The role of Melatonin in hormonal regulation and ageing has been described and reviewed in an elegant way by Pierpaoli in his book “The Key of Life” (2007). The fact remains that this molecule seems to be Universally conserved across animal but also plant species; this fact alone should draw attention to its likely universal importance.
It was named melatonin because of its ability in certain fish, reptiles and amphibians to lighten skin (Lerner et al. 1958).
5-methoxy-N-acetyltryptamine, is a hormone found in all living creatures from algae (Caniato et al, 2003) to humans, at levels that vary in a diurnal cycle. Since the rhythmic formation of melatonin has been demonstrated in unicellular organisms, invertebrates and vertebrates, it is hypothesized that this conserved molecule plays an important role in providing the clock and calendar information to all living organisms, including man. This large body of evidence permits the statement that melatonin is an (almost) ubiquitous substance. Ubiquity frequently indicates fundamental biological significance.
In higher animals, melatonin is produced by pinealocytes in the pineal gland (located in the brain) and also by the retina, lens and GI tract. It is naturally synthesized 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 (SCN) of the hypothalamus which receives information from the retina about the daily pattern of light and darkness. It is secreted from the pineal gland at night, from where it diffuses into the cerebro-spinal fluid and the blood stream. It seems to be responsible for the synchrony of circadian rhythm, modulating sleep patterns with day and night. The activity of the enzyme N-acetyltransferase increases 30 to 70 times during the nocturnal hours and consequently the maximum levels of melatonin are found between 24.00 and 4.00 hours. By contrast, melatonin produced by the retina and the gastrointestinal (GI) tract acts as a paracrine hormone (local action).
The pineal gland, a small gland located at the base of the brain, was viewed by the ancient Greeks as the seat of the soul. The ability of light when applied at night (or the dark phase of the light-dark illumination cycle) to shut down the enzymatic machinery required for nocturnal melatonin production, with subsequent dramatic decline in melatonin levels, is common to all animal species studied thus far.
Melatonin is metabolized in the brain and the liver and excreted in the urine; it acts as a neurotransmitter and neuromodulator; it also plays a major role in interactions between the neuroendocrine and immune systems. It has a half life of 35 to 50 minutes. Many studies confirm that the normal peak level of melatonin in human serum is 10-200 picogram/ml (1). Also, serum melatonin levels in humans vary markedly with age, showing consistent circadian pulses until the mid 20’s, after which the pulses decline with age until the 60’s (Carlson, 1994; Brzezinski, 1997; Yu & Reiter, 1993; Foulkes et al, 1997; Olcese, 2000; Bartness & Goldman, 1989; Reiter, 1993; Humbert & Pevet, 1994).
There are some foods that contain small amounts of melatonin. Oats, sweet corn, and rice are the best sources of melatonin. However, to get the same amount of melatonin that is found in a supplement pill, you would need to eat about 20 bowls of oats. Ginger, tomatoes, bananas, and barley also contain small amounts of melatonin.
Melatonin in Plants (Phytomelatonin)
The August 2001 review in Journal of Pineal Research notes that plant research on melatonin is in its infancy and is hampered by the use of melatonin analysis methods for animals that are not suitable for plant tissue. Detection, destruction during extraction procedures (Pape & Luning, 2006), and environmental factors such as soil quality, temperature, and stress (De la Puerta et al, 2007) affect melatonin levels in plants and may be part of the reason for the difference in levels observed.
In 1995, it was detected in a variety of edible plants, and it is known that melatonin from plant foods is absorbed from the gastrointestinal tract and incorporated in the blood stream. This indoleamine also crosses the blood brain barrier and the placenta, being incorporated at the subcellular level. Melatonin has been detected and quantified in roots, shoots, leaves, fruits and seeds of a considerable variety of plant species. The levels of melatonin in plant organs vary considerably, from picograms to micrograms per gram of plant material. Generally, seeds and leaves present the highest level of melatonin and fruits the lowest. (Dubbels et al, 1995; Hattori et al, 1995; Burkhardt et al, 2001; Manchester et al. 2000; Balzer & Hardeland, 1996; Van Tassel et al. 2001).
Melatonin is found in many fruits and vegetables. Grapes, red wine, tomatoes, olive oil, rice, beer, nuts and seeds have significant levels of the compound. Phytomelatonin has the same chemical structure as that produced by the human body. Some herbs (medicinal or not) present high levels of melatonin, in the order of micrograms/g dry weight, as is the case of Hypericum perforatum (St. John’s wort), Tanacetum parthenium (feverfew) and some Chinese medicinal herbs.( Murch et al, 1997; Chen et al, 2003; Murch et al, 2004; Simopoulos et al, 2005). Melatonin was found in most of the 108 medicinal herbs commonly used in traditional Chinese medicine. In 64 herbs, its amount was above 10 ng g-1 DW, in 34 above 100 ng g-1 DW and in 10 above 1,000 ng g-1 DW (Chen et al. 2003). It was very interesting that the highest melatonin concentrations were observed in the herbs used to retard aging and to treat diseases which associate with free radicals (e.g. neurological disorders) (Chen et al. 2003).
Melatonin is synthesized from trytophan, which is also a precusor to the important plant hormone, auxin. Melatonin may eventually become recognized as a plant hormone after its role in plants has been further researched. However, the exact role of melatonin in plants remains to be elucidated. Experimental data indicate a role similar to the auxin molecule (Hernandez-Ruiz, Cano, & Arnao, 2004, 2005) and a protective effect in germ cells has been proposed (Manchester et al., 2000). The high concentration of melatonin detected in seeds presumably provides antioxidative defense in a dormant and more or less dry system, in which enzymes are poorly effective and cannot be up-regulated. Melatonin may protect lipids stored in seeds against peroxidation, thus increasing seeds viability and vigor (Van Tassel and O’Neil 2001; Manchester et al. 2000). Generally, as it was mentioned before, the physiological concentrations of melatonin in the seeds studied were very high, for example, in white and black mustard seeds it was 129 and 189 ng g-1, respectively. This level of melatonin is much higher than the known physiological concentrations in the blood of many vertebrates.
As in animals, the amount of melatonin is higher in young, reproductive plant tissues and falls down during senescence.
According to new Italian research ( Iriti et al, 2010), melatonin has been identified in the key parts of the Mediterranean diet including grapes, wine, olive oil, tomatoes and beer. French, Spanish and Italian wines, especially reds, have all been shown to have levels much higher than other alcoholic drinks, such as whisky, gin, vodka and rum. The melatonin is thought to come directly from grapes. Melatonin was also found in olive oil, especially extra virgin, and in purslane, a commonly used salad ingredient in the region. The melatonin levels in the case of the extra virgin olive oil samples were roughly almost double those of both the refined olive and sunflower oil samples. Research also shows that consuming melatonin-rich food and drink leads to increased levels of the hormone in the blood. And in laboratory animals, melatonin levels increased threefold after eating walnuts.
One study, as yet unpublished, cited by the Italian team showed that blood levels of the hormone increased by 20 per cent one hour after drinking a 100ml glass of red wine. Does this partly explain why so many people can relax with a glass of wine? The well-established pharmaconutritional properties of this fruit may be due not only to the presence of polyphenolic nutrients, such as Resveratrol, anthocyanins and proanthocyanidins, but also to the powerful antioxidant activity of melatonin.
There is a correlation between dietary vegetable intake and blood levels of melatonin (Reiter, Manchester, & Tan, 2005; Reiter et al., 2001), demonstrating that this molecule is well absorbed and it readily raises blood plasma concentration of melatonin (Nagata, Nagao, Shibuya, Kashiki, & Shimizu, 2005; Reiter et al., 2001). One might postulate that the proven protective health benefits reported for fruits and vegetables against a broad range of diseases including cancer, heart disease and stroke (see Eccles, 2010) may be contributed to by their mealtonin content. Recent studies have demonstrated that dietary combinations of phytochemicals show enhancing health benefits by additive and synergistic effects (Jacobs & Steffen, 2003; Liu,2004).
Table taken from: Russel J. Reiter and Dan-Xian Tan. 2002. Melatonin: An antioxidant in edible plant.
Ann. N. Y. Acad. Sci. 957: 341-344. (Table 1)
Although the exact function of melatonin in plants is not well defined, it is hypothesised that it probably functions as a night signal, coordinating responses to diurnal and photoperiodic environmental cues. Melatonin was observed to be elevated in alpine and mediterranean plants exposed to strong UV irradiation, a finding amenable to the interpretation that melatonin’s antioxidant properties can antagonize damage caused by light-induced oxidants (Hardeland and Pandi-Perumal 2005; Afreen et al. 2006). In ripe tomato fruit, the level of melatonin is much higher than that in green ones. It may be connected with protection of fruit against high free radical generation during ripening (Dubbels et al. 1995).
The list of the potential functions of melatonin in humans continues to extend far beyond the sleep and jet lag correction that remain the most popular associations in the minds of those who have at least some knowledge of the molecule.
Its role in regulating hormonal systems such as thyroid and adrenal as well as the female sex hormone axis are reviewed elsewhere as are the apparent age-reversing effects; at least in animals. Recent research has concluded that melatonin supplementation in perimenopausal women produces a highly significant improvement in Thyroid function and gonadotropin levels, as well as restoring fertility and menstruation, delaying the onset of menopause (Bellipanni et al, 2001) and preventing the depression associated with the menopause (Bellipanni et al, 2005).
In animals and humans, it has been identified as a remarkable molecule signaling not only the time of day or year, but also promoting immunomodulatory and cytoprotective properties. Several characteristics of melatonin such as its direct, non-receptor-mediated free radical scavenging activity—distinguish it from a classic hormone (Tan et al. 2003).Many biological effects of melatonin are produced through activation of melatonin receptors (Boutin et al, 2005) while others are due to its role as a pervasive and extremely powerful antioxidant (Hardeland, 2005) with a particular role in the protection of nuclear and mitochondrial DNA (Reiter et al, 2001).
Since melatonin at low concentrations is soluble in both water and lipids (fats), it may be a hydrophilic and hydrophobic antioxidant. This fact together with melatonin’s small size makes it particularly able to migrate easily between cell compartments in order to protect them against excessive ROS. It can easily cross cell membranes and the blood-brain barrier (Hardeland, 2005). Its antioxidant activity seems to function via a number of means: (1) as a direct free radical scavenger, (2) by stimulating antioxidant enzymes, (3) by stimulating the synthesis of glutathione, (4) by its ability to augment the activities of other antioxidants (5) by protection of antioxidant enzymes from oxidative damage (6) by increasing the efficiency of mitochondrial electron transport chain thereby lowering electron leakage and thus reducing free radical generation (Tan et al. 2002; Kladna et al.
2003; Rodriguez et al. 2004; Leon et al. 2005). Melatonin induces synthesis of endogenous antioxidants such as superoxide dismutase (SOD).I t directly detoxifies the hydroxyl radical (OH), hydrogen peroxide, nitric oxide, peroxynitrite anion, peroxynitrous acid, and hypochlorous acid. Unlike other antioxidants, melatonin does not undergo redox cycling, the ability of a molecule to undergo reduction and oxidation repeatedly. The melatonin molecule presenting no pro-oxidative effects, while melatonin-intermediate products show antioxidant properties and an important synergistic action with other antioxidants, such as ascorbic acid, glutathione, etc. Melatonin is reported to be five times more powerful in fact than vitamin C and twice as strong as vitamin E. Because melatonin, once oxidized, cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals it has been referred to as a terminal (or suicidal) antioxidant (Tan et al , 2000). In animal models, melatonin has been demonstrated to prevent the damage to DNA by some carcinogens, stopping the mechanism by which they cause cancer (Karbownik et al, 2001).
It seems that exposure to Electromagnetic fields (EMFs) inhibits the nocturnal synthesis of melatonin, perhaps thereby increasing the risk of cancer. Melatonin´s radioprotective qualities have been reported and reviewed (Vijayalaxmi et al, 2004). There may be reduced levels of melatonin in people with cancer. Women with breast cancer have only a tenth of normal melatonin levels (Schernhammer & Hankinson,2005). While it is clear that melatonin interacts with the immune system (Carrillo-Vico et al, 2005; Arushanian & Beier, 2002) the details of this interaction are unclear. Over-illumination can create significant reduction in melatonin production. Reduced melatonin production has been proposed as a likely factor in the significantly higher cancer rates in night workers (Schernhammer et al, 2004), the effect of modern lighting practice on endogenous melatonin has been proposed as a contributory factor to the larger overall incidence of some cancers in the developed world (Pauley, 2004).
There have been few trials designed to judge the effectiveness of melatonin in disease treatment. Most existing data are based on small, incomplete, clinical trials. Melatonin has been shown to reduce tissue damage in rats due to ischemia in both the brain ( Lee et al, 2007) and the heart (Dominguez-Rodriguez et al, 2006); however, this has not been tested in humans. Several clinical studies indicate that supplementation with melatonin is an effective preventative treatment for migraines and cluster headaches (Dodick & Capobianco, 2001; Gagnier, 2001). Melatonin has been shown to be effective in treating one form of depression, Seasonal Affective Disorder (Hardeland, 2005) .Melatonin is involved in the regulation of body weight, and may be helpful in treating obesity (especially when combined with calcium) (Barrenetxe et al, 2004). One remarkable clinical study with melatonin has demonstrated stabilisation and reversal of Age related macular degenration using a dosage of 3mg (Changxian et al, 2005).
The list of actions described in the literature goes on. Melatonin has been shown to increase the average life span of mice by 20% in some studies (Ward Dean MD et al, 1993; Anisimov et al, 2003; Oaknin-Bendahan et al, 2003). Cross transplantation of old pineal glands into young mice (accelerated aging) and young pineal glands into old mice (decelerated aging) has provided evidence for a critical role of the pineal gland in senescence (Lesnikov & Pierpaoli ,1994; Pierpaoli & Regelson , 1993; Pierpaoli & Bulian 2001, 2005).
Because mice have a 2 year lifespan the effect of melatonin on ageing and longevity is easier to study than in humans. Long-term effects in humans remain to be clarified. However, some of the recent work emerging from Russia on pineal peptides and melatonin suggests that there may indeed be a rejuvenating and tissue preserving action in humans (Anisimov et al, 2001; Khavinson & Morozov,2003). Moreover, this work suggests that melatonin and other pineal peptides seem to play a crucial gene protective role. This may explain why as melatonin levels diminish in the fourth decade that cells are more likely to become unregulated and degenerative and why risk of almost all disease increases with ageing. I have reported that melatonin is found very commonly in plants and fruit and vegetables and that increased blood levels of melatonin are detected after eating such foods. It is interesting to postulate therefore, that a general lack of intake of phyto-melatonin in conjunction with other phytonutrients due to inadequate fruit and vegetable intake, especially in Western cultures (where it is estimated that the proportion of the general population eating 5 or more fruit and vegetable portions a day is in the order of 10%), offers another fascinating perspective on disease occurrence and a further explanation of why all the major diseases seem to be less common in people in various populations that have a greater intake of phytonutrients.
In the USA melatonin was released into the general health supplement market in 1993. Whereas in Britain you cannot buy melatonin over the counter (OTC). Melatonin is practically nontoxic and exhibits almost no short-term side effects. Melatonin derived from animal sources may be contaminated with viral material; synthetic melatonin can be taken to avoid this risk (Melatonin Information from Drugs.com). No studies have been conducted yet to determine whether there are any long-term side effects. Furthermore, exogenous melatonin normally does not affect the endogenous melatonin profile in the short or medium-term, merely advancing the phase of endogenous melatonin production in time.
Knowing what we do know about melatonin and its apparent lack of reported detrimental effects in the face of a multitude of possible benefits, not least the potential of slowing the biological ageing clock, it would seem to be a sensible thing to supplement this important universal regulator into our preventative health, well-being and anti-ageing programs.
Afreen F, Zobayed SM, Kozai T (2006) Melatonin in Glycyrrhiza uralensis: response of plant roots to spectral quality of light and UV-B radiation. J Pineal Res 41:108–115. and proposed functions. World Rev Nutr Diet 97:211–230
Anisimov V, Alimova I, Baturin D, Popovich I, Zabezhinski M, Rosenfeld S, Manton K, Semenchenko A, Yashin A (2003). "Dose-dependent effect of melatonin on life span and spontaneous tumor incidence in female SHR mice.". Exp Gerontol 38 (4): 449-61.
Anisimov VN, Arutjunyan AV, Khavinson, VK (2001). Effects of pineal peptide preparation Epithalamin on free-radical process in humans and animals. Neuroenocrinol lett 22 (1): 9-18 Arushanian E, Beier E (2002). "Immunotropic properties of pineal melatonin". Eksp Klin Farmakol 65 (5): 73 – 80
Balzer I, Hardeland R. Melatonin in algae and higher plants. Possible new roles as a phytohormone and antioxidant. Bot Acta 1996; 109:180-3.
Barrenetxe J, Delagrange P, Martínez J (2004). "Physiological and metabolic functions of melatonin.". J Physiol Biochem 60 (1): 61 – 72
Bartness TJ, Goldman BD. Mammalian pineal melatonin: A clock for all seasons. Experientia 1989; 45:939-45.
Bellipanni G, DI Marzo F, Blasi F, Di Marzo A (2005). "Effects of melatonin in perimenopausal and menopausal women: our personal experience.". Ann N Y Acad Sci 1057 (Dec): 393 – 402
Bellipanni,G; Bianchi, P; Pierpaoli, W et al (2001) Melatonin delays and reverses menopause in women, Experimental Gerontology 36, 297-310
Boca Raton, FL: CRC Press, 1993.
Boutin J, Audinot V, Ferry G, Delagrange P (2005). "Molecular tools to study melatonin pathways and actions.". Trends Pharmacol Sci 26 (8): 412-9.
Brzezinski A. Melatonin in humans. N Engl J Med 1997; 336:186-95.
Burkhardt S, Tan DX, Manchester LC, Hardeland R, Reiter RJ. Detection and quantification of the antioxidant melatonin in montmorency and balaton tart cherries. J Agric Food Chem 2001; 49:4898-902.
Caniato R, Filippini R, Piovan A, Puricelli L, Borsarini A, Cappelletti E (2003). "Melatonin in plants."Adv Exp Med Biol 527: 593-7.
Carlson N. Physiology of Behavior. 5th ed. Needham Heights, MA: Paramount Publishing, 1994.
Carrillo-Vico A, Guerrero J, Lardone P, Reiter R (2005). "A review of the multiple actions of melatonin on the immune system.". Endocrine 27 (2): 189 – 200.
Changxian y, Xiaoyan P, Hong Y, Mengxiang G, Pierpaoli, W (2005). Effects of melatonin in Age-related Macular degeneration. Ann NY Acad Sci, 1057, 384-392, Forth Stromboli Conference on Ageing and Cancer, Reversal of Ageing. Resetting the clock.
Chen G, Huo Y, Tan DX, Liang Z, Zhang W, Zhang Y (2003). Melatonin in Chinese medicinal herbs. Life Sci 73:19–26.
Coghill, R (2006). Melatonin - The Supermolecule the Government Ignores. ICON, http://www.canceractive.com/cancer-active-page-link.aspx?n=1062
De la Puerta C, Carrascosa-Salmoral MP, Garci´a-Luna PP, Lardone PJ, Herrera JL, Ferna´ndez-Montesinos 25. R, Guerrero JM, Pozo D. Melatonin is a phytochemical in olive oil. Food Chemistry, 2007; 104: 609-612.
Dodick D, Capobianco D (2001). "Treatment and management of cluster headache.". Curr Pain Headache Rep 5 (1): 83 – 91.
Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia-Gonzalez MJ, Kaski JC, Reiter RJ, Jimenez-Sosa A. A unicenter, randomized, double-blind, parallel-group, placebo-controlled study of Melatonin as an Adjunct in patients with acute myocardial infarction undergoing primary Angioplasty The Melatonin Adjunct in the acute myocardial infarction treated with Angioplasty (MARIA) trial: Study design and rationale. Contemp Clin Trials. 2006 Oct 17.
Dubbels R, Reiter RJ, Klenke E, Goebel A, Schnakenberg E, Ehlers C et al (1995) Melatonin in edible plants identified by radioimmunoassay and by high performance liquid chromatographymass spectrometry. J Pineal Res 18:28–31
Eccles NK (2010). Losing the War on Cancer. Part I. http://www.antiaging-systems.com/ENEWS-476/dr-nyjon-eccles-war-on-cancer.htm
Foulkes NS, Borjigin J, Snyder SH, Sassone-Corsi P. Rhythmic transcription: The molecular basis of circadian melatonin synthesis. Trends Neurosci 1997; 20:487-92.
Gagnier J (2001). "The therapeutic potential of melatonin in migraines and other headache types.". Altern Med Rev 6 (4): 383-9.
Hardeland R (2005). "Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance.". Endocrine 27 (2): 119-30.
Hardeland R, Pandi-Perumal SR (2005) Melatonin, a potent agent in antioxidative defense: actions as a natural food constituent, gastrointestinal factor, drug and prodrug. Nutr Metab Lond 2:22
Hattori A, Migitaka H, Iigo M, Itoh M, Yamamoto K, Ohtani-Kaneko R, Hara M, Suzuki T, Reiter RJ. Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates. Biochem Mol Biol Int 1995; 35:627-34.
Herna´ndez-Ruiz J, Cano A, Arnao MB (2004) Melatonin: a growth stimulating compound present in lupin tissue. Planta 220:140–144
Hernandez-Ruiz J, Cano A, Arnao MB (2005) Melatonin acts as a growth-stimulating compound in some monocot species. J Pineal Res 39:137–142
Humbert W, Pevet P. The decrease of pineal melatonin production with age. Ann NY Acad Sci 1994; 719:43-61.
Iriti, M, Varoni, EM, Vitalini, S (2010) Melatonin in traditional Mediterranean diets, Journal of Pineal Research, Volume 49, Issue 2, pages 101–105, September 2010
Jacobs, D. R., Jr., & Steffen, L. M. (2003). Nutrients, foods, and dietary patterns as exposures in research: a framework for food synergy.American Journal Clinical Nutrition, 78(3), 508S–513S.
Karbownik M, Reiter R, Cabrera J, Garcia J (2001). "Comparison of the protective effect of melatonin with other antioxidants in the hamster kidney model of estradiol-induced DNA damage.". Mutat Res 474 (1 – 2): 87 – 92.
Khavinson VK & Morozov, VG (2003) Peptides of the Pineal gland and thymus prolong human life. Neuroendocrinol lett 24 (3-4): 233-40
Kladna A, Aboul-Enien Hy, Kruk I (2003) Enhancing effect of melatonin on chemiluminescence accompanying decomposition of hydrogen peroxide in the presence of copper. Free Radic Biol
Lee MY, Kuan YH, Chen HY, Chen TY, Chen ST, Huang CC, Yang IP, Hsu YS, Wu TS, Lee EJ. Intravenous administration of melatonin reduces the intracerebral cellular inflammatory response following transient focal cerebral ischemia in rats. J Pineal Res. 2007 Apr; 42(3):297 – 309.
Leon J, Acuna-Castroviejo D, Escames G, Tan DX, Reiter RJ (2005) Melatonin mitigates mitochondrial malfunction. J Pineal Res 38:1–9
Lerner AB, Case JD, Takahashi Y, Lee TH, Mori W. Isolation of melatonin, a pineal factor that lightens melanocytes. J Am Soc 1958; 80:2587.
Lesnikov VA & Pierpaoli W (1994). Pineal Cross-transplantation: (Old-to-young And Vice Versa) As Evidence for an endogenous “Aging Clock”. Ann N.Y. Acad Sci, 719: 454-460 Liu, R. H. (2004). Potential synergy of phytochemicals in cancer prevention: mechanism of action. Journal of Nutrition, 134(12), 3479S–3485S.
Manchester LC, Tan D-X, Reiter RJ, Park W, Monis K, Qi WB (2000) High levels of melatonin in the seeds of edible plants—possible function in germ tissue protection. Life Sci 67:3023–3029 Med 12:1544–1554
Murch SJ, Simmons CB, Saxena PK. Melatonin in feverfew and other medicinal plants. Lancet 1997; 350:1598-9.
Murch SJ, Vasantha-Rupasinghe HP, Goodenowe D, Saxena PK. A metabolomic analysis of medicinal diversity in Huang-qin (Scutellaria baicalensis Georgi) genotypes: Discovery of novel compounds. Plant Cell Rep 2004; 23:419-25.
Nagata, C., Nagao, Y., Shibuya, C., Kashiki, Y., & Shimizu, H. (2005).Association of vegetable intake with urinary 6-sulfatoxymelatonin level. Cancer Epidemiology Biomarkers and Prevention, 14(5), 1333–1335.
Oaknin-Bendahan S, Anis Y, Nir I, Zisapel N (1995). "Effects of long-term administration of melatonin and a putative antagonist on the ageing rat.". Neuroreport 6 (5): 785-8.
Olcese J. Melatonin after four decades: An assessment of its potential. New York: Kluwer Academic, 2000.
Pape C, Luning K. Quantification of melatonin in phototrophic organisms.” Journal of Pineal Research, 23. 2006; 41: 157-165.
Pauley S (2004). "Lighting for the human circadian clock: recent research indicates that lighting has become a public health issue.". Med Hypotheses 63 (4): 588-96.
Pierpaoli W & Bulian D (2001). The Pineal Aging and Death Program. Grafting of Old pineal in Young mice accelerates aging. Journal of Anti-aging Medicine. 4:31-37.
Pierpaoli W & Bulian D (2005). Reversal of Aging. Resetting the Pineal clock. Ann N.Y. Acad. Sci. 1057: 133-144
Pierpaoli W & Regelson W (1993). Pineal Control of Aging: Effect of Melatonin and Pineal grafting on aging mice. In Pierpaoli, 2007, The Key of Life, Ed Morlacchi, Perugia Reiter R, Acuña-Castroviejo D, Tan D, Burkhardt S (2001). "Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system.". Ann N Y Acad Sci 939: 200-15.
Reiter RJ (1991) Pineal melatonin: cell biology of its physiological interactions. Endocr Rev 12:151–181
Reiter RJ, Melchiorri D, Sewerynek E, Poeggeler B, Barlow-Walden L, Chuang J-I, Ortiz GG, Acuna-Castroviejo D (1995) A review of the evidence supporting melatonin’s role as an antioxidant. J Pineal Res 18:1–18
Reiter RJ, Tan DX, Manchester LC, Somopoulos AP, Maldonado MD, Flores LJ, Terron MP (2007) Melatonin in edible plants (phytomelatonin): identification, concentrations, bioavailability
Reiter RJ. The melatonin rhythm: Both a clock and a calendar. Experientia 1993; 49:654-64. Rodriguez C, Mayo JC, Sainz RM, Antolin I, Herrera F, Martin V, Reiter RJ (2004) Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res 36:1–9 Russel J. Reiter and Dan-Xian Tan. 2002. Melatonin: An antioxidant in edible plant. Ann. N. Y. Acad. Sci. 957: 341-344.
Schernhammer E, Rosner B, Willett W, Laden F, Colditz G, Hankinson S (2004). "Epidemiology of urinary melatonin in women and its relation to other hormones and night work.". Cancer Epidemiol Biomarkers Prev 13 (62): 936-43.
Schernhammer, ES & Hankinson,SE (2005). Urinary Melatonin Levels and Breast Cancer Risk. Journal of the National Cancer Institute, Vol. 97, No. 14, 1084-7
Simopoulos AP, Tan DX, Manchester LC, Reiter RJ. Purslane: A plant source of omega-3 fatty acids and melatonin. J Pineal Res 2005; 39:331-2.
Tan D, Manchester L, Reiter R, Qi W, Karbownik M, Calvo J (2000). "Significance of melatonin in anti oxidative defense system: reactions and products.". Biol Signals Recept 9 (3 – 4): 137-59.
Tan DX, Manchester LC, Sainz RM, Reiter RJ (2003) Melatonin: a hormon, a tissue factor, an autocoid, a paracoid and an antioxidant vitamin. J Pineal Res 34:75–78
Tan DX, Reiter RJ, Manchester LC, Yan Mei-Ting, El-Sawi M, Sainz RM, Mayo JC, Kohen R, Allegra M, Hardeland R (2002) Chemical and physical properties and potential mechanisms: melatoninas a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem 2:181–197
Van Tassel DL, Roberts NJ, Lewy A, O’Neill SD. Melatonin in plant organs. J Pineal Res 2001; 31:8-15.
Vijayalaxmi, Affiliations · Department of Radiation Oncology, The University of Texas Health Science Center, San Antonio, Texas, USA · Reprint requests to: Vijayalaxmi, Ph.D., Department of Radiation Oncology, The University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. Tel: (210) 616-5648 end_of_the_skype_highlighting; Fax: (210) 949-5085 · Reiter, RJ, Affiliations · Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, TX, USA · Tan, D, Affiliations · Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, TX, USA · Herman, TS Affiliations ·Department of Radiation Oncology, The University of Texas Health Science Center, San Antonio, Texas, USA Thomas, CR (2004). Melatonin as a radioprotective agent: a review. International Journal of Radiation Oncology , 59,(3) , 639-653,
Ward Dean, John Morgenthaler, Steven William Fowkes (1993). Smart Drugs II: The Next Generation : New Drugs and Nutrients to Improve Your Memory and Increase Your Intelligence (Smart Drug Series, V. 2). Smart Publications.
Yu HS, Reiter RJ. Melatonin: Biosynthesis, physiological effects, and clinical applications. Boca Raton, FL: CRC Press, 1993.