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HYPOTHESIS AND THEORY
published: 16 July 2019
doi: 10.3389/fendo.2019.00391
Frontiers in Endocrinology | www.frontiersin.org 1July 2019 | Volume 10 | Article 391
Edited by:
James M. Olcese,
Florida State University, United States
Reviewed by:
Krystyna Skwarlo-Sonta,
University of Warsaw, Poland
Hana Zemkova,
Institute of
Physiology (ASCR), Czechia
*Correspondence:
Josephine Arendt
arendtjo@gmail.com
Specialty section:
This article was submitted to
Cellular Endocrinology,
a section of the journal
Frontiers in Endocrinology
Received: 15 March 2019
Accepted: 30 May 2019
Published: 16 July 2019
Citation:
Arendt J (2019) Melatonin: Countering
Chaotic Time Cues.
Front. Endocrinol. 10:391.
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
of melatonin—its undoubted ability to realign circadian rhythms and sleep—since this is
the author’s bias. It will touch briefly upon some other systems with prominent rhythmic
attributes including certain cancers, the cardiovascular system, the entero-insular axis
and metabolism together with the use of melatonin to assess circadian status. Many of
the ills of the developed world relate to deranged rhythms—and everything is rhythmic
unless proved otherwise.
Keywords: melatonin, circadian, seasonal, health, sleep, light, desynchrony
BACKGROUND
The essential physiological role of the pineal hormone melatonin is to provide information on
photoperiod (day length) for the organization of seasonal physiology (1). It does not appear to
have an essential function in the circadian system but has clear modulatory effects. These functions
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
field (4–6). Its profile of secretion reflects the length of the scotoperiod (night). Even humans with
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.
Most if not all vertebrate photoperiodic species depend on this signal to time seasonal breeding (1),
but see (8).
Melatonin is synthesized from tryptophan via 5-hydroxytryptophan and 5-hydroxytryptamine
(serotonin). Then N-acetylation of serotonin by N-acetyl transferase (arylalkylamine N-acetyl
Arendt Melatonin and Rhythms
transferase, AA-NAT) to N-acetylserotonin (NAT) and O-
methylation by acetylserotonin O-methyltransferase (ASMT),
[previously known as hydroxyindole-O-methyltransferase
(HIOMT)] to melatonin (N-acetyl-5-methoxytryptamine).
A major increase (7–150 fold) in the activity of AA-NAT at
night is usually rate limiting in melatonin production. The
rhythm of production is endogenous, being generated by clock
genes in the suprachiasmatic nuclei (SCN), the major central
rhythm-generating system or “clock” in mammals (9,10). The
rhythm, as for the circadian system in general, is synchronized
to 24 h primarily by the light-dark cycle acting via the retina and
the retinohypothalamic projection to the SCN (9).
Light of suitable intensity and spectral composition can
phase shift and entrain circadian rhythms. Light also suppresses
melatonin production at night (11). The amount of light required
for suppression varies from species to species, with time of night,
with spectral composition and with previous light exposure. In
humans,∼2,000 lux full spectrum light (domestic light is around
50 to 500 lux) is required for complete suppression at night.
However, much lower intensities will partially suppress and shift
the rhythm (12,13). A non-image forming photoreceptor system
of light sensitive retinal ganglion cells is implicated in these
effects, with a pivotal role of the photopigment melanopsin,
although in normal circumstances input from rods and cones
is also used (14,15). In humans maximum suppression and
phase shifting for equal numbers of photons is given by blue
light (460–480 nm).
In humans melatonin is metabolized, ∼70% to
6-sulphatoxy melatonin (aMT6s), primarily within the liver,
by 6-hydroxylation, followed by sulfate conjugation (with
some species variaions). A number of minor metabolites
are also formed, including the glucuronide conjugate.
N1-acetyl-N2-formyl-5-methoxykynuramine and N1-acetyl-
5-methoxy-kynuramine, were initially reported as brain
metabolites (1,16) but have proved difficult to detect in plasma
or urine except after administration of exogenous melatonin
(17). Exogenous oral fast release or intravenous melatonin has
a short metabolic half-life (20 to 60 min, depending on author
and species), with a large hepatic first pass effect and a biphasic
elimination pattern (18). Slow release/prolonged release/surge
sustained preparations are of course designed to extend the
time of high circulating melatonin [e.g., (19)]. It has low
bioavailability in general although transmucosal administration
increases bioavailability (20). A critical feature of exogenous
melatonin with regard to its clinical uses is its very low toxicity
and lack of addictive properties (21,22).
Source of Endogenous Melatonin
The pineal gland is the source of the vast majority of circulating
melatonin in mammals [e.g., (23–25)]. Its synthesis and presence
has been described in a large number of other structures,
but they do not appear to contribute significantly to blood
levels in, for example, humans and rodents, except following
specific manipulations of synthesis such as provision of excess
precursor (26,27). Pinealectomy leads to loss of the rhythm
and usually undetectable amounts of circulating melatonin in
mammals although with high sensitivity assays traces may
be found. This is curious in view of reported non-pineal
melatonin synthesis, sometimes in very large amounts, and
the highly lipophilic/amphipathic nature of the molecule which
penetrates all compartments rapidly (28,29). Superior cervical
ganglionectomy (denervation of the pineal) also abolishes the
rhythm (30). Retinal melatonin is of major interest [e.g., (31,32)]
but beyond the scope of this text.
Non-pineal melatonin has been considered to act locally (29).
Local effects have been invoked with regard to metabolism,
immune function, gut function, inflammation, membrane
fluidity, mitochondrial function, apoptosis (both stimulation and
inhibition), free radical scavenging, direct anti-oxidant activity,
influence on anti-oxidant enzymes, redox status, radioprotection,
and others (33). Protective therapeutic effects are reported with
regard to many various systems but notably neural, oncological
and cardiovascular. Some of these effects are thought not to
require receptor signaling, although melatonin receptors are now
found widely distributed.
Very recently it has been demonstrated that in the mouse
brain melatonin is exclusively synthesized in the mitochondrial
matrix. It is released to the cytoplasm, thereby activating a
mitochondrial MT1signal-transduction pathway which inhibits
stress-mediated cytochrome crelease and caspase activation:
these are preludes to cell death and inflammation. This is a
new mechanism whereby locally synthesized melatonin protects
against neurodegeneration. It is referred to as automitocrine
signaling (34). Another recent addition to our understanding
is the observation that a gut bacterium, Enterobacter aerogenes,
expresses an endogenous circadian clock that is responsive to
signals from the host’s circadian system, the hormone melatonin,
and changes in temperature. This establishes a prospective link
between melatonin as a peripheral circadian zeitgeber (time cue),
and the gut (35).
Peripherally administered exogenous melatonin (sometimes
in very high pharmacological doses) can presumably access the
various structures involved in local effects even though the non-
pineal endogenously synthesized melatonin does not apparently
get out. The gut is reported to contain several 100 fold more
melatonin than the pineal gland, but does not contribute to the
circulating rhythm of melatonin. It is said to sustain the (very
low) day time plasma levels (27). Although melatonin is present
in some foodstuffs (36), in the authors experience it is hard to
show an increase in plasma melatonin after a normal meal. This
area has been extensively reviewed by others and will also feature
in this volume.
In principle the established role of melatonin in rhythmic
function is not necessarily incompatible with the use of high
doses for ‘protective’ effects. Unless desensitization of the
melatonin membrane receptors occurs as a result of continuous
high circulating concentrations (37,38) and compromises
functions responsive to low levels of melatonin such as sleep and
circadian phase.
Melatonin Physiology
Seasonal Rhythms
A truly distinct physiological role for melatonin was initially
indicated by the fact that pinealectomy or ganglionectomy (which
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Arendt Melatonin and Rhythms
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).
Humans have residual seasonality as evidenced by numerous
physiological variables. and particularly by the existence of
seasonal affective disorder and its treatment by suitable light
exposure (and on occasion by melatonin as a chronobiotic) (44,
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
effects of high amounts in humans is quite substantial (46–
49), and an influence on pubertal development is possible but
not demonstrated. For example photoperiod, via melatonin
profile, times puberty in sheep (50), melatonin inhibits LHRH
stimulation of LH in the neonatal rat pituitary (46,51), and in a
case report of successful treatment of delayed puberty in a young
woman, her production of melatonin declined dramatically (52).
A serious attempt to develop it as a contraceptive was made some
25 years ago (53).
Circadian Rhythms
By contrast it is quite difficult to show major effects of
pinealectomy on circadian rhythms and even on sleep. Initial
investigations on pinealectomized rats showed little effect on
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
to an abrupt phase shift (as in jet lag), they adapted faster to
the new schedule without a pineal gland (56,57). This suggested
that the pineal, and by inference melatonin, acted as a brake on
abrupt changes of phase, these being undesirable in a natural
environment. This possibility is reinforced by the fact that
suppression of melatonin production by the beta blocker atenolol
leads to faster adaptation to light-induced phase-shifts in humans
(58). Ironically therefore whilst exogenous melatonin is used to
hasten adaptation, it is possible that a function of endogenous
production is to do the opposite.
Further support for a modulatory role in the circadian
system is evident from the fact that in constant bright light
pinealectomized animals, in comparison to sham operated
animals, show more disrupted rhythms in wheel running, general
activity, body temperature, and heart rate (54). Several authors
have suggested that a function of the pineal and melatonin is
to act as a coupling agent with regard to rhythmic systems
(“circadian glue”). This would fit with the suggested role of
FIGURE 1 | Desynchronized rhythms lead to lowered output of a
multi-oscillatory system. Simplified diagram of how melatonin might act
endogenously to maintain coupling and synchronization of its target outputs
and how desynchronized rhythms may lead to lowered production of
melatonin itself.
maintaining the status quo (Figure 1). It could also be considered
with respect to any effects on other periodicities.
Since melatonin is constantly referred to as the sleep hormone
in the media, it is worth stating that it is not essential to sleep
although we sleep better when in phase with rhythmic circulating
melatonin and the rest of the circadian system (59). It is, to say
the least, difficult to study pinealectomized humans before and
after pinealectomy. However, this has been done prospectively
with pre and post-operative polysomnography, the so-called gold
standard for sleep measures. No effects of the missing pineal on
sleep were seen (60). This was a small but careful and exceedingly
rare study, it merits serious attention. The final comment on
melatonin as a “sleep hormone” is that it most certainly is
not so in nocturnal rodents—it is a darkness hormone not a
sleep hormone.
COUNTERING CHANGES IN TIME CUES
The accumulated knowledge on the deleterious effects of abruptly
changing time cues in for example shift work and jet lag [e.g.,
(61–67)] lead to the suggestion that one function of endogenous
melatonin is to protect against abrupt short term changes of
phase by maintenance of the circadian status quo.
Effects on Circadian Rhythms
Early work indicated that timed exogenous melatonin treatment,
pharmacological in rats, close to, but still usually supra-
physiological in humans, could entrain activity rest cycles in
rats, shift circadian phase, assessed using endogenous melatonin
as a marker rhythm, and synchronize free-running rhythms in
humans. For references see (68).The most obvious manifestation
in humans is the timing of the sleep-wake cycle. Phase shifts
and entrainment after timed low dose melatonin treatment were
evident initially in the rhythm of sleep and of melatonin itself
and then in the timing of all the circadian rhythms observed
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Arendt Melatonin and Rhythms
FIGURE 2 | Melatonin phase shifts all measured rhythms in humans. 1.5 mg surge sustained release at 1600h 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
be induced dependent on the time of treatment (72) which can
be expressed as a Phase Response Curve or PRC. The melatonin
PRC is approximately the opposite of that to light pulses and
for maximum effect the two treatments can be combined with
careful timing (73,74). If the period of melatonin secretion is
considered to be “biological night” then low dose (0.5–5 mg)
treatment in the late afternoon will advance circadian phase and
sleep (75), whereas treatment in the early ’biological morning’
will cause phase delays. Thus, it is important to know or predict
circadian phase in order to time treatment correctly. The clearest
demonstration of entrainment could be seen in free-running
blind subjects (76,77) and in sighted subjects kept in a time free
environment (78).
Melatonin clearly has both a direct sleep inducing effect
coupled with a circadian phase shift (70). Importantly it was
shown to act directly at the level of the suprachiasmatic
nucleus (79) to modify its rhythmic activity, amplitude and
phase, via G-protein linked membrane receptors now extensively
characterized as MT1 and MT2 (MTR1A/Mel1a, Mel1b/MTR1B)
(2,3,79–81). MT1 was associated with suppression of SCN
electrical activity and MT2 with phase shifts, with some
redundancy and cooperation between these subtypes. However, a
recent report describes a lack of overlap in mouse brain structures
showing one or other of these receptors. The authors state that
“the expression and distribution of MT2 receptors are much
more widespread than previously thought, and there is virtually
no correspondence between MT1 and MT2 cellular expression”
(82). A third receptor MT1c is not found in mammals but a
related G-protein coupled receptor GPR50 has 45% identity in
amino-acid sequence with MT1 and MT2 and is thought to be
the ortholog of Mel1c in mammals (83). It may have a role in
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Arendt Melatonin and Rhythms
glucocorticoid receptor signaling with implications for peripheral
control of circadian rhythms (84). Melatonin may also directly
affect clock genes in the SCN [e.g., (85)].
Others will report in this volume in detail concerning
receptors and downstream signaling events. It is just noted here
that a recently reported signaling by melatonin receptors in the
SCN appears to require G-protein-coupled inwardly rectifying
potassium (GIRK)channels: a widely distributed physiological
neural communication system (86). The authors propose this as
some of the explanation for the variety of reported effects of this
hormone in mood and other neurological disorders.
In addition to effects on the central rhythm generating system,
melatonin also influences peripheral oscillators for example
in the pars tuberalis, the cardiovascular system, the skin, the
adrenal (87–90), various primate fetal tissues (91) and possibly
the expression of sirtuin 1 (a histone deacetylase) which is
thought to enhance circadian amplitudes and may prolong
survival (92). Melatonin clearly has the potential to influence all
rhythmic function by virtue of its universal distribution, however
very recent data indicates a major role for glucocorticoids in
entraining/synchronizing peripheral clocks (84). It is clear that
melatonin can manipulate the circadian system. It may well be
that a combination of melatonin, light and glucocorticoids could
provide the most efficient realignment of both centrally generated
and peripheral clocks.
Circadian Desynchrony
In a natural environment, changes in circadian rhythms occur
due to seasonal influences, notably changes in photoperiod
leading to shorter or longer melatonin secretion profiles (93).
In humans a seasonal effect is more commonly seen as delayed
rhythms in winter (94) especially in polar regions with no
sunlight for long periods of the year (95). A duration change
in melatonin profiles is rarely seen in humans in temperate
zones but can be elicited with artificial light/darkness (7). one
explanation is that the onset of secretion is delayed in winter,
but the subject is required to get up to work in the morning.
Thus, the full expression of the profile is curtailed by artificial
light suppression both in the evening and in the morning. In the
urban environment of today artificial light is everywhere leading
to changes in sleep. It is interesting to compare sleep in similar
rural communities with and without artificial light. Artificial light
clearly impacts the timing and duration of sleep (96).
The abrupt changes in the light dark cycle and consequent
desynchrony experienced by shift workers and time zone
travelers are now known to be associated with increased risk of
accidents, sleep deficits, lowered alertness and performance, gut
problems, lowered fertility, perhaps psychiatric problems, and
increased risk of major disease such as cancer, diabetes, metabolic
syndrome and heart disease (67,97).
The central pacemaker of the SCN adapts slowly to these
abrupt changes and peripheral oscillators adapt at different rates,
such that the body is in a state of both internal and external
desynchrony (63,65,98–103). Melatonin (and other rhythms
being driven by the SCN) is slow to adapt, endeavoring to
maintain the circadian status quo. It is out of phase during
adaptation and may be partly suppressed by sufficient light at
night (LAN), e.g., in shift workers, although not all studies
concur. This is thought to be a causal factor in the increased
risk of, for example, breast cancer by some authors and will
be discussed later (97,104,105). However, the entire circadian
system is disturbed in these circumstances, not just melatonin.
Out of phase rhythms with or without suppressed melatonin
may well be involved in the deleterious effects of shift work
(63,104,106,107). As yet there is no definitive linkage between
a particular degree of melatonin suppression and any deleterious
effects. Some people appear to lead perfectly normal lives with
very low or even undetectable melatonin. But there is no
long term information on disease risk in these low melatonin
secretors. Certainly desynchrony will be one cause of disordered
sleep, since we sleep better when in an appropriate phase
relationship with the melatonin rhythm. But when the entire
circadian system is dysregulated numerous other effects and
potential causes can be invoked.
SLEEP
Melatonin itself and its agonists have been developed primarily
to treat sleep disturbance (108) but with currently expanding
possibilities for clinical therapeutics. Its immediate effects
on sleep were initially investigated long ago, first by Aaron
Lerner who identified melatonin. Its immediate effects on
sleepiness/sleep are accompanied by a dose-dependent lowering
of core body temperature in near physiological doses (75,109),
and this has been invoked as part of the mechanism of action.
This phenomenon has been linked to sleep induction in a
series of careful trials (110,111). Melatonin has clear, time-
dependent direct (soporific) and phase shifting effects on human
sleep in near physiological/low pharmacological doses (70,112)
(see Figure 3). It’s rhythm is closely associated with the timing
of sleep and sleep propensity, and inversely with that of core
temperature (113).
When treatment with melatonin is related to the so-called
circadian rhythm sleep disorders (CRSDs) it is a logical
development exploiting both the direct and phase shifting
properties (68). CRSDs include delayed sleep phase, advanced
sleep phase, free-running sleep, and the sleep detriments of jet lag
and shift work. Although the endogenous central pacemaker has
a major role in timing sleep, humans exercise choice according
to desire or necessity, as to when they try to sleep. This means
that sleep rhythms are not a pure manifestation of the circadian
system. True circadian phase shift and/or entrainment requires
a demonstration that a marker rhythm such as melatonin,
cortisol or core temperature is entrained. If treatment is timed
to maximize the phase shifting and direct sleep inducing effects
of melatonin it can be very successful, particularly with respect to
mistimed sleep.
Delayed Sleep Phase Syndrome (DSPS)
Typically a subject reports inability to sleep before 2 to 6 a.m.
When not required to maintain their schedule—i.e., weekends,
holidays, etc.—they sleep without difficulty, and will awaken
spontaneously after a sleep period of normal length. Severe cases
of DSPS are relatively common in adults (114).The incidence
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Arendt Melatonin and Rhythms
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
be as high as 7%. An early meta-analysis (115) concluded that
there was no evidence for efficiency of melatonin in treating
secondary sleep disorders and sleep disorders associated with
sleep restriction. Sadly they did not specifically select publications
which gave treatment at the correct time but they did conclude
that DSPS was an area where melatonin could be useful. The
British Medical Journal published some “rapid responses” to
this publication which were highly critical of the summary
and conclusions.
Some very careful work has been carried out in adults and
children with DSPS, measuring circadian phase and timing
treatment to 5 h before melatonin onset for maximum phase
advance. Sleep timing was advanced, criteria of general health
were improved, there were no later effects on reproductive health
and in some cases treatment could eventually be withdrawn. A
meta-analysis (116) describes the quality studies in both children
and adults published up to 2010 and concludes that melatonin
treatment induced an earlier phase (melatonin onset, 1.18 h)
reduced sleep latency of 23 min and earlier clock onset of sleep
by 0.67 h. Timed melatonin treatment was recommended for
DSPS by the American Academy of Sleep Medicine (117). More
recent well-controlled trials have strongly supported the use of
timed melatonin with or without timed light exposure for DSPS
(118,119). However, by no means all diagnosed DSPS patients
have a circadian delay as well as a sleep delay (120).
For Advanced sleep phase syndrome (ASPS), there is little
information on melatonin treatment.
Shift Work
Another common situation with temporarily displaced sleep is
that of shift work. There is sparse evidence that melatonin can
help day time sleep during real life night shift and night time sleep
after return to day work, although anecdotally melatonin is used.
An early real life study reported greater day sleep duration after
night shift when subjects left work early (6 am, before conflicting
bright light) and took melatonin (5 mg) before day sleep (121).
A later real life timed study addressed both day and night time
sleep and was successful in its carefully timed use of melatonin
(3 mg) 1 h before bedtime (122). An increase in sleep duration
of 15–20 min was obtained and a reduction in sleepiness at work
(subjective measures). In a series of simulation shift work studies
Eastman and colleagues have clearly shown that timed melatonin
(1.8 mg sustained release) and bright light exposure will partially
shift phase, such that day sleep is improved when working nights
and subjects rapidly readapt on return to day work (73,123,124).
Data from real life shift work studies were positive in one review
(125) and the American Academy of Sleep Medicine approves its
use in shift work sleep disorder (117).
Jet Lag
There are now so many reviews of the use of melatonin in jet
lag, its dependence on timing and concomitant light exposure
that it is pointless to write another here, see for example (98).
In summary, successful studies used timed melatonin correctly,
unsuccessful studies [e.g., (126)] did not. The latter in particular
used a cohort who had flown from Norway to New York, stayed
4 days and then were studied on the flight back to Norway.
One can predict that their study population was unadapted to
New York time, phase shifted from Norwegian time, internally
and externally desynchronized, and individually different since
individual response to abrupt change of time cues is variable.
Their lack of useful effect is not surprising since this situation was
not taken into account.
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Arendt Melatonin and Rhythms
In 2006 a Cochrane Database review concluded that melatonin
was useful for jet lag (127). It is updated regularly. Timed
melatonin treatment is recommended for jetlag by the American
Academy of Sleep Medicine (128). Advice on how to time
melatonin and light exposure can be found in reference (98)
and elsewhere.
Sleep in the Elderly
Sleep problems in the elderly may be due to many factors one
of which may be disturbed circadian rhythms. Prolonged release
melatonin “circadin” is registered for use in sleep disorder of
the over 55 s. From the European Medicines Agency Website:
“Circadin was more effective than placebo at improving quality
of sleep and the patients’ ability to function normally on the
following day. When the results of all three studies were looked
at together, 32% of the patients taking Circadin (86 out of 265)
reported a significant improvement in symptoms after 3 weeks,
compared with 19% of those taking placebo (51 out of 272).” The
CHMP decided that, although Circadin has only been shown to
have a small effect in a relatively small number of patients, its
benefits are greater than its risks,” https://www.ema.europa.eu/
en/medicines/human/EPAR/circadin.
Use of melatonin in the very elderly, particularly suffering
from dementia, has been advocated but proved to have adverse
effects in some studies (129).
Sleep in Children
There has been considerable interest in the pediatric use
of melatonin for sleep disorder, initially in children with
neurodevelopmental disorders, in spite of the possible adverse
effects on reproductive function. A large multi-center RCT has
been conducted in the UK- the MENDS study (130). Escalating
doses from 0.5 to 12 mg 45 min before bedtime were used. The
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
most interesting. It is the expression of an individual circadian
clock periodicity. Each person has their own periodicity usually
slightly longer than 24 h (hence the tendency to delay over the
weekend) which manifests itself in the absence of strong time
cues, primarily the light dark cycle. Many blind people with
no conscious or unconscious light perception cannot properly
synchronize to the 24 h day (133–136). In expressing their own
periodicity they drift away from normal clock time such that
intermittently they will be in “night” phase during the day (e.g.,
secretion of melatonin, low alertness and performance) and day
phase during the night (low melatonin, poor sleep). It has been
described as a lifetime’s intermittent jet lag.
Melatonin (usually 0.5–5 mg daily, lower doses than 3mg are
often better) is able to synchronize this non-24 h sleep wake cycle
to 24 h in the vast majority of patients (76,137) (Figure 4). Until
a registered melatonin preparation became available in the UK
(circadin) (138), patients had to obtain melatonin on a named
patient basis. It is prescribed by Moorfields Eye Hospital (premier
eye hospital in the UK). Unfortunately the completely blind do
not often appear before a specialist, the condition is not correctly
diagnosed, and is often treated with straight hypnotics (which do
not work). A survey in New Zealand reported very little use of
melatonin to correct this cyclic sleep disorder (139).
In 1986 a blind man rang me up, said he had non 24h sleep
wake disorder, and could he have some melatonin? He had
seen my jet lag studies and worked it out for himself. After
a very successful double blind placebo controlled cross over
study [5 mg melatonin, (134)] he took this dose, prescribed on
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
use, refusing to lower the dose. We checked his biochemistry
and hematology after 10 years treatment and all was normal
for age. Since then quite a number of similar studies have
found the same synchronizing effect on sleep, and from the
year 2000 synchronization of the underlying circadian pacemaker
was shown in most, but not all patients. The tendency is to
start with very low doses and if necessary increase (or in one
FIGURE 4 | Diagram of melatonin-induced entrainment by phase advance of
a free-running sleep wake cycle and circadian phase, for example in a blind
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
dusk” before onset of melatonin secretion.
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Arendt Melatonin and Rhythms
publication decrease) the dose until it is effective. We recommend
starting treatment about an hour before bedtime when in a ’good’
sleep phase. Even without full circadian entrainment sleep can
be improved.
Non-specific Insomnia
As a treatment for non-specified insomnia melatonin also
appears to be quite useful. Some 3,000,000 Americans used
melatonin last year according to the following website (https://
nccih.nih.gov/research/statistics/NHIS/2012/natural-products/
melatonin), presumably for jet lag or for “poor sleep.” In the case
of non-specific “poor sleep” this is likely related in many cases to
the fact that our circadian rhythms are frequently not in optimal
phase in a “urban normal environment” (140) with insufficient
time cues or zeitgebers to maintain optimum circadian phase.
In these circumstances most people will delay the circadian
system, particularly over the weekend if there is no requirement
to get up in the morning. In this way the social need for sleep
is in advance of the circadian optimum time and melatonin
secretion in particular, and sleep suffers. The discrepancy has
been referred to as “social” jet lag (141). Popping a melatonin pill
in the evening has a good chance of advancing circadian phase to
a more appropriate time and thus better sleep.
Melatonin and Cancer
Animal experiments have shown clearly the increased risk of
cancer with abrupt phase shifts (97,142,143). In 2006 the World
Health Organization in Lyon, France held a week-long meeting
in which, on the basis largely of animal experiments, decided
that shift work was a probable carcinogen (97,144). A large
proportion of the population of developed countries (15–20%)
works shifts and thus this is of major health interest.
An association of the pineal gland with anti-cancer activity has
a very long history (145). Early work suggested that the gland
contained oncostatic activity initially not specified as melatonin.
Important evidence of the association included for example that
pinealectomy of rats led to much shorter survival times from
DMBA-induced cancer and secondly that exogenous melatonin
could substantially increase survival times (146). In the 1970s
melatonin treatment (very large doses 80–300 mg pd) to young
women was proposed for avoidance (prophylactic) of breast
cancer (48,53), and development proceeded to clinical trials in
combination with a progestagen. These trials were not successful.
But the subject continued of interest when light at night, thought
to suppress melatonin (at least partially) (147–149), was invoked
as the reason for an excess of breast cancer in nurses, working
rotating long term night shifts (104,144,150), and subsequently
other shift workers.
There is good reason to consider melatonin firstly as a
prophylactic, in the case of suppression by light during night
work, secondly to hasten adaptation of the circadian system to
abrupt phase shift when this is desirable. Thirdly it has been
very extensively researched with regard to its anti-cancer activity
in breast cancer and other neoplasms (151,152). Some of the
most convincing data linking physiological levels of melatonin
with anti-cancer growth concerns human breast cancer-mouse
xenograft studies. In a series of experiments Blask et al. could
show the protective effects of exogenous and endogenous
melatonin and the deleterious effects of extra light (153–156). The
xenograft approach is being applied to other cancers.
Most epidemiology agrees that there is an increased risk of
developing various cancers as a function of long term night shift
work (97,150). Melatonin has been used as adjuvant therapy in
various cancers for nearly 20 years notably by Lissoni et al. in very
advanced cancer [e.g., (157)] with positive effects but not usually
significant results. With all the suggestive background, several
clinical trials in different cancers using melatonin, usually as an
adjunct to conventional treatment, have now been conducted
(33)—but not enough. The results are quite positive in several
domains- survival time, progression of the disease, reduced
toxicity of treatment and in general well-being. An important
question is to what extent the effects are due to rhythm
optimization and/or improved sleep?
METABOLISM
A substantial early clinical literature exists concerning diurnal
and ultradian rhythms in metabolic function [e.g., (158)]. With
the application of constant routine technology it became possible
to identify endogenously generated (i.e., circadian) rhythms
from those derived from the external environment, meal times
etc. (159–161). This has now been extended to metabolomics.
For example simultaneous evaluation of many metabolites in
constant routine has shown that of 132 circulating metabolites
nearly half showed a 24 h rhythmicity (162). Following sleep
deprivation it was clear that many metabolites desynchronized
amongst themselves (163,164). With sequencing of the human
genome, this approach has now devolved to the level of genes
(67). Melatonin has been invoked as a supplementary treatment
for avoidance or reversal of metabolic syndrome but without
substantial evidence of efficacy [e.g., (165)].
The Entero-Insular Axis and Diabetes
The importance of rhythms to the entero-insular axis was also
evident early on, with variations in glucose tolerance and insulin
sensitivity (166). The subject has been very recently reviewed
(161). The circadian, SCN-driven nature of these rhythms is now
well established alongside the “masking” effects of mealtimes,
meal content and other external inputs (167,168). Triacylglycerol
(TAG) has a particularly marked circadian rhythm in constant
routine (167). During both simulated and real shift work,
standard meals taken at inappropriate times at night—biological
night when melatonin secretion is high-lead to evidence of
insulin resistance/glucose intolerance and higher TAG, both risk
factors for heart disease (167,169). This is therefore one possible
mechanism underlying the epidemiological data showing higher
risk of these major diseases.
Circadian re-adaptation in real shift workers resolves some
metabolic risk factors (169) (and see Gibbs M, Hampton SH,
Morgan L, Arendt J. Effect of shift schedule on offshore shift
workers’ circadian rhythms and health, 2004. http://www.hse.
gov.uk/research/rrhtm/rr318.htm). So there is good reason to
use the chronobiotic properties of melatonin (and timed light
exposure) to manipulate circadian phase. It remains to be
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Arendt Melatonin and Rhythms
determined to what extent central and peripheral oscillators
remain in synchrony/coupled in these circumstances.
Melatonin clearly influences glucose concentrations-
pinealectomy leads to increased glucose in nocturnal rats (170).
In MT1 and MT2 receptor knockout mice the SCN-driven
glucose rhythm is abolished independently of peripheral
oscillators in muscle, adipose tissue and liver (171). In
humans in one study, the decrease in glucose tolerance
from morning to evening was mostly influenced by the
endogenous circadian system compared to the sleep-wake
cycle. However, in apparent contrast to pinealectomy effects in
animals, melatonin administered during day time just prior to a
glucose tolerance test in healthy adults clearly impaired glucose
tolerance both in the morning and the evening (172,173),
an effect that was dependent on a common gain-of-function
variant of the melatonin receptor gene MTNR1B152 (see
below). Melatonin may also acutely decrease insulin secretion in
cultured human islets (174). Thus, some controversy exists in the
literature especially when comparing results in nocturnal rodents
with diurnal humans with both beneficial and detrimental
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
(175,176).
In view of pre-existing associations of the pineal and
melatonin with metabolic function the discovery of related
MT1 and MT2 receptor variants aroused enormous interest.
A common variant in MTNR1B—MTNR1B rs10830963 is
associated with increased risk of type 2 diabetes, increased
fasting plasma glucose levels and impaired early insulin secretion
(177,178). Moreover, late dinner, associated with elevated
melatonin concentrations (as in night shift workers, above),
impaired glucose tolerance in “gain of function” MTNR1B risk
allele carriers but not in non-carriers. These data suggest that
circulating melatonin is related to the development of Type 2
Diabetes, in a deleterious sense. Of course sleep restriction is
also associated with impaired glucose tolerance, increased risk
of metabolic syndrome and/or diabetes (179,180). So that the
usefulness of melatonin to address sleep problems may well
increase risk of metabolic abnormalities. Some controversies
have arisen and have been reviewed (181). The question is
not solved.
CARDIOVASCULAR SYSTEM
Rhythmicity is a cardinal feature of the cardiovascular system,
with demonstrable involvement of the SCN (182). Considerable
attention has been directed at research into the disorders of
rhythmic events and the timing of pharmacological interventions
e.g., for elevated blood pressure (183). Timing of treatment
clinically with anti-hypertensive drugs is accepted and current
practice (184). Does melatonin influence the cardiovascular
system? A recent review gives a positive report (185) with regard
to several cardiovascular effects. In a controlled experiment
melatonin was able to shift heart rate variability in company with
the major circadian rhythms of cortisol, core body temperature
and TSH (71). Evidently this corresponds to an effect on the
central circadian clock.
There is certainly some good evidence that melatonin
can lower blood pressure at night in patients with essential
hypertension and/or metabolic syndrome (186,187). Possibly
the accompanying increased day night amplitude of systolic
and diastolic rhythms was equally important and indicative of
strengthened function of the SCN. The mechanism involved is
not clear. The improved sleep reported in the subjects may well
have contributed to the result.
Melatonin has probably had more exposure as a potential
cardiovascular protective agent, with respect especially to
myocardial ischemia/reperfusion injury. Numerous animal
experiments suggest beneficial effects in a meta-analysis,
with anti-oxidant effects, free-radical scavenging, anti-apoptosis
and/or involvement of MT1 receptor suggested as mechanisms
(188). However, a later meta-analysis and experimentation using
melatonin in a combination with minocycline and magnesium
sulfate did not show efficacy (189). Several clinical trials appear
to be ongoing.
USE OF MELATONIN AS A CIRCADIAN
“MARKER” RHYTHM, PROVIDING
INFORMATION ON THE PHASE AND
TIMING OF THE CIRCADIAN SYSTEM FOR
BASIC RESEARCH, TIMED TREATMENTS
The rhythmic production of melatonin, normally high during the
dark phase in all species studied to date, is linked directly via
neural connections to the activity of the central circadian clock
or pacemaker in the SCN (9). It was possible to show that the
rate limiting synthetic enzyme pineal AA-NAT activity is closely
related to the plasma melatonin profile in rats (190), and that
the plasma profile is closely related to that of saliva in humans
(191). Moreover, the urinary excretion of 6-sulphatoxymelatonin
(aMT6s) the major metabolite in rats and humans reflects
faithfully the profile of plasma melatonin in humans (192,193).
Thus, the measurable melatonin/aMT6s profiles in plasma, saliva
or urine provide a ‘window’ on the clock. The melatonin rhythm
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).
The characteristics of melatonin secretion in normal healthy
volunteers have been studied for many years with increasing
technological sophistication. They have been reviewed previously
on numerous occasions. Similarly numerous publications
describe abnormalities in melatonin secretion related to
pathology. However, what is hardly ever considered is the
general circadian status of patients studied. For example if a
state of desynchrony exists, then an amplitude reduction in
centrally driven and possibly peripheral circadian rhythms is
likely (Figure 1) and low melatonin is not a specific symptom but
a reflection of rhythm status. Another consideration is whether
low (or high) melatonin amplitude is a cause or a consequence of
the pathological state.
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Arendt Melatonin and Rhythms
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,
not least because there is normally such a vast difference
in amplitude between individuals (195). This is probably the
feature that has been most exploited clinically- but mostly
for research purposes. The complete profile with sampling at
hourly intervals or less provides the most information, but
the timing of the onset of secretion in the evening in dim
light, known as the DLMO (the dim light melatonin onset),
is convenient and has been widely used to assess circadian
status (196). First it should be noted that a large change
in amplitude can look like a change in DLMO, depending
on how the calculations are performed. The DLMOFF (dim
light melatonin offset) in the morning is also useful as a
circadian marker as is the “Synoff”—the time when production
ceases (197). Urinary aMT6s provides less resolution, but even
with 4 h day time/waketime samples and 8 h/oversleep the
calculated acrophase is within 30 min of that derived from hourly
sampling (193).
Each of the 3 matrices—plasma, saliva and urine, has
advantages and disadvantages. Plasma is ideal and can be done
overnight during sleep but requires catheterization and volume
of blood loss is important. Saliva is practical but unless the subject
is woken frequently for overnight sampling, the onset can easily
be missed. Sequential urine samples have lower resolution but
can readily be collected and measured by subjects in field studies,
include the whole profile (much preferable to an early morning
urine) and carried out long term.
For example workers on North Sea oil rigs collected,
measured, aliquoted and froze urine continuously for 2–3 weeks
whilst on the platform (198,199). These samples provided a
continuous record of circadian adaptation to night shift, or not
depending on schedule. Similarly many blind subjects (135) and
the crew of an Antarctic ship (200) have collected urine for 48 h at
weekly intervals for 6 weeks or more. This approach provides an
evolving picture of circadian status. It was particularly important
in our work to judge the timing of melatonin treatment to
entrain free running rhythms in blind subjects (76) and to find
out to what extent particular shift schedules onshore, offshore
and in Antarctica lead to desynchrony with associated sleep
and metabolic problems (63). Melatonin profiling has been
extensively used in research to provide a way of normalizing
experimental subjects with diverse angles of entrainment relative
to the sleep wake cycle, for comparative purposes.
WHY MEASURE MELATONIN?
In what clinical circumstances is there a need to know circadian
status through melatonin measurement? Principally this is
to identify desynchrony, delayed, advanced or free-running
circadian status. Importantly it enables correct timing of
treatment with melatonin and/or light or alternative zeitgebers
as chronotherapies for disrupted rhythms, according to the
appropriate PRC. Numerous drugs have large diurnal changes in
pharmacokinetics which may or may not be circadian in nature
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Arendt Melatonin and Rhythms
(184). The important question of timing of drug treatment has
become more high profile in the clinic with the individualization
of treatment regimes especially for cancer and the melatonin
rhythm might well provide an individual circadian marker for
timing specification (201).
THE UMBRELLA REVIEW
There are now so many reviews (systematic and narrative) and
meta-analyses of the effects of melatonin on human and animal
pathology that Posadzki et al. (33) have conducted what they refer
to as “An umbrella review” or a “review of reviews” to pinpoint
areas where a consensus may exist (Box 1). They identified 195
eligible articles according to their quality criteria, providing a
valuable resource for evaluation of the evidence. Listed below and
highly simplified are those effects and associations of melatonin
in humans for which these authors found significant random
effects in quantitative synthesis of eligible meta-analyses. The
authors note that there is some overlap between the published
meta-analyses which they identify. Furthermore, some of the
analysis includes data from prolonged release melatonin circadin
(two reviews) and melatonin agonists ramelteon (four reviews),
agomelatine (two reviews), and tasimelteon (one review).
The conclusion from this tour de force is that the data
supports the notion that endogenous and exogenous melatonin
has benefits for health- a conclusion with which most people
would agree. However, given the vast number of potential
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.
CONCLUDING REMARKS
It seems that there are two major schools of research into the
clinical therapeutic effects of melatonin. Firstly its association
with biological rhythms from cells to organisms, and particularly
with the timing and quality of sleep. It acts via well-characterized
membrane receptors, which will be considered in depth by others
in this volume.
Secondly in the last 25 years the expanding field of protective
effects, often considered not to require receptor signaling, has
come into being. From a philosophical point of view it would be
very satisfying to reconcile these two approaches. It is probably
true to say that “everything is rhythmic unless proved otherwise.”
If so, melatonin as a rhythm optimizer (synchronization, re-
synchronization, entrainment, re-entrainment, coupling, phase
and amplitude adjustment, phase and amplitude maintenance,
periodicity), could well be invoked to explain many, even
most therapeutic protective effects. Or at least a part of
these effects.
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
events of therapeutic value. For example reducing the risk of
insulin resistance, metabolic syndrome, obesity, diabetes, all
Box 1 | Therapeutic effects and associations of melatonin, simplied, and
condensed from Pozadski et al. (33).
In brackets: number of significant random effects/total number of analyses
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
study (2/6/1871)
Pre-operative anxiety down (1/2/761)
Post-operative anxiety down (1/1/73)
Post-operative pain down (1/1/524)
Prevention of agitation (1/1/170)
Safety high (1/1/2912)
Sleep latency down (3/4/6452)
Sleep quality up (2/2/5830), one study as for latency
Shown in a separate category are the significant random effects meta-
analyses with insufficient data for quantitative synthesis:
In brackets: number of significant analyses/total number of subjects.
Breast cancer, risk of death at 1 year down (13 studies but no information
on total number of subjects)
Nocturnal hypertension, systolic and diastolic, down (3/72)
Sleep latency down (5/2234)
Sleep duration up (4/2417), largest study significant for latency as above
but non-significant for duration)
Melatonin onset (DLMO) (6/238)
Core temperature down (16/193)
A meta-analysis of the protective effects of melatonin in ischemic stroke in
rodents is included with 432 animals and a highly significant large effect size.
of which have been associated with poor and/or insufficient
sleep (see text). The association of melatonin with risk of
cancer and therapeutic intervention therein, is strongly related to
disordered rhythms.
Melatonin is good for human health, particularly via its ability
to optimize sleep timing and often duration and quality with a
multitude of downstream benefits. It can counter the debilitating
effects of modern lifestyles: insufficient circadian time cues
especially natural bright light, and exposure to artificial light at
unsuitable times—the 24 h society. It is questionable whether or
not long term use has deleterious effects and this is particularly
important in pediatrics.
Circadian and other rhythm status, and reproductive
function, during treatment with very large doses of melatonin
needs investigation.
Finally, from personal anecdotal evidence, having taken
melatonin in 2–5 mg oral fast release formulation on and off,
mostly on, since 1981 after a mastectomy, I know that it does
not prevent some of the pathologies associated with old age—
osteoarthritis, Type II diabetes, spinal stenosis, uterine cancer.
But I am still here!
DATA AVAILABILITY
All relevant data analyzed are included in this manuscript.
Frontiers in Endocrinology | www.frontiersin.org 11 July 2019 | Volume 10 | Article 391
Arendt Melatonin and Rhythms
AUTHOR CONTRIBUTIONS
The author confirms being the sole contributor of this work and
has approved it for publication.
ACKNOWLEDGMENTS
The author would like to thank all her numerous students and
colleagues over the years for their skills and insights, particularly
Dr. Benita Middleton and Professor Debra Skene.
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Conflict of Interest Statement: JA is director of two companies Stockgrand
Ltd and Surrey Assays Ltd which are concerned with measuring melatonin,
6-sulphatoxymelatonin, and other hormones. These companies had no influence
on the writing of this text.
Copyright © 2019 Arendt. This is an open-access article distributed under the terms
of the Creative Commons Attribution License (CC BY). The use, distribution or
reproduction in other forums is permitted, provided the original author(s) and the
copyright owner(s) are credited and that the original publication in this journal
is cited, in accordance with accepted academic practice. No use, distribution or
reproduction is permitted which does not comply with these terms.
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