Introduction: An In-Depth Exploration of Melatonin with the Botaneo Natural Ingredient Research Institute
Greetings from the Botaneo Natural Ingredient Research Institute. Our mission is to explore the infinite potential of nature through scientific inquiry and share this profound knowledge with you, our readers. For the next installment of our 'In-Depth Study of Natural Ingredients' series, we will delve into Melatonin, a molecule that is not just a 'sleep aid' but is fundamentally connected to life's most basic activities.
Melatonin is more than just a sleep-inducing substance. Found in nearly all living organisms, from bacteria to plants and humans, this remarkable molecule plays a fundamental role as old as life itself.1 This report will uncover everything from melatonin's scientific identity behind its romantic nickname, 'the hormone of darkness,' to its diverse roles within our bodies, all rigorously verified by SCI-grade papers. We will cover its chemical structure, biosynthesis, its functions beyond sleep regulation—including antioxidant, anti-inflammatory, immune-modulating, and anti-cancer effects—as well as its rich natural sources and industrial applications. By presenting a comprehensive overview of melatonin, we aim to provide deep insights for your healthy life.
The Identity of Melatonin: Chemical Structure and Biosynthesis
To understand the various benefits of melatonin, it is essential to first grasp what this molecule is and how it is produced in our bodies. The chemical profile and sophisticated biosynthesis of melatonin encapsulate the very mystery of life.
1. Chemical Profile of Melatonin
Melatonin is chemically named N-acetyl-5-methoxytryptamine and is an indolamine molecule derived from the essential amino acid tryptophan.4 As its name suggests, the core of the molecule is an indole ring structure, which forms the basis for its diverse biological activities.
Molecular Formula and Weight: Melatonin has the molecular formula C13H16N2O2 and a molecular weight of approximately 232.28 g/mol.4
Physicochemical Properties: In its pure state, melatonin is a colorless or off-white powder. It has a density of 1.175 g/cm³, a melting point of 116.5–118 °C, and a boiling point of 512.8 °C.4 These properties indicate that melatonin is a relatively stable compound.
2. The Body's Melatonin Factory: The Biosynthesis Process
Melatonin is synthesized in our bodies through a sophisticated series of enzymatic reactions. This process primarily occurs in the pineal gland, a small endocrine gland located in the center of the brain, but it is also locally synthesized in various other tissues such as the retina, gastrointestinal tract, bone marrow, and skin.1
The biosynthesis pathway in animals can be summarized in the following four steps:1
Step 1 (Hydroxylation): The process begins with Tryptophan, an essential amino acid that must be obtained through diet. Tryptophan is converted to 5-Hydroxytryptophan by the enzyme Tryptophan hydroxylase.
Step 2 (Decarboxylation): Aromatic L-amino acid decarboxylase removes a carboxyl group from 5-Hydroxytryptophan to produce Serotonin, a well-known neurotransmitter.
Step 3 (Acetylation): The resulting serotonin is converted to N-acetylserotonin by a key regulatory enzyme called Arylalkylamine N-acetyltransferase (AANAT).
Step 4 (Methylation): Finally, Hydroxyindole-O-methyltransferase (HIOMT) attaches a methyl group to N-acetylserotonin to complete the synthesis of Melatonin.
The most critical control point in this process is the AANAT enzyme in Step 3. The activity of this enzyme is strongly inhibited by light. The Suprachiasmatic Nucleus (SCN) in our brain acts as a biological clock, distinguishing day from night by detecting light information from the eyes. During the day, when light is detected, the SCN inhibits AANAT activity in the pineal gland, blocking melatonin synthesis. Conversely, when darkness falls, the SCN's inhibition is lifted, AANAT is activated, and melatonin is synthesized and secreted in large quantities, traveling through the bloodstream to the entire body. This is why melatonin is called the 'hormone of darkness.'6
From an evolutionary perspective, the existence of melatonin is very ancient. Melatonin is synthesized in the mitochondria, the energy factories of all living cells, and in the chloroplasts, the photosynthetic organs of plants. It is widely accepted that these two organelles originated from ancient bacteria that lived in symbiosis within cells (endosymbiotic theory).1 This strongly suggests that melatonin's primary function was not the complex regulation of the sleep-wake cycle in vertebrates, but rather its role as an antioxidant protecting the most fundamental units of life—cells, especially mitochondria, where oxidative stress is most prevalent. In other words, melatonin began as an ancient guardian of the cell and, through evolution, acquired the additional role of a signaling molecule that regulates circadian rhythms.
The Core Roles and Mechanisms of Melatonin: An In-Depth Efficacy Analysis Based on SCI-Grade Papers
The true value of melatonin lies not just in its ability to induce sleep, but in its role as a multifaceted regulator for maintaining the body's homeostasis. The diverse benefits of melatonin stem from its ability to regulate two fundamental systems: 'time' (circadian rhythm) and 'energy' (mitochondrial function and oxidative stress). Centered on these two key axes, we will conduct an in-depth analysis, based on SCI-grade research, of how melatonin is deeply involved in the nervous system, immune system, and cell survival.
1. Conductor of the Biological Clock: Regulating Sleep and Circadian Rhythms
Melatonin's most well-known function is regulating our body's 24-hour cycle, the circadian rhythm. This is achieved through its interaction with melatonin receptors located in the brain's suprachiasmatic nucleus (SCN).8
Mechanism of Action: Melatonin primarily acts through two types of high-affinity G-protein coupled receptors (GPCRs): MT1 and MT2.
MT1 Receptors: Activation of these receptors inhibits neuronal activity in the SCN, lowering the state of arousal and inducing drowsiness. They are known to be primarily involved in regulating REM sleep.8
MT2 Receptors: These receptors are responsible for shifting the 'phase' of the biological clock, either advancing or delaying the internal clock to synchronize with the external day-night cycle. They are mainly involved in regulating NREM sleep, or deep sleep.8
Clinical Efficacy for Insomnia: According to several meta-analyses, melatonin has been shown to reduce sleep onset latency (the time it takes to fall asleep) in patients with chronic insomnia by an average of about 7 minutes compared to a placebo.12 However, there is disagreement among expert groups regarding its overall efficacy for adult chronic insomnia. For example, European sleep guidelines recommend the use of prolonged-release melatonin for short-term treatment of insomnia in adults over 55, while the American Academy of Sleep Medicine (AASM) does not recommend melatonin for chronic insomnia due to low levels of evidence.13
Clinical Efficacy for Jet Lag: A systematic review of literature suggests that melatonin is likely effective in alleviating the symptoms of jet lag, especially when traveling eastward.16 This is because melatonin helps reset the biological clock to the nighttime of the new time zone.18
Clinical Efficacy for Shift Work Sleep Disorder (SWSD): Shift work is associated with the suppression of melatonin secretion, which can lead to health problems.19 Melatonin supplementation may help slightly increase daytime sleep duration after shift work, but its impact on other sleep metrics is limited due to the complexity of irregular work schedules, according to current research.21
2. The Invisible Guardian: Potent Antioxidant and Anti-Inflammatory Effects
One of melatonin's most fundamental and important roles is to protect cells as a powerful antioxidant. This is because melatonin has a unique and multi-layered defense mechanism that distinguishes it from other antioxidants.
Direct Antioxidant Action: Melatonin is exceptionally effective at directly neutralizing various reactive oxygen species (ROS) and reactive nitrogen species (RNS), including the highly destructive hydroxyl radical (•OH) and the peroxyl radical (ROO•), which causes lipid peroxidation.23
Indirect Antioxidant Action: Beyond sacrificing itself, melatonin strengthens our body's endogenous antioxidant defense system. It does this by promoting the synthesis and activity of key antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT).23
Antioxidant Cascade: This concept makes melatonin a particularly unique antioxidant. While most antioxidants lose their function after neutralizing a free radical, the metabolites produced when melatonin reacts with free radicals (e.g., AFMK, AMK) also possess potent antioxidant capabilities. These metabolites then eliminate other free radicals, creating an 'antioxidant cascade' where a single melatonin molecule can sequentially neutralize multiple free radicals, establishing a highly efficient defense system.6
Anti-Inflammatory Mechanism: Chronic inflammation is the root of numerous diseases. Melatonin inhibits the activity of nuclear factor kappa-B (NF-κB), a key regulator of the inflammatory response. Since NF-κB is a transcription factor that promotes the production of various inflammatory cytokines (e.g., TNF-α, IL-6), melatonin's inhibition of it fundamentally controls the inflammatory response.27
3. Protective Shield for Brain Cells: Neuroprotective Effects
The brain, with its high oxygen consumption, is extremely vulnerable to oxidative stress. Melatonin's potent antioxidant and anti-inflammatory capabilities form the basis for its significant protective effects in various neurodegenerative disease models.
Alzheimer's Disease (AD): Preclinical studies suggest that melatonin has the potential to mitigate the toxicity of amyloid-beta (Aβ) peptides, the main causative agent of Alzheimer's disease, improve the dysfunction of mitochondria (the energy factories of nerve cells), and protect nerve cells from oxidative stress.29
Parkinson's Disease (PD): Parkinson's disease is characterized by the death of dopamine-producing neurons, a process deeply involving oxidative stress and mitochondrial dysfunction. In animal models and small-scale human clinical trials, melatonin supplementation has been shown to reduce oxidative stress markers and restore mitochondrial function, suggesting its potential as an adjunctive therapy to slow disease progression.32
Melatonin performs a complex, 'double-edged sword' regulatory function on the immune system. This means it can either promote or suppress immune responses depending on the immune state and environment, demonstrating its role as a sophisticated immune modulator.
Immune Enhancement (Pro-inflammatory): In infectious situations, melatonin acts as an immune enhancer, promoting the activity of immune cells like macrophages and T-cells to improve defense against pathogens.27
Immune Suppression (Anti-inflammatory): Conversely, in situations where autoimmune diseases or excessive inflammatory responses are a problem, it acts as an anti-inflammatory and immune suppressor, inhibiting the production of inflammatory cytokines to prevent tissue damage.27 This context-dependent function signifies melatonin's key role in maintaining immune system balance.
Numerous studies, especially meta-analyses of randomized controlled trials (RCTs), strongly suggest that melatonin has remarkable potential as an adjuvant therapy in cancer treatment.
Improved Survival and Tumor Response Rates: A significant meta-analysis published in 2012 found that when solid tumor patients were given melatonin in conjunction with standard treatments like chemotherapy or radiotherapy, the 1-year survival rate significantly improved (relative risk 0.63), and the rates of complete and partial tumor response were also markedly enhanced.35
Anticancer Mechanisms: Melatonin's anticancer effects are expressed through several mechanisms:
Inhibition of Angiogenesis: It inhibits the formation of new blood vessels, which are essential for tumor growth and metastasis.37
Induction of Apoptosis: It promotes the natural death process of cancer cells.35
Immune Modulation: It enhances the activity of immune cells (e.g., NK cells, T-cells) that attack cancer cells.35
Reduction of Treatment Side Effects: One of the most clinically important findings is that melatonin combination therapy significantly reduced common chemotherapy-induced side effects such as asthenia, leucopenia, nausea and vomiting, and thrombocytopenia.35 This can greatly contribute to improving patients' quality of life and treatment compliance.
Melatonin is not only synthesized in our bodies but also naturally present in various animal and plant-based foods we consume daily. Melatonin from food (phytomelatonin) can be absorbed by the body, increasing blood melatonin levels, which may have positive health effects.2
Animal Sources
Among animal-based foods, eggs and fish have been reported to contain relatively high levels of melatonin.
Eggs: Raw eggs contain about 1.54 ng/g of melatonin.2
Fish: Fish like salmon have been found to contain about 3.7 ng/g of melatonin.2
Milk: Milk, especially milk collected at night, is known to have a higher melatonin content than milk collected during the day, which has gained attention for its potential to improve sleep quality.2
Plant Sources
The plant kingdom is a very rich and diverse source of melatonin. High levels have been found in some nuts, fruits, mushrooms, and grains.
Nuts: Pistachios may contain the highest levels of melatonin found in food to date. Some studies have reported extremely high values, reaching hundreds of thousands of ng per gram of dry weight, although it should be noted that there is a large variation in values depending on the study methodology.2
Walnuts are also a good source, containing several ng of melatonin per gram.2
Fruits: Tart cherries, especially the Montmorency variety, are high in melatonin and have been extensively studied for their sleep-improving effects.
They contain about 13.5 ng/g of melatonin on a fresh weight basis.2 Grapes, particularly the skins, also contain significant amounts of melatonin.2
Mushrooms and Grains: Some types of mushrooms boast very high melatonin content, and it is also found in grains such as corn, rice, barley, and oats.2
Sprouted Seeds and Legumes: Sprouting seeds or legumes has been shown to dramatically increase their melatonin content. For example, sprouted mung beans have been reported to have more than 11 times the melatonin content of unsprouted ones.2
The following table summarizes the melatonin content of major foods, providing a quick overview of which foods can be good sources of melatonin.
Food Group
Food Item
Melatonin Content (ng/g)
Notes
Nuts
Pistachios
230,000
Dry weight basis, large variation between studies 2
Walnuts
1.0–3.5
Varies by variety and condition 2
Fruits
Tart Cherries (Montmorency)
13.46Natural Ingredient Research
Fresh weight basis 2
Grapes (skin)
8.9–158.9
Dry weight basis, varies by variety 2
Mushrooms
Saffron milk cap (Lactarius deliciosus)
12,900
Dry weight basis 2
King bolete (Boletus edulis)
6,800
Dry weight basis 2
Grains
Corn
10–2,034
Dry weight basis, varies by variety 2
Rice
0–264
Dry weight basis, colored rice is higher 2
Animal Products
Eggs
1.54
Fresh weight basis 2
Salmon
3.7
Fresh weight basis 2
As the diverse physiological functions of melatonin have become known, there have been active efforts to utilize it in health supplements and pharmaceuticals. However, understanding how melatonin product ingredients are processed and regulated in different countries is crucial for consumer safety and informed choices.
1. Raw Material Processing and Manufacturing
Most melatonin products on the market are manufactured through chemical synthesis rather than natural extraction.
Chemical Synthesis: This is the primary method used for the industrial mass production of melatonin. It is typically synthesized through a multi-step chemical reaction starting from materials like 5-hydroxytryptamine hydrochloride or diethyl malonate.42 This method has the advantage of being able to supply high-purity melatonin in large quantities stably.
Natural Extraction (Phytomelatonin): This method involves extracting melatonin directly from plants. However, as noted earlier, the melatonin content in most plants is very low, making it economically unfeasible for commercial mass production. As a result, pure plant-extracted melatonin (phytomelatonin) products are very rare and expensive.5
2. Current Status as a Health Supplement and Pharmaceutical
The legal status and regulation of melatonin vary significantly by country, which is important information for consumers to be aware of. The regulatory differences between South Korea and the United States are particularly stark.
United States (FDA): The U.S. Food and Drug Administration (FDA) classifies melatonin as a 'Dietary Supplement.'46 This means it does not undergo pre-market approval for safety and efficacy from the FDA, unlike pharmaceuticals. This regulatory environment leads to serious quality control issues. In fact, several studies have shown that melatonin supplements on the U.S. market have significant discrepancies between the labeled and actual content (ranging from -83% to +478%), and some have even been found to contain impurities like the drug serotonin.14 This suggests a risk of consumers unintentionally overdosing or being exposed to harmful substances.
South Korea (Ministry of Food and Drug Safety, MFDS): The South Korean Ministry of Food and Drug Safety strictly regulates melatonin as a 'pharmaceutical ingredient.'49 Therefore, melatonin cannot be used as an ingredient in health functional foods or general foods, and its importation in any form as a food, including through international direct purchase, is prohibited.49 To use melatonin in South Korea, one must obtain a doctor's prescription and purchase it as a prescription drug.51
Europe: In Europe, melatonin is approved as a prescription drug for specific indications (e.g., insomnia in people over 55) and is used under prescription.13
These regulatory differences have important implications. The lack of regulation in the U.S. exposes consumers to potential quality and safety risks, while the strict regulations in South Korea ensure quality and safety but may limit access for patients with medical needs. This clearly shows the danger of perceiving melatonin as a simple 'sleep nutrient' and indiscriminately purchasing foreign products.
Conclusion: Final Recommendations from the Botaneo Natural Ingredient Research Institute
We have explored the in-depth world of melatonin with the Botaneo Natural Ingredient Research Institute. Through this report, we have confirmed that melatonin is not just a sleep-inducing substance, but a versatile biomolecule that orchestrates the body's biological clock, protects cells through powerful antioxidant and anti-inflammatory actions, modulates the immune system, and even holds potential as an adjuvant therapy in cancer treatment.
Based on these scientific facts, our institute offers the following recommendations for the healthy use of melatonin.
First, prioritize consumption in its natural form. Melatonin is naturally present in various foods on our table, such as pistachios, tart cherries, mushrooms, and grains. Consistently consuming these foods as part of a balanced diet is the safest and wisest first step to obtaining the benefits of melatonin without the worry of side effects.
Second, the use of supplements should be decided carefully and only after consulting a professional. It is crucial to remember that melatonin products sold as dietary supplements in countries like the U.S. are strictly regulated as pharmaceuticals in South Korea. Given the research findings that foreign products may have different actual content from what is labeled or contain impurities, indiscriminate international direct purchases should be avoided. If you are considering using melatonin for sleep problems or other health reasons, you must consult a doctor or pharmacist and use a product approved as a pharmaceutical according to the correct dosage and administration.
Melatonin is a fascinating molecule that holds the key to life's fundamental rhythms and health. The Botaneo Natural Ingredient Research Institute will continue to scientifically uncover the infinite potential of nature's gifts like melatonin and deliver accurate information to you. Thank you.
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