JOURNALOF

10.1177/0748730405277492
Arendt
/ MELATONIN
BIOLOGICALRHYTHMS / August 2005

MELATONIN

Melatonin: Characteristics,
Concerns, and Prospects
Josephine Arendt1
Centre for Chronobiology, School of Biomedical and Molecular Sciences,
University of Surrey, Guildford, Surrey, United Kingdom
Abstract Melatonin is of great importance to the investigation of human biological rhythms. Its rhythm in plasma or saliva provides the best available measure
of the timing of the internal circadian clock. Its major metabolite 6sulphatoxymelatonin is robust and easily measured in urine. It thus enables
long-term monitoring of human rhythms in real-life situations where rhythms
may be disturbed, and in clinical situations where invasive procedures are difficult. Melatonin is not only a hand of the clock; endogenous melatonin acts to
reinforce the functioning of the human circadian system, probably in many
ways. Most is known about its relationship to sleep and the decline in core body
temperature and alertness at night. Current perspectives also include a possible
influence on major disease risk, arising from circadian rhythm disruption.
Melatonin clearly has the ability to induce sleepiness and lower core body temperature during biological day and to change the timing of human rhythms
when treatment is appropriately timed. It can entrain free-running rhythms and
maintain entrainment in most blind and some sighted people. Used therapeutically it has proved a successful treatment for circadian rhythm disorder, particularly the non-24-h sleep wake disorder of the blind. Numerous other clinical
applications are under investigation. There are, however, areas of controversy,
large gaps in knowledge, and insufficient standardization of experimental conditions and analysis for general conclusions to be drawn with regard to most situations. The future holds much promise for melatonin as a therapeutic
treatment. Most interesting, however, will be the dissection of its effects on
human genes.
Key words melatonin, light, rhythms, human

The importance of melatonin in human circadian

biology means that most other sections of this edition
will consider it in relation to the specific area under
scrutiny. This review will discuss its use as a marker
rhythm for the timing of the internal clock and its
effects on the human circadian system.

Melatonin is a tiny molecule, but it has had a huge

impact on the field of biological rhythms. In fact, if
Web citations are a guide (1.9 106 citations), it is
almost as famous as serotonin (2.3 106) but not quite
as well known as DNA (42.5 106). It arouses interest
in fields as disparate as evolutionary biology and tran-

1. To whom all correspondence should be addressed: Josephine Arendt, Centre for Chronobiology, School of Biomedical and
Molecular Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UK; e-mail: arendtjo@aol.com.
JOURNAL OF BIOLOGICAL RHYTHMS, Vol. 20 No. 4, August 2005 291-303
DOI: 10.1177/0748730405277492
2005 Sage Publications

291

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JOURNAL OF BIOLOGICAL RHYTHMS / August 2005

scendental meditation. Why should this be? Its production by the pineal gland, Descartess Seat of the
Soul, and its colloquial sobriquet hormone of darkness no doubt explain some of the more irrational
interest. But the fact that it appears to be the only solidly established humoral method of signaling time of
day and time of year to other physiological systems
underpins its all pervasive presence in the
multidisciplinary field of chronobiology. Melatonin
suppression by bright light at night, and its
transduction of photoperiodic information in animals,
initiated the first light treatments of SAD (seasonal
affective disorder). Possible suppression of melatonin
during night shift work has been hypothesized to
increase the risk of major disease (Stevens and Davis,
1996). One of the first (and some subsequent) demonstrations that light pulses could shift the human circadian clock used melatonin as the marker rhythm. The
use of 6-sulphatoxymelatonin (aMT6s) as a
noninvasive marker of circadian timing has enabled
better definitions and new insights into human clock
timing in field studies (for a review, see Rajaratnam
and Arendt, 2001).
The suppression and phase-shifting of melatonin
by light has provided endpoints for the recent identification of a novel circadian photoreceptor system (see
this issue) maximally responsive to short wavelength
light.
The chronobiotic and sleep-inducing properties of
melatonin have led to its use to treat circadian rhythm
disorders such as the non-24-h sleep disorder of the
blind, delayed sleep phase syndrome, shift work, and
jet lag (see this issue). These properties have inspired
new pharmacological approaches to the treatment of
health problems. However, lack of consistency in field
trials of shift work and jet lag suggests that further
investigation is needed (see this issue).

IN THE BEGINNING
In the beginning, it would have been hard to predict
these developments. Aaron Lerner, who first identified and characterized melatonin (Lerner et al., 1958),
was looking for the most potent (amphibian) skinlightening factor known to be present in the pineal
gland. We now know that the primary and essential
physiological function of the changing melatonin profile in mammals is to convey information concerning
daylength to body physiology for the organization of

daylength-dependent (photoperiodic) seasonal functions (Arendt, 1995). In mammals, melatonin appears

to have a more modest role in the organization of adult
circadian physiology, mostly being associated with
sleep and the core temperature rhythm. It may be
more important in the perinatal period (Davis, 1997).
There is nevertheless evidence for an influence on systems such as glucose homeostasis (la Fleur et al., 2001),
the immune system (Maestroni, 1998), and cardiovascular function (Scheer et al., 2004). It is made at night
in all species investigated to date, thus any response to
the melatonin signal must differ in nocturnal and
diurnal animals, including humans, as it does in shortand long-day breeders (Arendt, 1995).

A HAND OF THE CLOCK

The secretion of melatonin from the pineal is probably the most direct peripheral link to the central circadian clock. This may be too simplistic, since evidence
exists for differential changes in melatonin and other
variables driven by the SCN (De Leersnyder et al.,
2001; Perreau-Lenz et al., 2004; Weibel et al., 1997).
Moreover, there is some evidence that shifting sleep
time can change melatonin phase without affecting
the core body temperature rhythm (Gordijn et al.,
1999). Investigation of pineal function in humans, and
a more precise and less masked representation of
the human clock than core body temperature, awaited
development of suitable measurement methods for
melatonin and subsequently its primary metabolite
aMT6s (for references to early assays, see Arendt,
1995).
To assess the basic characteristics of the human circadian system requires highly controlled conditions
(variants of constant routine methodology) and precise definitions of the rhythm characteristics (Duffy
and Dijk, 2002). At present, in controlled conditions,
melatonin is considered to be the best index of circadian timing in humans (Klerman et al., 2002). For clinical assessments of possible circadian abnormality, the
use of melatonin onsetthe start of the evening
risein plasma or saliva has been extensively used as
a phase marker of the internal clock, as it avoids overnight sampling (Lewy and Sack, 1989). There are disadvantages to this approach, as it provides no information on the duration of secretion, peak levels, and
total production. There is some evidence that 2 oscillators usually known as M (morning) and E (evening)

Arendt / MELATONIN

CHARACTERISTICS OF MELATONIN
SECRETION AND PRODUCTION
Profile Characteristics
Figure 1 illustrates the rhythm characteristics that
can be derived from profiles of plasma and saliva
melatonin (1 hourly sample or less) together with urinary aMT6s (3 to 4 hourly sampling or less, with a longer oversleep collection). No worthwhile data can be
derived from single time-point sampling. Very frequent sampling (<30 min) may lead to apparent episodic secretion (Geoffriau et al., 1999). This may be, at
least in part, an artifact of assay noise (Bojkowski et al.,
1987). The presence of 2 peaks of secretion has also
been noted at times (Arendt, 1985; Wehr et al., 1995)
and related to possible dual oscillator control of
melatonin synthesis. In healthy individuals, the timing, amplitude, and even the details of the profile can
be highly reproducible from day to day and week to
week rather like a hormonal fingerprint (Arendt, 1988;
Klerman et al., 2002), even without strictly controlled

Melatonin (plasma, saliva), 6-sulphatoxymelatonin (urine)

phase markers
80

plasma melatonin (pg /ml)

are concerned with the generation of the melatonin

rhythm. The rise is theoretically associated with E, and
the fall with M (Illnerova and Vanecek, 1988). Differential effects on the rise and fall, and even on the
details of the overnight profile, may well be clinically
important. There is extensive evidence for good correlations in both timing and amplitude between the
rhythms of plasma and saliva melatonin and the urinary metabolite aMT6s (Bojkowski et al., 1987; Elliott
et al., 2002; Nowak et al., 1987; Ross et al., 1995;
Voultsios et al., 1997). However, all have their disadvantages. Plasma sampling is invasive and is subject
to restrictions due to preservation of blood volume
but it can be accomplished during sleep, whereas 24-h
sampling of saliva implies disruption of sleep. Urine
collection for aMT6s production over 1-h intervals
provides data comparable to sampling for 4-h intervals with an 8-h oversleep collection (Naidoo, 1999)
but inevitably with less resolution than can be
obtained with blood or saliva. A prior knowledge of
circadian phase would certainly enhance the consistency of results obtained for treatment of conditions
such as jet lag and shift work with melatonin. To this
end, the development of a technique for rapid, simple
melatonin measurement (a biosensor, for example)
would find extensive use.

293

duration

70
60

50

acrophase (calculated peak time)

40
30

20
10

900

1100 1300 1500

25% rise/fall
onset/offset

*
*

1500 1700 1900 2100 2300

700

mid-range crossing

100

300

500

1700 1900 2100 2300

700
100

900
300

1100 1300 1500 1700

500

700

900

clock time h
circadian time h

biological night

Figure 1. The markers used to characterize melatonin and aMT6s

(6-sulphatoxymelatonin) rhythms are illustrated diagrammatically. Area under the curve or total 24-h excretion (aMT6s) is used
to assess total secretion. At present, there is no standard definition
of onset-offset (and hence duration). More sophisticated curve-fitting techniques have been employed and appear to give reliable
data (Brown et al., 1997; Gamst et al., 2004; Revell et al., 2005).

sampling conditions. The very large interindividual

variations have been ascribed to the size of the pineal
gland rather than to variations in enzymic activity, at
least in sheep (Gomez Brunet et al., 2002). Diurnal
preference (morningness) and short free-running circadian period are associated with earlier melatonin
phase (Duffy et al., 1999; Gibertini et al., 1999). No consistent gender differences have been found (notably if
body weight is taken into account). A small number of
apparently normal individuals have no detectable
melatonin in plasma at all times of day.
Seasonal and Lifetime Variations
There are seasonal variations in human melatonin
(and aMT6s), with an earlier phase in summer
(Bojkowski and Arendt, 1988; Broadway et al., 1987),
and, according to some reports, increased levels and
duration of secretion in winter in high latitudes
(Kauppila et al., 1987). Plasma melatonin declines
during development: this is likely to be due to constant production with increasing body weight
(Cavallo and Dolan, 1996). aMT6s excretion declines
in adults with age in most reports (Bojkowski and
Arendt, 1990; Kennaway et al., 1999), as does the

294
Table 1.

JOURNAL OF BIOLOGICAL RHYTHMS / August 2005

Some Miscellaneous Factors Influencing Human Melatonin Secretion

Factor

Effect(s) on Melatonin

Posture
Exercise
-adrenoceptor-A
5HT UI
NE UI
MAOA I
-adrenoceptor-A
Benzodiazepines

Standing (night)
Phase shifts
Synthesis
Fluvoxamine
Change in timing
May change phase
alpha-1, alpha-2
Variable Diazepam,
alprazolam
?

? Not clear
Inconsistent
Possible changes ?

Testosterone
OC
Estradiol
Menstrual cycle
Smoking
Alcohol
Caffeine

Aspirin, Ibuprofen
Chlorpromazine

Benserazide
Possible phase change,
Parkinson patients

Comment
Controversial
Hard exercise
Antihypertensives
Metabolic effect
Antidepressants
Antidepressants
GABA mechanisms
Treatment

Amenorrhea
Dose dependent
Delays clearance
(exogenous)
Metabolic effect
Aromatic amino-acid
decarboxylase-I

Reference(s)
*Nathan et al., 1998; Voultsios et al., 1997
Buxton et al., 2003
*
*Hartter et al., 2001
*
*
*
Mann et al., 1996; Monteleone et al., 1989; Monteleone
et al., 1997; Niles, 1991
*Luboshitzky et al., 1997
Kostoglou-Athanassiou et al., 1998; Wright and Badia, 1999
*Okatani et al., 2000
*Laughlin et al., 1991
Tarquini et al., 1994
Ekman et al., 1993
Hartter et al., 2003; Shilo et al., 2002; Wright et al., 1997
Murphy et al., 1996
*
*

*Most references prior to 1995 can be found in Arendt (1995). A recent revue addresses mostly animal in vivo and in vitro effects (Simonneaux
and Ribelayga, 2003). A = antagonist; U = uptake; I = inhibitor; MAO = monoamine oxidase; OC = oral contraceptives; 5HT = 5hydroxytryptamine; = increase; = decrease.

amplitude of the plasma melatonin rhythm (with

some exceptions). The subject of aging and the
melatonin rhythm is covered elsewhere in this issue.
aMT6s appears to have a progressively earlier
acrophase with aging (B. Middleton and J. Arendt,
unpublished data).
Abnormal Rhythms
The above comments apply strictly to healthy
unmedicated adults in a normal entrained environment. The normal melatonin profile provides the
basis from which the extent of any circadian rhythm
disruption can be assessed (for example, in blindness,
shift work, jet lag, and delayed and advanced sleep
phase). At present, different laboratories define their
own normal values. A variety of observations in disease states indicate that the amplitude and sometimes
the timing of the rhythm may be modified. It is hard to
draw any general conclusions, and it is rare for such
studies to control for all known masking factors. Abolition of the rhythm by destruction of pineal
innervation, pinealectomy (Zeitzer et al., 2000a; see
Arendt, 1995, for earlier references), and situations
affecting stimulation/inhibition of synthesis/metabolism have predictable effects on measured levels (see
Table 1).

Light Exposure
Recently, interest has been aroused in the possible
health hazards of light at night (LAN), one hypothesis
being that melatonin suppression is the culprit
(Stevens and Davis, 1996). Bright (>2500 lux, white)
light can suppress melatonin completely (Lewy et al.,
1980), but domestic-intensity light such as might be
encountered at night on the night shift, causes significant suppression (Bojkowski et al., 1987; Zeitzer et al.,
2000b). Moreover, previous light exposure can influence the amount of suppression (Hebert et al., 2002;
Owen and Arendt, 1992). There are inconsistent
reports of either increase, decrease, or no change in
melatonin amplitude in night shift workers. It will be
important to resolve this problem in large populations
with simultaneous measurements of light exposure.
The LAN hypothesis has been extended to suggest
that a lower incidence of cancer in blind people may be
due to greater melatonin production (Erren and
Stevens, 2002). Blind subjects with no conscious or
unconscious light perception may (and usually do)
show free-running rhythms or synchronized rhythms
with abnormal phase (see Skene, this issue). In limited
data so far available, they do not have either a higher
amplitude or a longer duration than sighted subjects
(Klerman et al., 2001; Lockley et al., 1997).

Arendt / MELATONIN

Electromagnetic Field Exposure

A related melatonin suppression hypothesis has
been applied to possible effects of EMF on melatonin.
Primarily cross-sectional studies investigating aMT6s
in urine have been used to investigate melatonin production in populations at risk. Very few of these studies have carried out complete 24- to 48-h sampling to
define amplitude and timing of the rhythm, and the
results are weak and inconsistent (Brainard et al.,
1999). In view of the very large interindividual variation, it is necessary to use subjects as their own controls in small studies. Recent laboratory investigations
of this kind on the acute effects of EMF on 24-h profiles
of plasma melatonin show no effects (Griefahn et al.,
2001; Warman G R et al., 2003).
Essentials
The timing and duration of melatonin secretion are
its critical features with regard to physiological functions. The relevance of small changes in melatonin
amplitude remains obscure, particularly in view of the
enormous individual variation between normal
healthy subjects.

EFFECTS OF MELATONIN ON
HUMAN RHYTHMS
Preface
Endogenous melatonin is concerned with biological timing. There is a vast literature concerned with
effects of exogenous melatonin that do not (at least for
the moment) appear to be directed primarily at timing
mechanisms. Such effects will not be considered here.
(For reviews, see, for example, Bartsch and Bartsch,
1997; Maestroni, 1998; Mahle et al., 1997; Reiter, 2003.)
Acute Effects
Aaron Lerner was the first person to show, 40 years
ago, that melatonin had sleep-inducing effects (cited
in Lerner and Nordlund, 1978). He had the courage
and scientific curiosity to take 100 mg and reported
sleepiness after the dose. Now it is clear that low (0.3
10 mg) doses of melatonin during the biological day,
that is, when endogenous melatonin levels are low,
can induce transient sleepiness or sleep, and lower
core body temperature, in suitably controlled circum-

295

stances (posture is important; the greatest effects are

seen with recumbent subjects in very dim light)
(Cajochen et al., 1997; Deacon and Arendt, 1995).
These effects are opposite to the acute effects of bright
light given at night. A substantial body of literature
has described effects on sleep and sleep structure comparable to but not identical with benzodiazepines
(Stone et al., 2000). There is little evidence to suggest
that it has important effects in normal sleepers if given
at habitual bedtime. The effects of melatonin on sleep
have been extensively reviewed recently (Brzezinski
et al., 2005; and see this issue).
Phase-Shifting Effects
Early work suggested that 2 mg melatonin taken in
the late afternoon could advance the timing of the
endogenous melatonin rhythm, as well as inducing
early sleepiness or fatigue (Arendt et al., 1985). In
the same dose range (0.510 mg), it is able to shift circadian timing to both later and earlier times when
administration is appropriately timed (Lewy et al.,
1992). There is, however, some controversy regarding
the ability of melatonin to phase-delay the circadian
system using a single morning dose (Wirz-Justice et al.,
2002). Phase advances (and possibly phase delays) are
dose-dependent using a single dose in the range 0.05 to 5
mg (Deacon and Arendt, 1995). As for light, appropriate timing of treatment to delay or advance can in
principle be predicted from a phase-response curve in
subjects whose body clock phase is known (Lewy et
al., 1998). The reported PRCs to melatonin are essentially the reverse of that to light.
On reflection, it is perhaps surprising that the
re ported PR C does not show evi dence of
multioscillator control of melatonin secretion. The
acute response of the onset and offset of both synthesis
(AANAT activity) and melatonin secretion differ with
respect to phase shifts by light (Illnerova and Vanecek,
1988; Warman V L et al., 2003). Early work also
showed possible differential effects of melatonin itself
on the onset and offset of endogenous melatonin
secretion (Arendt et al., 1985). If melatonin exerts its
effects via a putative morning and evening oscillator, a
more complex form of PRC might be expected. The
scatter of current PRC data may simply be obscuring
more interesting phenomena.
A recent controlled study showed that daily administration for 8 days of a surge sustained release
preparation (1.5 mg) of melatonin at 1600 h followed
by recumbency and very dim light for 16 h led to sub-

296

JOURNAL OF BIOLOGICAL RHYTHMS / August 2005

DIRECT EFFECT

75

* *

100

Sleep
efficiency
(%)

CIRCADIAN EFFECT

during mel

* **

100
75

after mel

50

50
after plac

after mel

25

25

1000
60

Plasma
melatonin
(pg/ml)
100

40

20
10
12

16

20

12

12

16

20

12

Clock time (h)

Figure 2. Separation of direct and circadian effects of melatonin. Mean sleep efficiency levels (polysomnography, % per hour +SEM, top
left and top right, n = 8) and mean plasma melatonin levels (bottom left and bottom right, n = 8) on the last day (D10 closed circles) and the
washout day (D11, open circles) of an 8-day melatonin treatment (1.5 mg surge-sustained release at 16 h, followed by 16 h recumbent in very
dim light). The direct, sleep-facilitating effect of melatonin (top left) is illustrated by comparing profiles on D10 and D11. The circadian
effect of melatonin (top right) is illustrated by comparing profiles on D11 after melatonin (mel) (closed circles) or placebo (plac) (open circles). Bottom left shows mean plasma melatonin profiles during treatment (closed circles) compared to after treatment had stopped (open
circles). Bottom right shows plasma melatonin levels during a constant routine (after the treatment period) with an advance in timing of the
endogenous melatonin profile (closed circles) compared to placebo (open circles) (reproduced with permission from Rajaratnam et al.,
2003).

stantial phase advances of a number of circadian

marker rhythms and an advanced timing and redistribution of sleep during the dark phase. No increase
in total sleep time was seen, reinforcing the view that
melatonin acts on the timing mechanisms of sleep
rather than being a conventional hypnotic. The experimental design was such that both acute sleep-inducing and phase-shifting effects could be differentiated
(Fig. 2) (Rajaratnam et al., 2003; Rajaratnam et al.,
2004).
Entrainment
A single melatonin treatment (5 mg fast release) at
the right time in controlled experiments can advance
the timing of the internal clock by up to ~1.5 h (Deacon

and Arendt, 1995). The inherent period of the human

circadian clock is, on average, about 24.18 h in forced
desynchrony experiments (Czeisler et al., 1999) and
24.33 h in constant very dim light with knowledge of
clock time (Middleton et al., 1997, 1996). Free-running
blind people may have a slightly longer average
period (~24.5 h) (Hack et al., 2003). Entrainment therefore requires on average a daily advance shift of ~0.2
to 0.5 h. Thus, melatonin should be eminently capable
of entraining free-running rhythms in both sighted
and blind people. However, unpredictable effects
such as conflicting light exposure and residual high
melatonin levels in a phase-delay region of the PRC
may compromise the desired result.
If there is no good reason to remain entrained to
normal clock time, one would predict (with hindsight)
that entrainment might be less efficient (with any

aMT6s acrophase time (h)

Arendt / MELATONIN

297

04

24

24

20
20

16

16

12

12
8

8
4

10

11

Days after 9h phase advance

10 11 12 13

Days
Night shift
18-06h

Day shift
06-18h

Figure 3. Large individual variations in the rate and direction of adaptation of the 6-sulphatoxymelatonin (aMT6s) rhythm after abrupt
forced phase shifts of 9 h (laboratory study) and 12 h (real shift work). Left panel: 7 subjects underwent a synchronized 9-h phase delay,
imposed by shifting exposure to bright light, darkness, and scheduled sleep by 3 h per day for 3 days and maintaining the 9-h shift in lightdark exposure and sleep time for a further 2 days. An abrupt 9-h phase advance (return of sleep-wake schedule to local clock time) was
imposed on day 5. Right panel: 11 subjects working on offshore oil installations underwent an abrupt shift in work time from 18000600 h to
06001800 h on day 7. The individual daily calculated peak time (acrophase) for aMT6s is shown in each case. This variability indicates that
timing of melatonin treatment to adapt to phase shift needs to be as a function of individual circadian phase. Adapted from Deacon and
Arendt (1996) (left panel) and Gibbs et al. (2002) (right panel) by permission.

zeitgeber). This was probably the case with sighted

subjects kept in a dim light environment conducive to
free-running but with knowledge of clock time.
Melatonin (5 mg daily, 2000 h) was able to maintain
entrainment to 24 h in these circumstances when treatment was started at the beginning of free-running conditions, albeit with fragmentation of sleep in 4 of 16
subjects (Middleton et al., 1997). However, when treatment was started at different circadian times after a
period of free run, advances, 1 delay, shortening of
period, and in some cases a period indistinguishable
from 24 h were shown by different individuals. The
sleep fragmentation patterns suggested that
melatonin may have split 2 coupled oscillators
influencing sleep timing.
There is no doubt that timed melatonin administration (0.55 mg at 24-h intervals, usually at desired bedtime) can fully entrain (or synchronize) the free-running circadian rhythms of most blind subjects, with a
consequent improvement in sleep and daytime alertness (even without entrainment, sleep is improved)
(Arendt et al., 1997; and see Skene, this issue). Evidently these subjects are motivated to remain in synchrony with clock time and it is likely that other
zeitgebers reinforce the effects of melatonin. Interestingly, if entrainment does not occur, shortening of

period is also seen in the blind. It is possible that one

action of melatonin is to shorten period, to the extent
that entrainment is possible by other time cues if
present.
Problems Using Melatonin as a Chronobiotic
Various factors may influence the ability of
melatonin to entrain both blind and sighted humans
i ncl u di ng dos e , f or mu l a ti on, i ndi vi du a l
pharmacokinetics, free-running period, receptor sensitivity, and behavior. In sighted subjects, unknown
circadian phase, unpredictable light exposure, and
self-selected sleep times are probably the reason for
some inconsistency in the clinical trials of melatonin in
shift work and jet lag. Figure 3 illustrates the diversity
of response to phase shift in untreated healthy adults.
Unless circadian phase is known, correct timing to
induce a shift in the desired direction is almost impossible to predict. There is, however, some scant evidence that appropriate melatonin treatment prior to
phase shift can dictate the direction in which the internal clock adapts (Arendt, 1995). Pre-phase-shift treatment has rarely been employed. Rigorous recent independent assessments of its usefulness do not agree. A
Cochrane review (Herxheimer and Petrie, 2002) con-

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JOURNAL OF BIOLOGICAL RHYTHMS / August 2005

cluded that there was good evidence for beneficial

effects in jetlag. However, a recent analysis by the
Agency for Healthcare Research and Quality (http://
www.ahrq.gov/news/press/pr2004/melatnpr.htm)
of the effects of melatonin supplements on sleep in
shift work, jet lag, and delayed sleep phase syndrome
(DSPS) concluded that there was only good evidence
for an effect in DSPS.
Oncostatic Effects of Melatonin,
Light at Night, and Clock Genes
There is now quite substantial evidence that
melatonin has some oncostatic activity in vitro (Blask
et al., 2002). Various mechanisms have been proposed
including inhibition of estrogen transduction pathways (in mammary cancer) (Hill et al., 2000) and inhibition of tumor fatty acid uptake (Sauer et al., 2001).
Melatonin receptors, particularly MT1, are implicated. However, there are frequent differences in
response even within the same cell line (e.g., the
human breast cancer cell line MCF 7). There is some
preliminary evidence for beneficial effects of combined chemotherapy or immunotherapy and
melatonin (Lissoni et al., 2000; Lissoni et al., 2003).
This subject is included here since there is evidence
that pinealectomy, photoperiod per se (for references,
see Arendt, 1995), and forced phase shifts of the lightdark cycle (Filipski et al., 2004) can influence growth
of tumors. In vivo, it has also been reported that
melatonin may increase or decrease tumor growth,
depending on photoperiod, in hamsters (Stanberry et al.,
1983).
It has been proposed that light at night during night
shift work suppresses melatonin and that this loss of
melatonin activity is responsible for the increased
cancer risk (e.g., Schernhammer and Schulmeister,
2004; Stevens and Davis, 1996). However, to attribute
any detrimental effects directly to loss of melatonin is
overspeculative. Light at night has numerous other
effects. The mere fact of frequent disruption of all circadian rhythms, not just melatonin, is effectively a
physiological insult.
Most important perhaps, light directly influences
the expression of the clock gene feedback loops driving circadian rhythms (Reppert, 2000). Disruption of
clock gene function is associated with increased risk of
cancer in recent animal studies (Fu and Lee, 2003).
Numerous potential mechanisms may be invoked in
view of the ubiquitous nature of circadian rhythms. A

particular length polymorphism in hper3 (the lark

variant; Archer et al., 2003) has been associated with
increased breast cancer risk in premenopausal women
(Zhu et al., 2005). This preliminary study will require
confirmation in larger numbers. Thus, a more plausible hypothesis regarding the risk of breast cancer in
subjects exposed to light at night would involve the
whole circadian axis. Perhaps here may lie one aspect
of the oncostatic activity of melatonin. By acting as a
circadian coupling agent countering desynchrony
among central and peripheral clocks, and optimizing
phase with respect to external time cues, cellular and
system processes may be optimized and defense systems augmented. These considerations may also
apply to risk of other major diseases associated with
shift work (for example, heart disease, metabolic
syndrome, possible decreased fertility).
MECHANISM OF ACTION
The locations and pharmacology of melatonin
receptors have recently been extensively reviewed.
Two cloned receptors, MT1 and MT2 (Masana and
Dubocovich, 2001; Reppert et al., 1995), are of particular importance with regard to rhythm physiology and
pharmacology. Using gene knockout technology in
mice and pharmacological manipulations, the results
to date suggest that the phase-shifting melatonin
receptor in the SCN is MT2, while MT1 is associated
with acute suppression of SCN electrical activity (Liu
et al., 1997). MT1 has important actions within the pars
tuberalis (PT) controlling seasonal prolactin variations in ruminants (de Reviers et al., 1989; Lincoln and
Clarke, 1994; Williams and Morgan, 1988). Genetic
polymorphism has been identified within melatonin
membrane receptors, and further investigation of
these polymorphisms in relation to photoperioidism,
human disease, sensitivity to melatonin, and so on, is
ongoing (Ebisawa et al., 2000; Migaud et al., 2002).
Probably the most interesting development in the
effects of melatonin concerns its influence on peripheral gene expression in the pars tuberalis (Messager
et al., 1999). Lincoln et al. (2003) suggested that the
photoperiodic melatonin signal is decoded via differential phasing of per and cry expression in the PT.
In rodent pars tuberalis cells, rhythmic expression of
the clock gene per1 appears to be dependent on sensitization of adenosine A2b receptors, which in turn
depend on melatonin activation of MT1 receptors
(von Gall et al., 2002). Clearly it is possible that the

Arendt / MELATONIN

melatonin signal is a widespread humoral mechanism

related to biological timing, acting through modification of peripheral clock gene expression. However, it
appears not to affect SCN clock gene expression
acutely (Poirel et al., 2003). The effects of melatonin on
peripheral, as well as central, clock gene expression
are likely to be a rich field of enquiry.
PHYSIOLOGICAL ROLE OF
MELATONIN IN HUMANS
The melatonin rhythm is not essential to human
life, or indeed human sleep and circadian rhythms. It
may even be disadvantageous in some circumstances
(working out of phase) in the 24/7/365 society. The
best evidence for a physiological role in human circadian rhythms concerns the timing and reinforcement
of night time physiology, for example, the nadir of
core temperature, alertness and performance, and the
timing of sleep. Any system with a circadian component may be susceptible to the influence of endogenous melatonin. It appears to modulate response to
changing time cues as an adjunct to light and, possibly,
in some circumstances, in conflict with light.
Important aspects of human seasonality include
changes in mood, sleep timing, immune system, conception rate (even the success of in vitro fertilization
better in long days; Rojansky et al., 2000). Roenneberg
and Aschoff (1990) found clear evidence of human
seasonality when analyzing a large number of
monthly birth rates worldwidewith an increase in
conception rate in spring. There is evidence that
melatonin signals daylength to human physiology, as
it does in other species (Arendt, 1999). There is even
some preliminary evidence that human pinealectomy
(which abolishes the melatonin rhythm) decreases
human seasonality (Macchi et al., 2002). Melatonin
clearly reinforced the effects of a shortened
photoperiod i n recent huma n experiments
(Rajaratnam et al., 2003). It is not inconceivable that
melatonin/photoperiod may have a therapeutic function with regard to human fertility. Since melatonin
has powerful physiological effects in photoperiodic
species, it behooves us to be certain of its uses and limitations, and long-term safety needs to be assessed.
There is very little evidence in the short term for toxicity or undesirable effects in humans. The extraordinary hype of the miraculous powers of melatonin in
the recent past did a disservice to acceptance of its
genuine benefits.

299

ACKNOWLEDGMENTS
I would like to thank all the very numerous colleagues with whom I have collaborated over the years.
This review was written during the tenure of grants
from the UK Health and Safety Executive, The Energy
Institute, The Antarctic Funding Initiative, and with
support from Stockgrand Ltd, University of Surrey.
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