MELATONIN
SYNTHESIS OF MELATONIN
Tryptophan
Serotonin (5 - hydroxy tryptamine)
Acetylating enzyme N -
acetyl transferase (NAT)
N - acetyl Serotonin
Hydroxy indole - 0 -
methyl transferase (HIOMT)
Melatonin(N - acetyl - 5 - methoxy tryptamine)
Melatonin is synthesized from the dietary
amino acid tryptophan. The hormone has
high lipid and water solubility and gains
access to various fluid, tissue, and cellular
compartments when released in the
circulation. Although melatonin may be
synthesized in several other tissues, the
circulating amounts of the hormone in
humans are exclusively of pineal origin
with an average secretion rate of 29 mcg/
day. Results
mainly from animal studies indicate that melatonin increases
the concentration of aminobutyric acid and serotonin in the
midbrain and hypothalamus and enhances the activity of py-
ridoxal-kinase, an enzyme involved in the synthesis of ami-
nobutyric acid, dopamine, and serotonin. Melatonin is
involved in the inhibition of gonadal development and in the
control of oestrus. It is also involved in protective changes in
skin coloration. There appears to be a diurnal rhythm of me-
latonin secretion: it is secreted during hours of darkness and
may affect sleep pattern. Because of its possible role in influ-
encing circadian rhythm, melatonin has been tried in the alle-
viation of jet lag and other disorders resulting from delay of
sleep. It is also being studied in insomnia and various depres-
sive disorders including seasonal affective disorder, and in
large doses for its contraceptive activity.
A number of melatonin analogues are being developed.
In the absence of external time-giving cues.
most biochemical. physiological, and
behavioural variables in humans exhibit
regular fluctuations within a period of
approximately 24 hours. These circadian
rhythms are endogenous in nature and
controlled by a central pacemaker in the
suprachiasmatic nuclei (SCN) of the
hypothalamus.
The external light/dark cycle is the major
synchronizer of the human circadian clock
to the daily changes in the environment.
The 24-hour profile of plasma melatonin.
With high levels during the night and low
levels during the day in both diurnal and
nocturnal species represents one of the
most robust circadian rhythms.
Circadian pacemaker in the SCN controls
pineal function via a multisynaptic
projection. ending in a sympathetic
projection from the superior cervical
ganglion to the pineal body. The activation
of this pathway during the night and the
resulting stimulation of pinealocyte beta-1
adrenoceptors trigger the enzymatic
sequence of melatonin synthesis.
In addition to the role of light us a main
synchronizer of the central circadian
pacemaker controlling melatonin
secretion, exposure to photic stimuli during
subjective night results in acute
suppression of pineal function.
CHARACTERISTICS OF
THE 24-HOUR MELATONIN
PROFILE
TIME OF DAY
The highest levels of plasma melatonin in
healthy adults can range from undetectable
amounts to values of 250 pg/ml with a
mean of 60 to 70 pg/ml. The melatonin
profile is a useful marker of human
circadian function with a well-defined
phase relationship to the 24-hour cortisol
and temperature rhythms.
CHANGES IN MELATONIN
LEVELS WITH AGE
Maternal melatonin crosses the placenta
and rodent data suggest that the hormone
acts as a synchronizing stimulus for the
circadian system of the foetus .The
endogenous melatonin rhythm appears at
9 to 12 weeks of age in normal full-term
infants.
After the initial maturation of pineal
function, human melatonin levels increases
reaching a lifetime peak between 3 and 5
years of age. It is proposed that the
subsequent decline in plasma
concentrations during late childhood and
adolescence may be related to the onset of
puberty .Mean adult concentrations are
reached in the mid to late teens and remain
relatively unchanged for several decades.
A final period of gradual decline occurs
during senescence and leads to a significant
decrease in the amplitude of the 24-hour melatonin
profile in the elderly subjects.
MECHANISM OF ACTION
Bioregulation
Two membrane bound melatonin-binding
sites belonging to pharmacologically and
kinetically distinct groups have been
identified: MLI (high affinity) sites and
ML2 (low affinity) sites. These receptors
are probably involved in the regulation
retinal function,circadian rhythms, and
reproduction. With the use of the
polymerase chain reaction (PCR),two
forms of a high-affinity melatonin receptor
which have been designated Mel la and
Mel Ib. were cloned From several
mammals, including humans. The Mel la
receptor is expressed in the hypophysial
pars tuberalis and the suprachiasmatic
nucleus (the presumed sites of the
reproductive and circadian actions of
melatonin, respectively). [he Mel Ib
melatonin receptor is expressed mainly in
the retina and, to a lesser extent, in the
brain.
Melatonin may also act at intracellular
Site.Through binding to cytosolic
calmodulin, the hormone may directly
affect calcium signalling by interacting
with target enzymes such as adenylate
cyclase and phosphodiesterase. as well as
with structural proteins.
Autoradiography and radioreceptor assays
have demonstrated the presence of
melatonin receptors in various regions of
the human brain and in the gut, ovaries,
and blood vessels. Neural receptors (e.g..
those in the suprachiasmatic nucleus of the
hypothalamus) are likely to regulate
circadian rhythms. Non-neural melatonin
receptors (such as those located in the pars
tuberalis of the pituitary) probably regulate
reproductive function. especially in
seasonally breeding species, and receptor
located in peripheral tissues (e.g.. arteries)
may he involved in the regulation of
cardiovascular function and body
temperature.
Scavenging Free-radicals
Both in vitro studies and in vivo studies
have shown that melatonin is a potent
scavenger of the highly toxic hydroxyl
radical and other oxygen centered radicals.
suggesting that it has actions not mediated
by receptors. In one study, melatonin
seemed to he more effective than other
known antioxidants (e.g. mannitol.
glutathione. and vitamin E) in protecting
against oxidative damage, therefore,
melatonin may provide protection against
diseases that cause degenerative or
proliferative changes by shielding
macromolecules, particularly DNA, from
such injuries.
Enhancement of Immune
Function
Melatonin may exert certain biologic
effects (such as the inhibition of tumor
growth and counteraction of stress induced
immunodepression) by augmenting the
immune response. Studies in mice have
shown that melatonin stimulates the
production of interleukin - 4 in bone
marrow T-helper cells and of granulocyte-
macrophage colony-stimulating factor in
stromal cells, as well as protecting bone
marrow cells from apoptosis induced by
cytotoxic compounds.
Onset of action and serum levels.
After oral administration of 3 mg
melatonin, peak plasma concentrations of
about 1300 pg/ml are achieved in 0.5-2
hours.
Bioavailability
Ranges from 3 - 76%
Metabolism
Melatonin undergoes extensive first pass
metabolism. The primary site for
metabolism is within the liver, and
secondarily, the kidney. The metabolites of
melatonin, 6-hydroxymelatonin and N-
acetylmelatonin are inactive.
Half- life
Mean half- life is 45 minutes.
Excretion
Most of the melatonin is excreted in the
urine as 6 - hydroxy melatonin sulphate
85%). Some amounts are also excreted
in the breast milk.
BIOLOGICAL RHYTHMS
AND SLEEP
The human pineal gland is believed lo play
a major role as a transducer of
environmental information, and the
secretory pattern of melatonin appears
related to the importance of light in human
physiology and the control of biological
rhythms.
Melatonin and Circadian
Rhythms
Melatonin can reset the phase and entrain
overt circadian rhythms. Single or repealed
doses of the hormone in humans result in
phase advances, when melatonin is given
during the late subjective day. or phase
delays, after early morning administration.
I he presence of high-affinity melatonin
receptors and the ability of the hormone lo
alter the level and phase of metabolic and
neuronal SON activity suggest that the
location of the mammalian circadian clock
is an important target for melatonin.
These properties of melatonin prompted
its use in the treatment of circadian
disorders associated with jet lag, shift
work, blindness, and abnormal sleep
phase syndromes. The results of a large
study indicate that the hormone can reduce
self-rated jet lag by an average of5()% with
the greatest improvement after longer
flights in the eastward direction. More
limited evidence suggests that melatonin
may improve daytime alertness and
facilitate resynchronization of some
biochemical and physiological rhythms
during the jetlag.
Delayed sleep phase insomnia (DSPI) is
a clinical problem associated with a
presumed circadian abnormality. Evening
administration of melatonin in subjects
with DSPI can significantly advance the
timing of sleep. Additional reports suggest
that the hormone can synchronize the
circadian rhythms of sleep/wakefulness
and pineal activity in some subjects with a
non-24-hour sleep disorder. However the
partial effectiveness of melatonin in blind
subjects with (his condition suggests that
melatonin acts mostly as a complement to
the strong effects of light on human
circadian rhythmicity.
Melatonin and Sleep
The timing of human sleep coincides with
the period of pineal secretory activity.
Several case reports also suggest an
association between the lack of pineal
melatonin and disturbed sleep.
Drugs that induce or maintain sleep when
the homeostatic drive to sleep is
insufficient (hypnotic agents), or reset the
phase of the circadian pacemaker so that
sleep propensity occurs at the desired time
(chronobiotic agents), are valuable
options in the treatment of sleep disorders.
Emerging evidence suggests that along
with its potential chronobiotic properties,
melatonin may have some sleep-promoting
activity. Daytime administration of
melatonin when the endogenous levels of
the hormone are low was shown to induce
subjective feelings of sleepiness and
fatigue, improve sleep quality, and alter
brain electroencephalographic activity.
Several studies have evaluated the effects
of the hormone in patients with insomnia
and/or deficits in pineal function,
Beneficial results were reported in young
subjects with artificially disrupted sleep,
and large-dose melatonin treatment of
chronic insomniacs for 14 days was
associated with a subjective increase in
sleep.
Because aging is associated with a decline
in pineal function and increased prevalence
of disturbed sleep, the potential use o1
melatonin for the treatment of sleep/wake
disorders in the elderly has attracted some
research efforts. Lower melatonin levels
have been reported in elderly insomniacs
and several studies using wrist actigraphy
as a measure of sleep quality indicate that
chronic melatonin treatment may result ir
reduced sleep latency, decreased nighttime
activity and awakenings, increased sleep
efficiency, and improved subjective sleep
quality in older subjects with sleep
problems.
INDICATIONS
1. SLEEP DISORDERS
- Insomnia
- Circadian Related Sleep Disorder
β’DSPS
β’ JET LAG
β’ SHIFT WORK
2. PSYCHIATRIC DISORDERS
3. NEUROLOGICAL DISEASES
4. CARDIOVASCULAR DISEASES
5. AGE-RELATED DISORDERS
CONTRAINDICATIONS:
Hypersensitivity lo any component of the
formulation.
Pregnancy and lactation
CAUTION:
β’ Liver disease
β’ History of cerebrovascular disease.
β’ Autoimmune disease
ADVERSE REACTIONS:
Drowsiness, fatigue. headache, contusion.
pruritus have been reported by few
patients. In the most extensive clinical trial
to date. a high dose of75 mg of Melatonin
per day was given as a contraceptive along
with progestin 0.3 mg to 1400 women in
the Netherlands for up to 4 years with no
ill effects. Melatonin is not carcinogenic
or mutagenic. Melatonin has no addiction
potential. Melatonin has no overdose
complications. Melatonin does not
interfere with any laboratory parameters.
An increase in seizure activity was noted
in 4 of 6 children with severe neurological deficits during
treatment with melatonin for sleeping disorders.' Seizure ac-
tivity returned lo base-line values when melatonin was
stopped and recurred on rechallenge.
Uses. Melatonin has been tried in a number of disorders
including, in large doses, as an adjunct to interleukin-2 thera-
py for malignant neoplasms and in combination with
norethisterone, as a contraceptive. It is possible that contra-
ceptive use of melatonin may be associated with a reduced
risk of breast cancer. However, the effects of long-term administration have yet to be assessed. Pre-
liminary studies have also suggested that melatonin ma~be
beneficial in hyperlipidaemia and cluster headaches.
Claims for its value as an anti-aging treatment and for use in
conditions such as Aizheimers disease and AIDS are un-
founded.
INSOMNIA. Although melatonin is considered to be poten-
tially useful in the management of various forms of insomnia,
especially those associated with circadian rhythm
disturbances, there is little evidence of efficacy from large
studies and its long term safety remains to be established. In
healthy subjects melatonin has been reported to reduce the
time to onset of sleep and lo increase (he time spent asleep.
Whether this is due to adjustment of the body clock or any
hypnotic action of melatonin is unclear, improved quality of
sleep has been reported in elderly patients Heated with mela-
tonin for insomnia.' and it might be of use in delayed sleep
phase syndrome' and insomnia in shift workers and totally
blind people. There has also been a report of a patient with
somnolence associated with melatonin deficiency after
pinealectomy who responded to treatment with melatonin.
However, melatonin might have a deleterious effect on sleep
patterns in some circumstances.
DOSAGE &
ADMINISTRATION:
The usual dose is one tablet lo be taken
half hour before sleep preferably at the
same time. Doses can be titrated to suit
individual needs in a range of 1 mg to 10
mg, once at bedtime.