Are melatonin doses employed clinically adequate for melatonin-induced cytoprotection?

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.

Impact of Melatonin on Skeletal Muscle and Exercise

“…Remarkably, a recent comprehensive review set the point on the urgency to fill the existing gap on the best therapeutic melatonin dosage in human diseases despite a a great deal of experience in rodents [195]. Currently, melatonin is not still administered at the best "clinical" dosage, from 40 to 100 mg/day, that is necessary to obtain the best results in metabolic and neurodegenerative diseases.…”

Efficacy of melatonin in non-intensive care unit patients with COVID-19 pneumonia and sleep dysregulation

“…In functional terms, melatonin exerts a host of effects that can be under the control of the SCN and has also direct effects in numerous peripheral organs. In particular, melatonin is involved in sleep initiation, vasomotor control, adrenal function, antiexcitatory actions, immunomodulation including anti-inflammatory properties, antioxidant actions, and energy metabolism, influencing mitochondrial electron flux, the mitochondrial permeability transition pore, and mitochondrial biogenesis (48,49).…”

Possible Protective Role of Melatonin in Pediatric Infectious Diseases and Neurodevelopmental Pathologies

“…7,12 Several lines of evidence reinforce the hypothesis of utility of melatonin preventing endotheliitis, and as pleiotropic cytoprotectant at high oral doses. 13,14 Melatonin may reduce viral infections based on its wide ranging effects as a potent antioxidant, 15 pollutants protector, 16 and anti-inflammatory agent 17 in addition to its direct modulation of intracellular and extracellular processes which is associated with improvements in energy metabolism and immune function. 15 There seems to be a few cellular functions that are not impacted by melatonin, which in high concentrations is rapidly taken up by the mitochondria.…”

“…48 Intracellular melatonin does not reach the extracellular space and doses of melatonin much higher than those employed as a chronobiotic are needed to modify its intracellular levels. 14 Neuroprotective properties of melatonin have been postulated for a long time in acute neurological pathologies such as ischemic stroke, 49 which showed an impairment of nocturnal urinary melatonin excretion, associated with immunological changes. 50 Recently, these neuroprotective properties have been demonstrated in all phases of hypoxic-ischemic encephalopathy of the newborn.…”