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Melatonin: The proven wonder drug?

By Bart B. Van Bockstaele     Jun 13, 2007 in Health
Melatonin is considered an important hormone that helps regulate our wake-sleep-cycle. Over the past 20 years, store-bought melatonin has nearly made it from fringe to mainstream. With this type of success, it really must have wonderful properties, yes?
What is melatonin?
It is a hormone that is mainly produced in the pineal gland (epiphysis cerebri) of the brain. This is a small pea-sized organ on the underside of the brain, just behind the third brain ventricle.
Melatonin plays a role in the regulation of our biological sleep-wake cycle. Production only starts after about three months. This explains at least in part why babies have such an erratic sleep-wake cycle. The levels increase during adolescence and they peak in early adulthood. The pineal gland then starts to shrink resulting in extremely low melatonin levels in the elderly.
Melatonin synthesis is regulated by the suprachiasmatic nucleus (SCN), a pair of pinhead sized structures containing approximately 20,000 neurons in total that is located in the hypothalamus, just above the point where the optic nerves cross each other.
The SCN is the seat of our biological clock. The functioning of the biological clock is far from understood. The biological clock is fairly precise and has a period of about 24 hours. It varies between individuals with periods of 23 to 25 hours, but the majority of people have a period of close to 25 hours.
Because earth has a 24 hour rhythm, there is a discrepancy with the biological clock. Light that is received by photo-receptors in the retina creates pulses that travel along the optic nerve to reach the SCN. Thanks to this, sunlight or other bright lights can reset the biological clock.
The clock can also be reset by other signals such as an alarm clock, meal timing, the mail coming in... These signals are called zeitgebers, German for time-givers. This way, most people's biological clock follows a 24 hour cycle instead of the innate 25 hour cycle.
The SCN controls the production of melatonin in the pineal gland and that the concentration of melatonin in the bloodstream is highest just prior to bedtime. Light suppresses the production of melatonin. The maximum effect is obtained by light with a wavelength of 460nm, i.e. blue.
Because of that, melatonin seems to play a function in the circadian sleep-wake cycle, although most of the mechanisms remain a mystery.
However, the synthesis of melatonin is well understood. It is a simple hormone for which tryptophan is the base material. Tryptophan is an aminoacid of vital importance for the growth of children and adult nitrogen balance. It is also an essential aminoacid. This means that the body cannot synthesize it, it needs to come from the ingestion of food.
In the pineal gland, tryptophan is hydroxylated to 5-hydroxytryptophan which is then decarboxylated to 5-hydroxytryptamine (serotonin). Serotonin is then converted by the enzyme N-acetyl transferase to the precursor of melatonin, N-acetylserotonin. This is methylated by the enzyme hydroxyindole-o-methyltransferase to produce melatonin.
Approximately 90 percent of melatonin is broken down during a single passage through the liver. A small portion of less than 1% is not metabolized and is excreted in the urine.
A little bit of history
The pineal gland has long been a scientific mystery. Until fairly recently, it was thought that it was essentially useless, a remnant of old evolutionary processes.
Descartes declared in the 16th century that the pineal gland was the seat of the soul because it was seen as the only non-duplicated organ in the brain and therefore very special. Others called it a "third eye".
In 1917, Carey Pratt McCord and Floyd Pierpont Allen did an experiment in which they added crushed pineal glands to water. Tadpoles that were released in the water changed colour from very dark to light, sometimes even nearly transparant. At the time, this could not be explained.
In the 1950s, Mark Altschule and Julian Kitay were able to show a significant relationship between the presence or the absence of the pineal gland and the weight of ovaries in rats.
Professor Aaron B. Lerner was the first to extract melatonin from the pineal glands of cattle in 1958. One year later, he discovered that it was actually synthesized in the pineal gland. Professor Lerner died recently, on February 3rd, 2007. He was 86 years old.
In 1959, Julius Axelrod and Herbert Weissbach found out that melatonin is actually a chemically modified version of serotonin and that it is stored together with norepinephrine in nerve terminals to be released at a later time. This was useful to explain the long-known discolouration effect in tadpoles: melatonin from the pineal glands in the water caused the skin pigmentation cells (melanophores) of the tadpoles to contract.
In 1961, Virginia Fiske claimed that light influences the weight of the pineal gland in rats and that these changes in lighting also had an influence on their sexual desire.
In 1962, Julius Axelrod and Richard J. Wurtman discovered that melatonin is a powerful neurotransmitter in the central nervous system and that it makes the pineal gland into a biological clock. They were also the authors of the so-called melatonin hypothesis which they published in 1965: according to this hypothesis, melatonin was secreted in response changes in environmental lighting conditions and that these changes did not only influence the pineal gland but also the reproductive functions of mammals.
In 1964, Julius Axelrod and Solomon H. Snyder were able to show that serotonin was important to maintain the sleep-cycle of rats.
The pineal glands of rats release large amounts of serotonin after 12 pm. This continues until 12 am after which it diminishes. Axelrod deduced from this that the pineal gland is a type of relay station for serotonin. Later on, he used the signal transduction theory for cellular communication developed by Martin Rodbell and called the pineal gland a neurochemical transducer in an article he published in 1976 in Science.
It is only in 1979 that it was first assumed that melatonin plays a role in the day-night rhythm of animals and humans.
The hormone became gradually more popular and this turned into a frenzy in the middle of the 90s when melatonin even got an article on the cover of Newsweek. Several popular books were written about it and alternologists* of all types started to promote it as a true wonder drug with countless applications.
Where can melatonin be found?
Melatonin can be found in most animals and plants. This has led the American Food and Drug Administration to declare it a dietary supplement and give it the GRAS (Generally Recognized As Safe) designation.
This presence in various foods must be qualified, however. For example, walnuts are reputed to have high concentrations. It turns out that these high concentrations are approximately 3.5ng +/- 1ng per gram of walnut. A typical dose in pill form is 1.5mg. In order to get this amount from walnuts, one would need to eat approximately 428 kilograms of walnuts.
Tomatoes are even worse. Their concentrations are about one third of those in walnuts. Not particularly practical.
Commercially available melatonin is either chemically synthesized or extracted from the pineal glands of beef cattle. Because natural melatonin is very expensive to isolate and because of health concerns with respect to mad cow disease, essentially all store-bought melatonin is chemically synthesized, even when the packaging displays the word "natural".
What is melatonin used for?
Melatonin is used in a wide range of applications such as acetaminophen toxicity, acute respiratory distress syndrome (ARDS), aging, aluminum toxicity, asthma, Alzheimer's disease (sleep disorders), antioxidant (free radical scavenging), attention deficit hyperactivity disorder (ADHD), benzodiazepine tapering, beta-blocker sleep disturbance, bipolar disorder sleep disturbances, cancer prevention and treatment, cardiac syndrome X, chemotherapy side effects, circadian rhythm entraining in the blind, cognitive enhancement, colitis, contraception, critical illness/ICU sleep disturbance, delayed sleep phase syndrome (DSPS), depression and related sleep disturbances, duodenal ulcer, edema (swelling), erectile dysfunction, fibromyalgia, gastroesophageal reflux disease (GERD), gentamicin-induced kidney damage, glaucoma, headache prevention, heart attack prevention, heart disease, high blood pressure (hypertension), HIV/AIDS, hyperpigmentation, immunostimulant, inflammatory bowel disease (IBS), insomnia (of unknown origin in the non-elderly), insomnia in the elderly, interstitial cystitis, intestinal motility disorders, itching, jet lag, kidney damage (amikacin-induced, cyclosporin-induced), lead toxicity, liver damage, melatonin deficiency, memory enhancement, multiple sclerosis, neurodegenerative disorders, noise-induced hearing loss, pancreatitis, Parkinson's disease, periodic limb movement disorder, polycystic ovarian syndrome (PCOS), postmenopausal osteoporosis, post-operative adjunct, post-operative delirium, preoperative sedation/anxiolysis, prevention of post-lung transplant ischemia-reperfusion injury, REM sleep behavior disorder, Rett syndrome, rheumatoid arthritis, sarcoidosis, schistosomiasis, schizophrenia (sleep disorders), seasonal affective disorder (SAD), sedation, sexual activity enhancement, seizure disorder (children), sleep disturbances due to pineal region brain damage, sleep disturbances in children with neuro-psychiatric disorders, sleep enhancement in healthy people, sleep in asthma, smoking cessation, stroke, sudden infant death syndrome (SIDS) prevention, tachycardia, tardive dyskinesia, thrombocytopenia (low platelets), tinnitus (ringing in the ears), tuberculosis, tuberous sclerosis, ulcerative colitis, ultraviolet light skin damage protection, wasting, withdrawal from narcotics, work shift sleep disorder and wound healing.
Such a list is truly impressive, but should also ring an alarm bell. Unfortunately, the alarm bell seems justified. For the vast majority of these uses, there is no credible evidence whatsoever of any benefits resulting from the use of melatonin.
What is melatonin useful for?
There is some minor evidence for benefits in the treatment of insomnia in the elderly, delayed sleep phase syndrome (DSPS), sleep disturbances in children with neuro-psychiatric disorders and sleep enhancement in healthy people. However, the studies are all of low quality and must be redone with more rigour.
There is strong evidence of benefits in up to 50% of the people who take it for the treatment of jet lag. In order to determine proper dosage, more tests are needed.
How safe is melatonin?
Since melatonin is not strictly regulated in the United States and Canada, caution is needed. There are essentially no guarantees whatsoever as to purity, quality, safety and strength of melatonin. Thoroughly reading the label and other enclosed instructions is vital. In spite of that, you must take into account that the data provided maybe wrong, either accidentally or by design. Do not start to use this product without prior consultation of a qualified physician. If you think that you are experiencing side effects, you must consult a physician immediately.
Melatonin is not only used in oral form, but also intranasally in an alcohol solution and even in the form of intramuscular injections.
Safety in children (younger than 18)
There is only limited study of melatonin in children. That means that there is not a known safe dose. Low doses seem safe for short term use. I was unable to find data regarding long term use. More studies are needed. You should not use melatonin in a child before consulting with its paediatrician.
Safety in adults (at least 18 years old)
There have been limited studies that show that doses of 0.5mg to 50mg taken by mouth every night are safe for short term use. There is no evidence of safety for long term use.
Side effects
These are some of the reported side-effects: abnormal heart rhythms, age-related maculopathy and myopia, allergic reactions, ataxia (difficulty walking and keeping balance), autoimmune hepatitis, blood clotting problems (especially in combination with warfarin), confusion, Crohn's disease symptoms, decreased sperm count and sperm motility, disorientation, dizziness, dropping blood pressure, dysphoria (sadness), fatigue, giddiness, glaucoma, gynecomastia (increased breast size) in men, hallucinations, headache, hyperglycemia (elevated blood sugar levels), hypoglycemia (decreased blood sugar levels), increased or decreased hormonal levels of luteinizing hormone, progesterone, estradiol, thyroid hormone (T4 and T3), growth hormone, prolactin, cortisol, oxytocin and vasopressin, increase of cholesterol levels, increased or decreased intraocular pressure, increased risk of seizure, irritability, nausea, paranoia, retinal damage, sleepiness, sleepwalking, vivid dreams and nightmares and vomiting.
Since melatonin has only been studied in a limited way, side effects have also been studied in a limited fashion. However, several effects have been reported. Most of these reports are anecdotal and although of interest, of little scientific value, just as the reported benefits of melatonin.
It should be noted however, that many reported side-effects seem to be related to overdoses of melatonin.
Drug interactions and contraindications
Patients taking melatonin should be careful while driving or operating machinery.
Patients who are taking anti-coagulants (blood-thinners) such as warfarin (Coumadin®), aspirin or heparin should avoid melatonin.
Patients taking anti-seizure medications should avoid taking melatonin.
Melatonin may interact with heart or blood pressure medications and lower or raise blood pressure, careful monitoring is advised.
Patients with diabetes can show reduced glucose tolerance and insulin sensitivity. Serum glucose levels should be monitored and their medications should be adjusted accordingly.
Melatonin may increase the neuromuscular blocking effect of succinylcholine, a muscle relaxant.
A combination of melatonin and echinacea may reduce immune function but the effects in humans are not clear.
Melatonin may also interact with other drugs, herbs or dietary supplement such as: alcohol, antidepressants,arginine, barbiturates (such as phenobarbital), benzodiazepines (such as lorazepam (Ativan®) or diazepam (Valium®)), beta-blockers (such as atenolol (Tenormin®) or metoprolol (Lopressor®, Toprol®)), caffeine, chasteberry (Vitex agnus-castus), cocoa, DHEA, ephedra, folate, hormone replacement therapy, hydralazine, loop diuretics, narcotics (such as codeine), non-steroidal anti-inflammatorie (including ibuprofen (Motrin®, Advil®) or naproxen (Naprosyn®, Aleve®)), oral contraceptives, metamphetamin, somatostatin, temazepam, theophylline, verapamil, vitamin B12 and zolpidem (Ambien®).
Conclusion
The only strong evidence for beneficial effects relates to jetlag problems but only in about 50% of sufferers. For the rest, melatonin seems of minimal or no value. Safe, dangerous and functional dosage levels have not been established.
In the United States, melatonin is generally recognized as safe due to its presence in many organic materials, and it is freely available as a dietary supplement. It is also freely available in Canada. The product is not strictly regulated, nor has it been studied in much depth. There is a whole range of side-effects, drug interactions and contraindications, most of which are probably mild in most people.
Melatonin seems safe for short term use. Long term safety has not been established.
Since there is no clear evidence of usefulness, the pharmaceutical industry does not make melatonin preparations for medicinal use. It must be bought as a dietary supplement with all the quality concerns this entails.
In short: to date, there are no valid reasons to buy or use melatonin, and there are several serious contraindications.
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*I define an alternologist as someone who practices or strongly supports and publishes about complementary and alternative medicine (CAM) which I call alternology.
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