By Julius Goepp, MD
To the surprise of doctors around the world, melatonin is demonstrating life-saving benefits that far exceed its common use as a sleep aid.1 Increasingly, researchers have shown that melatonin’s impressive ability to control oxidative damage in systems throughout the body can reduce the trauma of brain injury, prevent heart muscle damage, offer neuroprotection, increase cognitive functioning, and reduce the toxic effects of chemotherapy while enhancing its benefits.2-7 Cumulatively, these findings add up to important new roles for melatonin not only in disease prevention but in almost every field of medicine.
Much of the new evidence for melatonin’s versatile properties has been uncovered in just the past five years. As these findings continue to pour in, scientists are increasingly recognizing the wide ranging benefits of this remarkable hormone.
Long thought to be solely the product of the tiny pineal gland in the brain and to be secreted only at night, melatonin is now known to be produced in multiple body sites. This powerful hormone impacts virtually every cell with which it comes into contact as well as being able to cross the highly selective blood-brain barrier.8,9 Derived from the amino acid L-tryptophan, melatonin’s molecular structure gives it some of the most impressive antioxidant capabilities known. These properties help to protect tissues that take the brunt of oxidative and other injuries, including the stomach, pancreas, and liver,5,10-13 as well as those most vulnerable to such injuries, like the brain and spinal cord.3,9 Melatonin also protects against cardiovascular diseases,7,14 degenerative brain diseases,15,16 brain injuries,17-20 stroke,21 and numerous cancers.2,22-24 Let’s take a closer look at some of the most impressive data on melatonin’s actions.25-27
Melatonin and Inflammation
Melatonin’s powerful anti-inflammatory effects are similar to those of commonly used non-steroidal anti-inflammatory drugs (NSAID) such as ibuprofen.28 Both NSAID drugs and melatonin inhibit an enzyme called cyclooxygenase-2 (COX-2) that produces inflammatory chemicals in the body. Unlike these drugs, however, melatonin has far fewer side effects because it does not inhibit the COX-1 enzyme that helps to protect the stomach lining.29 Furthermore, melatonin not only reduces pain perception in animal models of inflammation, but can also increase the analgesic effects of NSAID drugs.30
Earlier this year, researchers in New Zealand reported that, in addition to its anti-inflammatory properties, melatonin can promote a healthy immune response early in the process of wound healing, improving the quality of wound healing and scar formation.31 Studies like this are revealing much about melatonin’s ability to modulate the inflammatory process, not only in the important area of wound healing, but in other forms of tissue injury that occur throughout the body.
Protection Against Brain Injury
Brain injury from stroke or trauma can quickly destroy one’s neurological function. Melatonin is showing important therapeutic benefits for this serious condition due its powerful free radical-scavenging and anti-inflammatory effects.
All types of serious brain injuries—including traumatic brain and spinal cord injury, ischemia/reperfusion due to atherosclerosis, and neurodegenerative diseases—involve dangerous oxidant stress and inflammation. While overt head trauma is most common in children and young adults, older adults also suffer from the same kinds of damage caused by chronic reductions in brain blood flow due to atherosclerosis, and to sudden interruptions in blood flow during a stroke. In both traumatic head injuries and in strokes, most of the damage is done when blood flow returns to areas that have been transiently deprived. The resulting ischemia/reperfusion injury releases waves of oxygen and other free radicals that literally “burn” cell membranes and impair function.32,33
A tremendous amount of attention is therefore focused on preventing the consequences of that oxidant release—something melatonin can do with remarkable efficiency.3,9,20,34,35
Swiss neurologists showed that mice treated for 30 days with melatonin 24 hours after an experimentally induced stroke had improved survival of brain cells and better recovery of injured cells.21 These changes were associated with long-lasting improvement of motor and coordination deficits (both common after human strokes).
Levels of melatonin, a potent neuroprotective agent,16 drop sharply in patients who suffer severe head injury.36 Animal studies have found that replenishing melatonin levels after head injury prevents both detectable tissue injuries and the cognitive deficits they produce.19
Laboratory studies worldwide have revealed that, in addition to its free radical-scavenging ability, melatonin reduces chemicals produced by brain cell oxidation,34,37 increases levels of other natural antioxidants such as vitamin C,18 and decreases activation of inflammatory systems in brain cells.38 These antioxidant effects are now credited with reducing the size of brain contusions (bruising) following head trauma.39
What is even more remarkable is melatonin’s ability to prevent the devastating cognitive outcomes of severe head injury. Turkish researchers studied damage to the hippocampus, a brain region known to be essential for proper memory function. They found that melatonin given immediately after head injury in rabbits not only reduced visible injury to the hippocampus, but actually improved memory deficits that prevented the animals from performing well in a maze.40
Melatonin has also been found to protect fetal animals from ischemia/reperfusion injuries that occur during pregnancy.35 These injuries can occur late in human pregnancies and are responsible for tragic consequences such as cerebral palsy and mental retardation in newborns. Studies have shown that melatonin prevents newborn learning disorders associated with brain injury in infant animals41 and that repeated doses of melatonin reduce injury even further.42
Scientists at Life Extension-funded laboratories long ago recognized the ability of melatonin to protect the brain against reperfusion injury. In experiments designed to see how long animals could survive at low temperatures with no blood flow, melatonin administered prior to surgery greatly extended the time that animals could undergo complex procedures and still recover.
Preventing Neurodegenerative Diseases
Dramatic advances have revealed that melatonin prevents many cognitive deficits associated with aging. This is especially because of melatonin’s ability to cross the blood-brain barrier and its ready absorption following oral dosing.3
A recent human study assessed the benefit of melatonin in 50 sufferers of mild cognitive impairment (MCI), a collection of conditions that precedes dementia and Alzheimer’s disease.43 After giving melatonin 3-9 mg daily at bedtime for 9-18 months to half of the study group, researchers found that the supplemented patients had significantly better performance on a host of neuropsychological tests while experiencing improvements in sleep quality and wakefulness.
Scientists have also discovered promising effects of melatonin on the amyloid-beta proteins that trigger inflammation and brain dysfunction in Alzheimer’s disease.44 Very low doses of melatonin given for 10 days substantially improved learning and memory in animals as well as reducing levels of inflammatory proteins.
Of course, not all deficits in cognition and memory are related to Alzheimer’s disease. Melatonin also seems to optimize brain cognitive function in the course of natural aging. One recent study, for example, found that daily administration of melatonin in drinking water at night significantly improved memory in aging animals tested on a maze, but had no effect on learning in young adult rats.26 And early human trials suggest that melatonin might provide benefits in degenerative disorders such as amyotrophic lateral sclerosis (ALS or Lou Gehrig’s Disease), in which motor function, not cognition, is lost.45
Melatonin is getting a lot of attention as a potential cardioprotective nutrient.46 As with its effects elsewhere in the body, melatonin efficiently scavenges free radicals produced during cardiac injury, while increasing antioxidant enzymes. These powerful anti-inflammatory actions prevent further oxidative damage and limit the size of an infarction (area of heart cell death).7,47 Melatonin also improves the strength of the heart’s pumping action following an infarction in laboratory animals48 and can even prevent heart muscle damage following potent cardio-toxic chemotherapy treatment.49,50 In addition, laboratory studies have demonstrated that melatonin protects mitochondria (the energy sources so vital to cardiac muscle function) during ischemia and reperfusion.51 Its effects on heart muscle are both short- and long-lived, potentially preventing heart attacks and minimizing their impact if they do occur.52
In a study of patients with stable narrowing of their coronary arteries, who are at risk for ischemic events (angina and heart attacks), researchers compared melatonin with conventional medical therapy with isosorbide dinitrate (Isordil®) and also tested the combination of both treatments.53 Sixty-five patients aged 44-69 were studied by echocardiography to evaluate heart wall motion and function. The findings revealed that patients who received melatonin plus drug treatment had significantly greater increases in heart muscle function than those on drug treatment alone as well as a beneficial decrease in heart size and increase in the amount of blood actively ejected from the heart with each beat.53 A large prospective randomized trial is now getting underway in Spain to determine whether melatonin treatment reduces infarct size, deaths, abnormal heart rhythm, shock, heart failure, and other potentially disastrous consequences of a heart attack.46
Melatonin has also been shown to regulate specific risk factors for cardiovascular diseases. Night-time hypertension is a known cardiovascular risk factor—people who don’t “dip” (safely decrease) their blood pressure at night are more likely to have cardiovascular events than those who do.54 In a recent study, 38 people (mean age 64 years) with night-time hypertension who were already receiving stable antihypertensive therapy, were given either controlled-release melatonin, 2 mg/night, or placebo two hours before bedtime for four weeks.55 The supplemented patients significantly reduced their nocturnal blood pressure (136 to 130 mmHg systolic, and 72 to 69 mmHg diastolic), while no difference was seen in the placebo group.55
A heart attack can also be triggered by stress-induced increases in blood-clotting tendency that are amplified by hypertension.56 Swiss researchers recently discovered that melatonin may influence blood clotting. They found that a single dose of oral melatonin (3 mg) given to a group of 46 healthy young men significantly reduces overall blood coagulation activity compared with placebo.57
These scientists also found that melatonin attenuates the stress-induced procoagulant response to acute psychosocial stress, a potent trigger of acute coronary disease, in the same group of healthy men.58
Gastrointestinal Tract Protection
The human gastrointestinal tract is the site of some of the most profound oxidative stresses our bodies experience, which may be why it produces more than 500 times as much melatonin as the pineal gland.59 The stomach takes the brunt of the damage because of its constant exposure to strong acid and/or powerful digestive enzymes, both of which generate “storms” of free radicals.
Melatonin not only reduces stomach injury caused by NSAIDs such as piroxicam or indomethacin by as much as 90% compared with controls, but also dramatically reduces measures of tissue oxidation with no significant adverse effects.60,61 European researchers have also shown that melatonin protects against damage to both the stomach and the pancreas and accelerates healing of chronic gastric ulcers by stimulating blood flow.5,10
Further research from Europe has revealed that melatonin reduces symptoms in patients with another painful condition called “functional dyspepsia,” or “sour stomach.”62 In a placebo-controlled trial, gastroenterologists treated 60 patients (aged 19-39 years) with functional dyspepsia with either melatonin 5 mg or placebo, once every evening for 12 weeks. Of the melatonin-treated group, 57% showed complete resolution of symptoms and 30% had partial improvement, but 93% of placebo recipients reported no change at all.
Melatonin has also been studied in alleviating gastroesophageal reflux disease (GERD, also known as “heartburn”), a potentially dangerous condition that can lead to esophageal cancer. In a head-to-head comparison, the researchers gave 175 patients standard treatment with the prescription drug omeprazole (Prilosec®), while 176 received a supplement containing melatonin, its precursor L-tryptophan, and B vitamins, over a 40-day treatment period. All patients in the supplement group reported complete regression of symptoms by the end of the study, compared with only 66% in the drug-treated group. Again, no significant side effects were reported in the supplemented patients.63
It is believed that melatonin protects against GERD by increasing blood flow and anti-inflammatory molecules in the esophageal mucous, thus preventing significant esophageal injury.64
Cancer Prevention and Control
Cancer, of course, is one of the most-dreaded final outcomes of lifelong exposures to oxidant stresses and the inflammation that can damage the body’s DNA. For patients undergoing anticancer therapies, melatonin is at the forefront of cancer immunotherapy (treatment and prevention of cancer using the body’s own immune system as an ally) by working synergistically with several of the body’s own anti-tumor systems and dramatically decreasing adverse effects of treatment.22
Much of the remarkable work in this area has come from the prolific group of researchers led by Dr. Paolo Lissoni, a radiation oncologist in Milan. In 1992, Dr. Lissoni broke new ground by providing melatonin at a dose of 10 mg/day to a group of patients with metastatic lung cancer.65 This group of patients, who had already failed chemotherapy, was randomly assigned to receive melatonin or supportive care only. Survival at one year and stabilization of disease were both significantly higher in the melatonin-treated group. Not only were there no drug-related toxic effects, but melatonin-treated patients actually showed a significant improvement in their overall performance status.
Subsequently, Dr. Lissoni’s group demonstrated that they could improve the tumor-killing power of the cytokine interleukin-2 (IL-2) by supplementing patients with 40 mg/day of melatonin beginning a week prior to treatment—again without side effects even at this substantial dose.66
By 1999, Dr. Lissoni’s group had progressed to a study of 250 patients with tumors that had metastasized.67 Subjects received melatonin 20 mg/day plus chemotherapy, or chemotherapy alone. This was a large group of patients with cancers in a variety of tissues, and who received a variety of chemotherapy regimens. Even in this very diverse group of patients, the melatonin-treated subjects had significantly higher one-year survival and greater tumor regression rates than those who received chemotherapy only. In addition, those supplemented with melatonin experienced far fewer episodes of chemotherapy-associated toxicity such as low platelet counts, neurotoxicity and cardiotoxicity, and mouth sores.
Devotion to improving the lives of cancer sufferers has led Dr. Lissoni and colleagues to continue to explore melatonin’s dramatic effects in patients with some of the most advanced cancers, with a steady stream of positive reports continuing up to the present moment.23,24,68-70
US researchers in Texas have found that melatonin also reduces prostate cancer cell growth rates,71,72 and other researchers from around the world are beginning to take notice. We can confidently predict that melatonin will play an increasingly important role in both the treatment and the prevention of cancer as we learn more about its remarkable properties.
Most experts believe that we are seeing just the tip of the iceberg represented by melatonin’s versatile, system-wide effects. This formerly “niche” hormone, long thought to be responsible only for day-night cycling and important effects on sleep, is turning out to be the “dark horse” of biomedicine in the early 21st century. We’ve seen how melatonin’s intense antioxidant activities, remarkable ability to modulate the immune system, and capacity to manage inflammatory consequences of tissue injury throughout the body are leading to its use in just about every conceivable setting. From the tragic consequences of severe head trauma to the neurological deficits experienced by Alzheimer’s and stroke patients, to the deadly effects of advanced cancers, melatonin has shown that it has important wide-ranging applications for medical treatment.
If you have any questions on the scientific content of this article, please call a Life Extension Health Advisor at 1-800-226-2370.
1. Stehle JH, von GC, Korf HW. Melatonin: a clock-output, a clock-input. J Neuroendocrinol. 2003 Apr;15(4):383-9.
2. Carrillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ. A review of the multiple actions of melatonin on the immune system. Endocrine. 2005 Jul;27(2):189-200.
3. Cervantes M, Morali G, Letechipia-Vallejo G. Melatonin and ischemia-reperfusion injury of the brain. J Pineal Res. 2008 Jan 9.
4. Escames G, cuna-Castroviejo D, Lopez LC, et al. Pharmacological utility of melatonin in the treatment of septic shock: experimental and clinical evidence. J Pharm Pharmacol. 2006 Sep;58(9):1153-65.
5. Jaworek J, Brzozowski T, Konturek SJ. Melatonin as an organoprotector in the stomach and the pancreas. J Pineal Res. 2005 Mar;38(2):73-83.
6. Oxenkrug GF. Genetic and hormonal regulation of tryptophan kynurenine metabolism: implications for vascular cognitive impairment, major depressive disorder, and aging. Ann NY Acad Sci. 2007 Dec;1122:35-49.
7. Tengattini S, Reiter RJ, Tan DX, et al. Cardiovascular diseases: protective effects of melatonin. J Pineal Res. 2008 Jan;44(1):16-25.
8. Reiter RJ, Tan DX, Manchester LC, et al. Medical implications of melatonin: receptor-mediated and receptor-independent actions. Adv Med Sci. 2007;52:11-28.
9. Reiter RJ, Tan DX, Manchester LC, Tamura H. Melatonin defeats neurally-derived free radicals and reduces the associated neuromorphological and neurobehavioral damage. J Physiol Pharmacol. 2007 Dec;58 Suppl 65-22.
10. Jaworek J, Nawrot-Porabka K, Leja-Szpak A, et al. Melatonin as modulator of pancreatic enzyme secretion and pancreatoprotector. J Physiol Pharmacol. 2007 Dec;58 Suppl 6:65-80.
11. El-Sokkary GH, Reiter RJ, Tan DX, Kim SJ, Cabrera J. Inhibitory effect of melatonin on products of lipid peroxidation resulting from chronic ethanol administration. Alcohol Alcohol. 1999 Nov;34(6):842-50.
12. Genc S, Gurdol F, Oner-Iyidogan Y, Onaran I. The effect of melatonin administration on ethanol-induced lipid peroxidation in rats. Pharmacol Res. 1998 Jan;37(1):37-40.
13. Guha M, Maity P, Choubey V, et al. Melatonin inhibits free radical-mediated mitochondrial-dependent hepatocyte apoptosis and liver damage induced during malarial infection. J Pineal Res. 2007 Nov;43(4):372-81.
14. Paulis L, Simko F. Blood pressure modulation and cardiovascular protection by melatonin: potential mechanisms behind. Physiol Res. 2007;56(6):671-84.
15. Gutierrez-Cuesta J, Sureda FX, Romeu M, et al. Chronic administration of melatonin reduces cerebral injury biomarkers in SAMP8. J Pineal Res. 2007 Apr;42(4):394-402.
16. Srinivasan V, Pandi-Perumal SR, Maestroni GJ, et al. Role of melatonin in neurodegenerative diseases. Neurotox Res 2005;7(4):293-318.
17. Ates O, Cayli S, Gurses I, et al. Effect of pinealectomy and melatonin replacement on morphological and biochemical recovery after traumatic brain injury. Int J Dev Neurosci. 2006 Oct;24(6):357-63.
18. Beni SM, Kohen R, Reiter RJ, Tan DX, Shohami E. Melatonin-induced neuroprotection after closed head injury is associated with increased brain antioxidants and attenuated late-phase activation of NF-kappaB and AP-1. FASEB J. 2004 Jan;18(1):149-51.
19. Mesenge C, Margaill I, Verrecchia C, et al. Protective effect of melatonin in a model of traumatic brain injury in mice. J Pineal Res. 1998 Aug;25(1):41-6.
20. Pei Z, Cheung RT. Pretreatment with melatonin exerts anti-inflammatory effects against ischemia/reperfusion injury in a rat middle cerebral artery occlusion stroke model. J Pineal Res. 2004 Sep;37(2):85-91.
21. Kilic E, Kilic U, Bacigaluppi M, et al. Delayed melatonin administration promotes neuronal survival, neurogenesis and motor recovery, and attenuates hyperactivity and anxiety after mild focal cerebral ischemia in mice. J Pineal Res. 2008 Feb 14.
22. Giannoulia-Karantana A, Vlachou A, Polychronopoulou S, Papassotiriou I, Chrousos GP. Melatonin and immunomodulation: connections and potential clinical applications. Neuroimmunomodulation. 2006;13(3):133-44.
23. Cerea G, Vaghi M, Ardizzoia A, et al. Biomodulation of cancer chemotherapy for metastatic colorectal cancer: a randomized study of weekly low-dose irinotecan alone versus irinotecan plus the oncostatic pineal hormone melatonin in metastatic colorectal cancer patients progressing on 5-fluorouracil-containing combinations. Anticancer Res. 2003 Mar;23(2C):1951-4.
24. Lissoni P. Biochemotherapy with standard chemotherapies plus the pineal hormone melatonin in the treatment of advanced solid neoplasms. Pathol Biol (Paris). 2007 Apr;55(3-4):201-4.
25. Karasek M. Does melatonin play a role in aging processes? J Physiol Pharmacol. 2007 Dec;58 Suppl 6:105-13.
26. Vinogradova IA. Comparative study of the effects of melatonin and epitalon on the protracted memory under the shuttle labyrinth test conditions in rats in the course of aging. Eksp Klin Farmakol. 2006 Nov;69(6):13-6.
27. Cutando A, Gomez-Moreno G, Arana C, cuna-Castroviejo D, Reiter RJ. Melatonin: potential functions in the oral cavity. J Periodontol. 2007 Jun;78(6):1094-102.
28. Cuzzocrea S, Costantino G, Mazzon E, Caputi AP. Regulation of prostaglandin production in carrageenan-induced pleurisy by melatonin. J Pineal Res. 1999;27:9-14.
29. Mayo JC, Sainz RM, Tan DX, et al. Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophages. J Neuroimmunol. 2005 Aug;165(1-2):139-49.
30. El-Shenawy SM, bdel-Salam OM, Baiuomy AR, El-Batran S, Arbid MS. Studies on the anti-inflammatory and anti-nociceptive effects of melatonin in the rat. Pharmacol Res. 2002 Sep;46(3):235-43.
31. Pugazhenthi K, Kapoor M, Clarkson AN, Hall I, Appleton I. Melatonin accelerates the process of wound repair in full-thickness incisional wounds. J Pineal Res. 2008 May;44(4):387-96.
32. Kirsch JR, Helfaer MA, Lange DG, Traystman RJ. Evidence for free radical mechanisms of brain injury resulting from ischemia/reperfusion-induced events. J Neurotrauma. 1992 Mar;9 Suppl 1S157-63.
33. D’Ambrosio AL, Pinsky DJ, Connolly ES. The role of the complement cascade in ischemia/reperfusion injury: implications for neuroprotection. Mol Med. 2001 Jun;7(6):367-82.
34. Ozdemir D, Uysal N, Gonenc S, et al. Effect of melatonin on brain oxidative damage induced by traumatic brain injury in immature rats. Physiol Res. 2005;54(6):631-7.
35. Wakatsuki A, Okatani Y, Shinohara K, Ikenoue N, Fukaya T. Melatonin protects against ischemia/reperfusion-induced oxidative damage to mitochondria in fetal rat brain. J Pineal Res. 2001 Sep;31(2):167-72.
36. Paparrigopoulos T, Melissaki A, Tsekou H, et al. Melatonin secretion after head injury: a pilot study. Brain Inj. 2006 Jul;20(8):873-8.
37. Cirak B, Rousan N, Kocak A, et al. Melatonin as a free radical scavenger in experimental head trauma. Pediatr Neurosurg. 1999 Dec;31(6):298-301.
38. Kerman M, Cirak B, Ozguner MF, et al. Does melatonin protect or treat brain damage from traumatic oxidative stress? Exp Brain Res. 2005 Jun;163(3):406-10.
39. Sarrafzadeh AS, Thomale UW, Kroppenstedt SN, Unterberg AW. Neuroprotective effect of melatonin on cortical impact injury in the rat. Acta Neurochir (Wien). 2000;142(11):1293-9.
40. Ozdemir D, Tugyan K, Uysal N, et al. Protective effect of melatonin against head trauma-induced hippocampal damage and spatial memory deficits in immature rats. Neurosci Lett. 2005 Sep 16;385(3):234-9.
41. Bouslama M, Renaud J, Olivier P, et al. Melatonin prevents learning disorders in brain-lesioned newborn mice. Neuroscience. 2007 Dec 12;150(3):712-9.
42. Carloni S, Perrone S, Buonocore G, et al. Melatonin protects from the long-term consequences of a neonatal hypoxic-ischemic brain injury in rats. J Pineal Res. 2008 Mar;44(2):157-64.
43. Furio AM, Brusco LI, Cardinali DP. Possible therapeutic value of melatonin in mild cognitive impairment: a retrospective study. J Pineal Res. 2007 Nov;43(4):404-9.
44. Shen Y, Zhang G, Liu L, Xu S. Suppressive effects of melatonin on amyloid-beta-induced glial activation in rat hippocampus. Arch Med Res. 2007 Apr;38(3):284-90.
45. Weishaupt JH, Bartels C, Polking E, et al. Reduced oxidative damage in ALS by high-dose enteral melatonin treatment. J Pineal Res. 2006 Nov;41(4):313-23.
46. Dominguez-Rodriguez A, breu-Gonzalez P, Garcia-Gonzalez MJ, et al. 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. 2007 Jul;28(4):532-9.
47. Chen Z, Chua CC, Gao J, Hamdy RC, Chua BH. Protective effect of melatonin on myocardial infarction. Am J Physiol Heart Circ Physiol. 2003 May;284(5):H1618-24.
48. Sallinen P, Manttari S, Leskinen H, et al. Long-term postinfarction melatonin administration alters the expression of DHPR, RyR(2), SERCA2, and MT(2) and elevates the ANP level in the rat left ventricle. J Pineal Res. 2008 Feb 13.
49. Guven A, Yavuz O, Cam M, et al. Melatonin protects against epirubicin-induced cardiotoxicity. Acta Histochem. 2007;109(1):52-60.
50. Ahmed HH, Mannaa F, Elmegeed GA, Doss SH. Cardioprotective activity of melatonin and its novel synthesized derivatives on doxorubicin-induced cardiotoxicity. Bioorg Med Chem. 2005 Mar 1;13(5):1847-57.
51. Petrosillo G, Di Venosa N, Pistolese M, et al. Protective effect of melatonin against mitochondrial dysfunction associated with cardiac ischemia- reperfusion: role of cardiolipin. FASEB J. 2006 Feb;20(2):269-76.
52. Lochner A, Genade S, Davids A, Ytrehus K, Moolman JA. Short- and long-term effects of melatonin on myocardial post-ischemic recovery. J Pineal Res. 2006 Jan;40(1):56-63.
53. Zaslavskaia RM, Shcherbakov EA, Logvinenko SI. Evaluation of different methods of treatment of patients with stable stenocardia combined with arterial hypertension according to echocardiographic data. Klin Med (Mosk). 2007;85(8):40-3.
54. Grossman E, Laudon M, Yalcin R, et al. Melatonin reduces night blood pressure in patients with nocturnal hypertension. Am J Med. 2006 Oct;119(10):898-902.
55. Kurpesa M, Trzos E, Drozdz J, Bednarkiewicz Z, Krzeminska-Pakula M. Myocardial ischemia and autonomic activity in dippers and non-dippers with coronary artery disease: assessment of normotensive and hypertensive patients. Int J Cardiol. 2002 May;83(2):133-42.
56. Wirtz PH, Ehlert U, Emini L, et al. Procoagulant stress reactivity and recovery in apparently healthy men with systolic and diastolic hypertension. J Psychosom Res. 2007 Jul;63(1):51-8.
57. Wirtz PH, Spillmann M, Bartschi C, Ehlert U, von KR. Oral melatonin reduces blood coagulation activity: a placebo-controlled study in healthy young men. J Pineal Res. 2008 Mar;44(2):127-33.
58. Wirtz PH, Bartschi C, Spillmann M, Ehlert U, von KR. Effect of oral melatonin on the procoagulant response to acute psychosocial stress in healthy men: a randomized placebo-controlled study. J Pineal Res. 2008 May;44(4):358-65.
59. Konturek SJ, Konturek PC, Brzozowski T, Bubenik GA. Role of melatonin in upper gastrointestinal tract. J Physiol Pharmacol. 2007 Dec;58 Suppl 6;23-52.
60. Bandyopadhyay D, Ghosh G, Bandyopadhyay A, Reiter RJ. Melatonin protects against piroxicam-induced gastric ulceration. J Pineal Res. 2004 Apr;36(3):195-203.
61. Bandyopadhyay D, Chattopadhyay A. Reactive oxygen species-induced gastric ulceration: protection by melatonin. Curr Med Chem. 2006;13(10):1187-202.
62. Klupinska G, Poplawski T, Drzewoski J, et al. Therapeutic effect of melatonin in patients with functional dyspepsia. J Clin Gastroenterol. 2007 Mar;41(3):270-4.
63. Pereira RS. Regression of gastroesophageal reflux disease symptoms using dietary supplementation with melatonin, vitamins and aminoacids: comparison with omeprazole. J Pineal Res. 2006 Oct;41(3):195-200.
64. Konturek SJ, Zayachkivska O, Havryluk XO, et al. Protective influence of melatonin against acute esophageal lesions involves prostaglandins, nitric oxide and sensory nerves. J Physiol Pharmacol. 2007 Jun;58(2):361-77.
65. Lissoni P, Barni S, Ardizzoia A, et al. Randomized study with the pineal hormone melatonin versus supportive care alone in advanced nonsmall cell lung cancer resistant to a first-line chemotherapy containing cisplatin. Oncology. 1992;49(5):336-9.
66. Lissoni P, Barni S, Tancini G, et al. A randomised study with subcutaneous low-dose interleukin 2 alone vs interleukin 2 plus the pineal neurohormone melatonin in advanced solid neoplasms other than renal cancer and melanoma. Br J Cancer. 1994 Jan;69(1):196-9.
67. Lissoni P, Barni S, Mandala M, et al. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status. Eur J Cancer. 1999;35:1688-92.
68. Lissoni P. Is there a role for melatonin in supportive care? Support Care Cancer. 2002 Mar;10(2):110-16.
69. Lissoni P, Malugani F, Brivio F, et al. Total pineal endocrine substitution therapy (TPEST) as a new neuroendocrine palliative treatment of untreatable metastatic solid tumor patients: a phase II study. Neuro Endocrinol Lett. 2003 Jun;24(3-4):259-62.
70. Lissoni P. Biochemotherapy with immunomodulating pineal hormones other than melatonin: 5-methoxytryptamine as a new oncostatic pineal agent. Pathol Biol (Paris). 2007 Apr;55(3-4):198-200.
71. Sainz RM, Reiter RJ, Tan DX, et al. Critical role of glutathione in melatonin enhancement of tumor necrosis factor and ionizing radiation-induced apoptosis in prostate cancer cells in vitro. J Pineal Res. 2008 Apr 2.
72. Sainz RM, Mayo JC, Tan DX et al. Melatonin reduces prostate cancer cell growth leading to neuroendocrine differentiation via a receptor and PKA independent mechanism. Prostate. 2005 Apr 1;63(1):29-43.
73. Srinivasan V, Spence DW, Pandi-Perumal SR, Trakht I, Cardinali DP. Jet lag: therapeutic use of melatonin and possible application of melatonin analogs. Travel Med Infect Dis. 2008 Jan;6(1-2):17-28.
74. Daghighi MH, Rezaei V, Zarrintan S, Pourfathi H. Intracranial physiological calcifications in adults on computed tomography in Tabriz, Iran. Folia Morphol (Warsz). 2007 May;66(2):115-9.
75. Swietoslawski J. The age-related quantitative ultrastructural changes in pinealocytes of gerbils. Neuro Endocrinol Lett. 1999;20(6):391-6.
76. Kunz D, Bes F, Schlattmann P, Herrmann WM. On pineal calcification and its relation to subjective sleep perception: a hypothesis-driven pilot study. Psychiatry Res. 1998 Jun 30;82(3):187-91.
77. Kunz D, Schmitz S, Mahlberg R, et al. A new concept for melatonin deficit: on pineal calcification and melatonin excretion. Neuropsychopharmacology. 1999 Dec;21(6):765-72.
78. Schmitz SA, Platzek I, Kunz D, Mahlberg R, Wolf KJ, Heidenreich JO. Computed tomography of the human pineal gland for study of the sleep-wake rhythm: reproducibility of a semi-quantitative approach. Acta Radiol. 2006 Oct;47(8):865-71.
79. Mahlberg R, Walther S, Kalus P, et al. Pineal calcification in Alzheimer’s disease: an in vivo study using computed tomography. Neurobiol Aging. 2008 Feb; 29(2):203-9.
80. No authors. Melatonin. Monograph. Altern Med Rev. 2005 Dec;10(4):326-36.
81. Available at: http://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/mel_0286.shtml. Accessed March 16, 2007.