Adjunct Treatments
Melatonin: A Primer
By
Patricia Keller
Melatonin, known scientifically as the indoleamine
N-acetyl-5-methoxytryptamine, is a hormone with neurotransmitter modulatory
activity, and it can be found in most living things from some of the simplest
plants to humans. It is produced in minute quantities by the pineal gland when
the eyes detect decreasing light, total darkness, or during sleep. Melatonin is
also produced by the retina and, in vastly greater amounts, by the
gastrointestinal system.[1] In fact, 400 times more melatonin can be found in
the gastrointestinal system than in the pineal gland or bloodstream, where
levels typically range from 0.1 to 10 nmol/L.[2] Melatonin receptors are
present in central nervous system tissues, peripheral tissues, and
steroidogenic tissues, including myometrial tissues of both pregnant and
non-pregnant women. It is naturally synthesized in humans from the amino acid
tryptophan (via synthesis of serotonin) by the enzyme
5-hydroxyindole-O-methyltransferase. Production of melatonin by the pineal
gland is under the influence of the suprachiasmatic nucleus of the hypothalamus
(SCN) which receives information from the retina about the daily pattern of
light and darkness. Melatonin is also synthesized in various plants, such as
onions, bananas, corn and cherries, and ingested melatonin has been shown to be
capable of reaching and binding to melatonin binding sites in the brains of
mammals.
Melatonin is a substance that an increasing number of people are taking
without being knowledgeable about its variety of possible benefits, side
effects and dosages. Many companies currently manufacture melatonin as a
supplement. There are two kinds of non-prescription melatonin
available--synthetic or natural (animal derived). If you are not going to be
taking a prescription grade formula, it is often recommended to take a
synthetic version of the supplement which is close to the molecular make-up of
our own naturally produced melatonin. The “natural“ melatonin
supplements may contain animal parts through which viruses and diseases can be
carried, or proteins that could cause an antibody response.
A little historical perspective: one theory examines the common
evolutionary origin of cells in the pineal gland and retina. David Klein, Ph.D.
has theorized that in the ancestor of today's higher animals, the conversion of
serotonin to melatonin increased at night as a way to make vision more
sensitive to low light conditions. The conversion kept serotonin from combining
with retinaldehyde (a form of vitamin A) at night, when it was needed to detect
low levels of light, so that these ancestral animals could function well under
dim light. Since this required a steady supply of serotonin as a precursor,
which in turn depleted retinaldehyde (needed for low light vision), a second
photoreceptor cell evolved which functioned to produce its own melatonin.
Eventually these melatonin-making cells evolved into what is now the pineal
gland. Dr. Klein points out that the photoreceptor cells of the retina strongly
resemble the cells of the pineal gland and that the pineal cells of sub-mammals
(such as fish, frogs and birds) detect light. In addition, melatonin's origin
in the ancestral photoreceptor cell is indicated by the capacity of the retinas
of mice, fish, frogs, and birds to make small amounts of melatonin. [3]
Melatonin is being studied for its possible benefits regarding a host of
medical issues including cluster headache. A frequently cited Italian study
looking into the circadian secretion of melatonin, demonstrated that episodic
cluster headache patients were shown to have low blood plasma melatonin levels
during cluster periods. [4] The following year some of the same researchers
followed up with a study of both episodic and chronic patients in a
double-blind placebo-controlled study of 10 mg. oral melatonin doses, showing
some positive results for the episodic group. [5] While the effectiveness of
melatonin for cluster headache remains unclear because of conflicting studies,
its role, if any, may be in the initial prevention of attacks, theoretically by
resetting the circadian rhythm.
Melatonin has become a frequent target of scientific and commercial
interest in recent years. Besides melatonin’s benefit for some cluster
headache sufferers, it has been studied for a wide variety of other medical
issues. Smaller studies of melatonin have been done for conditions from sleep
issues such as jet lag and insomnia to its possible effect on Alzheimer's
disease, cancer treatment, psychological disorders, HIV, and many others. A
study published in November of 2006 looked at the use of melatonin for ALS
patients.
It suggested that high-dose melatonin is suitable for clinical
trials aimed at neuroprotection through antioxidation in ALS. [6] A promising
study for gastro esophageal reflux disease was performed because melatonin has
known inhibitory activities on gastric acid secretion and nitric oxide
biosynthesis. When melatonin was combined with a group of other supplements and
compared with omeprazole, there was a significant positive result with the
melatonin with no significant side effects. [7] Because of its antioxidant
properties, melatonin is getting some attention for possible use in
strengthening the immune system. Melatonin’s immunoenhancing properties
was discussed and confirmed in a study which strongly suggested our immune
systems also have melatonin receptors, but there hasn’t been enough work
done in this area to show the mechanism of this function. [8] Melatonin in
combination with cancer treatments is showing some promising results. A number
of studies showed that patients who used melatonin supplements had consistently
better chemotherapeutic responses, significantly fewer side effects, and
significantly higher survival rates overall compared to patients who did not
use melatonin. Some of the cancers included in these data include lung,
colorectal, and breast. A notable study was performed to assess the 5-year
survival results in metastatic non-small cell lung cancer patients who combined
melatonin with their chemotherapy regimen. The study suggested the possibility
to improve the efficacy of chemotherapy in terms of both survival and quality
of life by a concomitant administration of melatonin. [9] It should be noted
that in many of the studies mentioned here, the melatonin administered to the
subjects was of a pure pharmaceutical grade and in therapeutic level doses.
Along with the increased attention by medical research, commercial
interests have begun to show interest in melatonin. Two pharmaceutical
companies have recently brought melatonin related products to market for sleep
issues. In the EU, Neurim Pharmaceuticals Ltd has received approval for their
product Circadin 2 mg (prolonged-release melatonin) as monotherapy for the
short-term treatment of primary insomnia. In the United States and elsewhere,
Takeda Pharmaceuticals North America is aggressively marketing Rozerem
(ramelteon) for insomnia, particularly for delayed sleep onset. Ramelteon is a
melatonin receptor agonist, and it is thought to promote more normal sleep
patterns by restoring maintenance of the circadian rhythm. It is the first in a
new class of sleep agents that selectively binds to the melatonin receptors in
the suprachiasmatic nucleus (SCN), versus binding to GABA-A receptors, such as
with drugs like zolpidem, eszopiclone, and zaleplon. Unlike earlier classes of
sleep agents, ramelteon has not been shown to produce dependence and so far has
demonstrated no potential for abuse. No published studies have indicated
whether ramelteon is more or less safe or effective than melatonin supplements
which are widely available in the U.S. in a less expensive non-prescription
form. Commercial interest in melatonin has also spread to the
“natural” supplement and cosmetic industries. It is not unusual to
find melatonin included in the ingredient lists of numerous products from
“miraculous” anti-ageing pills to wrinkle creams.
There are reported risks involved in the use of melatonin. Based on
available studies and clinical use, melatonin is generally regarded as safe in
recommended doses for short-term use. Available trials report that overall
adverse effects are not significantly more common with melatonin than placebo.
However, case reports raise concerns about risks of blood clotting
abnormalities (particularly in patients taking warfarin), increased risk of
seizure, and disorientation with overdose, including increased risk of seizure
in children with severe neurological disorders. Melatonin supplementation
should be avoided in women who are pregnant or attempting to become pregnant,
based on possible hormonal effects. Commonly reported adverse effects include
fatigue, dizziness, headache, irritability, and sleepiness, although these
effects may occur due to jet-lag and not to melatonin itself. Fatigue may
particularly occur with morning use or high doses, and irregular sleep-wake
cycles may occur. Disorientation, confusion, sleepwalking, vivid dreams and
nightmares have also been noted, with effects often resolving after cessation
of melatonin. Due to risk of daytime sleepiness, those driving or operating
heavy machinery should take caution. [10]
In conclusion, melatonin has been used successfully to help alleviate
circadian rhythm imbalances, including imbalances in some cluster headache
sufferers. While its use for these issues is becoming more widely accepted,
research has a long way to go before its benefits can be applied to all the
areas of health care that are trying to lay claim to melatonin’s possible
uses. Most clinical research has used pharmaceutical grade melatonin in higher
doses than can be obtained in over the counter supplements. As with any new
supplement or prescription regimen, always consult your healthcare provider
first to make certain that you will not be incurring adverse interactions with
other drugs you may be taking.
References
1. Bubenik GA. Localization, physiological significance and possible clinical implication of gastrointestinal melatonin. Biol Signals & Receptors. 2001;10:350-366.
2. Bubenik GA. Gastrointestinal melatonin: Localization, function, and clinical relevance. Digest Dis & Sci. 2002;47:2336-2348.
3. http://www.nih.gov/news/pr/aug2004/nichd-12.htm
4. http://www.blackwell-synergy.com/links/doi/10.1046/j.1468-2982.1995.015003224.x
5. http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=8933994&dopt=Abstract
6. http://www.blackwell-synergy.com/doi/abs/10.1111/j.1600-079X.2006.00377.x?prevSearch=
7. http://www.blackwell-synergy.com/doi/abs/10.1111/j.1600-079X.2006.00359.x
8. http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=11899099&dopt=AbstractPlus
9. http://www.blackwell-synergy.com/doi/abs/10.1034/j.1600-079X.2003.00032.x
10. http://www.nlm.nih.gov/medlineplus/druginfo/natural/patient-melatonin.html
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