The Therapeutic Potential of Melatonin: A Review of the Science

Samir Malhotra, MD; Girish Sawhney, MD; Promila Pandhi, MD

Disclosures
In This Article

Antioxidant Uses

The antioxidant effects of melatonin have been well described[93,94,95] and include both direct as well as indirect effects. The mechanism of antioxidant effects has also been evaluated. Melatonin administration leads to increased expression of the antioxidant enzymes superoxide dismutase and glutathione peroxidase[96]

Central Nervous System

Melatonin has been found to prevent cell death and methylphenyltetrahydropyridine- (MPTP) induced damage to the substantia nigra in experimental parkinsonism, and thus prevented disease progression in these animals.[97] Melatonin pretreatment reduced cerebral infarct size and edema after middle cerebral artery occlusion and ischemia-reperfusion injury in rats.[98] Melatonin has been suggested as a candidate neuroprotective compound for patients with amyotrophic lateral sclerosis.[99] Furthermore, a study examining the neuroprotective effects of melatonin in various regions of the central nervous system demonstrated an antioxidant effect of melatonin in the total spinal cord, optic nerve, brain, and spinal cord white matter, with the most potent effects seen in the spinal cord white matter.[100]

In a rodent model of Alzheimer's disease, melatonin reduced plasma homocysteine and lipid levels,[101] and the investigators suggested that the antioxidant effect of melatonin may have been responsible for these results. In patients with Alzheimer's disease, cerebrospinal fluid melatonin levels have been found to be significantly reduced.[102] In a study of 14 patients at various stages of Alzheimer's disease,[103] melatonin supplementation for 22-35 months improved sleep and significantly reduced the incidence of "sundowning." Furthermore, patients experienced no cognitive or behavioral deterioration during the study period. The neuroprotective effects of melatonin are not mediated by membrane melatonin receptors and, thus, they may result from the antioxidant and antiamyloidogenic property of melatonin.[104]

Cardiovascular System

Cardioprotective activity,[105,106,107,108,109] mediated by antioxidant effects of melatonin,[109] has been observed in experimental models of myocardial ischemia-reperfusion[105,107] and myocardial infarction.[105,106] Melatonin reduced infarct size, suppressed the frequency as well as duration of ventricular tachycardia and fibrillation, and improved survival in these models.

One review noted that melatonin has cut cholesterol levels by 38% in human subjects and has reduced blood pressure and catecholamine levels, perhaps via relaxation of smooth muscles in aortic walls.[108] Melatonin also inhibits copper-induced oxidation of low-density lipoprotein (LDL),[109] thereby potentially contributing to an antiatherosclerotic effect. A study of 5 patients with cardiac syndrome X found that nocturnal melatonin levels were markedly reduced.[110]

Gastrointestinal System

Gastroprotective effects of melatonin have been observed in various models of gastric ulcers at several laboratories, including ours.[111,112,113] These effects may also be related to the antioxidant effects of melatonin. In experimental models of acute pancreatitis, melatonin has shown beneficial effects.[114,115] Other diseases for which melatonin may be added to existing therapies include irritable bowel syndrome, ulcerative colitis, and diarrhea.[3]

Renal Diseases

Melatonin has been found to be protective against glycerol-induced renal failure because of its antioxidant effect.[116] Melatonin also reduced interstitial renal inflammation and improved hypertension in spontaneously hypertensive rats.[117] More evidence from well-conducted clinical trials is required before a final recommendation can be made.

Miscellaneous Conditions

An animal study found melatonin and vitamins C and E to be protective against lung injury.[118] A series of 3 cases reported that melatonin improved platelet counts in patients with idiopathic thrombocytopenic purpura.[119] Melatonin was also found to be useful in cisplatin-[120] and cyclosporine-[121] induced acute renal injury, doxorubicin-induced cardiotoxicity,[122] and a number of other drug-induced diseases. The beneficial effects of melatonin in this field have been reviewed.[123]

Comparison of Melatonin With Vitamins C and E in Animal Models

A few studies have compared the antioxidant effects of melatonin with other antioxidants.[124,125,126] Melatonin has been found to be more efficient than vitamin C in reducing the extent of oxidative stress in an experimental model of Alzheimer's disease.[124] In another animal model, melatonin was found to be at least as effective as a combination of vitamins C and E in reducing the oxidative stress induced by chlorpyrifos-ethyl in rats.[125] Melatonin was also found to reduce markers of oxidative stress more significantly than vitamin E or N-acetylcysteine against acetaminophen toxicity in mice.[126]

The antioxidant benefit of pharmacologic melatonin therapy has been questioned, however.[127] Moreover, in a 2003 study,[128] in ion-free medium, melatonin did not scavenge hydrogen peroxide and was found to be devoid of direct antioxidant effects. Only placebo-controlled, randomized trials with hardcore clinical end points will provide a definite answer.

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