Best Practice & Research Clinical Endocrinology and Metabolism

Vol. 17, No. 2, pp. 273 –285, 2003

doi:10.1053/ybeem.2003.249, www.elsevier.com/locate/jnlabr/ybeem

Melatonin: clinical relevance

Russel J. Reiter* PhD

Professor
Department of Cellular and Structural Biology, Mail Code 7762, The University of Texas Health Science Center,
7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA

This chapter reviews the neural connections between the retinas and the pineal gland and
summarizes the role of the light:dark cycle and the biological clock, i.e. the suprachiasmatic
nuclei, in regulating pineal melatonin synthesis and secretion. The cellular mechanisms
governing the nocturnal production of melatonin are described together with the way in which
the misuse of light interferes with the circadian melatonin cycle and the total quantity of the
indole generated. The chapter describes the nature of the membrane melatonin receptors and
their signal transduction mechanisms in peripheral organs. The clinical implications and
potential uses of melatonin in terms of influencing the biological clock (e.g. sleep and jet lag),
immune function, and cancer initiation and growth are noted. Additionally, the chapter includes
a description of the newly discovered free radical scavenging and antioxidant activities of
melatonin; it also includes a list of clinical situations in which melatonin has been used with
beneficial effects.

Key words: melatonin; pineal gland; oxidative stress; sleep; jet lag; circadian rhythms; cancer;
light:dark cycle.

Melatonin (N-acetyl-5-methoxytryptamine) was characterized after its isolation from

bovine pineal tissue by Lerner et al1,2 roughly 50 years ago; this indole is now known
to be the major secretory product of the pineal gland in all mammals, including man.
The impetus for the characterization of melatonin was the fact that earlier studies in
tadpoles had shown that it is a potent skin-lightening agent, i.e. it inhibits the
dispersion of melanin in epidermal melanocytes. Shortly after its discovery,
melatonin was tested for this property in humans and found to be ineffective in
this regard.
In the intervening years since its structural identification, melatonin has been
functionally linked in various species to the regulation of circadian3 and seasonal4
rhythms, immune function5, retinal physiology6, tumour inhibition7 and, most
recently, it has been found to be a free radical scavenger and antioxidant.8,9 The
review of the literature that follows discusses the regulation of melatonin synthesis,
its mechanisms of action at the peripheral level and the clinical implications of these
findings.

* Tel.: þ 1-210-567-3859; Fax: þ1-210-567-6948.

E-mail address: reiter@uthscsa.edu (R. J. Reiter).

1521-690X/03/$ - see front matter Q 2003 Elsevier Science Ltd. All rights reserved.
274 R. J. Reiter

REGULATION OF PINEAL FUNCTION

Unlike classical endocrine organs, the pineal gland in general, and melatonin synthesis in
particular, is not markedly influenced by hormones from other ductless glands or cells.
Rather, the major regulator of melatonin production is the prevailing light:dark
environment. In this regard, the pineal gland is an end organ of the visual system not
unlike the visual cortex.10 Only during darkness at night does the pineal gland produce
melatonin in abundance. What this means, of course, is that information about light
perception at the level of the retinas must be transferred to the pineal gland. This is
accomplished by a series of neurons that originate in the retinas and eventually end in
the pineal gland.
The classical photoreceptor cells, i.e. the rods and cones, seem not to be involved in
light perception that modulates pineal melatonin production. Rather, there are
specialized neurons which contain a unique photopigment in the retina that respond to
light.11,12 This information is transduced into a neural message which is transferred to
the anterior hypothalamus via axons of retinal ganglion cells in the optic nerve; this is
part of the so-called retino-hypothalamic tract. In the hypothalamus, the axons from the
retina terminate in the suprachiasmatic nuclei (SCN), a type of nucleus whose neurons
exhibit inherent circadian electrical rhythms; these nuclei constitute the biological clock
or the central circadian pacemaker.13 Between the SCN and the pineal gland, the neural
pathways, at least centrally, are somewhat less defined but are believed to be as follows:
SCN, paraventricular nuclei, intermediolated cell columns of the upper thoracic cord
(preganglionic sympathetic neurons), superior cervical ganglia (postganglionic sym-
pathetic neurons), pineal gland (Figure 1). This circuitous pathway conveys information
about the light:dark environment to the pineal gland and thereby determines the
melatonin synthesis cycle.
The regulation of melatonin production in the pineal gland has been defined in
significant detail.14,15 The primary neurotransmitter released from the postganglionic
sympathetic terminals that terminate in the pineal gland is norepinephrine (NE)

Pineal gland
Cerebrum
Post-ganglionic
SCN sympathetic neuron

Cere-
bellum
Eye
Pituitary
gland
Superior
cervical ganglion

Upper
thoracic
cord
Pre-ganglionic
Intermediolateral sympathetic
cell column neuron
Figure 1. The circuitous neural connections between the eyes and pineal gland involve neurons in both the
central and peripheral sympathetic nervous system. Interruption of the innervation to the pineal gland, for
example, by superior cervical ganglionectomy, renders the pineal non-functional.
 Melatonin 275

(noradrenalin); during darkness at night, NE is discharged onto the pinealocytes, the

endocrine cells of the gland, where it couples especially to beta-adrenergic receptors.
This leads to a marked rise in intracellular cAMP levels, to de novo protein synthesis
and eventually to the stimulation of the rate-limiting enzyme in melatonin production,
arylalkylamine-N-acetyltransferase (AA-NAT). AA-NAT N-acetylates serotonin to N-
acetylserotonin (NAS), the immediate precursor of melatonin (Figure 2). Once
generated, NAS is quickly O-methylated, a step catalyzed by hydroxyindole-O-
methyltransferase (HIOMT); this reaction requires the transfer of a methyl group
from 5-adenosylmethionine to the 5-hydroxy group of NAS. The dramatic rise in AA-
NAT drives melatonin synthesis and, consequently, the melatonin content of the pineal
increases substantially at night.
Unlike other endocrine organs, the pineal does not store melatonin for later release
after it is synthesized. Rather, melatonin quickly diffuses out of the pinealocytes into the
rich capillary bed16 within the gland and possibly directly into the cerebrospinal fluid
(CSF) of the third ventricle.17 As a result, blood and CSF levels rise at night and the
concentration of melatonin in these fluids is generally accepted as an index of its
concurrent synthesis within the pineal gland; circulating nocturnal levels of melatonin
are commonly 10 – 20 times higher than concentrations measured during the day.
The amount of melatonin produced in the pineal is genetically determined. Among
individuals of the same age, the night-time rises in blood melatonin concentrations vary
widely. Thus, while some individuals exhibit what is considered to be a robust nocturnal
increase in blood nocturnal melatonin concentrations, in others the amplitude of the
peak may be severely attenuated. Given that the amplitude of the melatonin rhythm is
repeated with great fidelity from night to night, clearly some individuals over the course
of their lifetime produce much more melatonin than others. The significance of these
marked differences in the lifetime quantities of melatonin generated by the pineal gland
remain unknown.
The introduction of artificial light has significantly compromised the quantity of
melatonin the human pineal gland produces inasmuch as light is used indiscriminately
during the normal periods of darkness. Light at night prevents the SCN from signalling
the pineal gland to activate the molecular machinery to produce melatonin. For
example, while the light:dark cycle at the equinoxes is 12:12 (in h), the actual duration
of darkness humans witness is usually significantly less. As a result, the use of artificial
light (sometimes referred to as the misuse of light) truncates the period of melatonin
synthesis to an interval shorter than it would normally be, thereby limiting the total
amount of melatonin produced.18 In this case, light acts a ‘drug’ to reduce melatonin
levels.19 Light exposure has two basic functions on the melatonin synthesis cycle: acute
light exposure at night (even of very short durations) inhibits melatonin production
while alternating periods of light (and darkness) serve to synchronize the melatonin
rhythm to 24 h. When these regularly alternating periods of light:dark are disturbed, so
too is the rhythm of the biological clock, i.e. the SCN, and the melatonin synthesis cycle.
The degree of inhibition of melatonin synthesis by mistimed light depends on its
wavelength, intensity and the circadian phase at which the exposure occurs.
A second major factor that influences the quantity of melatonin synthesized in the
pineal gland is age.20 While the melatonin rhythm described above is typical of young to
middle-aged individuals, in elderly humans, the amplitude of the nocturnal melatonin
increase can be severely attenuated although there seem to be significant variations
among individuals in the rate at which melatonin is lost.21 The gradual waining of the
synthetic capability of the pineal gland probably relates to several factors, including a
reduction of the number of beta-adrenergic receptors on the pinealocyte membranes,
 276 R. J. Reiter
Postganglionic sympathetic nerve
Capillary NE NE Capillary
Extracellular Space Ca2+

Pinealocyte PI
membrane β AC PLC α1
DG
Gs + + PKC G _
Tryptophan IP
TH c AMP ATP
Ca2+
5-Hydroxytryptophan
AAAD
NAT N-Acetyl HIOMT
Serotonin Melatonin
Serotonin
MAO
HIOMT Other Metabolites
5-Methoxytryptamine

Figure 2. Interactions of NE (noradrenalin) released from postganglionic sympathetic fibres with beta-adrenergic receptors in the pinealocyte membrane. This interaction
initiates a series of intracellular events which culminate in a large rise in the acetylation of serotonin to N-acetylserotonin by the enzyme N-acetyltransferase (NAT). Once
produced, melatonin is quickly discharged into the capillary bed in the pineal gland and possibly directly into the CSF of the third ventricle.
 Melatonin 277

deterioration of the melatonin synthetic machinery within the pineal gland and a
progressively weakening signal from the SCN.

MELATONIN METABOLISM IN PERIPHERAL TISSUES

In the liver, melatonin undergoes 6-hydroxylation followed by conjugation, primarily to

sulphate.14 The resulting product, 6-hydroxymelatonin sulphate, is excreted in the
urine as a major melatonin metabolite. The quantity of this product in the urine is
greater at night than during the day, reflecting the pineal melatonin synthesis and
secretion cycle.
Melatonin is also converted, presumably in all cells, to cyclic 3-hydroxymelatonin.22
This metabolite is formed when melatonin directly scavenges two hydroxyl radicals and
it can likewise be measured in the urine where the quantity is proportional to the
degree of oxidative stress an individual has experienced.20

SITES OF MELATONIN ACTION

Melatonin has a variety of means by which it influences the physiology of the organism;
some of these actions are receptor-mediated while others are receptor-independent.
Besides its classical endocrine effects, melatonin has autocrine and paracrine actions
and also functions as a direct scavenger of free radicals.23
Membrane melatonin receptors were initially defined on the basis of their
pharmacological and kinetic characteristics. The known melatonin receptors have
seven transmembrane domains and they are in the superfamily of G-protein-coupled
receptors.24 Two receptor subtypes with high affinity for melatonin have been cloned
and characterized in a variety of animals/tissues, including in the human SCN; according
to the IUPHAR classification, these receptors are identified as MT1 and MT2.25 A third
high-affinity membrane melatonin receptor has been cloned but it is yet to be found in
mammals. The likelihood is great that other receptors and/or isoforms that bind
melatonin will be uncovered.
The distribution of the known melatonin receptors is remarkably widespread in
mammalian tissues, although less is known of their localization in humans. Those
mammalian tissues in which melatonin receptors are most consistently found include the
SCN26 and the pars tuberalis27 of the adenohypophysis but, in reality, as data continue to
accumulate, it seems that few tissues are devoid of membrane receptors, for melatonin.
The signal transduction pathways for the known melatonin receptors have been
described. The cloning of melatonin receptor cDNA resulted in the development of cell
lines in which MT1 or MT2 recombinant receptors were expressed. When the human
melatonin receptors (hMT1 and hMT2) were cloned and expressed in a variety of cells,
they were found to inhibit forskolin-stimulated cAMP. Activation of recombinant hMT1
receptors induces a variety of cellular responses that are mediated by both pertussis
(PTX)-sensitive and PTX-insensitive G-proteins. The recombinant hMT2 receptor is
also coupled to inhibition of adenylyl cyclase activity via a PTX-sensitive G-protein. The
significant pharmacology of the membrane melatonin receptors is under intense
investigation.
Given melatonin’s high lipophilicity and the ease with which it enters cells,
investigations into potential intracellular binding sites have also been initiated.
278 R. J. Reiter

Melatonin has been shown to bind calmodulin in the cytosol,28 and nuclear binding sites
or receptors have been pharmacologically characterized in white blood cells of
humans.29 The role of these binding sites in determining the day-to-day actions of
melatonin remains to be fully defined. Additionally, within cells, melatonin functions as
a direct scavenger of free radicals, and as an indirect antioxidant.30,31 The former of
these activities is a receptor-independent function of the indole and the direct
scavenging effects of melatonin, which do not require receptor mediation, have been
shown to exist in cell membranes, in the cytosol and in the nucleus.

CLINICAL ASPECTS OF MELATONIN

Chronobiotic effects

Melatonin acts at the level of the SCN to modulate its activity and influence circadian
rhythms. Properly timed melatonin administration shifts circadian rhythms, facilitates
re-entrainment to a novel light:dark cycle and alters the metabolic activity of the central
circadian pacemaker, i.e. the SCN. The direction in which melatonin phase-shifts the
circadian system depends on its time of administration. When given late in the
subjective day (at dusk), melatonin phase advances the clock while its administration
early in the subjective day (at dawn) phase delays circadian rhythms. Likewise, the ability
of melatonin to re-entrain rhythms after a phase advance of the light:dark cycle, for
example, travelling from the USA to Europe, is also time-of-day dependent; thus, taking
melatonin at the time of the former dark onset (in the USA) reduces the rate of re-
entrainment, while melatonin administration at the new dark onset (in Europe) hastens
the rate of re-entrainment.32 The chronobiotic effects of melatonin explain its benefit in
reducing the severity and/or duration of jet lag33 and in promoting restful sleep.34
Melatonin’s influence on sleep processes has been widely investigated and the
relationships seem to be highly complex. There is a common misconception that pineal
melatonin synthesis at night requires sleep; this is not the case. The only requirement
for increased melatonin production is darkness at night. Conversely, the night-time
rises in circulating levels of melatonin seem to promote sleep onset and maintain restful
sleep in some individuals. Currently, there is general agreement that melatonin is
probably not a direct soporific or hypnotic. Rather, the most commonly proposed
mechanisms for melatonin to induce sleepiness relates to its effects on the circadian
clock, i.e. it ‘opens the sleep gate’35 and also it slightly reduces body temperature36
which promotes sleep. Melatonin has these effects over a wide range of doses from
physiological (250 mg) to pharmacological (1– 10 mg) levels. When used to improve
sleep, i.e. to decrease sleep latency and/or cause more prolonged sleep, it is taken
roughly 30 min prior to bedtime. Melatonin has been successfully used with various
degrees of effectiveness to enhance sleep processes in elderly individuals with insomnia
and in individuals with restless leg syndrome, REM sleep disorder behaviour, delayed
sleep phase syndrome, manic patients with insomnia and in patients with fibromyalgia.37

Oncostatic effects

A considerable amount of evidence has been amassed which documents the efficacy of
melatonin in reducing tumour growth. While the bulk of these data have accurred from
studies on experimental animals7,38, trials in humans39 with a wide variety of different
cancers are also suggestive of the oncostatic actions of melatonin.
 Melatonin 279

As with the sleep-promoting function of melatonin, the concentrations of the indole

that reduce cancer cell proliferation, tumour growth and the incidence of metastases
vary from physiological to pharmacological. If, in fact, physiological levels of melatonin
normally restrain tumour growth, the age-associated reduction in melatonin production
may be contributory to the increased frequency of cancer in the elderly. There is also
some evidence to indicate that the efficacy of melatonin in limiting tumour cell
proliferation depends on time of day of its administration, with melatonin given late in the
light phase being more effective.38 In humans, the use of melatonin in some cases reduced
tumour growth and prolonged survival of cancer patients compared with individuals
given conventional cancer therapy.39 Importantly, melatonin administration, when
combined with standard chemotherapies, often improve the quality of life. This probably
relates to melatonin’s ability to reduce the toxicity of chemotherapeutic agents.8 The
findings in humans are made more remarkable by the fact that melatonin was used as a
cancer treatment only after all other therapies were found to be essentially ineffective.
Mechanistically, how melatonin inhibits tumour cell proliferation has been, in part,
defined, and it apparently involves a number of mechanisms. In the case of experimental
hepatomas and human breast cancer xenografts, melatonin acts on specific membrane
receptors to limit the transport of linoleic acid (LA), a growth factor, into tumour cells.7
With decreased LA uptake, intracellular 13-hydroxyoctadecadienoic acid (13-HODE)
levels drop; 13-HODE is a mitogenically active metabolite that normally increases
tumour cell proliferation via MAPK.
There are, however, a variety of other actions that have been implicated to explain
melatonin’s oncostatic effects. In oestrogen-receptor-positive human breast cancer cells,
melatonin is thought to modulate oestrogen receptor expression and transactivation.40 Still
other potential mechanisms include melatonin’s ability to reduce angiogenesis in tumours,
to delay the G1 to S phase transition in the cell cycle, to improve cellular communication
between normal and cancer cells, and to alter the intracellular redox state.
Besides inhibiting established tumours, melatonin may also decrease their initiation.
As an antioxidant (see below), melatonin has been found to be particularly effective in
reducing free-radical-mediated damage to DNA.41 Damaged DNA, if it goes
unrepaired, may mutate and initiate a tumour. As a significant portion of the cancer
humans acquire is believed initially to involve DNA damage as a consequence of toxic
oxygen and nitrogen by-products, antioxidants that protect DNA from such mutilation
would be expected to reduce cancer incidence; the evidence is strong that melatonin
protects DNA from such damage more effectively than other classic antioxidants.41

Effects on the immune system

Interactions between melatonin and the immune system have been known for roughly
30 years, and in virtually all cases, melatonin has been proven to have immunoenhancing
effects. The number of publications on this subject are extensive and the findings are
summarized in several reviews.42,43 In humans, daily oral melatonin administration
increases natural killer (NK) cell activity.5,42 Additionally, melatonin reportedly
regulates gene expression of several immunomodulatory cytokines including tumour
necrosis factor-a (TNFa), transforming growth factor beta (TGFb) and stem cell factor
(SCF) by peritoneal macrophages as well as the levels of interleukin-1beta (IL-1b),
interferon gamma (INFg), TNFa and SCF by splenocytes.43 The rise in blood melatonin
levels in humans at night stimulates associated rises in the thymic production of
peptides including thymosin 1a and thymulin.44 Finally, melatonin is a potent inhibitor
of apoptosis in immune cells.45
280 R. J. Reiter

The actions of melatonin on immunocompetent cells seem to be mediated by both

membrane and nuclear binding sites. On both human lymphocytes and monocytes,
receptor sites for melatonin have been characterized; binding sites with similar
pharmacological characteristics have been identified in a variety of immune cells from
animals. Additionally, however, in both animal and human immune cells, nuclear binding
sites for melatonin have been documented.5 The binding of melatonin to these sites is
displaced by a specific ligand of the putative nuclear melatonin receptor RZR/ROR.46
Thus, immune cells apparently possess two reasonably well-characterized receptors,
i.e. membrane and nuclear. The interactions of melatonin with the immune system are
summarized in the hypothetical scheme shown in Figure 3.
Given that melatonin is generally considered to be immunostimulatory, the question
as to whether it should be taken by individuals with an autoimmune disease has been
raised. To date, the information is meager regarding this issue, although in one case of
Crohn’s disease, a condition of excessive immune reactivity of the gut wall, melatonin
did aggravate the condition.47 Whether this will be a general finding in autoimmune
diseases, however, remains to be established.

Respiratory
Phagocytic burst
activity ⊕ ⊕

Circulating N BL
neutrophils CD19+

lipoxygenase

⊕ NO
MEL
Thymus ⊕ ROI
M
Epithelial CD14+
⊕ cell CD4+ TF
thymosin α1
⊕
Th1
IL-2
⊕
IL-6

CD3+
⊕ ⊕ TNF
IL-
1

thymulin CD4+
IF ⊕
N
⊕ Circulating
M

lymphocytes
IO

⊕
S

Thymocyte CD16+
⊕ monocytes
⊕ GM-CFU
thymosin α1 ⊕ ⊕
NK activity ADCC
Bone
marrow
Figure 3. A summary of the presumptive actions of melatonin on immunocompetent cells. By influencing the
activity of the monocyte (CD14þ/CD4þ cells) and T cell, melatonin increases NK cell activity, as well as
antibody-dependent cellular cytotoxicity (ADCC) and stimulates the production of progenitor cells for
granulocytes and macrophages (GM-CFU). Furthermore, melatonin inhibits 5-lipoxygenase activity by B cells
and increases thymosin 1a and thymulin by thymic epithelial cells. MIOS, melatonin-induced opioid system;
ROI, reactive oxygen intermediates; NO, nitric oxide; TF, tissue factor.
 Melatonin 281

Antioxidant effects

Slightly over a decade ago, melatonin was found to be a highly effective scavenger of free
radicals and general antioxidant.48 In the intervening years, these effects of melatonin
have been documented in hundreds of published reports and it has been found to
reduce oxidative damage in numerous models where free radicals contribute to the
aetiology of a particular condition.8,9,30,31,49
Melatonin directly neutralizes a number of toxic oxygen- and nitrogen-based
reactants, including the hydroxyl radical (zOH), hydrogen peroxide (H2O2), hypochlor-
ous acid (HOCl), singlet oxygen (1O2) and the peroxynitrite anion (ONOO2) or
peroxynitrous acid (OHOOH).9,31 Furthermore, melatonin has indirect antioxidative
actions, including stimulating the synthesis of another important intracellular
antioxidant, i.e. glutathione (GSH)50, as well as promoting its enzymatic recycling in
cells to ensure it remains primarily in its reduced form.30 Finally, melatonin preserves the
functional integrity of other antioxidative enzymes, including the superoxide dismutases
and catalase. Melatonin may also reduce free radical generation in mitochondria by
improving oxidative phosphorylation, thereby lowering electron leakage, and increasing
ATP generation (Figure 4).51
Free radical damage has been implicated in a wide variety of diseases and in
experimental models of a diverse range of these conditions; melatonin has been
shown in all of these cases to be protective.52,53 Examples of situations in which
melatonin has been found to lower induced oxidative damage include ischaemia/
reperfusion injury (in the brain, heart, gut, liver, lung, urinary bladder), toxic drug
exposure, bacterial toxin exposure, schistosomias, heavy metal toxicity, amyloid b
(Ab) protein exposure (as a model of Alzheimer’s disease)54, 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine (MPTP) exposure (as a model of Parkinsonism)55, etc. The
finding that melatonin reduces Ab damage to neurons54 prompted its use in
Alzheimer’s patients where it improved the status of these individuals.56 – 58
Melatonin has also been successfully used as an adjuvant treatment in neonates
with sepsis (a high free radical condition)59 and with transient ischaemia/
reperfusion.60 Other conditions in humans where melatonin has been shown to
be beneficial include the following: skin erythema due to exposure to ultraviolet
radiation61, iron and erythropoietin administration62 and tardive dyskinesia.63 Each of
these is believed to involve, as part of the destructive processes, free radical damage
to essential macromolecules. Given the virtual absence of toxicity of melatonin8,
reports of its use in humans to combat free radical damage will probably continue to
appear.

CONCLUDING REMARKS

In such a brief summary, it is not possible to mention all the data which document the
clinically relevant aspects of melatonin. Metatonin has been administered in both
physiological and pharmacological amounts to humans and animals, and there is
widespread agreement that it is a non-toxic molecule. Furthermore, melatonin limits
tissue damage induced by drugs whose toxicity is a consequence of free radical
generation.8
The actions of melatonin summarized herein suggest that it is generally a highly
beneficial molecule for reducing tissue and cellular deterioration and possibly for
lowering the incidence of some diseases. Many of the molecular mechanisms by which
 282 R. J. Reiter
Inhibits pro-oxidative
Stimulates antioxidative Wide intracellular
enzyme
enzymes distribution

Detoxifies oxygen-based Reduces NF-κB

radicals/reactive species Melatonin
binding to DNA
O
O Reduces pro-inflammatory
Detoxifies nitrogen-based H3C NH CH3 cytokines
radicals/reactive species Reduces adhesion
N molecules
H

Crosses all Stabilizes cellular Increases efficiency of

morphophysiological membranes oxidative phosphorylation
barriers

Figure 4. This figure summarizes the multiple actions whereby melatonin protects cells from oxidative damage. Both receptor independent processes, for example, direct
scavenging of free radicals, and receptor-mediated actions, for example, stimulation of antioxidative enzymes, presumably account for the highly protective effects of this
molecule in vivo.
 Melatonin 283

melatonin achieves these changes require further definition. While the pharmacological
use of melatonin is well established, how the gradual reduction in endogenous
melatonin levels due to ageing—or its suppression by excessive light exposure—effects
humans remains unknown.
Finally, whereas melatonin is generally classified as a hormone, it is in fact a molecule
with paracrine, autocrine and antioxidant actions.23 In reference to its antioxidative
actions in humans, physiological blood levels of melatonin positively correlate with the
total antioxidant capacity of that fluid.64 Considering its diverse actions via both
receptor and receptor-independent actions, to classify melatonin exclusively as a
hormone seems inappropriate.

Practise points
† do not overlook the importance of a regular light: dark cycle in good health
† bright light exposure after darkness onset at night should be avoided since it
disrupts the melatonin rhythm and the circadian clock are altered as a
consequence
† when used for night-time sleep promotion, melatonin is taken 30 min in
advance of desired sleep onset
† melatonin is a highly effective antioxidant

Research agenda
† the role of excessive light exposure (decreased dark exposure) at night should
be examined in terms of its impact on human health
† trials are needed regarding the oncostatic effects of melatonin
† the efficacy of melatonin in reducing the toxicity of a variety of prescription
drugs requires examination
† trials on the benefits of melatonin in the aged are warranted, particularly in
reference to neurodegenerative disease

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