Please cite this paper as:

Cardinali, D. 2019. Are melatonin doses employed clinically adequate for melatonin-induced cytoprotection?. Melatonin Research. 2, 2 (Jun. 2019), 106-132. DOI:https://doi.org/https://doi.org/10.32794/mr11250025.

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.

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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 neuronal death (3, 4). The global prevalence of dementia among people aged ≥60 years is 5% to 7% (5).  In 2010, approximately 35.6 million people lived with dementia, and this number is expected to double every 20 years. Approximately two-thirds of dementia cases are attributed to AD. The prevalence of dementia increases exponentially with age. For the age-group of 60 to 64 years, the prevalence is 2% and 0.6% for Caucasian and Chinese people, respectively; while for the age-group of 80 to 84 years, it increases to 13% and 9.4%, respectively. The annual incidence rate (per 1000 individuals) of dementia worldwide was estimated to be 7.5 (6). Although the regular intake of antioxidants has been recommended for prevention of neurodegenerative diseases in ageing, the effectiveness of this treatment has been discussed (7). In this context, the use of melatonin as a cytoprotective agent merits consideration.

     Melatonin, an unusual phylogenetically conserved compound present in all known aerobic phyla, has a promising significance as a cytoprotective molecule in addition to its chronobiotic properties (8). The pineal gland is the demonstrable source of circulating melatonin in humans, the decrease in plasma melatonin being one of the characteristics of the advancing age (9). This article is focused on the clinical use of melatonin in obesity-related disorders and AD. The discussion of the basic biological data is restricted to its relevance for melatonin doses potentially employable in humans. Medical literature was identified by searching databases including (MEDLINE, EMBASE), bibliographies from published literature and clinical trial registries / databases. Searches were last updated on May 1, 2019.

2. BASIC BIOLOGY OF MELATONIN RELEVANT FOR CYTOPROTECTION

    As a chronobiotic / cytoprotective agent, melatonin occupies a special place in the prevention and treatment of MS and AD (10, 11). Melatonin improves sleep efficiency and has antioxidant and anti-inflammatory properties, in part because of its function as a metabolic regulator and mitochondrial protector (12-14). Melatonin, an unusually phylogenetic conserved molecule present in all known aerobic organisms, is effective both as a chronobiotic and as a cytoprotective agent.

     The light-dark variation in the synthesis of melatonin by pinealocytes is the essential fact that explains the role of melatonin as a chronobiotic that coordinates the physiology of biological rhythms (15). The action of melatonin as a chronobiotic is twofold: on the one hand, it "opens the doors of sleep" by inhibiting the promoting activity of late awakening driven by suprachiasmatic nuclei (SCN) (16, 17). On the other hand, melatonin is the "hormone of darkness", a chemical code of the duration of the night, and has established itself as crucial in the transmission of information from light to the neuroendocrine system. Melatonin represents a "hand" of the biological clock in the sense that it responds to the signals of the SCN, the temporal variation of the melatonin rhythm indicating the state of the clock, both in terms of phase (time in the internal clock in relation to external time) and amplitude (18).

     In mammals, circulating melatonin is derived almost exclusively from the pineal gland (9). In addition, melatonin is synthesized locally in many cells, tissues and organs, including lymphocytes, bone marrow, thymus, gastrointestinal tract, skin and eyes, where it can play an autocrine or paracrine role (19). Indeed, there is now strong evidence that melatonin is produced in every animal cell that has mitochondria (20, 21). In both animals and humans, melatonin participates in diverse physiological functions that indicate not only the duration of the night, but also improve the elimination of free radicals and the immune response, showing relevant cytoprotective properties (22).

     The chronobiotic action of melatonin is mediated via the melatonin receptors, which have been identified both in the CNS and in the periphery (23).  MT₁ and MT₂ receptors all belonging to the superfamily of membrane receptors associated with G proteins (G-protein coupled receptors, GPCR) have been cloned. More recently, another member, GPR50, was included in the melatonin receptor subfamily. GPR50 shows high sequence homology to MT₁ and MT₂ but does not bind to melatonin or any other known ligand. An interesting feature of these receptors is their capacity to form homo- and heteromers between each other and also with other GPCRs (24).

     Due to its liposolubility, melatonin penetrates all membranes and is associated with cytoplasmic proteins such as calmodulin and tubulin, which causes important changes in the cytoskeleton (25). Melatonin also accesses the cell nucleus where it may act indirectly via sirtuin‐1 activation of the oscillator component RORα (26).

     The cytoprotective activity of melatonin exceeds that mediated via receptors. Almost every cell in the human body contains melatonin, in quantities much higher than those circulating in blood derived from the pineal gland (19). The mitochondrial capacity to synthesize melatonin is now confirmed, but for reasons that remain unexplained, intracellular melatonin does not get the extracellular space. To modify intracellular melatonin levels, doses much higher than those employed as a chronobiotic are needed (27, 28). Most studies on neuroprotective and anti-inflammatory effects in animals employ pharmacological doses, which clearly exceed the saturation of the receptor.

     In both the cytoplasm and the cell nucleus, melatonin has important antioxidant and scavenging effects on free radicals, which are largely independent of receptors (29). These effects are exerted in three ways: (a) melatonin is a free radical scavenger; (b) melatonin is metabolized to compounds with high antioxidant activity; (c) melatonin is an indirect antioxidant, which stimulates the synthesis of antioxidant enzymes and inhibits that of prooxidant enzymes. Melatonin has a proven superiority to vitamin C and E in protection against oxidative damage and in the elimination of free radicals (30). In addition, melatonin potentiates the effects of other antioxidants, such as vitamin C and Trolox. Several antiapoptotic and cytoprotective effects of melatonin are exerted under conditions of ischemia (unrelated to free radicals) and can be attributed to the stabilizing activity of the mitochondrial membrane (28).

     Melatonin is also an immunological modulator that shows proinflammatory and anti-inflammatory properties (31, 32). The anti-inflammatory actions are of medicinal interest, since they are observed in high-grade inflammation such as sepsis, ischemia/reperfusion and brain injury, as well as in the low-grade inflammation seen in MS, neurodegenerative disorders and aging. Melatonin has significant anti-inflammatory properties presumably by inhibiting the binding of nuclear factor κB (NF κB) to DNA, thus decreasing the synthesis of proinflammatory cytokines, by inhibiting cyclooxygenase (Cox) (33) in particular Cox- 2 (34), and by suppressing the expression of the inducible gene of nitric oxide synthase (35). In addition, other pathways of secondary signaling are involved (32).

3. EVIDENCE FOR THE THERAPEUTIC VALUE OF MELATONIN IN ANIMAL MODELS OF MS

     Treatment with melatonin in rats can reduce obesity, type 2 diabetes and hepatic steatosis (36, 37). In several animal models of hyperadiposity, the injection of melatonin could normalize most of the observed alterations and correct the altered biochemical proinflammatory profile (Table 1). In addition, melatonin is effective in animal models of ischemic and nonischemic heart failure, an important comorbidity of MS (Table 2).

     Melatonin treatment of streptozotocin-induced type 1 diabetic rats induces the regeneration and proliferation of β-cells in the pancreas leading to a decrease in blood glucose (38) (Table 1). Loss of melatonin in circulation after pinealectomy results in hyperinsulinemia and accumulation of triglycerides in the rat liver (39). The long-term administration of melatonin improves lipid metabolism in type 2 diabetic rats via restoring insulin sensitivity (40). Melatonin treatment increases glycogen content in the liver of rats (41) while in high fat diet-induced diabetic mice the intraperitoneal injection of 10 mg/kg melatonin improved glucose utilization and insulin sensitivity and ameliorated hepatic steatosis (42).

Table 1. Effect of melatonin on animal models of MS. The human equivalent dose (HED) of melatonin for a 75 kg adult is calculated by normalization of body surface area (43)

     As shown in Table 1, melatonin administration is usually very effective in reversing hyperadiposity in animal models of MS. The reasons for the decrease in body weight after melatonin in the absence of significant differences in food intake is worth to be explored. A key piece of evidence in this regard is the observation that melatonin plays a role in seasonal changes in adiposity by increasing the activity of the sympathetic nervous system innervating white and brown fat (87). Melatonin not only affects white adipose tissue, but also increases the recruitment of brown adipocytes and increases their metabolic activity in mammals (88-91). It was speculated that the hypertrophic effect and functional activation of brown adipose tissue induced by melatonin can likely be applied to treatment of human obesity. 

     From the doses of melatonin used in the experiment listed in Table 1, the human equivalent dose (HED) of melatonin for a 75 kg adult was calculated by normalization of body surface area (43). Body surface area correlates well across several mammalian species with several parameters of biology, including oxygen utilization, caloric expenditure, basal metabolism, blood volume, circulating plasma proteins, and renal function, and has been advocated as a factor to be used when converting a dose for translation from animals to humans (43). Noteworthy, theoretical human equivalent doses calculated from Table 1’s results ranged from 2- to 3-orders of magnitude greater than those usually employed in humans.

     Table 2 summarizes the effect of melatonin on animal models of ischemic and non-ischemic heart disease. One of the first observations derived from this laboratory. In a model of rat myocardial infarction (by ligation of the left anterior descending coronary artery for 3 h before) melatonin reduced 87% of the area of injury and 80% of the number of injured myocardial areas (92). Several studies indicated the efficacy of melatonin to reduce cardiac damage markers, to augment cardiac antioxidant defense system and to normalize the lipid profile in rats (93-99) and mice (100-102). The same was observed in cardiomyopathy induced by streptozotocin (103) or doxorubicin (104). In a murine model of myocardial infarction treated with cardiac progenitor cells, exposure of cells to melatonin enhances therapeutic efficacy of cardiac progenitor cells for myocardial infarction (105). Collectively, the results of Tables 1 and 2 indicate that the administration of melatonin effectively counteracts some of the disrupting effects seen in diet-induced obesity in animals insulin resistance, dyslipidemia and obesity, and the consequences of ischemic and non-ischemic heart disease.

 Table 2. Effect of melatonin on animal models of ischemic and non-ischemic heart disease. The human equivalent dose (HED) of melatonin for a 75 kg adult is calculated by normalization of body surface area (43)

     As in the case of Table 1, the HED of melatonin for a 75 kg adult calculated by normalization of body surface area (43) yielded values greater than 60 mg/day (Table 2). Interestingly, a recent study examining the subcellular distribution of the melatonin in the heart of rats indicates that at a dose of 40 mg/kg b.w, maximal concentration of melatonin was reached in the nucleus and mitochondrion. The authors concluded that doses of melatonin ≥ 112 mg/day are required for therapeutic purpose s in a 70 kg adult (115).

4. EVIDENCE FOR THE THERAPEUTIC VALUE OF MELATONIN IN ANIMAL MODELS OF AD

     The pathological signatures of AD are the extracellular deposits of amyloid ß (Aß)-formed senile plaques and the intracellular accumulation of neurofibrillary tangles microtubules (3, 4). Aß plays an important role in the promotion of neuronal degeneration in AD neurons that become vulnerable to age-related increases in levels of oxidative stress and an altered cellular energy metabolism. Hyperphosphorylated tau protein promotes the assembly of microtubules and is an important factor in stabilizing microtubules (3, 4).

Cell line studies regarding AD and melatonin have delineated important melatonin mediated mechanisms in AD prevention. For a comprehensive review on melatonin activity to reverse disrupted signaling mechanisms in neurodegeneration, including proteostasis dysfunction, disruption of autophagic integrity, and anomalies in the insulin, Notch, and Wnt/β-catenin signaling pathways see ref.  (116).

     Table 3 summarizes the effect of melatonin treatment in transgenic models of AD. The data are compatible with the view that melatonin regulates Aß metabolism mainly at the initial phases of the pathological process. From the doses of melatonin used in these different transgenic models, the HED of melatonin for a 75 kg adult can be calculated by normalization of body surface area (43). As for the experiments of Table 1, theoretical human equivalent doses calculated from Table 3’s results ranged from 2- to 3-orders of magnitude greater than those employed in humans.

Table 3. Effect of melatonin on transgenic models of AD. The human equivalent dose (HED) of melatonin for a 75 kg adult is calculated by normalization of body surface area (43) 

     The way in which melatonin exerts its inhibitory effect on the generation of Aβ remains undefined. Melatonin interacts with Aß₄₀ and Aß₄₂ and inhibits progressive β-sheet and/or amyloid fibrils (133, 134), an interaction which appears to depend on structural melatonin characteristics rather than on its antioxidant properties (133). Via blockage of formation of secondary sheets, melatonin may facilitate peptide clearance by increasing proteolytic degradation.

     Aß-induced neurotoxicity and cell death involves oxidative stress, and melatonin effectively protects cells against it in vitro (135, 136) and in vivo (118, 137-139). Protection from Aβ toxicity by melatonin was observed, especially at the mitochondrial level.

     Concerning tau hyperphosphorylation, melatonin efficiently attenuates it by affecting protein kinases and phosphatases in N2a and SH-SY5Y neuroblastoma cells exposed to wortmannin (140), calyculin A (141, 142) or okadaic acid (143-145). Melatonin also antagonizes the oxidative stress that arises by the action of these agents (146, 147).

     An important recent observation by Pappolla and co-workers indicate that the administration of melatonin to AD transgenic mice augments the glymphatic clearance of Aβ (132). Relevant to this, melatonin is known to preserve slow wave sleep in patients (148). During sleep, the elimination of Aβ peptides increases considerably (149). Thus, the sleep disturbance found as a comorbidity in AD may contribute to the development and progression of the disease via a failure of Aβ clearance (150).

     Another factor in the pathogenesis of AD is the activation of microglia with the consequent increased expression of proinflammatory cytokines (26, 32), epidemiological studies suggesting that the use of anti-inflammatory drugs may decrease the incidence of AD (3, 4). Melatonin attenuated the microglial production of proinflammatory cytokines induced by Aß, NF kB and nitric oxide (139). In addition, the DNA binding activity of NF kB was inhibited by melatonin (26, 32).

5. CLINICAL STUDIES ON MELATONIN THERAPEUTIC VALUE IN MS AND AD

     Type 2 diabetic patients have low circulating levels of melatonin (151) with a simultaneous and expected regulation of mRNA expression of the melatonin membrane receptor (152). In addition, allelic variants for melatonin receptors were associated with an increase in fasting blood glucose levels and / or an increased risk of type 2 diabetes (153-155) and with the polycystic ovarian syndrome (PCOS) (156).

     Patients with coronary artery disease show a decrease in melatonin secretion (157-160) and among elderly hypertensive patients, nocturnal urinary melatonin excretion was inversely associated with the non-dipper pattern of hypertensive disease (161). Melatonin administration (≤ 5 mg/day) proved capable of reducing nocturnal blood pressure in hypertensives (162-165) and attenuated age-dependent disturbances of cardiovascular rhythms (166).

     Treatment with melatonin (≤ 5 mg/day) improves MS in obese (167, 168) and PCOS patients (169), as well as in bipolar and schizophrenic patients receiving second generation antipsychotics (170-172). The administration of melatonin normalizes MS in elderly hypertensive patients (173) and improves the enzyme profile in patients with alcoholic hepatic steatosis (174, 175). The combination of melatonin and zinc acetate, when used alone or in combination with metformin, improved the glycemic control in type 2 diabetic patients (176).

     It must be noted that some results deny the capacity of melatonin to improve glucose tolerance and to reduce insulin resistance in humans. Melatonin administration in the morning decreased glucose tolerance, already in nondiabetic young individuals (177), an observation confirmed by recent studies (178, 179). In vitro, melatonin inhibits insulin secretion, an effect that is logical in humans if one presumes that melatonin suppresses insulin during the night to sensitize the pancreatic β-cells in preparation for breakfast. Additional information concerning a glucose tolerance-reducing property of melatonin in humans came from the detection of melatonin receptor polymorphisms. To date, several single nucleotide polymorphisms (SNPs) located near or inside the gene encoding MTNR1B with an association with type 2 diabetes mellitus have been identified in Asian (Indian, Sri Lankan, Chinese, Korean, Japanese) and European ethnicities (153, 180-185). Among these SNPs, rs10830963 appears the most strongly associated with an increase in fasting plasma glucose, glucose area under the curve, glycated hemoglobin (HbA1C) and a decrease in pancreatic β-cell function, basal insulin secretion and plasma insulin (186). This G allele that carries the SNP rs10830963 is prodiabetic and is overexpressed in pancreatic β-cells, causing a more intense decrease in cyclic adenosine monophosphate (cAMP) upon melatonin stimulation and consequently suppressing more strongly the cAMP-dependent secretion of insulin (187). It appears to affect β-cell function directly and is associated with a defective early insulin response and a decreased β-cell glucose sensitivity (187-189). In clinical studies, the presence of the G allele worsens the decrease in glucose tolerance induced by melatonin (190). However, it must be noted that a reduction in insulin secretion is not necessarily associated with insulin resistance in the target organs, clearly improved by melatonin in most studies.  Moreover, other MT₂receptor variants with entirely different properties have been found to be also associated with type 2 diabetes. Some of them are dysfunctional because of their incapability of binding melatonin, and others were found to be unable to interact with G_i proteins (191, 192). Thus, the absence of melatonin signaling is presumably diabetogenic.

     An important point to consider in human studies is the discrimination of core symptoms (glucose homeostasis) from diabetes-associated pathologies, including those derived from an enhanced oxidative stress like liver steatosis, cardiovascular disease, retinopathy, nephropathy or osteoporosis. In most of these associated pathologies melatonin has a demonstrated therapeutic efficacy.

     Concerning AD, CSF melatonin levels decrease even in preclinical stages of the disease when the patients do not manifest any cognitive impairment, suggesting that the reduction in CSF melatonin may be an early trigger and marker for AD (193). Although it is not known whether the relative melatonin deficiency is either a consequence or a cause of neurodegeneration, it seems clear that the loss in melatonin aggravates the disease and that early circadian disruption can be an important deficit to be considered. Significant differences were observed in melatonin levels between mild cognitive impairment (MCI) and AD patients with a negative correlation between neuropsychological assessment of dementia and melatonin levels (194).

     Two recent meta-analyses endorsed the view that melatonin therapy is effective in improving sleep in patients with dementia (195, 196). Moreover, the melatonergic agonist ramelteon was reported as effective to treat delirium, an acute state of mental confusion that can lead to many adverse sequelae in intensive care unit elder patients (197).

     Whether melatonin has any value in treating fully developed AD remains uncertain. It must be noted that one of the problems with AD patients with fully developed pathology is the heterogeneity of the group examined. Moreover, the reduced hippocampal expression of MT₂ melatonin receptors in AD patients and of MT₁ receptors in the circadian apparatus at later stages the disease may explain why melatonin treatment is less effective or erratic at this stage (198).

     An analysis of published data of the use of melatonin in the early stages of cognitive decline consistently showed that administration of melatonin, every night before retiring, improves the quality of sleep and cognitive performance in this phase of the disease (199). In our Laboratory, we carried out a retrospective analysis of 25 patients with MCI who in the past three years had received a daily dose of 3-9 mg of melatonin along with their usual medication. Compared to an untreated group melatonin treated patients significantly improved cognitive and emotional performance and quality of sleep / wake rhythm (200). We also reported another series of 96 outpatients with a diagnosis of minimal cognitive impairment, 61 of who had received 3-24 mg of melatonin daily for 15 to 60 months. Patients treated with melatonin showed a significantly better performance in various neuropsychological tests. They also had lower scores in the Beck Depression Inventory concomitantly with improvement in the quality of sleep and wakefulness (201). Therefore, melatonin treatment can be effective in the early stages of neurodegenerative disease.

6. CONCLUSIONS

     Melatonin exhibits both hypnotic and chronobiotic properties and has been used therapeutically for the treatment of insomnia related to age, as well as other primary and secondary insomnia (202, 203). Several meta-analyses support this role (204-206). A consensus of the British Association of Psychopharmacology on the evidence-based treatment of insomnia, parasomnia and sleep disorders in the circadian rhythm concluded that melatonin is the first-choice treatment when a hypnotic is indicated in patients older than 55 years (207).

     As discussed in this article, studies using 2-5 mg of melatonin / day are not adequate to provide an adequate comparison with data on the protection of MS or AD derived from animal studies. Hence, clinical trials with doses in the 40-100 mg/day range are urgently needed

     It should be noted that melatonin is remarkably non-toxic, and its safety is very high. The lethal dose 50 for the intraperitoneal injection of melatonin was determined for rats (1168 mg / kg) and mice (1131 mg / kg), but the oral administration of melatonin (tested up to 3200 mg / kg in rats) could not be determined and for melatonin subcutaneous injection (tested up to 1600 mg / kg in rats and mice) (208). In humans, melatonin has a high safety profile and, in general, is very well tolerated (Table 4).

Table 4. Safety for off label prescription of melatonin

       Unfortunately, the pharmaceutical industry is refractive to support those studies because of the lack of protective patents for a natural compound. Hence, only with the involvement of governmental and non-profit organizations such a goal can be achieved. At present, the only option for the attending physician interested in the use of melatonin as a cytoprotective is the off-label indication of the drug.

     Off label use of medications are defined as the uses of medicines that are not included in the indications or dosing regimens listed by the administrative body that registers, controls and authorizes medications. the US Food and Drug Administration (221). The off label use of medications is common in many clinical areas, such as psychiatry, pediatrics, oncology and intensive care unit (222-225). In general, no law prohibits the unauthorized use of medicines and the prescription of unauthorized medicines is legally accepted in most legislations (226). The prescription of medications by physicians is limited only by the common requirement of physicians’ duty to act and drive with care and attention.

     In Argentina, the National Administration of Medicines, Food and Medical Technology (ANMAT) approved melatonin (3 mg capsules or tablets) as an over-the-counter drug in 1995. In 2017, ANMAT authorized a prolonged-release preparation of 2 mg of melatonin (Circadin^R) as a prescription medication. Although ANMAT cannot authorize the use of a drug for an indication that is not listed in the package leaflet, it does not mean that the indication of a drug for other clinical situations is prohibited. According to ANMAT, the unauthorized prescriptions are "the sole responsibility of the attending physician, who performs them in the full exercise of their professional activity, based on their experience and available scientific knowledge, motivated by the need to provide an answer to health problems for which there are no treatment standards or, if they exist, they are very difficult to access".

     In many countries, melatonin is widely used as a dietary supplement or dietary products. The European Food Safety Authority (EFSA) has admitted that melatonin reduces sleep onset latency. This allows the introduction of melatonin as a food to improve the "regulation of the sleep-wake cycle", the "relaxation" and the "sleep patterns" (227, 228). Melatonin, melatonin-rich foods and their bio-extracts are now being developed to serve as nutritional supplements, dietary products and medications. The target group was defined by the EFSA as the general population and, as such, these extracts can be marketed in all EU countries.

     Different studies indicate that, as in animal tissues, melatonin reduces oxidative stress in plants. In fact, its discovery in plants two decades ago has opened an emerging field of research that has made substantial progress in understanding the actions of melatonin that contribute to the ecological success of the plant. Overexpression of melatonin in plants facilitates the germination of seeds and improves the development and maturation of the roots, protecting plants from biotic and abiotic stress (229-231). Therefore, the presence of melatonin in plants has implications not only for plant growth and crop yield, but also in terms of human and animal nutrition. When plant products containing melatonin are consumed, the compound is easily absorbed and exerts its functions at the cellular level. Therefore, in animals and plants, melatonin is a highly useful molecule that neutralizes the physiopathological processes that compromise a healthy lifestyle. The enrichment of melatonin in foods seems to be necessary to achieve the amounts that provide effective protection. Therefore, an area of interest is the development of functional foods with high levels of melatonin. In parallel, the toxicity of long-term use of melatonin should be evaluated.

     In conclusion, from studies in animals, several potentially useful effects of melatonin, such as those in MS and AD, require high doses of melatonin to be evident. If melatonin is expected to be effective in improving health, especially in the elderly, it is likely that the low doses of melatonin commonly used are not very beneficial (232). The question of whether melatonin has a therapeutic value in the prevention or treatment of MS or AD deserves further analysis. Multicenter double-blind studies are needed to explore and further investigate the potential and utility of melatonin. The doses of melatonin used should be re-evaluated in view of the equivalent human doses of melatonin derived from preclinical data. Unfortunately, of the 64 clinical trials related to melatonin in an initial state (recruitment and non-recruitment) listed in PubMed (ClinicalTrials.gov Search results 01/05/2019) none is directed to this query.

ACKNOWLEDGEMENT

     DPC is an Emeritus Superior Investigator from the Argentine National Research Council (CONICET) and Emeritus Professor, University of Buenos Aires.

CONFLICT OF INTEREST

 The author declares that there are no commercial or financial relationships that could be construed as a potential conflict of interest.

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