Sandbox mela

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Sandbox mela
File:Melatonin2.svg
Clinical data
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
Pharmacokinetic data
Bioavailability30 – 50%
MetabolismHepatic via CYP1A2 mediated 6-hydroxylation
Elimination half-life35 to 50 minutes
ExcretionUrine
Identifiers
CAS Number
PubChem CID
DrugBank
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC13H16N2O2
Molar mass232.278 g/mol

Melatonin, 5-methoxy-N-acetyltryptamine, is a hormone found in all living creatures from algae[1] to humans, at levels that vary in a diurnal cycle.

Many biological effects of melatonin are produced through activation of melatonin receptors,[2] while others are due to its role as a pervasive and extremely powerful antioxidant[3] with a particular role in the protection of nuclear and mitochondrial DNA.[4]

Melatonin was released into the general health supplement market in the United States in 1993, and met with good consumer acceptance and enthusiasm.[5]

Production

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.

Melatonin is also synthesized by various plants, such as rice, and ingested melatonin has been shown to be capable of reaching and binding to melatonin binding sites in the brains of mammals.[6][7]

Dangerous Side Effects

Asthma

A study indicates that patients with nocturnal asthma may experience adverse effects from melatonin supplements. According to the study “Immunomodulatory Effects of Melatonin in Asthma”, even small amounts of supplemental melatonin worsen the symptoms of the inflammatory disease asthma by causing the body to release chemicals which provoke inflammation. The inflammatory chemicals include increased production of interleukin-1, interleukin-6, and tumor necrosis factor-alpha [8].

Arthritis

An animal study indicates that there may be an association between melatonin and increased severity of arthritis in certain individuals. The scientific article titled "The pineal hormone melatonin exaggerates development of collagen-induced arthritis in mice." showed that mice who were injected with melatonin at day 1-10 developed more severe arthritis while those injected at onset did not differ significantly from corresponding controls. The study's results support the hypothesis that the pineal gland can exaggerate the development of CIA via a high release of melatonin, probably via enhancement of T-cell priming. [9].

Testis Size

An animal study indicates that there is an association between melatonin and reduced testis size in hamsters. The scientific article is titled "Effects of melatonin and 6-methoxybenzoxazolinone on photoperiodic control of testis size in adult male golden hamsters." In this study, testis widths were determined at 2-3 week intervals, and after 66-73 days testes were removed and weighed. The study found that melatonin significantly influenced testis size in each experiment.[10]

Distribution

Melatonin produced in the pineal gland acts as an endocrine hormone since it is released into the blood. By contrast, melatonin produced by the retina and the gastrointestinal (GI) tract acts as a paracrine hormone.

Roles

Biological clock

See also: Phase response curve

In humans, melatonin is produced by the pineal gland, a gland about the size of a pea, that is located in the center of the brain, on the dorsal surface of diencephalon. The melatonin signal forms part of the system that regulates the circadian cycle, but it is the Central nervous system that controls the daily cycle in most components of the paracrine and endocrine systems[11][12] rather than the melatonin signal (as was once postulated).

Normally, the production of melatonin by the pineal gland is inhibited by light and permitted by darkness. For this reason melatonin has been called "the hormone of darkness." The secretion of melatonin peaks in the middle of the night, and gradually falls during the second half of the night. Until recent history, humans in temperate climates were exposed to up to eighteen hours of darkness in the winter. In this modern world, artificial lighting typically reduces this to eight hours or less per day all year round. Even low light levels inhibit melatonin production to some extent, but 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,[13] and 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.[14] As inadequate as blood concentrations may be in brightly-lit environments, some scientists now believe that people's overnight output of melatonin can be further jeopardized each time they interrupt their sleep and turn on a bright light (suggesting that the lower brightness level of a nightlight would be safer). Others suggest that such short exposures do no harm.[15]

Antioxidant

Although the primary site of melatonin's action in humans is the melatonin receptors, it first evolved as an antioxidant. In many lower life forms, it serves only this purpose.[16]

Melatonin is a powerful antioxidant that can easily cross cell membranes and the blood-brain barrier.[3] Unlike other antioxidants, melatonin does not undergo redox cycling, the ability of a molecule to undergo reduction and oxidation repeatedly. Redox cycling may allow other antioxidants (such as vitamin C) to act as pro-oxidants, counterintuitively promoting free radical formation. Melatonin, once oxidized, cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals. Therefore, it has been referred to as a terminal (or suicidal) antioxidant.[17]

Recent research indicates that the beginning of the melatonin antioxidant pathway may be N(1)-acetyl-N(2)-formyl-5-methoxykynuramine or AFMK rather than the common, excreted 6-hydroxymelatonin sulfate. AFMK alone is detectable in unicellular organisms and metazoans. A single AFMK molecule can neuralize up to 10 ROS/RNS since many of the products of the reaction/derivatives (including melatonin) are themselves antioxidants, and so on. This capacity to absorb free radicals extends at least to the quaternary metabolites of melatonin, a process referred to as "the free radical scavenging cascade". This is not true of other, conventional antioxidants.[16]

In animal models, melatonin has been demonstrated to prevent the damage to DNA by some carcinogens, stopping the mechanism by which they cause cancer.[18]

The antioxidant activity of melatonin may reduce damage caused by some types of Parkinson's disease, may play a role in preventing cardiac arrhythmia and may increase longevity; it has been shown to increase the average life span of mice by 20% in some studies.[19][20][21]

Immune system

Template:POV-check-section While it is clear that melatonin interacts with the immune system,[22][23] the details of those interactions are unclear. 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 is an immunoregulator that can enhance T cell production. When taken in conjunction with calcium, it is an immunostimulator and is used as an adjuvant in some clinical protocols; conversely, the increased immune system activity may aggravate autoimmune disorders.

Dreaming

Many supplemental melatonin users have reported an increase in the vividness or frequency of dreams. High doses of melatonin (50mg) dramatically increased REM sleep time and dream activity in both narcoleptics and normal people.[24]

Many psychoactive drugs, such as LSD and cocaine, increase melatonin synthesis.[24] It has been suggested that nonpolar (lipid-soluble) indolic hallucinogenic drugs emulate melatonin activity in the awakened state and that both act on the same areas of the brain.[24]

In a 2005 editorial of the British Journal of Psychiatry, Ben Sessa suggested that psychotropic drugs be readmitted in the field of scientific enquiry and therapy.[25] Melatonin, being two endogenous hallucinogenic indoles like N,N-dimethyltryptamine (DMT), is likely to be research priorities in this reemerging field of psychiatry.[26]

Medical applications

Melatonin appears to have some use against circadian rhythm sleep disorders, such as jet lag and delayed sleep phase syndrome. It has been studied for the treatment of cancer, immune disorders, cardiovascular diseases, depression, seasonal affective disorder (SAD), and sexual dysfunction. A study by Alfred J. Lewy and other researchers at Oregon Health & Science University found that it may ameliorate SAD and circadian misalignment,[27] but as of 2006 it is known to affect the timing of endogenous melatonin production, raising the risk that it can exacerbate both clinical depression and SAD.[28] Basic research indicates that melatonin may play a significant role in modulating the effects of drugs of abuse such as cocaine.[29]

Preventing ischemic damage

Melatonin has been shown to reduce tissue damage in rats due to ischemia in both the brain[30] and the heart;[31] however, this has not been tested in humans.

Learning, memory and Alzheimers

Melatonin receptors appear to be important in mechanisms of learning and memory in mice,[32] and melatonin can alter electrophysiological processes associated with memory, such as long-term potentiation (LTP). Melatonin has been shown to prevent the hyperphosphorylation of the tau protein in rats. Hyperphosphorylation of tau protein can result in the formation of neurofibrillary tangles, a pathological feature seen in Alzheimer's disease. Thus, melatonin may be effective for treating Alzheimer's Disease.[33] These same neurofibrillary tangles can be found in the hypothalamus in patients with Alzheimer's, adversely affecting their body's production of melatonin. Those Alzheimer's patients with this specific affliction often show heightened afternoon agitation, called "sundowning," which has been shown in many studies to be effectively treated with melatonin supplements in the evening.[34]

ADHD

ADHD is most commonly treated with methylphenidate which may cause insomnia in approximately 94% of its users. Research shows that after melatonin is administered to the patients, the time needed to fall asleep is significantly reduced. Before the melatonin was administered, the time needed to fall asleep ranged from 15 minutes to 240 minutes. After the melatonin was administred, the time needed to fall asleep ranged from 15 minutes to 64 minutes. Furthermore, the effects of the melatonin after three months showed no change from its effects after one week of use.[35]

Fertility

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 and preventing the depression associated with the menopause.[36]

Some resources warn women trying to conceive not to take a melatonin supplement.[37]

Headaches

Several clinical studies indicate that supplementation with melatonin is an effective preventative treatment for migraines and cluster headaches.[38][39]

Depression

Melatonin has been shown to be effective in treating one form of depression, Seasonal Affective Disorder. [1]

Other

Some studies have shown that melatonin has potential for use in the treatment of various forms of cancer, HIV, and other viral diseases; however, further testing is necessary to confirm this.[40]

Histologically speaking, it is also believed that melatonin has some effects for sexual growth in higher organisms. (*Quoted from Ross Histology and Wheather's Functional Histology.)

Dietary supplement

The primary motivation for the use of melatonin as a supplement is as a natural aid to better sleep, with other incidental benefits to health and well-being due to its role as an antioxidant and its stimulation of the immune system and several components of the endocrine system.

Victor Herbert, M.D., J.D., of the Mt. Sinai School of Medicine, cites studies from Massachusetts Institute of Technology that say melatonin pills sold as supplements contain three to 10 times the amount needed to produce the desirable physiologic nocturnal blood melatonin level for enhancement of nighttime rest. Dosages are designed to raise melatonin levels for several hours to enhance quality of sleep, but some studies suggest that smaller doses are just as effective at improving sleep quality.[41] High dose melatonin can even be counterproductive: Lewy & al[42] provide support to the "idea that too much melatonin may spill over onto the wrong zone of the melatonin phase-response curve." In their study, 0.5 mg of melatonin was effective while 20 mg wasn't. A practical implication of these results is that effective melatonin supplementation (for sleep problems) thus becomes very accessible: it costs a fraction of what most researchers thought it might cost. Melatonin supplementation for sleep problems is available without prescription in most cases in the United States. Melatonin supplements are available as oral supplements and transdermal melatonin or "melatonin sleep patch".

Melatonin is involved in the regulation of body weight, and may be helpful in treating obesity (especially when combined with calcium).[43]

Safety

Template:POV-check-section Melatonin is practically nontoxic and exhibits almost no short-term side effects. However, melatonin derived from animal sources may be contaminated with viral material; synthetic melatonin may be taken to avoid this risk.[44] No studies have been conducted yet to determine whether there are any long-term side effects.

Even though it is seen as a relatively safe, benign drug, especially to herbal enthusiasts, it can cause some unwanted side effects, especially at high doses. The bodies of people under age 35 are usually able to produce an adequate supply of melatonin on their own.[citation needed] Ingesting melatonin supplements can cause hormone fluctuations,[2] irritability,[3] reduced blood flow (see below), and increased sleep disturbances, including vivid nightmares.[4]

Melatonin taken in combination with monoamine oxidase inhibitors (MAOIs) can lead to overdose because MAOIs inhibit the breakdown of melatonin by the body. 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.

In individuals with auto-immune disorders, there is concern that melatonin supplementation may exacerbate symptoms due to stimulation of the immune system.[45]

Melatonin causes somnolence, and therefore should not be taken within five hours[citation needed] before driving, operating machinery, etc. As melatonin is almost always taken at the end of the waking day, this is generally not an issue.

Individuals who experience orthostatic intolerance, a cardiovascular condition that results in reduced blood pressure and blood flow to the brain when a person stands, may experience a worsening of symptoms when taking melatonin supplements, a study at Penn State College of Medicine's Milton S. Hershey Medical Center suggests. Melatonin can exacerbate the symptoms by reducing nerve activity in those who experience the condition, the study found.[46]

Role in zoology

Many animals use the variation in duration and quantity of melatonin production in each day as a seasonal clock.[47] In seasonal breeders which do not have long gestation periods, and which mate during longer daylight hours, the melatonin signal controls the seasonal variation in their sexual physiology, and similar physiological effects can be induced by exogenous melatonin in animals including mynah birds[48] and hamsters.[49] 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. The reproduction of long-day breeders is repressed by melatonin and the reproduction of short-day breeders is stimulated by melatonin.

Melatonin is also related to the mechanism by which some amphibians and reptiles change the color of their skin.[50][51]

In popular culture

See also

References

  1. ↑ Caniato R, Filippini R, Piovan A, Puricelli L, Borsarini A, Cappelletti E (2003). "Melatonin in plants". Adv Exp Med Biol. 527: 593–7. PMID 15206778.
  2. ↑ Boutin J, Audinot V, Ferry G, Delagrange P (2005). "Molecular tools to study melatonin pathways and actions". Trends Pharmacol Sci. 26 (8): 412–9. PMID 15992934.
  3. ↑ 3.0 3.1 Hardeland R (2005). "Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance". Endocrine. 27 (2): 119–30. PMID 16217125.
  4. ↑ 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. PMID 11462772.
  5. ↑ Lewis, Alan (1999). Melatonin and the Biological Clock. McGraw-Hill. pp. pp. 7. ISBN 0879837349.
  6. ↑ Hattori A, Migitaka H, Iigo M, Itoh M, Yamamoto K, Ohtani-Kaneko R, Hara M, Suzuki T, Reiter R (1995). "Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates". Biochem Mol Biol Int. 35 (3): 627–34. PMID 7773197.
  7. ↑ Uz T, Arslan A, Kurtuncu M, Imbesi M, Akhisaroglu M, Dwivedi Y, Pandey G, Manev H (2005). "The regional and cellular expression profile of the melatonin receptor MT1 in the central dopaminergic system". Brain Res Mol Brain Res. 136 (1–2): 45–53. PMID 15893586.
  8. ↑ E. Rand Sutherland, Richard J. Martin, Misoo C. Ellison and Monica Kraft (2002). "Immunomodulatory Effects of Melatonin in Asthma". American Journal of Respiratory and Critical Care Medicine. 166: 1055–1061. PMID 12379548.
  9. ↑ Hansson I, Holmdahl R, Mattsson R. (1992). "The pineal hormone melatonin exaggerates development of collagen-induced arthritis in mice". Journal of Neuroimmunology. 39(1-2): 23–30. PMID 1619037.
  10. ↑ Anderson KD, Nachman RJ, Turek FW. (1988). "Effects of melatonin and 6-methoxybenzoxazolinone on photoperiodic control of testis size in adult male golden hamsters". Journal of Pineal Research. 5(4): 351–65. PMID 3210136.
  11. ↑ Richardson G (2005). "The human circadian system in normal and disordered sleep". J Clin Psychiatry. 66 Suppl 9: 3–9, quiz 42-3. PMID 16336035.
  12. ↑ Perreau-Lenz S, Pévet P, Buijs R, Kalsbeek A (2004). "The biological clock: the bodyguard of temporal homeostasis". Chronobiol Int. 21 (1): 1–25. PMID 15129821.
  13. ↑ 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. PMID 15184249.
  14. ↑ 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. PMID 15325001.
  15. ↑ Harder B (2006). "Bright Lights, Big Cancer: Melatonin-depleted blood spurs tumor growth". Science News. 169 (1): 8–10. Retrieved 2006-07-21. Unknown parameter |month= ignored (help)
  16. ↑ 16.0 16.1 Dun-Xian Tan, Lucien C. Manchester, Maria P. Terron, Luis J. Flores, Russel J. Reiter (2007). "One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species?". Journal of Pineal Research. 42 (1): 28–42. PMID 17198536.
  17. ↑ 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. PMID 10899700.
  18. ↑ 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. PMID 11239965.
  19. ↑ 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. ISBN 0-9627418-7-6.
  20. ↑ 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. PMID 12670632.
  21. ↑ 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. PMID 7605949.
  22. ↑ 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. PMID 16217132.
  23. ↑ Arushanian E, Beier E (2002). "Immunotropic properties of pineal melatonin". Eksp Klin Farmakol. 65 (5): 73–80. PMID 12596522.
  24. ↑ 24.0 24.1 24.2 Lewis, Alan (1999). Melatonin and the Biological Clock. McGraw-Hill. pp. pp. 23. ISBN 0879837349.
  25. ↑ Sessa, Ben (2005). "Can psychedelics have a role in psychiatry once again?". The British Journal of Psychiatry: 457–458. PMID 15928353.
  26. ↑ Sessa, Ben (2005). "Endogenous psychoactive tryptamines reconsidered: an anxiolytic role for dimethyltryptamine". Med Hypotheses. 5 (64): 930–7. PMID 15780487.
  27. ↑ Lewy A, Sack R, Miller L, Hoban T (1987). "Antidepressant and circadian phase-shifting effects of light". Science. 235 (4786): 352–4. PMID 3798117.
  28. ↑ Sankaran M, Subramanian P (2006). "Modulation of biochemical circadian rhythms during long-term melatonin treatment in rats". Singapore Med J. 47 (1): 42–7. PMID 16397720.
  29. ↑ Uz T, Akhisaroglu M, Ahmed R, Manev H (2003). "The pineal gland is critical for circadian Period1 expression in the striatum and for circadian cocaine sensitization in mice". Neuropsychopharmacology. 28 (12): 2117–23. PMID 12865893.
  30. ↑ 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. PMID 17349029
  31. ↑ 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. PMID 17123867.
  32. ↑ Larson J, Jessen R, Uz T, Arslan A, Kurtuncu M, Imbesi M, Manev H (2006). "Impaired hippocampal long-term potentiation in melatonin MT2 receptor-deficient mice". Neurosci Lett. 393 (1): 23–6. PMID 16203090.
  33. ↑ Wang X, Zhang J, Yu X, Han L, Zhou Z, Zhang Y, Wang J (2005). "Prevention of isoproterenol-induced tau hyperphosphorylation by melatonin in the rat". Sheng Li Xue Bao. 57 (1): 7–12. PMID 15719129.
  34. ↑ Volicer L, Harper D, Manning B, Goldstein R, Satlin A (2001). "Sundowning and circadian rhythms in Alzheimer's disease". Am J Psychiatry. 158 (5): 704–11. PMID 11329390.
  35. ↑ Tjon Pian Gi CV, Broeren JP, Starreveld JS, Versteegh FG (2003). "Melatonin for treatment of sleeping disorders in children with attention deficit/hyperactivity disorder: a preliminary open label study". Eur J Pediatr. 162 (7): 554–555. PMID 12783318.
  36. ↑ 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. PMID 16399909.
  37. ↑ "Melatonin". About.com: Sleep Disorders: 4. Unknown parameter |link= ignored (help)
  38. ↑ Dodick D, Capobianco D (2001). "Treatment and management of cluster headache". Curr Pain Headache Rep. 5 (1): 83–91. PMID 11252143.
  39. ↑ Gagnier J (2001). "The therapeutic potential of melatonin in migraines and other headache types". Altern Med Rev. 6 (4): 383–9. PMID 11578254.
  40. ↑ Maestroni G (1999). "Therapeutic potential of melatonin in immunodeficiency states, viral diseases, and cancer". Adv Exp Med Biol. 467: 217–26. PMID 10721059.
  41. ↑ Zhdanova I, Wurtman R, Regan M, Taylor J, Shi J, Leclair O (2001). "Melatonin treatment for age-related insomnia". J Clin Endocrinol Metab. 86 (10): 4727–30. PMID 11600532.
  42. ↑ Lewy AJ, Emens JS, Sack RL, Hasler BP, Bernert RA (2002). "Low, but not high, doses of melatonin entrained a free-running blind person with a long circadian period". Chronobiol Int. 19 (3): 649–58. PMID 12069043. line feed character in |title= at position 81 (help)
  43. ↑ Barrenetxe J, Delagrange P, Martínez J (2004). "Physiological and metabolic functions of melatonin". J Physiol Biochem. 60 (1): 61–72. PMID 15352385.
  44. ↑ Information from Drugs.com http://topmeds10.com/?aid=73e86866e5&q=melatonin Information from Drugs.com Check |url= value (help). Missing or empty |title= (help)
  45. ↑ Morera A, Henry M, de La Varga M (2001). "[Safety in melatonin use]". Actas Esp Psiquiatr. 29 (5): 334–7. PMID 11602091.
  46. ↑ "Study Shows Melatonin Supplements May Make Standing A Hazard For The Cardiovascular-Challenged" (Press release). Penn State College of Medicine, Milton S. Hershey Medical Center. September 2003. Retrieved 2006-07-21. (MS Word Format)
  47. ↑ Lincoln G, Andersson H, Loudon A (2003). "Clock genes in calendar cells as the basis of annual timekeeping in mammals — a unifying hypothesis". J Endocrinol. 179 (1): 1–13. PMID 14529560.
  48. ↑ CM Chaturvedi. "Effect of Melatonin on the Adrenl and Gonad of the Common Mynah Acridtheres tristis". Australian Journal of Zoology. 32 (6): 803–809. doi:10.1071/ZO9840803.
  49. ↑ Chen H (1981). "Spontaneous and melatonin-induced testicular regression in male golden hamsters: augmented sensitivity of the old male to melatonin inhibition". Neuroendocrinology. 33 (1): 43–6. PMID 7254478.
  50. ↑ Filadelfi A, Castrucci A (1996). "Comparative aspects of the pineal/melatonin system of poikilothermic vertebrates". J Pineal Res. 20 (4): 175–86. PMID 8836950.
  51. ↑ Sugden D, Davidson K, Hough K, Teh M (2004). "Melatonin, melatonin receptors and melanophores: a moving story". Pigment Cell Res. 17 (5): 454–60. PMID 15357831.

External links

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