Vol. 2, # 39
October 8, 2005

Q: What is melatonin and what is it used for? - Technical

A: The pea-sized, light-responsive pineal gland is buried in the middle of your brain 3 – 4" behind the center of your eyebrows. For most of the 20th century the pineal was believed to be left-over and of little interest, even though it is the first organ to develop in the fetus, being discernable about three weeks after conception. Ancient wizards called the pineal the “third eye”, and imbued it with great powers over mood, sexuality and consciousness. Recent science shows that the ancients were pretty close to the truth.

Chemical structure of melatonin.

3D model of melatonin.

Melatonin
5-methoxy-N-acetyltryptamine
Empiric formula C13H16N2O2
Molecular weight 232.28
Bioavailability 30 - 50%
Metabolism Liver
Elimination half life 32 - 40 minutes
Excretion Urine
Pregnancy category ?
Delivery

1mg, 2.5mg, 3mg, and 5mg capsules;
1mg/mL or 1mg/4mL liquid;
.5mg and 3mg lozenges;
2.5mg sublingual tablets;
1mg, 2mg, and 3mg timed-release tablets

Indicated for:

  • insomnia
  • jet lag
  • sleep disorders

Melatonin, or 5-methoxy-N-acetyltryptamine, is a hormone produced by pinealocytes in the pineal gland, located in the brain, but also in the retina and GI tract. It is a derivative of the amino acid tryptophan.

Melatonin produced in the pineal gland acts as an endocrine hormone since it is released into the blood. On the other hand, melatonin produced by the retina and the GI tract is considered a paracrine hormone.

Melatonin helps regulate sleep-wake or circadian rhythms. Normally, production of melatonin by the pineal gland is stimulated by darkness and inhibited by light. Melatonin can suppress libido by inhibiting secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary gland -- especially in mammals that have a breeding season when daylight hours are long, such as sheep. Nobel Prize laureate Julius Axelrod performed many of the seminal experiments elucidating the role of melatonin and the pineal gland in circadian rhythms. Beta blockers decrease nocturnal melatonin release.

Melatonin is synthesized by various plants such as rice and ingested melatonin was shown to be capable of reaching and binding to melatonin binding sites in the brain of mammals.

In recent times, melatonin has become available as a drug and a dietary supplement. It appears to have some use against insomnia, jet lag, and circadian misalignment. Melatonin is a powerful antioxidant which can easily cross cell membranes including the blood-brain barrier. It has been studied for the treatment of cancer, immune disorders, cardiovascular diseases, depression, seasonal affective disorder, and sexual dysfunction; the results of most of these studies remain inconclusive. However, it has been shown to clearly ameliorate seasonal affective disorder and circadian misalignment, in studies by Alfred J. Lewy (OHSU) and other researchers.

Melatonin is referred to by some biochemists and human physiologists as the master hormone, because it regulates the production of most human hormones, both paracrine and endocrine. In addition, melatonin, taken alone, is an immunoregulator that enhances T cell production somewhat. However, when melatonin is taken in conjunction with calcium, it is a very potent immunostimulator of the T cell response. This is the reason it is used extensively as an adjuvant in many treatment protocols. Because it does not have to be prescribed, and since it is in the public domain, few doctors care to publicize its advantages. For the same reason, few clinical trials have been done to see its effectiveness in treating various diseases, such as cancer, obesity, h.i.v. infection, and others.

To synthesize melatonin, serotonin is converted to N-acetylserotonin by the enzyme 5-HT N-acetyltransferase. N-acetylserotonin is then converted to melatonin by the enzyme 5-hydroxyindole-O-methyltransferase. See serotonin for details on how tryptophan is converted to serotonin.

Melatonin has been shown to increase the lifespan of mice by 20% in some studies 

Other studies have noted that wearing garments such as bras are linked to a decrease in melatonin production. 


In 1958, Aaron Lerner, a dermatologist at the Yale University, discovered that the pineal secretes a powerful hormone, which he named melatonin.  It took another 20 years to establish that melatonin is the circadian pacemaker of the human body, without which you would lose the temporal organization of the hormone cascade, with consequent progressive degenerative changes in the brain and other organ systems.


Though it cost Yale over 10 million dollars for Lerner to first isolate and then synthesize a few milligrams of melatonin, the ingredients for this hormone are so simple, it now costs only pennies to make. Because of its near zero toxicity, melatonin has become commonplace in public use, both as a sleep aid and to combat jet lag, for which purposes it works reasonably well.  Consequently, many folk think of this most powerful hormone merely as a trivial remedy. 


In animals that are seasonal breeders, including birds, melatonin controls their annual cycle, from the sprouting of antlers in deer, to animal and bird migrations, to sexuality and reproduction, to seasonal changes in fur and plumage, even birdsong.  In the low light of winter, melatonin rises to lower testosterone, and shrivel the gonads of male animals, and eliminate the menstrual cycle, and dry the mucous membranes of females. It also changes body odor and other sexual cues, thereby reducing sexual behavior to near zero.


Because we disrupt our circadian rhythms (and those of our domestic animals) with artificial light, modern humans (and their pets) can breed anytime, and scientists used to believe that human reproduction was no longer under melatonin�s influence.  No way!  Inuit women, who live in the traditional way, stop menstruating when the dark winter months of the North greatly raise their melatonin.  The return of daylight in spring lowers melatonin, allowing the menstrual cycle to re-start and return them to fertility.


Even in Western Society, in both males and females, testosterone and estrogen are depressed by the high levels of melatonin released in winter. There is a sound scientific basis for seasonal affective disorder (SAD), which is relieved by sitting under lights that mimic bright natural sunlight and thereby lower melatonin.  Come spring and sunshine, melatonin drops, and SAD disappears.  In all of us testosterone, estrogen, emotional tone, and sexuality all rise promptly with Spring, giving strong scientific support to the old adage, �a young man�s fancy lightly turns to thoughts of love.�

At age 25 melatonin output is about 50 pg/ml per day.  By age 50 it drops to about 20 pg/ml, and to 10 pg/ml by age 70, too low to maintain circadian rhythms.  Lack of sufficient melatonin is one big reason why many people over 40 don�t sleep well: hence its popularity as a sleep aid.  But insomnia is a minor disturbance compared with the huge degenerative changes taking place in every organ and system in the body, because they have lost their melatonin timing mechanism.

Benign prostatic hypertrophy, for example is present in most men over 50, and many remedies are used to prevent the night disturbance of the urine cycle.  Yes, even your bladder has a cycle driven by melatonin, and low melatonin is now firmly linked to frequent night urination.  In a recent study representative of the evidence, men given just 2.0 mg of timed-release melatonin at night, experienced immediate relief of symptoms.

Low melatonin levels are also linked to low immunity and susceptibility to colds, flus, pains and sprains, bruises and contusions.  Degenerative diseases too.  One of the nastiest diseases now linked to melatonin decline is rheumatoid arthritis, in which your immune system turns on you and attacks healthy flesh.  Despite a mass of experimental evidence on animals, stretching back some 20 years, this link is still not considered in conventional treatment of rheumatoid arthritis. 

In a nutshell, when rheumatoid arthritis is experimentally induced, the immune system becomes disordered via a melatonin pathway through the autonomic nervous system to the lymph nodes when melatonin is low.  The immune system goes out of control.  Pre-treatment with physiological doses of melatonin (you don�t need much) prevents this disorder.  It is likely that melatonin is the main synchronizer of immune function, essential to keep it within the healthy limits it was designed for.

Even more serious, the initiation and rate of growth of certain cancers is linked to disrupted circadian rhythms.  Medical research now terms this previously unknown cause of cancer chronodisruption.  It is now linked to the higher rates for certain cancers in night-shift workers, those who travel across numerous time zones for their work, and others whose age or lifestyle choices result in damage to the pineal gland�s ability to make melatonin.

Worst of all, low melatonin devastates the brain.  It is one of the main endogenous brain antioxidants that protects our brain cells from free radicals.  More than that, new research shows that melatonin also supports human cognition, and that chronic low levels of melatonin are linked to neurodegenerative disease.  We know, for example that chronically low melatonin promotes depression.  Alzheimer�s patients also have chronically low melatonin.  So strong is melatonin�s control of the temporal patterning of neural and endocrine structures in the midbrain, it is now considered a major organizer of cogntion.

This essential hormone used to be banned in Canada but recently started appearing in the stores, a big health boost for Canadians.  Whether government is turning a blind eye, or it is now officially approved is difficult to discover.  The Canadian Health Food Association mandates that any sale of melatonin would require an application to government for approval, and issue of a drug identification number (DIN).  Clearly the bureaucrats have not been looking in the stores lately as many brands do not carry the DIN.
 
No one knows the exact doses of melatonin to use.  There is likely a wide range of individual differences in need, depending on age, health, genetic tendencies and environmental light levels
 
.According to one report, "10 percent of the users said the hormone did nothing for them, and another 10 percent complained of side effects such as nightmares, headaches, morning groginess, mild depression, and low sex drive. In past studies, researchers have given people up to 600 to 3,000 times the usual doses - without causing any toxicity." 
 
Certain people should avoid melatonin use. "Those include women who are pregnant or nursing (since no one knows how excessive exposure to the hormone might affect a fetus or infant); people with severe allergies or autoimmune diseases (melatonin could exacerbate such conditions by stimulating the immune system); people with immune-system cancers such as lymphoma or leukemia (for the same reason), and healthy children (who already produce it in abundance). Women trying to conceive should also think twice about taking the hormone, since high doses can act as a contraceptive." As with any substance introduced into your body, if you have a medical condition you should always consult your physician first before taking melatonin.There is no evidence to support this claim as it relates to humans. However, a 1995 rodent study suggests that taking small amounts of melatonin on a regular basis may prevent the age-related decline in testosterone levels, allowing men to be more active sexually in their later years.
 
Melatonin is one of the least toxic substances known. People have taken as much as 6 grams (600 to 3000 times the normal dosage) of the substance in carefully monitored studies with no sign of toxicity. Only four complaints regarding melatonin have been report to the FDA (USA's Food and Drug Administration). The only consistent side effect of high doses has been drowsiness and a slower reaction time. In the most extensive clinical trial to date a high dose of 75 milligrams of melatonin per day was given to 1400 women in the Netherlands for up to four years with no ill effects. The FDA reports that in the more than two years melatonin has been available for sale over-the-counter in the United States, no alarming side effects have been reported. Melatonin taken with MAOI drugs can also lead to overdose because MAOIs inhibit the breakdown of melatonin by the body.
 
Melatonin should only be taken at nighttime, usually about thirty minutes prior to going to bed. If you are traveling on a long trip you may want to take a dosage prior to getting on your flight and a higher dosage pill prior to going to bed. If you commonly sleep during the night, melatonin should not normally be taken during the day - and vice versa - because melatonin plays a role in setting the body's daily clock.
 
You should normally wake up well refreshed and full of energy. If you wake up feeling a little tired you should reduce your dosage until you wake up feeling well refreshed. You will not have the hangover effect you may experience with over the counter or prescription sleeping pills.
 
Natural, animal, or bovine grade melatonin contains the actual extracts of the pineal gland. Because it comes from animal tissue, this grade of melatonin may be accompanied by viruses or proteins that could cause an antibody response. I  highly recommend that people stay away from it.

The alternative is synthetic or pharmacy grade melatonin, which is produced from pharmaceutical grade ingredients. This form is molecularly identical to the melatonin that we produce in our own bodies, without unwanted extras.

Men require more melatonin than women. Need increases with age. Because of differences in the pattern of melatonin release at night, some people require timed-release melatonin, others require sublingual rapid-release melatonin, still others require a combination of the two.

If you take melatonin you must do it very consistently, every night, right at bedtime.  Irregular use or timing interferes with sleep patterns, and very likely with the function of multiple organs and systems.

 
Here is a dosage table.  Each person has to experiment within the ranges and types to find what suits.  Remember, despite its apparent lack of toxicity, no one knows the long-term effects of melatonin replacement, so if you use melatonin, you do so at your own choice and risk.  Happy dreams!

Age Males Females   
30-40 2.0-5.0 mg 0.25-3.0 mg   
40-50 2.5-7.5 mg 1.0-4.0 mg   
50-60 3.0-9.0 mg 2.0-5.0 mg   
60-70 4.0-10.0 mg 2.5-6.0 mg   
70+ 5.0-12.0 mg 3.0-9.0 mg 

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DISCLAIMER:  The information in this column, is NOT intended to diagnose and/or treat any health related issues and is provided solely for informational purposes only. Consult the appropriate healthcare professional before making any changes to your healthcare regime. Even what may seem like simple changes in the diet for example, can interact with, and alter, the efficiency of medications and/or the body's response to the medications. Many herbs and supplements exert powerful medicinal effects. Neither the author, nor the website designers, assume any responsibility for the reader's use or misuse of this information.

� 2002 Nature's Corner