young
the least, difficult to study pinealectomized humans before and
woman, her production of melatonin declined dramatically (52).
after pinealectomy. However, this has been done prospectively
A serious attempt to develop it as a contraceptive was made some
with pre and post-operative polysomnography, the so-called gold
25 years ago (53).
standard for sleep measures. No effects of the missing pineal on
sleep were seen (60). This was a small but careful and exceedingly
Circadian Rhythms
rare study, it merits serious attention. The final comment on
By contrast it is quite difficult to show major effects of
melatonin as a “sleep hormone” is that it most certainly is
pinealectomy on circadian rhythms and even on sleep. Initial
not so in nocturnal rodents—it is a darkness hormone not a
investigations on pinealectomized rats showed little effect on
sleep hormone.
activity rest cycles (54). These have been reinforced by a very
recent study, again indicating that removal of the pineal has no
effect on rodent sleep (55). However, if animals were subjected COUNTERING CHANGES IN TIME CUES
to an abrupt phase shift (as in jet lag), they adapted faster to
the new schedule without a pineal gland (56, 57). This suggested The accumulated knowledge on the deleterious effects of abruptly
that the pineal, and by inference melatonin, acted as a brake on changing time cues in for example shift work and jet lag [e.g.,
abrupt changes of phase, these being undesirable in a natural (61–67)] lead to the suggestion that one function of endogenous
environment. This possibility is reinforced by the fact that melatonin is to protect against abrupt short term changes of
suppression of melatonin production by the beta blocker atenolol phase by maintenance of the circadian status quo.
leads to faster adaptation to light-induced phase-shifts in humans
(58). Ironically therefore whilst exogenous melatonin is used to Effects on Circadian Rhythms
hasten adaptation, it is possible that a function of endogenous Early work indicated that timed exogenous melatonin treatment,
production is to do the opposite. pharmacological in rats, close to, but still usually supra-
Further support for a modulatory role in the circadian physiological in humans, could entrain activity rest cycles in
system is evident from the fact that in constant bright light rats, shift circadian phase, assessed using endogenous melatonin
pinealectomized animals, in comparison to sham operated as a marker rhythm, and synchronize free-running rhythms in
animals, show more disrupted rhythms in wheel running, general humans. For references see (68).The most obvious manifestation
activity, body temperature, and heart rate (54). Several authors in humans is the timing of the sleep-wake cycle. Phase shifts
have suggested that a function of the pineal and melatonin is and entrainment after timed low dose melatonin treatment were
to act as a coupling agent with regard to rhythmic systems evident initially in the rhythm of sleep and of melatonin itself
(“circadian glue”). This would fit with the suggested role of and then in the timing of all the circadian rhythms observed

FIGURE 2 | Melatonin phase shifts all measured rhythms in humans. 1.5 mg surge sustained release at 1600 h daily for 8 days, recumbent, <5 lux, 1600–0800 h,
evaluated in constant routine. Data derived and redrawn from Rajaratnam et al. (19), Middleton et al. (69), and Vandewalle et al. (71). CR1, 1st constant routine; CR2,
2nd constant routine; TSH, thyroid-stimulating hormone; HRV-SDNN, heart rate variability- standard deviation of the interbeat interval of normal sinus beats.
(19, 69, 70) (Figure 2). Both phase advances and phase delays can shown to act directly at the level of the suprachiasmatic
be induced dependent on the time of treatment (72) which can nucleus (79) to modify its rhythmic activity, amplitude and
be expressed as a Phase Response Curve or PRC. The melatonin phase, via G-protein linked membrane receptors now extensively
PRC is approximately the opposite of that to light pulses and characterized as MT1 and MT2 (MTR1A/Mel1a, Mel1b/MTR1B)
for maximum effect the two treatments can be combined with (2, 3, 79–81). MT1 was associated with suppression of SCN
careful timing (73, 74). If the period of melatonin secretion is electrical activity and MT2 with phase shifts, with some
considered to be “biological night” then low dose (0.5–5 mg) redundancy and cooperation between these subtypes. However, a
treatment in the late afternoon will advance circadian phase and recent report describes a lack of overlap in mouse brain structures
sleep (75), whereas treatment in the early ’biological morning’ showing one or other of these receptors. The authors state that
will cause phase delays. Thus, it is important to know or predict “the expression and distribution of MT2 receptors are much
circadian phase in order to time treatment correctly. The clearest more widespread than previously thought, and there is virtually
demonstration of entrainment could be seen in free-running no correspondence between MT1 and MT2 cellular expression”
blind subjects (76, 77) and in sighted subjects kept in a time free (82). A third receptor MT1c is not found in mammals but a
environment (78). related G-protein coupled receptor GPR50 has 45% identity in
Melatonin clearly has both a direct sleep inducing effect amino-acid sequence with MT1 and MT2 and is thought to be
coupled with a circadian phase shift (70). Importantly it was the ortholog of Mel1c in mammals (83). It may have a role in

glucocorticoid receptor signaling with implications for peripheral night (LAN), e.g., in shift workers, although not all studies
control of circadian rhythms (84). Melatonin may also directly concur. This is thought to be a causal factor in the increased
affect clock genes in the SCN [e.g., (85)]. risk of, for example, breast cancer by some authors and will
Others will report in this volume in detail concerning be discussed later (97, 104, 105). However, the entire circadian
receptors and downstream signaling events. It is just noted here system is disturbed in these circumstances, not just melatonin.
that a recently reported signaling by melatonin receptors in the Out of phase rhythms with or without suppressed melatonin
SCN appears to require G-protein-coupled inwardly rectifying may well be involved in the deleterious effects of shift work
potassium (GIRK) channels: a widely distributed physiological (63, 104, 106, 107). As yet there is no definitive linkage between
neural communication system (86). The authors propose this as a particular degree of melatonin suppression and any deleterious
some of the explanation for the variety of reported effects of this effects. Some people appear to lead perfectly normal lives with
hormone in mood and other neurological disorders. very low or even undetectable melatonin. But there is no
In addition to effects on the central rhythm generating system, long term information on disease risk in these low melatonin
melatonin also influences peripheral oscillators for example secretors. Certainly desynchrony will be one cause of disordered
in the pars tuberalis, the cardiovascular system, the skin, the sleep, since we sleep better when in an appropriate phase
adrenal (87–90), various primate fetal tissues (91) and possibly relationship with the melatonin rhythm. But when the entire
the expression of sirtuin 1 (a histone deacetylase) which is circadian system is dysregulated numerous other effects and
thought to enhance circadian amplitudes and may prolong potential causes can be invoked.
survival (92). Melatonin clearly has the potential to influence all
rhythmic function by virtue of its universal distribution, however SLEEP
very recent data indicates a major role for glucocorticoids in
entraining/synchronizing peripheral clocks (84). It is clear that Melatonin itself and its agonists have been developed primarily
melatonin can manipulate the circadian system. It may well be to treat sleep disturbance (108) but with currently expanding
that a combination of melatonin, light and glucocorticoids could possibilities for clinical therapeutics. Its immediate effects
provide the most efficient realignment of both centrally generated on sleep were initially investigated long ago, first by Aaron
and peripheral clocks. Lerner who identified melatonin. Its immediate effects on
sleepiness/sleep are accompanied by a dose-dependent lowering
Circadian Desynchrony of core body temperature in near physiological doses (75, 109),
In a natural environment, changes in circadian rhythms occur and this has been invoked as part of the mechanism of action.
due to seasonal influences, notably changes in photoperiod This phenomenon has been linked to sleep induction in a
leading to shorter or longer melatonin secretion profiles (93). series of careful trials (110, 111). Melatonin has clear, time-
In humans a seasonal effect is more commonly seen as delayed dependent direct (soporific) and phase shifting effects on human
rhythms in winter (94) especially in polar regions with no sleep in near physiological/low pharmacological doses (70, 112)
sunlight for long periods of the year (95). A duration change (see Figure 3). It’s rhythm is closely associated with the timing
in melatonin profiles is rarely seen in humans in temperate of sleep and sleep propensity, and inversely with that of core
zones but can be elicited with artificial light/darkness (7). one temperature (113).
explanation is that the onset of secretion is delayed in winter, When treatment with melatonin is related to the so-called
but the subject is required to get up to work in the morning. circadian rhythm sleep disorders (CRSDs) it is a logical
Thus, the full expression of the profile is curtailed by artificial development exploiting both the direct and phase shifting
light suppression both in the evening and in the morning. In the properties (68). CRSDs include delayed sleep phase, advanced
urban environment of today artificial light is everywhere leading sleep phase, free-running sleep, and the sleep detriments of jet lag
to changes in sleep. It is interesting to compare sleep in similar and shift work. Although the endogenous central pacemaker has
rural communities with and without artificial light. Artificial light a major role in timing sleep, humans exercise choice according
clearly impacts the timing and duration of sleep (96). to desire or necessity, as to when they try to sleep. This means
The abrupt changes in the light dark cycle and consequent that sleep rhythms are not a pure manifestation of the circadian
desynchrony experienced by shift workers and time zone system. True circadian phase shift and/or entrainment requires
travelers are now known to be associated with increased risk of a demonstration that a marker rhythm such as melatonin,
accidents, sleep deficits, lowered alertness and performance, gut cortisol or core temperature is entrained. If treatment is timed
problems, lowered fertility, perhaps psychiatric problems, and to maximize the phase shifting and direct sleep inducing effects
increased risk of major disease such as cancer, diabetes, metabolic of melatonin it can be very successful, particularly with respect to
syndrome and heart disease (67, 97). mistimed sleep.
The central pacemaker of the SCN adapts slowly to these
abrupt changes and peripheral oscillators adapt at different rates, Delayed Sleep Phase Syndrome (DSPS)
such that the body is in a state of both internal and external Typically a subject reports inability to sleep before 2 to 6 a.m.
desynchrony (63, 65, 98–103). Melatonin (and other rhythms When not required to maintain their schedule—i.e., weekends,
being driven by the SCN) is slow to adapt, endeavoring to holidays, etc.—they sleep without difficulty, and will awaken
maintain the circadian status quo. It is out of phase during spontaneously after a sleep period of normal length. Severe cases
adaptation and may be partly suppressed by sufficient light at of DSPS are relatively common in adults (114).The incidence

FIGURE 3 | Exogenous melatonin has both direct and indirect effects on sleep. 1.5 mg surge sustained release at 1600 h daily for 8 days, recumbent, < 5 lux,
1600–0800 h, evaluated in constant routine. Mean sleep efficiency levels (% per hour: n = 8). The direct, sleep-facilitating effect of melatonin (left) is illustrated by a
comparison between sleep efficiency profiles on the last day of melatonin treatment and sleep efficiency on the following washout day. Increased sleep efficiency
(direct effect) is observed for the first 2–3 h during melatonin treatment. The circadian effect of melatonin on sleep (right) is shown by comparing the sleep efficiency
on the washout day (the day after melatonin or placebo). On the washout day, placebo was administered to all participants. A shift in the distribution of sleep can be
observed after melatonin treatment, with the major bout of sleep occurring earlier in the sleep opportunity. On the corresponding day after placebo, the major bout of
sleep occurred later in the sleep opportunity, although an initial rise in sleep efficiency is noted at around the commencement of the sleep opportunity. With Permission
from Rajaratnam et al. (70). *Significant difference between CR1 and CR2.
of clinically important DSPS in students/adolescents may well help day time sleep during real life night shift and night time sleep
be as high as 7%. An early meta-analysis (115) concluded that after return to day work, although anecdotally melatonin is used.
there was no evidence for efficiency of melatonin in treating An early real life study reported greater day sleep duration after
secondary sleep disorders and sleep disorders associated with night shift when subjects left work early (6 am, before conflicting
sleep restriction. Sadly they did not specifically select publications bright light) and took melatonin (5 mg) before day sleep (121).
which gave treatment at the correct time but they did conclude A later real life timed study addressed both day and night time
that DSPS was an area where melatonin could be useful. The sleep and was successful in its carefully timed use of melatonin
British Medical Journal published some “rapid responses” to (3 mg) 1 h before bedtime (122). An increase in sleep duration
this publication which were highly critical of the summary of 15–20 min was obtained and a reduction in sleepiness at work
and conclusions. (subjective measures). In a series of simulation shift work studies
Some very careful work has been carried out in adults and Eastman and colleagues have clearly shown that timed melatonin
children with DSPS, measuring circadian phase and timing (1.8 mg sustained release) and bright light exposure will partially
treatment to 5 h before melatonin onset for maximum phase shift phase, such that day sleep is improved when working nights
advance. Sleep timing was advanced, criteria of general health and subjects rapidly readapt on return to day work (73, 123, 124).
were improved, there were no later effects on reproductive health Data from real life shift work studies were positive in one review
and in some cases treatment could eventually be withdrawn. A (125) and the American Academy of Sleep Medicine approves its
meta-analysis (116) describes the quality studies in both children use in shift work sleep disorder (117).
and adults published up to 2010 and concludes that melatonin
treatment induced an earlier phase (melatonin onset, 1.18 h) Jet Lag
reduced sleep latency of 23 min and earlier clock onset of sleep There are now so many reviews of the use of melatonin in jet
by 0.67 h. Timed melatonin treatment was recommended for lag, its dependence on timing and concomitant light exposure
DSPS by the American Academy of Sleep Medicine (117). More that it is pointless to write another here, see for example (98).
recent well-controlled trials have strongly supported the use of In summary, successful studies used timed melatonin correctly,
timed melatonin with or without timed light exposure for DSPS unsuccessful studies [e.g., (126)] did not. The latter in particular
(118, 119). However, by no means all diagnosed DSPS patients used a cohort who had flown from Norway to New York, stayed
have a circadian delay as well as a sleep delay (120). 4 days and then were studied on the flight back to Norway.
For Advanced sleep phase syndrome (ASPS), there is little One can predict that their study population was unadapted to
information on melatonin treatment. New York time, phase shifted from Norwegian time, internally
and externally desynchronized, and individually different since
Shift Work individual response to abrupt change of time cues is variable.
Another common situation with temporarily displaced sleep is Their lack of useful effect is not surprising since this situation was
that of shift work. There is sparse evidence that melatonin can not taken into account.

In 2006 a Cochrane Database review concluded that melatonin cues, primarily the light dark cycle. Many blind people with
was useful for jet lag (127). It is updated regularly. Timed no conscious or unconscious light perception cannot properly
melatonin treatment is recommended for jetlag by the American synchronize to the 24 h day (133–136). In expressing their own
Academy of Sleep Medicine (128). Advice on how to time periodicity they drift away from normal clock time such that
melatonin and light exposure can be found in reference (98) intermittently they will be in “night” phase during the day (e.g.,
and elsewhere. secretion of melatonin, low alertness and performance) and day
phase during the night (low melatonin, poor sleep). It has been
Sleep in the Elderly described as a lifetime’s intermittent jet lag.
Sleep problems in the elderly may be due to many factors one Melatonin (usually 0.5–5 mg daily, lower doses than 3 mg are
of which may be disturbed circadian rhythms. Prolonged release often better) is able to synchronize this non-24 h sleep wake cycle
melatonin “circadin” is registered for use in sleep disorder of to 24 h in the vast majority of patients (76, 137) (Figure 4). Until
the over 55 s. From the European Medicines Agency Website: a registered melatonin preparation became available in the UK
“Circadin was more effective than placebo at improving quality (circadin) (138), patients had to obtain melatonin on a named
of sleep and the patients’ ability to function normally on the patient basis. It is prescribed by Moorfields Eye Hospital (premier
following day. When the results of all three studies were looked eye hospital in the UK). Unfortunately the completely blind do
at together, 32% of the patients taking Circadin (86 out of 265) not often appear before a specialist, the condition is not correctly
reported a significant improvement in symptoms after 3 weeks, diagnosed, and is often treated with straight hypnotics (which do
compared with 19% of those taking placebo (51 out of 272).” The not work). A survey in New Zealand reported very little use of
CHMP decided that, although Circadin has only been shown to melatonin to correct this cyclic sleep disorder (139).
have a small effect in a relatively small number of patients, its In 1986 a blind man rang me up, said he had non 24 h sleep
benefits are greater than its risks,” https://www.ema.europa.eu/ wake disorder, and could he have some melatonin? He had
en/medicines/human/EPAR/circadin. seen my jet lag studies and worked it out for himself. After
Use of melatonin in the very elderly, particularly suffering a very successful double blind placebo controlled cross over
from dementia, has been advocated but proved to have adverse study [5 mg melatonin, (134)] he took this dose, prescribed on
effects in some studies (129). a named patient basis by his GP, for the rest of his life. He died
8 years ago, of prostate cancer at 83 years old, after 24 years
Sleep in Children use, refusing to lower the dose. We checked his biochemistry
There has been considerable interest in the pediatric use and hematology after 10 years treatment and all was normal
of melatonin for sleep disorder, initially in children with for age. Since then quite a number of similar studies have
neurodevelopmental disorders, in spite of the possible adverse found the same synchronizing effect on sleep, and from the
effects on reproductive function. A large multi-center RCT has year 2000 synchronization of the underlying circadian pacemaker
been conducted in the UK- the MENDS study (130). Escalating was shown in most, but not all patients. The tendency is to
doses from 0.5 to 12 mg 45 min before bedtime were used. The start with very low doses and if necessary increase (or in one
primary outcome was sleep duration by diaries, and objective
measures (actigraphy) were also used. They were able to show
(130, 131) 23 min longer sleep and shortened sleep latency by
45 min. Evidently this success has inspired further treatment.
Pediatric use of melatonin for sleep problems has covered
autism, ADHD and intellectual disability (ID) (132) and now has
expanded hugely to more general use. According to a serious UK
newspaper- The Guardian- there are safety concerns: Despite the
fact it is not licensed for use by any other age group, (other than
over 55 s) 117,085 people under 18 were given melatonin “off
label”—the term used for when a drug is given for an unapproved
indication or in an unapproved age group—to aid sleep in the
2017–18 financial year. (https://www.theguardian.com/society/
2018/nov/02/rise-in-melatonin-use-to-help-children-sleep-
leads-to-safety-warning).
Non 24 h Sleep Wake Cycle (Irregular Sleep

Wake Cycle, Free-Running Sleep-Wake or
Non-24)
This condition is the least numerous of the CRSDs but the FIGURE 4 | Diagram of melatonin-induced entrainment by phase advance of
most interesting. It is the expression of an individual circadian a free-running sleep wake cycle and circadian phase, for example in a blind
clock periodicity. Each person has their own periodicity usually subject with no conscious or unconscious light perception. Treatment is best
initiated in a period of good sleep prior to desired sleep time in the “biological
slightly longer than 24 h (hence the tendency to delay over the
dusk” before onset of melatonin secretion.
weekend) which manifests itself in the absence of strong time

publication decrease) the dose until it is effective. We recommend show the protective effects of exogenous and endogenous
starting treatment about an hour before bedtime when in a ’good’ melatonin and the deleterious effects of extra light (153–156). The
sleep phase. Even without full circadian entrainment sleep can xenograft approach is being applied to other cancers.
be improved. Most epidemiology agrees that there is an increased risk of
developing various cancers as a function of long term night shift
Non-specific Insomnia work (97, 150). Melatonin has been used as adjuvant therapy in
As a treatment for non-specified insomnia melatonin also various cancers for nearly 20 years notably by Lissoni et al. in very
appears to be quite useful. Some 3,000,000 Americans used advanced cancer [e.g., (157)] with positive effects but not usually
melatonin last year according to the following website (https:// significant results. With all the suggestive background, several
nccih.nih.gov/research/statistics/NHIS/2012/natural-products/ clinical trials in different cancers using melatonin, usually as an
melatonin), presumably for jet lag or for “poor sleep.” In the case adjunct to conventional treatment, have now been conducted
of non-specific “poor sleep” this is likely related in many cases to (33)—but not enough. The results are quite positive in several
the fact that our circadian rhythms are frequently not in optimal domains- survival time, progression of the disease, reduced
phase in a “urban normal environment” (140) with insufficient toxicity of treatment and in general well-being. An important
time cues or zeitgebers to maintain optimum circadian phase. question is to what extent the effects are due to rhythm
In these circumstances most people will delay the circadian optimization and/or improved sleep?
system, particularly over the weekend if there is no requirement
to get up in the morning. In this way the social need for sleep METABOLISM
is in advance of the circadian optimum time and melatonin
secretion in particular, and sleep suffers. The discrepancy has A substantial early clinical literature exists concerning diurnal
been referred to as “social” jet lag (141). Popping a melatonin pill and ultradian rhythms in metabolic function [e.g., (158)]. With
in the evening has a good chance of advancing circadian phase to the application of constant routine technology it became possible
a more appropriate time and thus better sleep. to identify endogenously generated (i.e., circadian) rhythms
from those derived from the external environment, meal times
Melatonin and Cancer etc. (159–161). This has now been extended to metabolomics.
Animal experiments have shown clearly the increased risk of For example simultaneous evaluation of many metabolites in
cancer with abrupt phase shifts (97, 142, 143). In 2006 the World constant routine has shown that of 132 circulating metabolites
Health Organization in Lyon, France held a week-long meeting nearly half showed a 24 h rhythmicity (162). Following sleep
in which, on the basis largely of animal experiments, decided deprivation it was clear that many metabolites desynchronized
that shift work was a probable carcinogen (97, 144). A large amongst themselves (163, 164). With sequencing of the human
proportion of the population of developed countries (15–20%) genome, this approach has now devolved to the level of genes
works shifts and thus this is of major health interest. (67). Melatonin has been invoked as a supplementary treatment
An association of the pineal gland with anti-cancer activity has for avoidance or reversal of metabolic syndrome but without
a very long history (145). Early work suggested that the gland substantial evidence of efficacy [e.g., (165)].
contained oncostatic activity initially not specified as melatonin.
Important evidence of the association included for example that The Entero-Insular Axis and Diabetes
pinealectomy of rats led to much shorter survival times from The importance of rhythms to the entero-insular axis was also
DMBA-induced cancer and secondly that exogenous melatonin evident early on, with variations in glucose tolerance and insulin
could substantially increase survival times (146). In the 1970s sensitivity (166). The subject has been very recently reviewed
melatonin treatment (very large doses 80–300 mg pd) to young (161). The circadian, SCN-driven nature of these rhythms is now
women was proposed for avoidance (prophylactic) of breast well established alongside the “masking” effects of mealtimes,
cancer (48, 53), and development proceeded to clinical trials in meal content and other external inputs (167, 168). Triacylglycerol
combination with a progestagen. These trials were not successful. (TAG) has a particularly marked circadian rhythm in constant
But the subject continued of interest when light at night, thought routine (167). During both simulated and real shift work,
to suppress melatonin (at least partially) (147–149), was invoked standard meals taken at inappropriate times at night—biological
as the reason for an excess of breast cancer in nurses, working night when melatonin secretion is high-lead to evidence of
rotating long term night shifts (104, 144, 150), and subsequently insulin resistance/glucose intolerance and higher TAG, both risk
other shift workers. factors for heart disease (167, 169). This is therefore one possible
There is good reason to consider melatonin firstly as a mechanism underlying the epidemiological data showing higher
prophylactic, in the case of suppression by light during night risk of these major diseases.
work, secondly to hasten adaptation of the circadian system to Circadian re-adaptation in real shift workers resolves some
abrupt phase shift when this is desirable. Thirdly it has been metabolic risk factors (169) (and see Gibbs M, Hampton SH,
very extensively researched with regard to its anti-cancer activity Morgan L, Arendt J. Effect of shift schedule on offshore shift
in breast cancer and other neoplasms (151, 152). Some of the workers’ circadian rhythms and health, 2004. http://www.hse.
most convincing data linking physiological levels of melatonin gov.uk/research/rrhtm/rr318.htm). So there is good reason to
with anti-cancer growth concerns human breast cancer-mouse use the chronobiotic properties of melatonin (and timed light
xenograft studies. In a series of experiments Blask et al. could exposure) to manipulate circadian phase. It remains to be

determined to what extent central and peripheral oscillators and TSH (71). Evidently this corresponds to an effect on the
remain in synchrony/coupled in these circumstances. central circadian clock.
Melatonin clearly influences glucose concentrations- There is certainly some good evidence that melatonin
pinealectomy leads to increased glucose in nocturnal rats (170). can lower blood pressure at night in patients with essential
In MT1 and MT2 receptor knockout mice the SCN-driven hypertension and/or metabolic syndrome (186, 187). Possibly
glucose rhythm is abolished independently of peripheral the accompanying increased day night amplitude of systolic
oscillators in muscle, adipose tissue and liver (171). In and diastolic rhythms was equally important and indicative of
humans in one study, the decrease in glucose tolerance strengthened function of the SCN. The mechanism involved is
from morning to evening was mostly influenced by the not clear. The improved sleep reported in the subjects may well
endogenous circadian system compared to the sleep-wake have contributed to the result.
cycle. However, in apparent contrast to pinealectomy effects in Melatonin has probably had more exposure as a potential
animals, melatonin administered during day time just prior to a cardiovascular protective agent, with respect especially to
glucose tolerance test in healthy adults clearly impaired glucose myocardial ischemia/reperfusion injury. Numerous animal
tolerance both in the morning and the evening (172, 173), experiments suggest beneficial effects in a meta-analysis,
an effect that was dependent on a common gain-of-function with anti-oxidant effects, free-radical scavenging, anti-apoptosis
variant of the melatonin receptor gene MTNR1B152 (see and/or involvement of MT1 receptor suggested as mechanisms
below). Melatonin may also acutely decrease insulin secretion in (188). However, a later meta-analysis and experimentation using
cultured human islets (174). Thus, some controversy exists in the melatonin in a combination with minocycline and magnesium
literature especially when comparing results in nocturnal rodents sulfate did not show efficacy (189). Several clinical trials appear
with diurnal humans with both beneficial and detrimental to be ongoing.
effects of melatonin reported. It is intriguing to note that
the rare condition ’familial insulin resistance’ or Rabden-
Mendenhall syndrome is associated with pineal hyperplasia USE OF MELATONIN AS A CIRCADIAN
(175, 176).
In view of pre-existing associations of the pineal and
“MARKER” RHYTHM, PROVIDING
melatonin with metabolic function the discovery of related INFORMATION ON THE PHASE AND
MT1 and MT2 receptor variants aroused enormous interest. TIMING OF THE CIRCADIAN SYSTEM FOR
A common variant in MTNR1B—MTNR1B rs10830963 is BASIC RESEARCH, TIMED TREATMENTS
associated with increased risk of type 2 diabetes, increased
fasting plasma glucose levels and impaired early insulin secretion The rhythmic production of melatonin, normally high during the
(177, 178). Moreover, late dinner, associated with elevated dark phase in all species studied to date, is linked directly via
melatonin concentrations (as in night shift workers, above), neural connections to the activity of the central circadian clock
impaired glucose tolerance in “gain of function” MTNR1B risk or pacemaker in the SCN (9). It was possible to show that the
allele carriers but not in non-carriers. These data suggest that rate limiting synthetic enzyme pineal AA-NAT activity is closely
circulating melatonin is related to the development of Type 2 related to the plasma melatonin profile in rats (190), and that
Diabetes, in a deleterious sense. Of course sleep restriction is the plasma profile is closely related to that of saliva in humans
also associated with impaired glucose tolerance, increased risk (191). Moreover, the urinary excretion of 6-sulphatoxymelatonin
of metabolic syndrome and/or diabetes (179, 180). So that the (aMT6s) the major metabolite in rats and humans reflects
usefulness of melatonin to address sleep problems may well faithfully the profile of plasma melatonin in humans (192, 193).
increase risk of metabolic abnormalities. Some controversies Thus, the measurable melatonin/aMT6s profiles in plasma, saliva
have arisen and have been reviewed (181). The question is or urine provide a ‘window’ on the clock. The melatonin rhythm
not solved. has been extensively used to investigate the characteristics of
human circadian rhythms. It is considered to be the best circadian
marker rhythm, at least for the moment (Figure 5).
CARDIOVASCULAR SYSTEM The characteristics of melatonin secretion in normal healthy
volunteers have been studied for many years with increasing
Rhythmicity is a cardinal feature of the cardiovascular system, technological sophistication. They have been reviewed previously
with demonstrable involvement of the SCN (182). Considerable on numerous occasions. Similarly numerous publications
attention has been directed at research into the disorders of describe abnormalities in melatonin secretion related to
rhythmic events and the timing of pharmacological interventions pathology. However, what is hardly ever considered is the
e.g., for elevated blood pressure (183). Timing of treatment general circadian status of patients studied. For example if a
clinically with anti-hypertensive drugs is accepted and current state of desynchrony exists, then an amplitude reduction in
practice (184). Does melatonin influence the cardiovascular centrally driven and possibly peripheral circadian rhythms is
system? A recent review gives a positive report (185) with regard likely (Figure 1) and low melatonin is not a specific symptom but
to several cardiovascular effects. In a controlled experiment a reflection of rhythm status. Another consideration is whether
melatonin was able to shift heart rate variability in company with low (or high) melatonin amplitude is a cause or a consequence of
the major circadian rhythms of cortisol, core body temperature the pathological state.

FIGURE 5 | The melatonin rhythm as a marker of circadian status. Diagram of a stylized plasma or saliva melatonin or urinary 6-sulphatoxymelatonin rhythm with the
characteristics that have been used to define circadian status. Each body fluid has advantages and disadvantages from a practical point of view. Plasma is the most
precise, with short interval sampling, saliva and aMT6s are the most useful for field studies. For long term monitoring of circadian status urinary aMT6s is
well-tolerated. From Arendt (194), by permission.
A change in timing of the rhythm is easier to interpret, For example workers on North Sea oil rigs collected,
not least because there is normally such a vast difference measured, aliquoted and froze urine continuously for 2–3 weeks
in amplitude between individuals (195). This is probably the whilst on the platform (198, 199). These samples provided a
feature that has been most exploited clinically- but mostly continuous record of circadian adaptation to night shift, or not
for research purposes. The complete profile with sampling at depending on schedule. Similarly many blind subjects (135) and
hourly intervals or less provides the most information, but the crew of an Antarctic ship (200) have collected urine for 48 h at
the timing of the onset of secretion in the evening in dim weekly intervals for 6 weeks or more. This approach provides an
light, known as the DLMO (the dim light melatonin onset), evolving picture of circadian status. It was particularly important
is convenient and has been widely used to assess circadian in our work to judge the timing of melatonin treatment to
status (196). First it should be noted that a large change entrain free running rhythms in blind subjects (76) and to find
in amplitude can look like a change in DLMO, depending out to what extent particular shift schedules onshore, offshore
on how the calculations are performed. The DLMOFF (dim and in Antarctica lead to desynchrony with associated sleep
light melatonin offset) in the morning is also useful as a and metabolic problems (63). Melatonin profiling has been
circadian marker as is the “Synoff ”—the time when production extensively used in research to provide a way of normalizing
ceases (197). Urinary aMT6s provides less resolution, but even experimental subjects with diverse angles of entrainment relative
with 4 h day time/waketime samples and 8 h/oversleep the to the sleep wake cycle, for comparative purposes.
calculated acrophase is within 30 min of that derived from hourly
sampling (193). WHY MEASURE MELATONIN?
Each of the 3 matrices—plasma, saliva and urine, has
advantages and disadvantages. Plasma is ideal and can be done In what clinical circumstances is there a need to know circadian
overnight during sleep but requires catheterization and volume status through melatonin measurement? Principally this is
of blood loss is important. Saliva is practical but unless the subject to identify desynchrony, delayed, advanced or free-running
is woken frequently for overnight sampling, the onset can easily circadian status. Importantly it enables correct timing of
be missed. Sequential urine samples have lower resolution but treatment with melatonin and/or light or alternative zeitgebers
can readily be collected and measured by subjects in field studies, as chronotherapies for disrupted rhythms, according to the
include the whole profile (much preferable to an early morning appropriate PRC. Numerous drugs have large diurnal changes in
urine) and carried out long term. pharmacokinetics which may or may not be circadian in nature

(184). The important question of timing of drug treatment has

become more high profile in the clinic with the individualization Box 1 | Therapeutic effects and associations of melatonin, simplified, and
condensed from Pozadski et al. (33).
of treatment regimes especially for cancer and the melatonin
rhythm might well provide an individual circadian marker for In brackets: number of significant random effects/total number of analyses
timing specification (201). synthesized/total number of participants.
Risk of breast cancer up, related to low melatonin (3/3/3001)
Depression, response to treatment (1), remission (1), same
THE UMBRELLA REVIEW study (2/6/1871)
Pre-operative anxiety down (1/2/761)
There are now so many reviews (systematic and narrative) and
Post-operative anxiety down (1/1/73)
meta-analyses of the effects of melatonin on human and animal
Post-operative pain down (1/1/524)
pathology that Posadzki et al. (33) have conducted what they refer
Prevention of agitation (1/1/170)
to as “An umbrella review” or a “review of reviews” to pinpoint
Safety high (1/1/2912)
areas where a consensus may exist (Box 1). They identified 195
Sleep latency down (3/4/6452)
eligible articles according to their quality criteria, providing a
Sleep quality up (2/2/5830), one study as for latency
valuable resource for evaluation of the evidence. Listed below and
Shown in a separate category are the significant random effects meta-
highly simplified are those effects and associations of melatonin analyses with insufficient data for quantitative synthesis:
in humans for which these authors found significant random In brackets: number of significant analyses/total number of subjects.
effects in quantitative synthesis of eligible meta-analyses. The Breast cancer, risk of death at 1 year down (13 studies but no information
authors note that there is some overlap between the published on total number of subjects)
meta-analyses which they identify. Furthermore, some of the Nocturnal hypertension, systolic and diastolic, down (3/72)
analysis includes data from prolonged release melatonin circadin Sleep latency down (5/2234)
(two reviews) and melatonin agonists ramelteon (four reviews), Sleep duration up (4/2417), largest study significant for latency as above
agomelatine (two reviews), and tasimelteon (one review). but non-significant for duration)
The conclusion from this tour de force is that the data Melatonin onset (DLMO) (6/238)
supports the notion that endogenous and exogenous melatonin Core temperature down (16/193)
has benefits for health- a conclusion with which most people A meta-analysis of the protective effects of melatonin in ischemic stroke in
would agree. However, given the vast number of potential rodents is included with 432 animals and a highly significant large effect size.
therapeutic uses for this hormone (as opposed to the accepted
uses in sleep disorder) there are very few sufficiently large,
randomized, multi-center, placebo-controlled, double blind trials
in specific applications. Hopefully more are on the way. of which have been associated with poor and/or insufficient
sleep (see text). The association of melatonin with risk of
CONCLUDING REMARKS cancer and therapeutic intervention therein, is strongly related to
disordered rhythms.
It seems that there are two major schools of research into the Melatonin is good for human health, particularly via its ability
clinical therapeutic effects of melatonin. Firstly its association to optimize sleep timing and often duration and quality with a
with biological rhythms from cells to organisms, and particularly multitude of downstream benefits. It can counter the debilitating
with the timing and quality of sleep. It acts via well-characterized effects of modern lifestyles: insufficient circadian time cues
membrane receptors, which will be considered in depth by others especially natural bright light, and exposure to artificial light at
in this volume. unsuitable times—the 24 h society. It is questionable whether or
Secondly in the last 25 years the expanding field of protective not long term use has deleterious effects and this is particularly
effects, often considered not to require receptor signaling, has important in pediatrics.
come into being. From a philosophical point of view it would be Circadian and other rhythm status, and reproductive
very satisfying to reconcile these two approaches. It is probably function, during treatment with very large doses of melatonin
true to say that “everything is rhythmic unless proved otherwise.” needs investigation.
If so, melatonin as a rhythm optimizer (synchronization, re- Finally, from personal anecdotal evidence, having taken
synchronization, entrainment, re-entrainment, coupling, phase melatonin in 2–5 mg oral fast release formulation on and off,
and amplitude adjustment, phase and amplitude maintenance, mostly on, since 1981 after a mastectomy, I know that it does
periodicity), could well be invoked to explain many, even not prevent some of the pathologies associated with old age—
most therapeutic protective effects. Or at least a part of osteoarthritis, Type II diabetes, spinal stenosis, uterine cancer.
these effects. But I am still here!
It has been referred to as “circadian glue” but its influence on
rhythms extends to other periodicities. Moreover, its “beneficial”
effects on sleep may lead to a multitude of downstream DATA AVAILABILITY
events of therapeutic value. For example reducing the risk of
insulin resistance, metabolic syndrome, obesity, diabetes, all All relevant data analyzed are included in this manuscript.

AUTHOR CONTRIBUTIONS ACKNOWLEDGMENTS

The author confirms being the sole contributor of this work and The author would like to thank all her numerous students and
has approved it for publication. colleagues over the years for their skills and insights, particularly
Dr. Benita Middleton and Professor Debra Skene.
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HYPOTHESIS AND THEORY

published: 16 July 2019

Melatonin: Countering Chaotic Time

Frontiers in Endocrinology | www.frontiersin.org 1 July 2019 | Volume 10 | Article 391

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abolished the rhythm of circulating melatonin) abolished the

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Non 24 h Sleep Wake Cycle (Irregular Sleep

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(184). The important question of timing of drug treatment has

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AUTHOR CONTRIBUTIONS ACKNOWLEDGMENTS

REFERENCES of reproductive hormones. J Clin Endocrinol Metab. (2003) 88:4303–9.

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Frontiers in Endocrinology | www.frontiersin.org 16 July 2019 | Volume 10 | Article 391

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