Melatonin Res. 2019, Vol 2 (2) 106-132; doi: 10.32794/mr11250025 106 Review Are melatonin doses employed clinically adequate for melatonin-induced cytoprotection? Daniel P. Cardinali* Faculty of Medical Sciences, Pontificia Universidad Católica Argentina, Buenos Aires, Argentina. *Correspondence: daniel_cardinali@uca.edu.ar; danielcardinali@fibertel.com.ar; Tel: +54 11 43490200 ext 1192 Running title: Melatonin dose in clinical practice Received: May 1, 2019; Accepted: June 3, 2019 ABSTRACT This review article discusses the special role that melatonin, a molecule with chronobiotic/cytoprotective properties, may have in prevention and treatment of the metabolic syndrome (MS), ischemic and non-ischemic cardiovascular diseases and Alzheimer´s disease (AD). Prevention of these diseases is a major goal for governmental and non-governmental organizations, and melatonin, an unusual phylogenetically conserved molecule present in all aerobic organisms, merits consideration in this respect. In humans, circulating melatonin levels are consistently reduced in MS, ischemic and non-ischemic cardiovascular diseases and AD, the potential therapeutic value of melatonin being suggested by a limited number of clinical trials generally employing melatonin in the 2-5 mg/day range. In animal model studies of MS, ischemic and non-ischemic cardiovascular diseases and AD melatonin was very effective to curtail symptomatology. However, calculations derived from animal studies indicate projected cytoprotective melatonin doses for humans in the 40-100 mg/day range, doses that are rarely employed clinically. Hence, controlled studies employing melatonin doses in this range are urgently needed. Since the pharmaceutical industry is refractive to support them because of the lack of protective patents for a natural compound, only the involvement of governmental and non-profit organizations can achieve that goal. Within this prospect, the off-label use of melatonin is discussed. Keywords: aging; Alzheimer’s disease; cytoprotection; inflammation; melatonin; metabolic syndrome; mild cognitive impairment; neurodegeneration; off-label use; oxidative stress. 1. INTRODUCTION Chronic, endemic disorders such as the metabolic syndrome (MS) and Alzheimer´s disease (AD) are major health problems and their prevention is presently a fundamental goal for governmental and non-governmental organizations. The prevalence of MS varies from 15 to 30% depending on the region of the world considered (1, 2). An increase of 1.5 to 2.5 times in cardiovascular mortality occurs when MS is present. AD and related dementia are disorders characterized by a progressive deterioration of the structure and function of the brain, with symmetric losses of neurons in the cognitive, motor or sensory systems. Several interrelated processes, such as free radical-mediated damage, mitochondrial dysfunction, low degree of inflammation and excitotoxicity, have been identified as pathophysiological mechanisms for