![[ MELATONIN ]](melatonin.jpg)
![[ SEROTONIN ]](serotonin.jpg)
by Ben Best
[Many of the unreferenced statements in this essay come from the book MELATONIN by Russell J. Reiter, PhD and Jo Robinson (1995). Reiter has been studying melatonin for about 40 years and has written many papers on the subject for peer-reviewed journals. The book MELATONIN is well referenced to peer-reviewed journal articles.]
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Melatonin was discovered in 1958 and named for its skin-bleaching effect upon melanin (skin pigment). Melatonin is N-Acetyl-5-Methoxytryptamine, which is a mammalian hormone synthesized by methylation of serotonin by SAMe, mainly in the pineal gland, but some is also synthesized in the retina, bone marrow and lymphocytes. The pineal gland and the retina synthesize melatonin in the absence of light, ie, at night or in darkness. Light does not inhibit melatonin synthesis in other tissues. Green light (505 nanometers) is the most effective for suppressing melatonin production [ THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; Brainard,GC; 86(11):433-436 (2001)].
Melatonin is not only a natural mammalian hormone, it is widely found in nature, including foods
such as oats (1.8 nanogram melatonin per gram of oats).
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Melatonin is a natural sleep-inducing agent. Because daylight reduces melatonin production, blood levels of melatonin are usually high at night and low during the day. Artificial light reduces melatonin production. Shift-workers who sleep in darkened rooms with their eyes closed can increase melatonin production during daylight hours. For people who sleep "normal hours", natural melatonin production peaks between 2 am and 4 am, with the peaks becoming smaller with advancing age after early childhood.
Melatonin given as supplements during daytime causes feelings of sleepiness and fatigue, which can adversely affect performance [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Dollins,AB; 91(5):1824-1828 (1994)]. The fact that melatonin production declines so drastically with age probably explains many of the sleep disturbances seen in the elderly. Low doses of melatonin (0.3 mg) given as a supplement seem to be as effective for inducing sleep as higher doses. But because the plasma half-life of melatonin is less than an hour, time-release supplements of higher doses are more effective for sustaining sleep. Studies with 2 mg (2 milligrams) of prolonged-release melatonin in insomnia patients over age 55 showed significantly reduced sleep onset latency (9 minutes) as well as improved sleep quality and morning alertness [JOURNAL OF SLEEP RESEARCH; Lemoine,P; 16(4):372-380 (2007) and INTERNATIONAL CLINICAL PSYCHOPHARMACOLOGY; Luthringer,R; 24(5):239-249 (2009)].
Benzodiazepines (eg, valium) increase Stage 2 sleep, while decreasing the other Stages, including Slow Wave Sleep and REM sleep [JOURNAL OF SLEEP RESEARCH; Perlis,L; 6(3):179-188 (1997)]. Unlike sleep induced by benzodiazepine drugs, melatonin-induced sleep does not suppress Rapid Eye Movement (REM) sleep and slow-wave sleep — and does not result in "hangover" feelings the next day [CLINICAL PHARMACOLOGY AND THERAPEUTICS; Zhdanova,IV; 57(5):552-558 (1995)]. Nonsteroidal anti-inflammatory drugs such as aspirin (which disturbs sleep), decrease plasma melatonin levels [PHYSIOLOGY & BEHAVIOR; Murphy,PJ; 55(6):1063-1066 (1994)].
(For more on the subject of sleep, see my essay
The Nature of Sleep and its Impact on Health.)
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Melatonin plasma levels in mammals decline considerably with aging after early childhood, which might be a factor in the greater vulnerability of elderly people to infections. People over age 60 may show no increase in melatonin production at night. Lifespan studies on mice and rats have shown significant lifespan increase as a result of melatonin supplementation, when given to older rodents and when co-administered with Thyrotropin-Releasing Hormone (TRH is also produced in the pineal gland) [JOURNAL OF ANTI-AGING MEDICINE; Pierpaoli,W; 2(4):343-348 (1999)]. Typically, only supplements given at nighttime are effective.
In children, nocturnal melatonin production decreases significantly at puberty. The decrease is more strongly associated with the stage of puberty than with chronological age [THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; Salti,R; 85(6):2137-2144 (2000)].
Rhesus monkeys subjected to Caloric Restriction with Adequate Nutrition show no decline of melatonin with age, not simply a delay in the decline of melatonin [JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; Roth,GS; 86(7):3292-3295)].
(For background on free radicals and antioxidants, see THE FREE RADICAL THEORY OF AGING and General AntiOxidant Actions.)
Melatonin is a very powerful anti-oxidant. Unlike Vitamin C or glutathione, which are only active in aqueous (watery) phase and Vitamin E, which is only active in lipid (oily) phase, melatonin is effective in both aqueous and lipid phases. Unlike Vitamin E and Vitamin C, which cannot readily cross the blood-brain barrier, melatonin easily crosses the blood-brain barrier [EXPERIMENTAL BIOLOGY AND MEDICINE; Reiter, RJ; 230:104-117 (2005)]
Melatonin is twice as effective at protecting cell membranes from lipid peroxidation as Vitamin E [PHARMACOLOGY LETTERS; Pieri,C; 55(15):271-276 (1994)]. Melatonin is five times more effective than glutathione for neutralizing hydroxyl radicals — the free radicals normally responsible for more than half of all free radical damage in the body (causing lipid peroxidation, DNA damage and protein oxidation). Melatonin and adenosine may be particularly important in protecting brain cells because glutathione concentrations are not very high in the brain. Melatonin in combination with deprenyl significantly counteracts hydroxyl radical production associated with dopamine autoxidation in the brain, and the combination effect is significantly greater than the effect of either agent alone [JOURNAL OF PINEAL RESEARCH; Khaldy,H; 29(2):100-107 (2000)].
In one study, melatonin was more than 60 times more effective than Vitamin C or water-soluble Vitamin E in protecting DNA from DNA damage [ENVIRONMENTAL HEALTH PERSPECTIVES; Qi, W; 108:399-402 (2000)]. Melatonin may bind to DNA, providing further protection beyond anti-oxidant activity.
Melatonin concentrations are particularly high in mitochondria and the cell nucleus. DNA in mitochondria are particularly vulnerable to damage because mitochondria have fewer DNA-repair enzymes than nuclear DNA and because mitochondrial DNA lack the protective histone proteins which nuclear DNA have. By its ability to penetrate readily into mitochondria, by directly protecting mitochondrial DNA and by inducing antioxidant enzymes in mitochondria, melatonin may greatly protect mitochondria. Melatonin demonstrably protects mitochondrial DNA from the damaging effects of ethyl alcohol binges in brain, heart and skeletal muscle, as well as in the liver [JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS; Mansouri,A; 298(2):737-743 (2001)]. Twenty-five years after proposing the free-radical theory of aging, Denham Harman proposed a mitochondrial free-radical theory of aging based on the observation that mitochondria are the source of most cellular free radicals [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Harman,D; 78(11):7124-7128 (1981)]. Fruit flies given melatonin increased maximum lifespan by one-third and median lifespan by one-eighth [EXPERIMENTAL GERONTOLOGY; Bonilla,E; 37:629-638 (2002)]. Along with its antioxidant actions, melatonin directly facilitates mitochondrial electron transport chain enzymes in the production of ATP [THE INTERNATIONIAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY; Martin,M; 34(4):348-357 (2002)].
In addition to the hydroxyl & peroxyl radical, melatonin neutralizes superoxide, singlet oxygen, hydrogen peroxide and hypochlorous acid [ANNALS OF THE NEW YORK ACADEMY OF SCIENCES 959:238-250 (2002)]. Melatonin inhibits peroxynitrite formation by inhibition of the enzyme nitric oxide synthetase in some brain tissues [LIFE SCIENCES; Leon, J.; 75:765-790 (2004)]. Melatonin increases gene expression and activity of the anti-oxidant enzymes glutathione peroxidase, superoxide dismutase and catalase [JOURNAL OF PINEAL RESEARCH; Rodriguez,C; 36(1):1-9 (2004)]. The effect of glutathione peroxidase induction is considerable — a four-fold increase of the antioxidant enzyme in brain mitochondria and an eightfold increase in liver mitochondria with a 100 nanoMolar melatonin concentration [THE FASEB JOURNAL; Martin,M; 14(12):1677-1679 (2000)].
The chief metabolite of melatonin, 6-hydroxymelatonin (formed in the liver) has as much anti-oxidant activity as melatonin. In fact, the reaction products of melatonin with hydroxyl radical and hydrogen peroxide are themselves anti-oxidants [ACTA BIOCHEMICA POLONICA; Reiter,RJ; 54(1):1-9 (2007)]. Vitamin C can become a toxic pro-oxidant when exposed to free iron, and most anti-oxidants become weak free radicals after having neutralized a free radical. But melatonin's antioxidant action involves donation of two electrons, not one electron, thereby ensuring that melatonin does not become a free radical.
Anti-oxidants are also typically very useful against ischemia-reperfusion injury and melatonin is no exception. Melatonin has been shown to reduce cardiac arrythmias and to reduce oxidized lipids in the ischemic heart. Melatonin also reduces superoxide production and myeloperoxide (an enzyme in neutrophils which produces hypochlorous acid) during ischemia-reperfusion [CARDIOVASCULAR RESEARCH; Reiter, RJ; 58:10-19 (2003)]. Pretreatment of rats with melaonin 30 minutes before ischemia significantly reduced nitric oxide production, but 5mg/kg was twice as effective as either 1.5mg/kg or 50mg/kg [JOURNAL OF PINEAL RESEARCH;Pei,Z; 34:110-118 (2003)]. A similar experiment of ischemia-reperfusion in fetal rat brain mitochondria demonstrated a significant reduction in lipid peroxidation products [JOURNAL OF PINEAL RESEARCH; Wakatsuki,A; 31(2):167-172 (2001)]. Melatonin readily crosses the blood-brain barrier, and can protect neurons from excitotoxicity [EXPERIMENTAL BIOLOGY AND MEDICINE; Reiter, RJ; 230:104-117 (2005)]
Melatonin can also protect against ischemia-reperfusion injury by inhibiting inducible nitric oxide production, at least partially by means of inhibiting activation of the pro-inflammatory transcription factor NF-κB and blockage of NF-κB binding to DNA [THE FASEB JOURNAL; Gilad,E; 12(9):685-693 (1998)]. Nitric oxide has been shown to exacerbate apoptosis due to calcium release from the mitochondrial pool and activation of the Mitochondrial Permeability Transition Pore (MPTP) [THE FASEB JOURNAL; Horn,TFW; 16(12):1611-1622 (2002)].
Alteration of the amount of daylight from season-to-season affects melatonin secretion, and thereby can affect seasonal fertility in many mammals. In deer, the decreased light during the Fall season leads to increased fertility and breeding. For hamsters, increased melatonin during Fall and Winter leads to testicular regression in males and estrus inhibition in females. Melatonin can suppress libido by inhibiting secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary gland. Humans may be similar to hamsters because pituitary-gonadal function and conception rates are lower for people living in the Arctic during Winter months [THE NEW ENGLAND JOURNAL OF MEDICINE; Brzezinski,A; 336(3):186-195 (1997)]. Melatonin can inhibit ovulation in women and has even been suggested for use in conjunction with other contraceptives [ THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; Voordouw,BCG; 74(1):108-117 (1992)]. A small study of men, however, showed no suppression of reproductive hormones with melatonin [HUMAN REPRODUCTION; Luboshitzky,R; 15(1):60-65 (2000)].
Melatonin interacts with the hypothalamic-pituitary-adrenal hormonal system to reduce the harmful effects of excessive glucocorticoids — notably damage to the hippocampus [NEUROENDOCRINOLOGY; Konakchieva,R; 67:171-180 (1998)].
Melatonin is necessary for normal sexual maturation. Melatonin supplementation improves thyroid function and can delay the onset of menopause [ANNALS OF THE NEW YORK ACADEMY OF SCIENCES; Lopez,BP; 1057:337-364 (2005) and Bellipanni,F; 1057:393-402 (2005)]. Melatonin enhances memory consolidation under psychological stress [PSYCHOPHARMACOLOGY; Rimmele,U; 202(4):663-672 (2009)].
Immune system cells are typically very vulnerable to free radical damage, which is why anti-oxidants such as melatonin are generally very effective in boosting the immune system. Melatonin may also reduce the age-related decline in thymus gland function [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Pierpaoli,W; 91(2):787-791 1994)].
Melatonin is of benefit for both cellular and humoral immunity. Melatonin stimulates production of the cytokines InterLeukin−2 (IL−2), InterLeukin−6 (IL−6), and InterLeukin−12 (IL−12). Melatonin stiumulates the production of progenitor cells for granulocytes, macrophages, natural killer (NK) cells and certain helper T−cells (CD4+), while lowering harmful CD8+ cell concentrations [IMMUNITY & AGEING; Srinivasan,V; 2:17 (2005)]. The combination of low T−cell proliferation and low CD4/CD8 ratio was highly predictive of low 2−year survival in a study of people in the 86−92 age range [JOURNALS OF GERONTOLOGY 50A(6):B378-B382 (1995)].
(For more on the subject of the immune system and aging, see THE IMMUNE SYSTEM AND AGING .)
Melatonin reduces estradiol levels in the blood and inhibits aromatase expression in human breast cancer cells, both of which suggest that melatonin could be of of value in the prevention and treatment of breast cancer [JOURNAL OF PINEAL RESEARCH; Sanchez-Barcelo,EJ; 38(4):217-222 (2005)]. Because melatonin protects against the side effects of radiation, it could be a useful adjunct to radiotherapy in cancer treatment [JOURNAL OF RADIATION RESEARCH; Shirazi,A; 48(4):263-272 (2007)].
The most worrisome experiments involving melatonin are those that show increasing incidence of cancer in certain species of mice (usually female mice) that are given melatonin. Ironically, a study of this kind showed an overall 5.4% increase in mean lifespan and a 17% increase in maximum lifespan despite the increased incidence of tumors [JOURNALS OF GERONTOLOGY; Anisimov,VN; 56A:B311-B323 (2001)]. By contrast, melatonin in other strains of female mice has been shown to suppress tumors [JOURNAL OF PINEAL RESEARCH; Subramanian,A; 10(3):136-140 (1991) and BREAST CANCER RESEARCH AND TREATMENT; Rao,GN; 64(3):287-296 (2000)]. The anti-cancer effects of melatonin are also seen in rats [BREAST CANCER RESEARCH; Lenoir,V; 7(4):R470-R476 (2005)].
Studies of human cancer cells show that treatment with melatonin reduces their proliferation and metastatic capacity [ENDOCRINE-RELATED CANCER; Sanchez-Barcelo,EJ; 10(2):153-159 (2003) and JOURNAL OF PINEAL RESEARCH; Cos,S; 32(2):90-96 (2002)]. Melatonin has been shown to directly inhibit breast cancer cells by 75% — optimally at normal youthful body levels rather than higher doses [JOURNAL OF NEURAL TRANSMISSION; Blask, DE; 21:433-449 (1986)]. Melatonin is not mutagenic according to the Ames Test and, in fact, has been shown to reduce the mutagenicity of a number of chemicals [MUTATION RESEARCH; Musatov,SA; 417(2-3):75-84 (1998)].
A study of totally blind women (who would have less exposure to light and more exposure to melatonin) found them to have less than two-thirds the normal risk of breast cancer [BRITISH JOURNAL OF CANCER; Kliukiene,J; 84(3):397-399 (2001)]. Similar epidemiological studies on people with varying levels of light exposure provide further confirmation of the hypothesis that melatonin reduced cancer risk in humans. Other epidemiological studies have found no correlation between cancer and blood melatonin levels.
With aging there is a decline in both serotonin transporters [LIFE SCIENCES; Yamamoto,M; 71(7):751-757 (2002)] and serotonin receptors [NEUROPSYCHOPHARMACOLOGY; Meltzer,MD; 71(7):751-757 (2002)]. Serotonin is the precursor for melatonin in the brain.
Although it remains unproven, there is evidence that free radicals may cause or aggravate Alzheimer's Disease. Elderly Alzheimer's Disease patients have half the blood levels of melatonin as normal people the same age. The amyloid-beta protein which is the most commonly implicated marker of Alzheimer's is most neurotoxic and most resistant to proteolytic degradation when it aggregates into beta-sheets. Melatonin inhibits the aggregation of amyloid-beta into beta-sheets [JOURNAL OF BIOLOGICAL CHEMISTRY; Pappolla,M; 273(13):7185-7188 (1998) and BIOCHEMISTRY; Poeggeler,B; 40(49):14995-15001 (2001)]. Melatonin also reduces the hyperphosphorylation of tau protein, which leads to the neurofibrillary tangles of Alzheimer's Disease [ACTA PHARMACOLOGICA SINICA; Wang,J;27(1):41-49 (2006) and CURRENT NEUROPHARMACOLOGY; Oritz,GG; 6(3):203-214 (2008)].
For melatonin, more is not better. Blood concentrations which are ten times normal youthful levels can cleave heme molecules to liberate iron and induce oxidative stress [NEUROCHEMISTRY; Clapp-Lilly,KL; 12(6):1277-1280 (2001)]. Even higher levels of melatonin concentrations deplete reduced glutathione levels [LIFE SCIENCES; Osseni,RA; 502:127-131 (2001)].
Melatonin can counteract the effectiveness of steroid drugs, can worsen allergic responses and can worsen auto-immune disease. Melatonin readily crosses the placenta, but the effects of above-normal quantities on a developing fetus or a pregnant woman have not been thoroughly studied. Melatonin is freely available in the United States and has been safely used by large numbers of people, so there are few financial incentives for large controlled clinical trials. Adolescents should not take melatonin supplements because melatonin can interfere with the growth and development that occurs after puberty. Consultation with a physician may be advised before taking melatonin supplements.
Although supplement doses a hundred times the typical 3 mg per day have proven to be safe, higher doses may be unnecessary or even harmful. Doses in the 1 mg to 5 mg range should be safe and sufficient insofare as these doses produce blood levels 10 to 100 times higher than the usual nighttime peaks [THE NEW ENGLAND JOURNAL OF MEDICINE; Brzezinski,A; 336(3):186-195 (1997)].
Night-time blood levels of melatonin peak at about 120 picograms per milliliter just before the age of puberty. By age 30 blood levels have fallen by half and by age 60 the levels of melatonin in the blood are usually about 5 picograms per milliliter or less. Melatonin supplementation is of much more value for older adults, because their natural production of melatonin is so low [EXPERIMENTAL GERONTOLOGY; Pandi-Perumal,SR; 40(12):911-925 (2005)].
Because melatonin can cause drowsiness and is not very effective when taken in daylight, one or two time-release capsules or tablets daily at bedtime is preferable. Dosages in excess of 3 to 6 mg (milligrams) should not be necessary, and often lower doses are preferred, and equally effective for induction of sleep (if not the other benefits).
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