Melatonin as an adjunctive therapy in cardiovascular disease management

Abstract

Melatonin, N-acetyl-5-methoxytryptamine, is a neuroendocrine hormone secreted by the pineal gland. This pleiotropic indoleamine possesses amphiphilic properties, allowing it to penetrate most biological barriers and exert its effects at the subcellular level. Importantly, melatonin also plays a crucial role in regulating the body's response to circadian rhythms, adapting to internal and external environmental cues. Melatonin functions as a powerful antioxidant and free radical scavenger, protecting cells from oxidative damage. Its diverse physiological roles include maintaining the functional integrity of endothelial cells, thereby preventing atherosclerosis, a major contributor to cardiovascular disease. Additionally, melatonin exhibits antioxidant and free radical scavenging properties, potentially improving metabolic disorders. These combined effects suggest a unique adjunctive therapeutic potential for melatonin in treating cardiovascular diseases. This review aims to explore the mechanisms by which melatonin interacts with the cardiovascular system and investigates its potential use as an adjunctive therapeutic agent in managing cardiovascular disease.

Introduction

Cardiovascular disease (CVD) is one of the leading noncommunicable diseases, significantly impacting global morbidity and mortality, alongside cancer, diabetes, and respiratory diseases. ¹ Epidemiological studies estimate that CVD accounts for approximately one-third of worldwide deaths, with over 95% attributed to six specific conditions: ischemic heart disease, stroke, hypertensive heart disease, cardiomyopathy, rheumatic heart disease, and atrial fibrillation. ² Dyslipidemia and hypertension are modifiable risk factors at the individual level, alongside diabetes, smoking, alcohol consumption, and obesity. Current treatment strategies for CVD encompass lifestyle modifications, lipid-lowering medications, antithrombotic drugs, interventions for ventricular remodeling, and invasive surgical procedures. Despite the combined use of these approaches, the partial progression of CVD necessitates the exploration of preventive and interventional strategies based on the pathophysiological mechanisms of the disease. Melatonin, a pleiotropic molecule with free radical scavenging, antioxidant, ³ circadian regulatory, and anti-inflammatory properties, has the potential to delay CVD development. ⁴

Melatonin is primarily synthesized and released by the pineal gland during nocturnal hours. Its secretion rhythm is regulated by an intrinsic circadian clock located in the suprachiasmatic nucleus (SCN). Consequently, melatonin levels fluctuate in accordance with the circadian cycle. ⁵ It is now understood that melatonin interacts with the cardiovascular system through both neural and hormonal pathways. ⁶ Melatonin's effects are mediated by MT1 and MT2 receptors, members of the G protein-coupled receptor family. ⁷ Polymorphisms in these receptors have been implicated in human circadian rhythm disturbances. ⁸ Furthermore, MT2 receptors within the human retina and brain play a pivotal role in inducing circadian rhythms within the SCN. ⁶ Endothelial damage, inflammation, and dyslipidemia are key contributors to the pathogenesis of vascular atherosclerosis.^9,10 Galectin-3 (Gal-3), a galactose-binding protein, is a critical mediator of arterial inflammation. Melatonin has been shown to attenuate atherosclerosis by downregulating Gal-3, stimulating autophagy, suppressing inflammation, and reducing endothelial activation. ¹¹ While melatonin is considered a potential arrhythmia modulator, its efficacy and safety in this context remain to be established.

This review examines the current understanding of how melatonin may impact various aspects of CVD, including endothelial cell injury, abnormal lipid metabolism, atherosclerosis, hypertension control, and arrhythmias. The goal is to explore the potential of melatonin as a complementary therapy for CVD treatment. The review methodology is guided by the Scale for the Assessment of Narrative Review Articles (SANRA). ¹²

Effect of melatonin on atherosclerosis

Endothelial cells form a single, cobblestone-shaped monolayer lining the inner surface of blood vessels. They separate the blood vessel lumen from surrounding tissues, creating a semipermeable barrier that regulates the passage of substances. Endothelial cells contribute to cardiovascular health by synthesizing and degrading vascular-active substances, thereby maintaining blood pressure balance, and regulating vascular development. These cells also facilitate molecular exchange, ensuring the dynamic equilibrium of the cardiovascular system. ¹³ Atherosclerosis is a chronic, unresolved inflammatory disease of the blood vessels. The integrity of the endothelial cell layer plays a crucial role in preventing immune cell and circulating leukocyte infiltration into the subendothelial space, acting as a preventive measure in the earliest stages of atherosclerosis. Physiologically, endothelial cells prevent thrombosis formation through various antiplatelet and anticoagulant mechanisms. ¹⁴ Endothelial activation occurs when vascular endothelial cells are subjected to external stimuli such as oxidative stress, metabolic disorders, and stress states, and pyroptosis is a pro-inflammatory form of regulatory cell death, which is a particular type of endothelial activation. ¹⁵ Damaged endothelial cells allow low-density lipoprotein (LDL) to enter the arterial intima, where it can be oxidized, further damaging the intima. Macrophages then phagocytose the oxidized LDL, transforming it into foam cells. Accumulation of foam cells and lipids within the intima leads to the development of atheromatous plaques, which can ultimately contribute to cardiovascular events. ¹⁶ Gal-3 is a β-galactoside-binding lectin found primarily in the cytoplasm that binds proteins in a carbohydrate-dependent and nondependent manner and is widely expressed in human tissues, including epithelial cells, endothelial cells, macrophages, histiocytes, and mast cells. ¹⁷ Research has demonstrated that galectin-3 is a pivotal factor in macrophage activation, cellular proliferation, and apoptosis. Moreover, it serves as a mediator of localized inflammatory responses in pathological conditions and is a recognized biomarker for both inflammation and fibrosis. ¹⁸ Inflammatory cell infiltration leads to endothelial cell activation, which ultimately causes an increase in endothelial cell permeability, thus causing atherosclerosis. ¹⁵ Melatonin exhibits promise in slowing the progression of early atherosclerosis. It achieves this effect by promoting gal-3 autophagy in macrophages, thereby reducing the secretion of inflammatory cytokines. ¹¹ Interestingly, serum gal-3 levels are reportedly positively correlated with carotid intima-media thickness, and patients with carotid artery atherosclerosis demonstrate significantly higher levels than healthy individuals.^17,19 Chemokines, also known as chemotactic cytokines, induce the migration and infiltration of inflammatory cells, such as leukocytes and interleukin-1, when activated. They subsequently enhance vascular endothelial permeability, thereby initiating an inflammatory cascade. ²⁰ Multiple murine studies have demonstrated that melatonin significantly decreases the mRNA expression of chemokines CCL12 and CXCL10 while concurrently reducing inflammasome and macrophage abundance. These combined actions lead to reduced endothelial activation and a delay in the progression of atherosclerosis. ¹⁵ Monocyte chemotactic protein-1 is localized to macrophages, and recent experiments have shown that it may also be involved in cardiac repair. However, the capacity of melatonin to similarly inhibit this protein and consequently decelerate cardiac recovery remains experimentally unverified. ²¹ Conversely, melatonin deficiency is associated with increased serum levels of triglycerides, very LDL (VLDL), free fatty acids, and glucose. Triglyceride-rich VLDL can be hydrolyzed intravascularly, converting into cholesterol-rich and triglyceride-deficient residues. These residues are more susceptible to oxidation, leading to endothelial dysfunction and the production of inflammatory cytokines.^22,23 The heterogeneity of the vascular endothelium is contingent upon its integrity, with calcium ions serving as essential regulators of numerous vascular response mechanisms intimately linked to vascular inflammation and permeability. ²⁴ Research has established that circulating calcium ion levels contribute to the regulation of endothelial inflammatory responses, ²⁵ and there is a direct correlation between calcium ion levels and atherosclerosis. Melatonin has a unique mechanism for regulating calcium ion influx and mobilization, thereby maintaining calcium homeostasis and ensuring the integrity of cellular endothelial function. ²⁶ It is now understood that melatonin slows the onset of cardiovascular atherosclerosis through positive effects such as influencing chemokines and maintaining the integrity of endothelial cells, and the effective concentration at which melatonin acts varies from individual to individual and is still not well understood.

Influence of circadian rhythm of melatonin on metabolism

Sleep is a critical component of human health, and disruptions can contribute to or worsen certain diseases. It plays a vital role in regulating various biological functions, particularly metabolism. A normal circadian rhythm helps maintain the body's metabolic balance, and its disruption can have a significant impact. Melatonin, a hormone regulated by the circadian rhythm, can influence metabolism by promoting homeostasis. It can directly or indirectly regulate energy uptake and metabolism in a rhythmic fashion.^27,28 During sleep, energy storage leads to a decrease in insulin release, insulin resistance, hepatic gluconeogenesis, and increased leptin secretion. Animal studies have shown that mice lacking a pineal gland exhibit increased nighttime insulin resistance and higher levels of hepatic triglycerides and cholesterol esters. ²³ A controlled experiment was conducted on male rats exhibiting elevated triglycerides, total cholesterol, serum insulin concentrations, and insulin response profiles following 4 or 6 weeks of a high-sugar diet. Subsequently, these rats were administered varying doses of melatonin daily. The high-dose group (10 mg/kg) demonstrated superior efficacy compared to the low-dose group (1 mg/kg) in ameliorating serum insulin response profiles and insulin resistance. These findings indicate that exogenous melatonin supplementation can enhance glucose tolerance and insulin sensitivity in the context of hyperglycemia. ²⁹ Similarly, dyslipidemia observed in individuals with shift work or sleep disorders is linked to decreased melatonin secretion. Conversely, strong evidence suggests that melatonin deficiency can lead to significant hyperinsulinemia and decreased tissue insulin sensitivity following pineal gland removal.^30,31 A 2013 study by Juliana et al. ³² demonstrated that melatonin activates a specific pathway between the hypothalamus and the liver, thereby regulating hepatic gluconeogenesis and maintaining glycemia. In addition, Elmar et al. ³³ proposed that melatonin receptors MT1 and MT2 interact with different G proteins, influencing glucagon and insulin secretion through α, β, and δ cells of the pancreas. Elevated blood glucose levels significantly increase the risk of CVD, stroke, and mortality. The combined presence of abnormal blood glucose and metabolic syndrome has a synergistic effect, exacerbating the burden of diffuse atherosclerosis in CVD. The blood lipid profile is comprised of high-density lipoprotein (HDL), LDL, triglycerides, and cholesterol. LDL has received particular attention in clinical practice as a core factor in atherosclerosis and CVD events. ³⁴ Recent studies have demonstrated a positive correlation between triglyceride-rich lipoproteins and the severity of atherosclerosis. ³⁵ A meta-analysis identified elevated triglyceride levels as an independent risk factor for coronary heart disease. ³⁶ Dyslipidemia is a major risk factor for CVD. Melatonin, a potent natural antioxidant, protects the liver from damage caused by free fatty acids and reactive oxygen species, thereby facilitating the transformation and transport of blood lipids. ³⁷ A 2019 study by Akira et al. in rats demonstrated that continuous melatonin administration improved insulin resistance, impaired adipokine status, and attenuated increases in triglycerides. The study also observed an increase in HDL concentrations. However, the specific mechanism by which melatonin improves hyperfructose-induced hyperuricemia remains unclear. ²⁹ Melatonin exhibits a multifaceted influence on blood lipid levels. Studies have demonstrated its ability to improve insulin resistance and adipokine status in animal models. Furthermore, melatonin administration attenuated increases in triglycerides while elevating HDL concentrations. Beyond these observations, melatonin exerts additional lipid-lowering effects. It accelerates the breakdown of cholesterol into bile acids, ³⁸ inhibits cholesterol synthesis and LDL receptor activity, ³⁹ and directly impacts fat metabolism through specific MT1 and MT2 receptors. ⁴⁰ Melatonin may also play a role in restoring autophagy in damaged organs, potentially contributing to improved lipid profiles. ⁴¹ Interestingly, melatonin increases the volume and activity of brown adipose tissue, improving blood lipid levels, arteriosclerosis, and obesity severity.^42,43 A clinical meta-analysis suggests that melatonin reduces body weight without affecting food intake. This effect may be mediated by its interaction with leptin, a key molecule regulating food intake and energy balance. Paradoxically, obese individuals often exhibit high circulating leptin levels, a phenomenon linked to leptin resistance. ⁴⁴ Studies suggest that melatonin and leptin share a signaling pathway, with melatonin potentially mimicking leptin's role to counteract the body's response and ultimately correct energy imbalance. ⁴⁵ However, this represents just one aspect of the complex interplay between these two molecules, necessitating further investigation. Interestingly, it has been suggested that melatonin inhibits glucose levels in rats and humans during exercise,^5,46 which can promote fat-burning and, therefore, weight loss. ⁵ Importantly, melatonin's lipid-lowering mechanism in liver cells differs from that of statins. Melatonin does not affect the binding affinity of LDL molecules to LDL receptors, offering a distinct approach for delaying atherosclerosis and reducing CVD risk. ⁴⁷ The complex regulatory mechanisms governing melatonin secretion and action, which are frequently disrupted in various pathophysiological states, coupled with the hormone's relatively short half-life, render the maintenance of sustained therapeutic melatonin concentrations challenging, particularly in the elderly population.

Melatonin and ventricular remodeling

As CVD progresses and risk factors exert their influence, some patients inevitably develop heart failure. Ventricular remodeling, a compensatory response to heart failure, can take a pathological turn. This pathological remodeling involves myocyte elongation and interstitial fibrosis, contributing to ventricular hypertrophy, increased ventricular volume, and altered ventricular morphology. These changes ultimately lead to increased myocardial oxygen consumption and alterations in ventricular wall stress. ⁴⁸ Current treatment strategies aimed at improving myocardial contractility by enhancing cardiomyocyte regenerative capacity have proven elusive. Cardiac injury is primarily driven by sympathetic overactivation, ischemia, oxidative stress, and fibrosis.^49,50 A close link exists between sympathetic nervous system activation and CVD. Cardiac sympathetic hyperactivity leads to increased myocardial ischemia, impaired atrial and ventricular function (systole and diastole), and ultimately, ventricular remodeling. Conversely, inhibition of cardiac sympathetic hyperactivity has been shown to improve ventricular remodeling. ⁵¹ A controlled animal study revealed that daily melatonin supplementation (30 mg/kg) for 7 weeks significantly reduced blood pressure in hypertensive rats compared to controls without altering body weight or food intake. Conversely, proteinuria and urine flow were significantly increased in the control group. Additionally, intravenous melatonin administration markedly decreased plasma epinephrine and norepinephrine levels in hypertensive rats compared to baseline values. This reduction in catecholamines is hypothesized to normalize renal sympathetic nerve activity, thereby contributing to the observed blood pressure reduction and potential cardioprotective effects. ⁵² Myocardial ischemia and hypoxia are the primary stimuli for free radical generation, which is highly destructive to the heart's molecular physiology, particularly at the mitochondrial level. Melatonin, in addition to its direct free radical scavenging ability, also plays a role in inhibiting oxidative damage in the heart. ⁵³ Postmyocardial infarction ventricular remodeling remains a major contributor to heart failure. Its pathogenesis involves postmyocardial infarction compensation, which promotes mechanical stretching of cardiac tissues and activation of hypertrophic pathways. To a lesser extent, it also involves disturbances in energy metabolism and changes in the extracellular matrix, leading to myocardial fibrosis. ⁵³ A retrospective study found that reduced serum melatonin concentrations after myocardial infarction predicted ventricular remodeling and were associated with a poor prognosis. ⁵⁴ Furthermore, basal melatonin levels were identified as an independent predictor of ventricular remodeling. ⁵⁵ Several animal studies have demonstrated that melatonin's multifaceted effects target various pathophysiological mechanisms involved in cardiac remodeling after myocardial infarction. Melatonin supplementation has been shown to inhibit the release of potentially harmful neurohumoral factors and improve ventricular function. These benefits are achieved through distinct mechanisms. Firstly, melatonin reduces ventricular fibrosis by decreasing hydroxyproline concentrations in both insoluble and total collagen within cardiac tissue. ⁵⁶ Secondly, it attenuates myocardial fibrosis in hypoxic rats by significantly decreasing the mRNA expression of genes associated with myocardial hypertrophy (TGFβ1 and PC1). ⁵⁷ Percutaneous coronary artery stenting, the primary treatment for myocardial infarction, can salvage some cardiomyocytes in the infarct border zone. However, reperfusion after ischemia leads to the generation of reactive oxygen species and free radicals, which contribute to cardiac hypertrophy and cardiomyocyte death. ⁵⁸ These events ultimately trigger ventricular and mitochondrial remodeling, leading to a decrease in myocardial energy supply. Melatonin has been shown to alleviate mitochondrial dysfunction and restore mitochondrial efficiency, thereby improving energy provision to the myocardium and promoting favorable ventricular remodeling. ⁵³ In conclusion, emerging evidence suggests that melatonin is a promising therapeutic molecule for heart failure. It appears to exert cardioprotective effects by mitigating cardiac deterioration while maintaining a favorable safety profile.

Melation and arrhythmias

Circadian rhythms are endogenous biological cycles with a period of approximately 24 hours. These rhythms enable organisms to anticipate and adapt to daily environmental fluctuations, thereby minimizing their adverse effects. The heart, like most mammalian organs, is significantly influenced by circadian rhythms. Discordance between daily behavior or external cyclical changes and the internal body clock can induce changes in cardiac electrophysiology. Disruptions in the cardiomyocyte clock can ultimately trigger arrhythmias such as supraventricular tachycardia, ventricular tachycardia, and atrial fibrillation. ⁵⁹ A study investigating spontaneous discharge in neonatal cardiomyocytes revealed that the cellular discharge rhythm coincided with the frequency of intrinsic cellular oscillations in cardiomyocyte clock proteins. This finding suggests that a circadian rhythm inherent to cardiomyocytes drives this temporal pattern. ⁶⁰ Conversely, another study demonstrated that cardiac rhythm disturbances can lead to repolarization changes, causing circadian rhythm attenuation and ultimately ventricular arrhythmias. ⁶¹ Melatonin has been shown to reduce the incidence of ventricular tachycardia and ventricular fibrillation by shortening baseline activation time and repolarization interval, thereby improving overall repolarization time. ⁶² Preclinical studies suggest that melatonin may offer benefits in preventing or mitigating cardiac arrhythmias. Animal models, including those with myocardial ischemia, heart failure, and hypokalemia, have shown that melatonin administration at a dose of 10 mg/kg per day for 7 days promotes more complete repolarization recovery in cardiomyocytes. ⁶³ This effect is attributed, at least in part, to enhanced ventricular gap junctions and increased expression of connexin-43, a protein critical for cell-to-cell communication within the heart muscle.^63,64 Connexin-43 upregulation by melatonin may be particularly relevant in the treatment of arrhythmias associated with these conditions. The suprachiasmatic nucleus acts as the body's master circadian clock, synchronizing various biological rhythms with the 24-hour light–dark cycle. Melatonin acts within the SCN to modulate arousal signals, promoting sleep and facilitating the restoration of normal cellular cycles throughout the body. ⁶⁵ This synchronization may also help align the rhythms of cardiomyocytes, potentially reducing the occurrence of arrhythmias. Cardiac conduction relies not only on intercellular gap junction coupling but also on proper cardiac sodium channel expression and function. Melatonin has been shown to enhance sodium channel-mediated impulse conduction, potentially reducing arrhythmia susceptibility. While the precise role of melatonin's interaction with the sympathetic nervous system in its antiarrhythmic effects remains a subject of ongoing investigation, available evidence suggests that its antioxidant properties may not be the primary mechanism. Interestingly, animal models with chronic melatonin administration demonstrate a more comprehensive or expedited recovery of electrophysiological parameters following myocardial ischemia. ⁶³ Despite promising preclinical findings, the use of melatonin in the clinical treatment of cardiac arrhythmias remains limited. Further research is warranted to definitively establish its specific efficacy in this context.

Discussion and future directions

Melatonin exhibits a broad range of potential therapeutic applications beyond its well-established role in adjusting circadian rhythms and sleep-wake cycles in humans. Importantly, nocturnal animals interpret nighttime melatonin signals differently than humans, and melatonin does not induce sleep in these creatures. Emerging evidence suggests its involvement in slowing down the aging process, protecting the heart, and even acting as an adjuvant therapy for tumors. ⁶⁶ Recent studies have explored the potential of melatonin's antioxidant properties as a multitargeted treatment for osteoarthritic cartilage degeneration. ⁶⁷ Its mild and long-lasting effects make it a promising therapeutic option for elderly patients. Furthermore, melatonin may play a role in suppressing tumor growth through various mechanisms, including antiangiogenesis, activation of the immune system, and modulation of epigenetic information that controls cancer cell behavior. Our primary interest lies in understanding the potential influence of melatonin on CVD. Circadian rhythms significantly impact various factors involved in the coagulation cascade, including platelet function, coagulation factors, antithrombin, fibrinolytic factor activity, and endothelial cell function. Antiplatelet aggregation inhibition is a cornerstone of preventing and treating atherosclerosis. Several agonists, such as adenosine diphosphate (ADP), arachidonic acid, and thrombin, induce platelet aggregation. Studies suggest that melatonin may act in a concentration-dependent manner to antagonize these factors, thereby exerting an antiplatelet effect. However, the precise mechanisms underlying this action remain unclear. Melatonin supplementation offers the potential for sustained suppressive concentrations, potentially impacting cardiovascular health. Studies have not identified contraindications between melatonin and common antiplatelet medications like aspirin and clopidogrel. Melatonin's unique gastroprotective effect may even reduce bleeding risk. Furthermore, its ability to inhibit coagulation factors and fibrinogen levels may decrease the likelihood of thrombosis, as demonstrated in animal studies. ⁶⁸ A cohort study showed that healthy men taking regular melatonin supplementation had significantly lower fibrinogen and D-dimer levels compared to controls, supporting a potential role for melatonin in antithrombotic therapy. ⁶⁹ The past few years have witnessed a burgeoning interest in the relationship between platelets and melatonin. Platelets are a significant source of serotonin, a precursor molecule necessary to initiate the melatonergic pathway in various body cells, including cardiomyocytes. Platelets are also capable of effluxing melatonin. ⁷⁰ Given the presence of melatonin in heart tissue, as shown in a preliminary study, ⁷¹ the regulation of platelet serotonin release may be of some importance to cardiomyocyte function and melatonin production. Future research should investigate the presence of the melatonergic pathway in cardiomyocyte and endothelial mitochondria, particularly considering the high mitochondrial density in cardiomyocytes. Melatonin's multifaceted effects, including neurohumoral and molecular actions, have been shown to improve the prognosis of myocardial infarction and heart failure through various mechanisms. These findings suggest its potential as an effective adjunctive therapy for patients with myocardial infarction, heart failure, and arrhythmias.

Melatonin is widely available in the United States. In the European Union, the drug can only be purchased on prescription and is indicated for the treatment of insomnia in people over 55 years of age. The cardioprotective effect of melatonin was proposed to prevent doxorubicin-induced cardiotoxicity in 2004, ⁷² a systematic review indicated that melatonin combination therapy reduced the cardiotoxicity of doxorubicin in most cases, and the pharmacological effects of melatonin were not discussed in the text. ⁷³ A clinical study found that 4 weeks of 2 mg of slow-release melatonin at bedtime resulted in significantly lower nocturnal systolic blood pressure in the control group than in the placebo group (P = 0.01) and that melatonin was more effective in combination with angiotensin-converting enzyme inhibitors and diuretics. ⁷⁴ Surprisingly, there was no significant antihypertensive effect in combination with calcium channel blockers. In a controlled experiment in mice with hypertension, mice fed melatonin at 10 mg/kg/day experienced a decrease in blood pressure and improvement in cardiac fibrosis, but melatonin had no effect on the weight of the left ventricle. ⁵⁶ Another study found that a 5 mg per night melatonin fast-release dosage form combined with a calcium channel blocker led to elevated blood pressure and increased heart rate, ⁷⁵ making it important to be cautious about the efficacy of melatonin in hypertension treatment. Due to the pharmacokinetic problems of melatonin, such as poor bioavailability and short half-life, which limit its uptake and utilization by the body, various formulations of melatonin, including immediate-release, extended-release, and surge sustained-release formulations, have been developed to improve human health. ⁷⁶ Extended-release formulations allow for a slower release of the drug, avoiding the surge effect that can occur with immediate-release tablets. ⁷⁷ However, the risk of prolonged supraphysiological levels of melatonin is significantly increased with high-dose or surge sustained-release dosage forms. However, there is no clear evidence that high-dose melatonin supplementation leads to serious side effects. ⁷⁸ In addition, multiple routes of administration, such as oral, transnasal, and transmucosal methods, affect the time to peak and duration of action of melatonin. Multiple clinical studies have demonstrated the benefits of extended-release melatonin preparations (circadian rhythm hormones) and melatonin analogs (agomelatine and ramelteon) in the regulation of circadian rhythm sleep disorders and insomnia. ⁷⁹ Melatonin-related agents follow a phasic response curve in mammals, ⁸⁰ and exogenous supplementation corrects phasic misalignments and coordinates whole-body circadian regulation of phasicity and amplitude; therefore, the optimal mode of administration is a low dose during the sensitive period ⁸¹ and is recommended from 8 to 11 pm. Medication guidelines suggest a minimum dose of melatonin for a proper regimen; larger measurements do not result in greater health benefits. ⁸² In contrast, in some countries, melatonin is used as a dietary supplement and is available over-the-counter in grocery stores or pharmacies, with concerns regarding its content and purity. ⁸³ One of the children's chewable tablets had the greatest variation in melatonin concentration differences, with melatonin levels exceeding normal values by six times, although a double-blind, placebo-controlled study found no serious adverse effects from long-term high-dose melatonin ⁸⁴ ; however, it has been studied in a specific population and is not representative of all. Children's medications, usually calculated based on age or weight, adjust for differences in physiology and drug metabolism that differ from those of adults. ⁸⁵ The first-line treatment for sleep disorders in children under 18 years of age is not pharmacological, but the proportion of children ingesting melatonin is increasing yearly. ⁸⁶ The European Medicines Agency ⁸⁷ suggests that for children over 4 years of age, a starting dose of 1 to 5 mg is recommended, with gradual dosage increases to achieve therapeutic effects. A single-center retrospective study revealed that ingestion of melatonin-containing gummies was significantly more likely to be symptomatic than ingestion of vitamins (20% vs. 2.9%). Major discomforts, including drowsiness and gastrointestinal reactions, were reported, ⁸⁸ which may be linked to the timing and dosage of the medication. Surprisingly, a small-sample melatonin gummy product research study found fluctuating levels of melatonin and cannabidiol, and clinicians are advised to use them with caution, ⁸⁹ and a rigorous monitoring system should be established. To date, there is no evidence suggesting that exogenous melatonin induces a classical negative feedback mechanism, implying that melatonin supplementation does not result in pineal gland atrophy. ⁹⁰ Despite being theoretically suitable for long-term use, it is essential to note the potential adverse effects of exogenous melatonin in specific populations, such as pregnant and lactating women. ⁹¹ Moreover, high doses or prolonged administration should be approached with caution due to the unknown long-term endocrine implications. ⁶³ Consequently, strategies to augment endogenous melatonin production without compromising health are of paramount importance. ⁴

Conclusion

CVD poses a significant global health burden. Despite existing strategies for primary and secondary prevention, substantial challenges remain. Current therapeutic approaches for CVD focus on preventing and delaying atherosclerosis, stabilizing circadian rhythms, reducing blood lipid levels, and managing risk factors. Melatonin has emerged as a promising candidate for CVD treatment due to its multifaceted effects and limited side effects. However, large-scale clinical trials specifically designed to validate melatonin's efficacy in CVD are still lacking. Further research is crucial to fully elucidate the pathophysiological mechanisms underlying melatonin's potential benefits in CVD. This knowledge is essential for establishing its role as a potential baseline therapy.