Melatonin &amp; the High Dose Mystery: The Yin-Yang
Authors: Siddiqui Amna , Aaqil Syeda Ilsa , Haider Ramsha , Adnan Alishba , Ochani Sidhant , Vaid Rayyan , Choudhary Anood 
Published: January 2023

Background & Aim: Melatonin is primarily involved in the regulation of circadian rhythm and sleep and with its neuroprotective, anti-inflammatory, antihypertensive, oncostatic and immunomodulatory roles, it has become a popular supplement. However, limited literature is available regarding the side effects associated with its consumption, particularly at high dosages. Our review offers a critical insight into the adverse events of melatonin supplementation above the recommended dosage i.e., 5mg/day.Methodology:A literature search was executed using controlled vocabulary, involving Medical Subject Headings (MeSH) through electronic databases like PubMed and Clinicaltrials.gov from inception to 19thJune 2022. Additional papers were subsequently added through hand-searching citations contained within retrieved articles, relevant systemic reviews, and meta-analysis, without any restriction regarding date or language. The inclusion criteria for studies were: 1) Freely accessible, full articles 2) Original studies, observational and interventional, Randomised Controlled Trials, and 3) Published trials in peer-reviewed journals that reported any adverse events. The studies excluded were 1) irrelevant to the subject of the review, such as studies that did not use melatonin as the exposure; 2) insufficient data to report the adverse events after the dose; 3) duplicate studies or overlapping participants, and 4) reviews, editorials, conference papers, case reports or animal experiments. Articles were further excluded if melatonin was only given in combination with other interventions, whereby the independent effect of melatonin could not be assessed.Results:After the final screening, 16 articles were retained for a full review. Various adverse events associated with the high dosage of melatonin were noticed. In the healthy population, the adverse events included reduced insulin release after the morning dose, impaired insulin release after the evening dose, suppression of Luteinizing hormone and ovulation, reduction in selective attention and visual reacting time, sleepiness or loss of sleep, exacerbation or onset of depression, anger or psychotic symptoms, weight loss, fatigue, and confusion. While in healthy sports people, a negative impact on performance and agility after morning doses in females, reduced performance in hand-grip strength, squat jump, and counter-movement jump tests were noticed, with the report of a rocking sensation among the travelling sports officials. Multiple other side effects were also noticed in the population with a high risk for/pre-existing comorbidities.Challenges and Discussion: The use of melatonin supplementation, especially as a self-medication, has seen a significant rise in recent times, owing to the correction of sleep disturbances that could be linked with prevalent mental health issues, a diminished sensation of control, or insomnia associated with different disorders. However, as sleep irregularities can typically be corrected with minor adjustments in lifestyle, diet, and physical activity, the excessive use of the supplements, without supervision and/or awareness regarding the adverse effects and possible drug interactions, is alarming. In addition to highlighting the adverse events related to higher dosages of Melatonin, we also discuss potential adjuncts to Melatonin supplementation for sleep irregularities and minor disturbances that lead to Melatonin use.Conclusion:Melatonin, is undoubtedly an asset to the field, but is related to a variety of adverse effects when taken in higher doses. Thus, consideration needs to be done before its regular consumption, specifically in individuals with pre-existing comorbidities or those with high risk, among whom the reports of adverse events were higher. Further cohorts and randomized controlled trials with a larger sample size are needed to further explore this domain. Similarly, additional emphasis should be given to the prevention of the widespread use of melatonin as a self-medication for minor disturbances and the drug should only be used when seriously needed, under strict instructions regarding dosage and consumption by healthcare officials.