Melatonin
Description
Melatonin (N-acetyl-5-methoxytryptamine) is a hormone synthesized and secreted primarily by the pineal gland (Lerner et al: “Isolation of melatonin, the pineal factor that lightens melanocytes.” J.Am. Chem. Soc.1958(80):2587). The pineal gland is small and lies deep within the brain forming part of the endocrine system together with : the pituitary, thyroid, parathyroid, adrenal, testes, ovaries, and the pancreatic islets of Langerhans. The pineal gland, via melatonin, not only works with these other parts of the endocrine system, some authorities designate it as the “master gland” controlling biological cycles and immune functions.
Melatonin is synthesized from serotonin which is derived from the amino acid tryptophan. When light hits the eye, nerve impulses cause an increase in serotonin. Apart from the pineal gland, the eye is the most acknowledged independent site of melatonin synthesis in vertebrates (G.Huether: “Melatonin synthesis in the gastrointestinal tract and the impact of nutritional factors on circulating melatonin.” Ann. N.Y. Acad. Sciences: 1994,719:146-58). The human appendix was the first site outside the pineal where the occurrence of melatonin could be demonstrated (Raikhlin et al: “Melatonin may be synthesized in enterochromaffin cells.” Nature [Lond.] 1975,255:344-5.) The biosynthesis of melatonin was demonstrated in the gut the following year ( Quay & Ma: “Demonstration of gastrointestinal HIOMT.” Int. Rep. Clin. Sci. Med. Sci. Lib. Compend. 1976, 4: 563.) Melatonin is widely available as an individual food supplement.
The pineal gland is magnetosensitive and photosensitive. It is still largely shrouded in mystery but there are identifiable factors relating to human health. Primary interest lies in the circadian rhythmicity of melatonin production, which is increased tenfold by darkness and suppressed by light. Secretion increases from around dusk, reaches is peak at 2 a.m. and declines to low levels by sunrise. Specifically, normal daytime levels will be around 10 pg/ml increasing to around 80 pg/ml during the night (2 - 4 a.m.). Supplementation with as little as 0.1 mg will sharply elevate even the daytime level to peak nighttime levels. Larger doses of 10 mgs could effect levels of as much as 10,000 pg/ml. [Dollins et al: Proc. Natl. Acad. Sci. 1994(91): 1824-28.]. With aging (particularly after 70), the peak in melatonin levels occurs about one hour later than normal and the peak is only half the level of young adults.
The length of day also has a seasonal component, particularly at extremes of latitude which may also involve geomagnetic and solar radiation influences.
Such influences complicate efforts to measure the epidemiological link between various illnesses (e.g. leukemia) and electromagnetic fields (EMF’s) associated with contemporary urban life.
Method of Action
Reiter has coined the expressive description: “Melatonin: the chemical expression of darkness.” (Mol. Cell. Endocrin. 1991(79): C153-8.)
Supplemental melatonin is taken up, in the identical manner as the endogenous form, by the bloodstream and finds the same binding sites. Presumably, the additional melatonin restores normal levels if there is a deficiency; or manipulates levels (turning night into day) in order to effect a change of the biological rhythm, useful when preparing for, or recovering from, a flight across several time zones.
Therapeutic Approaches
Aging
With so many important roles in numerous bodily functions, the decreasing melatonin production accompanying the aging process, may represent an exciting avenue for research. Are the retardation of the aging process and life extension merely awaiting melatonin supplementation ?
Caloric restriction is a well-established means of extending lifespan in laboratory animals. Such restriction may mediate some of its effects via the preservation of melatonin release (Stokkan et al: Brain Res. 1991(545):66-72.). The melatonin rhythm can be substantially preserved during aging by calorie restriction and administering melatonin to non-restricted animals (fed freely: “ad libitum”) also increases their survival (Pierpaoli et al: Int. J. Neuroscience 1990(51):334-42.).
Prescription for the elderly
Research suggests that many centrally active drugs that have shown promise as neuroprotective and anti-aging compounds, including deprenyl, ergot alkaloids and acetylcarnitine, may function through their restoration, or stimulation, of melatonin release (Poeggeler, et al.: J. Pineal Res. 1993(14): 151-68.).
Calcium metabolism of old age
Dysfunctions in calcium metabolism are common with advancing age in both men and women in their cardiovascular, nervous and skeletal systems. One of the most prevalent age-related disorders is osteoporosis which afflicts 20 million people in the US alone, mostly post-menopausal women.
Menopause is associated with a substantial decline in melatonin secretion and pineal melatonin regulates calcium and phosphorous metabolism (Sandyk et al: Int. J. Neuroscience 1992(62): 215-25.). Melatonin functions as a ‘fine tuner’ of calcium homeostasis. “The fall of melatonin plasma levels during the early stage of menopause may be an important contributory factor in the development of postmenopausal osteoporosis (Sandyk et al: Int. J. Neuroscience 1992(62): 215-25.).”
Antioxidants
Another interesting line of melatonin research is its role as a scavenger of free radicals, particularly the hydroxyl radical (Tan et al: Endocr. J. 1993(1): 57-60.). Hydroxyl (-OH) radicals are considered the most damaging of the free radicals. In vitro evidence proved that melatonin was a more powerful quencher of hydroxyl radicals than either glutathione or mannitol, respectively, heretofore the best known scavengers (Radi: Toxicol. Indust. Health 1993(9):53-62.) In vivo experiments support this, although they are not yet definitive (Reiter et al: Ann.N.Y.Ac. Sciences 1994,719:1-12.).
Melatonin has exhibited a close affinity for the nuclei of cells, enabling it to efficiently protect the nucleotide from oxidative damage (Tan et al: Cancer Lett. In press.).
Most antioxidants also exhibit devastating prooxidant actions (Halliwell & Gutterridge: Free Radicals in Biology and Medicine. Oxford.1991.) No such activity has been found for melatonin (Reiter et al: Unpublished.)
There are many diseases that may have free radical damage to cells and organs as their basis including: Parkinson’s disease, multiple sclerosis, muscular dystrophy, rheumatoid arthritis, repurfusion injury following organ transplantation, malaria, emphysema, atherosclerosis, autoimmune nephrotic syndrome, pancreatitis, cataractogenesis etc.
Additionally, “sunburn” due to solar radiation, or radiotherapy, are a consequence of free radical attack. Finally, aging may relate to accumulative damage consequent to oxidative stress. In conclusion: Melatonin’s antioxidant actions may be its “primary significance as well as the basis for its evolution.”(Reiter et al: Ann.N.Y.Ac. Sciences 1994,719:1-12.).
Cancer
Given its immune function, it is not surprising that melatonin has proven to be useful in preventing cancer development (Bartsch et al; Oncology 1992(49):27-30.). Melatonin inhibits carcinogenesis from a chemically-induced source (e.g. smoke tars) as well as suppressing spontaneous cancer development in high risk subjects with a genetic predisposition to cancer (Subramanian & Kothari; J. Pineal Res. 1991(10):136-40.).
Several mechanisms have been elucidated so far. In breast cancer, melatonin is thought to work directly by supplanting estrogen at tumor cell receptor sites. In the initiation phase of carcinogenesis, melatonin was only effective in animals with an intact pineal gland. In the promotion phase, melatonin benefited animals with, or without, pineal glands. This opened up the possibility that melatonin promotes the release of other biologically active compounds by the pineal gland that work in synergism with it.
Production of glutathione, an important antioxidant and its dependent enzymes, is increased (Kothari & Subramanian:Anticancer Drugs, 1992(3): 623-8.). This reduces damage from free radicals to cells and DNA.
It is intriguing to study the epidemiology of blind persons, lacking the light cue which signals lower levels in the circadian melatonin cycle in sighted persons. The blind often have continuously elevated melatonin levels; which may provide some protection against breast cancer (Coleman & Reiter: Eur. J. Cancer 1992(28):501-3.).
It is also true that many different forms of cancer (including: breast ,prostate, lung, colon, skin and stomach) significantly depress melatonin levels (Bartsch et al: Cancer,1991(67): 1681-4 and Clin, Chim, Acta. 1992(209): 153-67.). This may be due to a depression of interleukin-2 (IL-2) production. An interrelationshiup exists between IL-2 and the pineal gland and IL-2 immunotherapy will often restore melatonin levels in cancer patients (Vivian et al: J. Pineal Res. 1992(12):114-7.).
Probably, melatonin and the pineal gland play a central role in both cancer prevention and tumor destruction.
Cancer treatment
Many researchers have begun to examine the use of melatonin, both alone and in conjunction with other chemotherapies and immunotherapies. One group of terminal cancer patients, with no other therapeutic options, were given melatonin. One-third of them had their cancer growth controlled as well as improved quality of life (Lissoni et al: Oncology 1992(48): 448-50.).
Melatonin has also shown promise for melanomas, a notoriously treatment resistant form of skin cancer (Gonzales et al: Melanoma Res. 1991(1):237-43.).
As an adjunct therapy, melatonin has been found to augment the anti-tumor effect of tamoxifen on breast cancer (Wilson et al: J. Clin. End. Metab. 1992(75): 669-70.).
Combining melatonin with IL-2 may allow lower and better tolerated doses of IL-2 to be used while, at the same time, increasing its efficacy (Lissoni et al: Br. J. Cancer 1992(66): 155-8.).
Consequently, the outlook for melatonin research is very promising.
Electromagnetic radiation
Although the sun’s, and to a lesser extent the earth’s, magnetic field control melatonin synthesis by the pineal gland; we are now exposed to numerous additional electromagnetic influences: radio, television, powerlines, even household appliances and microcellular telephones deluge us with a constant bombardment of electromagnetic radiation. Such radiation has generally been ignored but recent evidence is suggestive of various negative health effects.
Extremely low frequency fields, such as those found near power lines, can alter neural function and suppress melatonin levels (Lerchl et al: J. Pineal Res. 1991(10): 109-16.). The increased breast cancer in industrialized countries may even be attributed to the suppression of melatonin release due to nighttime light and/or electromagnetic radiation (Stevens et al: FASEB J. 1992(6): 853-60.)
Melatonin supplementation may be an antidote to some of the health effects of modern society.
Endocrine function
Although endogenous melatonin release makes it difficult to examine the effect of melatonin supplementation, one study involved an individual whose pineal gland had been destroyed in the course o treatment for a pineal tumor. (Patterborg et al: Brain res. Bull. 1991(27):181-5) Melatonin not only improved sleep and mood but also produced a peak in nocturnal growth hormone.
Other studies have found that melatonin inhibits stress-induced gastric ulceration (Kahn et al: Experientia: 1990(46):860-2.0.
Menstrual Cycle
The best known monthly cycle is the menstrual period. It has now been shown that there is an interaction between the hypothalamic-pituitary axis and the ovaries. Specifically, the pineal gland, through the action of melatonin, modifies the oscillatory frequency of the hypothalamic gonadotropin releasing hormone (GnRH) pulse generator. A role for abnormal levels of melatonin is speculated upon with regards several disorders of the menstrual cycle including amenorrhea, whether exercise-related, or malnutrition-induced. (Sandyk: “The pineal gland and the menstrual cycle.” Int. J. Neurosci. 1992(63): 197-204.).
Immune function
There is strong evidence that there are specific binding sites for melatonin on immune cells (Guerrero et al: Endocr. Res. 1992(18):91-113.). The pineal gland has been viewed as the crux of a sophisticated immunoendocrine network (Maestroni: J. Pineal Res. 1993(14)1-10.)
Melatonin is also highly lipophilic which facilitates its antioxidant properties by allowing it to easily enter cells and subcellular compartments. The diffusibility of melatonin, therefore, provides protection both to the cell membrane and subcellular compartments.
Sleep disorders
The findings that melatonin secretion is increased by darkness and that high levels can induce drowsiness led to the use of melatonin to regulate sleep disorders, including the insomnia which commonly affects the elderly.
In the case of insomnia, melatonin administration was found to increase the subjective assessment of total sleep time and daytime alertness (McFarlane et al: Biol. Psychiatry. 1991(30): 371-6).
Delayed sleep phase disorder (DSPD) is a specific form of insomnia where persons are unable to fall asleep at the desired clock time but have little difficulty in falling asleep if bedtime is delayed for several hors. The duration of sleep is usually normal. Upon awakening, however, people with DSPD are plagued by drowsiness and fatigue. Melatonin has proven effective in helping people with DSPD fall asleep earlier and awaken refreshed.
Circadian rhythms are inevitably abnormal during shift work or jet travel, hence the common term: “jet lag”. Symptoms include: fatigue, early awakening, headache, insomnia, irritability, difficulty concentrating, vulnerability to infections. (Samel et al: J. Biol. Rhythms.1991(6):235-48.) Numerous studies have documented the positive effects of melatonin for both types of desynchronization (Claustrat et al: Biol. Psychiatry. 1992 (32)705-11.)
Melatonin supplements are normally taken at night, merely to augment the natural rhythm. Or, in the case of shift-workers, before their bedtime. The timing appears to be critical. The phase-response curve has been studied (Lewy et al; Chronobiol. Int. 1992():380-92.). Given within a few hours of normal bedtime, melatonin seems to have little impact upon the circadian rhythm, although many people will feel drowsy within an hour.
People with insomnia should find that taking a supplement 2 - 3 hours before the desired bedtime can help them to fall asleep. For people with no sleep disorder, who simply want to boost their natural levels, a supplement may be taken an hour or so before bedtime. To bring the sleep cycle forward, supplement 2 - 3 hours before the desired bedtime.
It is also important to be consistent, so that the supplement and bedtime always go together. If you are up late one night until 1 a.m. do not take the supplement before gong to bed as it may disrupt your pattern. It is better to skip than to initiate a new rhythm.
Since everyone is an individual, alter your supplementation to obtain the best results. If you wake up tired, take melatonin earlier, or a smaller dose. If you wake up in the middle of the night, take the melatonin somewhat later in the evening, or increase the dose.
Dosage is important. People under 40 who have no sleep disorder and don’t want to change their circadian rhythm, should take 1 mg or less of melatonin. Older persons and those wishing to change their circadian cycle can take a larger dose, such as 3 mgs. Some older people take multiple dosages, a small dose early in the evening, followed by a larger dose an hour or two before bedtime. Absorption varies from person to person so experimentation may be necessary. No more than 9 mgs is usually required. Older people with additional medications, especially, need to consult with their physician before embarking upon melatonin supplementation.
Toxicity Factors
Melatonin appears to be safe even in quite large doses (well over usual doses of under 10mgs). Massive amounts of melatonin (300 mg daily) for extended periods (up to 5 years) failed to produce untoward side-effects in one human study (Reiter et al: Ann. N.Y.Ac. Sciences 1994,719:1-12.).
However, some people have naturally higher levels, associated with neurological disorders, so supplementation could intensify their problems, such as epileptic seizures. (Sandyk et al: “Melatonin as a proconvulsive hormone in humans.” Int. J. Neuroscience.1992(63):125-35.)
You will have noticed that the amounts of melatonin administered are very small, although varying amounts have been used. A suggestion is one 3mg capsule at bedtime or maybe half to one hour before bedtime. This has been shown to work for most people. However, some people may need two.
It may also be necessary to vary the times for taking the dose to find the best time for you.
If you do wake during the night and can't get back to sleep you can take another capsule.
The Life Extension Foundation makes the following recommendation:
1) Experiment with different doses ranging from 1mg to 20mg right before bedtime. Don't be afraid to take additional melatonin if you don't enter the deep sleep state you are seeking.
2) Take melatonin on an empty stomach. Melatonin works for most people even when they have a full stomach, but if you cannot avoid eating before going to bed, you can try emptying the capsule under your tongue and holding it there for two minutes, and then washing the remainder down.'
Melatonin should not be taken by the following groups: adolescents, pregnant or lactating women, people taking cortisone (Persengieu et al: Int. J. Biochem.1991(23)1483-5. ) or people with kidney disease. (Viljoen et al: Nephron. 1992(60):138-43.).
Testosterone
Male animals, that are seasonal breeders, exhibit a direct relationship between season and hormonal levels, both melatonin and testosterone. This has caused concern that melatonin supplementation might inhibit testosterone levels and retard genital development, for example. The injection of massive doses (equivalent to 1000 mgs per day) in an animal experiment tended to support this hypothesis but the effects were reversed by the simple administration of tocopherol (vitamin E).
In fact, the highest levels of testosterone were found in animals receiving both melatonin and vitamin E! Standard levels of melatonin taken orally should present no problems, especially if 100-400 i.u. of vitamin E is taken on a regular basis.
Because it is temperature sensitive, melatonin should be kept tightly closed and refrigerated to maintain full potency.
NSAID
A dosage of 400 mg of ibuprofen (see under NSAID) may also reduce nighttime melatonin secretion by 75%.
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