Adverse events associated with oral administration of melatonin: A critical systematic review of clinical evidence

Foley, Hope; Steel, Amie

doi:10.1016/j.ctim.2018.11.003

Cited by 96 publications

(70 citation statements)

References 77 publications

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“…Melatonin shows a high safety profile in humans (Cardinali, 2019b;Foley and Steel, 2019) and, in general, is very well tolerated. Therefore, melatonin holds a promise in management of infants with HIE (Hendaus et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

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An Assessment of Melatonin’s Therapeutic Value in the Hypoxic-Ischemic Encephalopathy of the Newborn

Cardinali

2019

Front. Synaptic Neurosci.

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Hypoxic-ischemic encephalopathy (HIE) is one of the most frequent causes of brain injury in the newborn. From a pathophysiological standpoint, a complex process takes place at the cellular and tissue level during the development of newborn brain damage in the absence of oxygen. Initially, the lesion is triggered by a deficit in the supply of oxygen to cells and tissues, causing a primary energy insufficiency. Subsequently, high energy phosphate levels recover transiently (the latent phase) that is followed by a secondary phase, in which many of the pathophysiological mechanisms involved in the development of neonatal brain damage ensue (i.e., excitotoxicity, massive influx of Ca 2+ , oxidative and nitrosative stress, inflammation). This leads to cell death by necrosis or apoptosis. Eventually, a tertiary phase occurs, characterized by the persistence of brain damage for months and even years after the HI insult. Hypothermia is the only therapeutic strategy against HIE that has been incorporated into neonatal intensive care units with limited success. Thus, there is an urgent need for agents with the capacity to curtail acute and chronic damage in HIE. Melatonin, a molecule of unusual phylogenetic conservation present in all known aerobic organisms, has a potential role as a neuroprotective agent both acutely and chronically in HIE. Melatonin displays a remarkable antioxidant and anti-inflammatory activity and is capable to cross the bloodbrain barrier readily. Moreover, in many animal models of brain degeneration, melatonin was effective to impair chronic mechanisms of neuronal death. In animal models, and in a limited number of clinical studies, melatonin increased the level of protection developed by hypothermia in newborn asphyxia. This review article summarizes briefly the available therapeutic strategies in HIE and assesses the role of melatonin as a potentially relevant therapeutic tool to cover the hypoxia-ischemia phase and the secondary and tertiary phases following a hypoxic-ischemic insult.

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Section: Discussionmentioning

confidence: 99%

“…As far as a potential therapy for HIE in newborns, melatonin has many advantages. It crosses readily the blood-brain barrier, its antioxidant and anti-inflammatory effects are readily exerted and it has an excellent safety profile (Gitto et al, 2001(Gitto et al, , 2009Welin et al, 2007;Foley and Steel, 2019).…”

Section: Basic Biology Of Melatonin Relevant To Hiementioning

confidence: 99%

An Assessment of Melatonin’s Therapeutic Value in the Hypoxic-Ischemic Encephalopathy of the Newborn

Cardinali

2019

Front. Synaptic Neurosci.

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“…In addition, the increase in consumption of melatonin supplements in recent years for reasons that go beyond the specifications related to sleep (e.g., as an antioxidant, in anti-aging, as a hunger regulator, etc. ), makes it interesting to bet on active materials of natural origin, in addition to raising quality levels and their controls [75]. This has given rise to "green" objectives for obtaining dietary supplements rich in phytomelatonin rather than synthetic melatonin.…”

Section: 3-diphthalimidopropane Hydroxy-bromo-propylphthalimidementioning

confidence: 99%

Development of a Phytomelatonin-Rich Extract from Cultured Plants with Excellent Biochemical and Functional Properties as an Alternative to Synthetic Melatonin

et al. 2020

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Melatonin is a pleiotropic molecule with multiple and various functions. In recent years, there has been a considerable increase in the consumption of melatonin supplements for reasons other than those related with sleep (as an antioxidant, for anti-aging, and as a hunger regulator). Although the chemical synthesis of melatonin has recently been improved, several unwanted by-products of the chemical reactions involved occur as contaminants. Phytomelatonin, melatonin of plant origin, was discovered in several plants in 1995, and the possibility of using raw plant material as a source to obtain dietary supplements rich in phytomelatonin instead of synthetic melatonin, with its corresponding chemical by-products was raised. This work characterizes the phytomelatonin-rich extract obtained from selected plant material and determines the contents in phytomelatonin, phenols, flavonoids, and carotenoids. Additionally, the antioxidant activity was measured. Finally, a melatonin-specific bioassay in fish was carried out to demonstrate the excellent biological properties of the natural phytomelatonin-rich extract obtained.Antioxidants 2020, 9, 158 2 of 18 melatonin in in vivo and in vitro experimental models have appeared [12,[20][21][22]. Thus, the roles of melatonin in many tumors, both in growth, proliferation, apoptosis, and metastasis have been demonstrated [23,24]. The treatments of melatonin with chemo-and radiotherapy improves the sensitivity of tumors to nonproliferation by drugs, acting as a synergistic molecule in the control of cancer cells. Additionally, melatonin mitigates acute damage in normal cells, protecting them against drug toxicity, possibly enhancing immunomodulation [25][26][27][28]. More recently, the use of electrophile-melatonin derivatives as chemopreventive agents on cancer cells has been demonstrated, calling them new "intelligent" molecules [29]. However, without a doubt, the most known and well-studied roles of melatonin are those related with sleep regulation and circadian rhythms. In this sense, melatonin is produced by the pineal gland in the night, increasing blood melatonin levels during the first period of sleep to around 150-220 pmoles/mL, acting on sleep initiation, reducing sleep latency and fragmentation and increasing sleep duration and sleep quality [30][31][32]. Additionally, melatonin, being a powerful chronobiological molecule that contributes to the correct circadian behavior of physiological functions, acts as an internal synchronizer of the circadian sleep-wake cycle and seasonal rhythmicity. In this sense, many sleep disorders have been treated with melatonin, including delayed sleep phase syndrome, night shift-work sleep disorder, seasonal affective disorder, sleep disorders in the blind and aging, and patho-physiological disorders of children, with notable improvements in sleep quality [9,[32][33][34][35][36]. The most widespread disorder treated with melatonin is jet-lag, a de-phasing in the sleep-wake rhythms following trans-oceanic flights [37][38][39].

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“…Accordingly, a recent phase I study has shown that high doses of melatonin (0.3 mg/kg; maximum 20 mg) were well tolerated in pediatric patients with relapsed solid tumors . However, special mention should be made of a recent systematic review that has reported 24 studies with significant adverse events attributed to melatonin; a lot of them were short life (sleepiness, headache, or fatigue), whereas other more serious side effects were seen at very high doses or in specific populations . In this context, some reports have evidenced that short‐term melatonin can sometimes lead to opposite effects to those expected, and as probable cause of diarrhea, gynecomastia, or as trigger of Crohn's disease .…”

Section: The Safety Profile Of Melatonin Treatment In Humansmentioning

confidence: 99%

The emergence of melatonin in oncology: Focus on colorectal cancer

Gil‐Martín

Egea

Reíter

et al. 2019

Medicinal Research Reviews

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Within the last few decades, melatonin has increasingly emerged in clinical oncology as a naturally occurring bioactive molecule with substantial anticancer properties and a pharmacological profile optimal for joining the currently available pharmacopeia. In addition, extensive experimental data shows that this chronobiotic agent exerts oncostatic effects throughout all stages of tumor growth, from initial cell transformation to mitigation of malignant progression and metastasis; additionally, melatonin alleviates the side effects and improves the welfare of radio/chemotherapy‐treated patients. Thus, the support of clinicians and oncologists for the use of melatonin in both the treatment and proactive prevention of cancer is gaining strength. Because of its epidemiological importance and symptomatic debut in advanced stages of difficult clinical management, colorectal cancer (CRC) is a preferential target for testing new therapies. In this regard, the development of effective forms of clinical intervention for the improvement of CRC outcome, specifically metastatic CRC, is urgent. At the same time, the need to reduce the costs of conventional anti‐CRC therapy results is also imperative. In light of this status quo, the therapeutic potential of melatonin, and the direct and indirect critical processes of CRC malignancy it modulates, have aroused much interest. To illuminate the imminent future on CRC research, we focused our attention on the molecular mechanisms underlying the multiple oncostatic actions displayed by melatonin in the onset and evolution of CRC and summarized epidemiological evidence, as well as in vitro, in vivo and clinical findings that support the broadly protective potential demonstrated by melatonin.

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Adverse events associated with oral administration of melatonin: A critical systematic review of clinical evidence

Cited by 96 publications

References 77 publications

An Assessment of Melatonin’s Therapeutic Value in the Hypoxic-Ischemic Encephalopathy of the Newborn

An Assessment of Melatonin’s Therapeutic Value in the Hypoxic-Ischemic Encephalopathy of the Newborn

Development of a Phytomelatonin-Rich Extract from Cultured Plants with Excellent Biochemical and Functional Properties as an Alternative to Synthetic Melatonin

The emergence of melatonin in oncology: Focus on colorectal cancer

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