Melatonin (DB01065): A Comprehensive Pharmacological and Clinical Monograph

Section 1: Identification and Physicochemical Profile

This section establishes the fundamental identity of melatonin, collating its various chemical identifiers and physical properties from multiple authoritative sources. This serves as the foundational data layer for the entire monograph.

1.1. Nomenclature and Chemical Identifiers

Melatonin is a well-characterized small molecule with a consistent set of identifiers across major chemical and pharmacological databases.

• Primary Name: Melatonin.[1]
• Systematic (IUPAC) Name: The formally recognized chemical name is N-[2-(5-methoxy-1H-indol-3-yl)ethyl]acetamide.[2]
• Synonyms: The compound is known by several synonyms in scientific literature and commercial products, including Melatonine, N-Acetyl-5-methoxytryptamine, 5-Methoxy-N-acetyltryptamine, and the brand name Circadin.[1]
• Chemical Identifiers: A comprehensive list of unique identifiers facilitates unambiguous cross-referencing in research and regulatory contexts.
• CAS Number: 73-31-4.[1]
• DrugBank ID: DB01065.[1]
• PubChem CID: 896.[1]
• ChEBI ID: CHEBI:16796.[1]
• ChEMBL ID: ChEMBL45.[1]
• KEGG ID: C01598.[1]
• UNII: JL5DK93RCL.[1]
• NSC Numbers: NSC-113928, NSC 56423.[1]
• InChIKey: DRLFMBDRBRZALE-UHFFFAOYSA-N.[2]
• SMILES: CC(=O)NCCC1=CNC2=C1C=C(C=C2)OC.[2]

1.2. Molecular Formula, Structure, and Weight

• Molecular Formula: The empirical formula for melatonin is C13​H16​N2​O2​.[2]
• Molecular Weight: The average molecular weight is consistently reported as approximately 232.28 g/mol.[2]
• Chemical Classification: Melatonin is an indoleamine neurohormone, structurally classified as a member of the acetamides and functionally related to tryptamine.[2] The Classyfire chemical taxonomy system further categorizes it as a 3-alkylindole, with an indole moiety carrying an alkyl chain at the 3-position. This detailed classification is critical for understanding its chemical reactivity and the structure-activity relationships of its analogues.[5]

1.3. Physical and Chemical Properties

• Physical Description: In its solid state, melatonin appears as a crystalline powder. Its color is variously described as white, pale-white, white-cream, or as pale yellow leaflets, a variation that may reflect differences in purification methods or the presence of minor impurities across different suppliers.[2]
• Melting Point: The melting point is a reliable indicator of purity and is consistently reported within the range of 116–120 °C.[2]
• Solubility: The solubility profile of melatonin is a critical determinant of its formulation and bioavailability. It is poorly soluble in water (approximately 0.1 mg/ml) and very slightly soluble in petroleum ether. Its solubility is significantly better in organic solvents such as ethanol (8–10 mg/ml) and DMSO (50 mM).[3] Crucially, its dissolution and subsequent absorption are pH-dependent. Due to its pKa, melatonin requires an acidic environment with a pH below 5.0 to be effectively ionized and absorbed.[7] This chemical property presents a major challenge for oral drug delivery, as the environment of the small and large intestines, where most drug absorption occurs, is neutral to alkaline. This limitation has been a primary driver for the development of advanced controlled-release formulations designed to overcome poor absorption in the distal gastrointestinal tract.
• Stability: Melatonin is a stable molecule under appropriate storage conditions. It has a reported stability of at least four years, with long-term preservation recommended at -20 °C.[3]

Table 1: Summary of Melatonin Identifiers and Physicochemical Properties

Property	Value	Source(s)
IUPAC Name	N-[2-(5-methoxy-1H-indol-3-yl)ethyl]acetamide	2
CAS Number	73-31-4	1
DrugBank ID	DB01065	1
Molecular Formula	C13​H16​N2​O2​	2
Molecular Weight	232.28 g/mol	2
Physical Appearance	White to pale yellow crystalline powder	2
Melting Point	116–120 °C	2
Solubility (Water)	~0.1 mg/ml	3
Solubility (Ethanol)	8–10 mg/ml	3
Stability	≥ 4 years (with proper storage)	6

Section 2: Endogenous Melatonin: Physiology and Biological Roles

This section transitions from the chemical nature of melatonin to its biological significance as an endogenous molecule, detailing its synthesis, regulation, and its multifaceted functions that extend well beyond sleep regulation.

2.1. Biosynthesis and Circadian Regulation

Melatonin is a biogenic amine synthesized in the body from the essential amino acid L-tryptophan.[5] Its primary site of production is the pineal gland, a small endocrine organ strategically located in the center of the brain but outside the blood-brain barrier, allowing it to secrete melatonin directly into the bloodstream.[2] While the pineal gland is responsible for the circulating levels of melatonin that govern systemic circadian rhythms, the hormone is also produced in numerous extra-pineal tissues, including the retina, gastrointestinal tract, skin, and bone marrow. In these peripheral sites, melatonin is believed to function primarily as a local paracrine or autocrine agent, providing on-site antioxidant protection rather than contributing significantly to systemic levels.[8]

The synthesis and secretion of pineal melatonin are under the master control of the suprachiasmatic nucleus (SCN) of the hypothalamus, the body's central circadian pacemaker. This regulation is dictated by the environmental light-dark cycle: exposure to light, detected by the retina, transmits an inhibitory signal to the SCN, which in turn suppresses melatonin production. Conversely, darkness removes this inhibition, stimulating the pineal gland to synthesize and release melatonin.[2] This tight regulation creates a robust circadian rhythm, with blood concentrations rising in the mid- to late evening, peaking in the middle of the night (typically between 2:00 and 4:00 AM), and declining to nearly undetectable levels during daytime hours.[12]

This rhythmic production profile changes throughout the human lifespan. A regular melatonin rhythm is first established in infants around the third month after birth.[1] Production levels reach their peak in early childhood (ages 1–3) and then begin a gradual decline with advancing age.[8] During adolescence, a notable phase shift occurs, delaying the onset of nocturnal melatonin secretion. This physiological shift contributes to the common adolescent tendency for later sleep and wake times, increasing the risk for delayed sleep phase disorder.[1] The age-related decline in overall melatonin production is hypothesized to be a contributing factor not only to the increased prevalence of insomnia in older adults but also to a reduced capacity for endogenous antioxidant defense, potentially linking it to the pathophysiology of various age-related diseases.[8]

2.2. The Chronobiotic Function: Regulating the Sleep-Wake Cycle

The most well-established physiological role of melatonin is as a chronobiotic agent, a substance that helps regulate and synchronize the body's internal biological rhythms.[1] It functions as the primary hormonal signal of darkness to all body tissues, chemically inducing drowsiness and promoting a decrease in core body temperature, both of which are critical physiological prerequisites for sleep onset.[2] Furthermore, circulating melatonin provides crucial feedback to the SCN itself, acting on MT1 and MT2 receptors within the nucleus to help stabilize and entrain the body's master clock to the 24-hour external day-night cycle.[15]

2.3. Pleiotropic Effects: Antioxidant and Immunomodulatory Functions

Beyond its role as a "sleep hormone," research since the 1990s has revealed that melatonin is a pleiotropic molecule with profound protective functions. This conceptual shift from a simple chronobiotic to a systemic regulator of cellular health underpins the rationale for its investigation in a wide array of pathological conditions.

Melatonin is an exceptionally potent and versatile antioxidant, a property first identified in 1993.[1] Its unique amphiphilic character, being both lipophilic and hydrophilic, grants it the ability to diffuse freely across all cellular and subcellular membranes, including the blood-brain barrier and the inner mitochondrial membrane. This allows it to exert protective effects in every compartment of the cell.[9] Its antioxidant mechanism is twofold:

1. Direct Free Radical Scavenging: As an electron-rich indoleamine, melatonin directly neutralizes a broad spectrum of damaging reactive oxygen species (ROS) and reactive nitrogen species (RNS), including the hydroxyl radical (OH∙), superoxide anion (O2−∙​), and nitric oxide (NO∙).[1] It has been reported to be twice as efficacious as vitamin E, a well-known potent antioxidant, in scavenging the highly damaging peroxyl radical.[1]
2. Indirect Antioxidant Activity: Melatonin indirectly bolsters the cell's antioxidant defenses by stimulating the genetic expression and enzymatic activity of key endogenous antioxidant enzymes, such as superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GRd), and catalase. Concurrently, it has been shown to suppress the activity of pro-oxidant enzymes.[1]

This protective capacity is particularly significant within the mitochondria. Melatonin concentrates in the mitochondrial matrix at levels far exceeding those in the plasma, placing it at the primary site of cellular ROS production.[1] This strategic localization allows it to efficiently protect mitochondrial components from oxidative damage, preserve mitochondrial integrity, and prevent the initiation of apoptosis, leading to its classification by many researchers as a "mitochondria-targeted antioxidant".[14]

Melatonin also exhibits significant immunomodulatory and anti-inflammatory properties, though the precise mechanisms are still being fully elucidated.[1] Its most prominent effect appears to be anti-inflammatory. It acts on MT1 and MT2 receptors, which are expressed on various immunocompetent cells, to modulate the production of cytokines. For instance, it has been shown to inhibit the NLRP3 inflammasome, a key component in the inflammatory response.[1] Preclinical studies also suggest it can promote the proliferation of helper T-cells, potentially mitigating certain immunodeficiencies.[1]

Section 3: Pharmacodynamics: Molecular Mechanisms of Action

Melatonin exerts its diverse physiological effects through a dual mode of action, comprising both receptor-mediated signaling pathways and receptor-independent activities as a direct chemical scavenger. This section provides a detailed molecular-level explanation of these mechanisms.

3.1. Receptor-Mediated Mechanisms: The MT1 and MT2 G-Protein Coupled Receptors

The primary hormonal and chronobiotic effects of melatonin are transduced through its binding to and activation of two high-affinity G-protein coupled receptors (GPCRs), designated MT1 (formerly Mel1a) and MT2 (formerly Mel1b).[15] A third melatonin binding site, MT3, has been identified as the enzyme quinone reductase 2. The inhibition of this enzyme by melatonin may contribute to its overall antioxidant capacity, but the MT1 and MT2 receptors are considered the principal mediators of its neuroendocrine and sleep-regulating functions.[10]

3.1.1. Receptor Distribution and Signaling Cascades

The MT1 and MT2 receptors, while sharing significant sequence homology, exhibit distinct tissue distributions and couple to different downstream signaling cascades, which underlies their specialized physiological roles.

• Distribution: MT1 receptors are highly expressed in the SCN, the pars tuberalis of the pituitary gland, the hippocampus, and the amygdala.[11] MT2 receptors are also found in the central nervous system, particularly the retina and the reticular nucleus of the thalamus, but have a broader distribution in peripheral tissues, including the lungs, heart, immune cells, and adipocytes.[5]
• MT1 Signaling: The MT1 receptor primarily couples to pertussis toxin-sensitive inhibitory G-proteins (Gi​). Its activation leads to the inhibition of the enzyme adenylyl cyclase, which in turn causes a decrease in intracellular levels of cyclic adenosine monophosphate (cAMP). This reduction in cAMP leads to decreased activity of Protein Kinase A (PKA) and reduced phosphorylation of the transcription factor CREB (cAMP response element-binding protein).[5] The MT1 receptor has also been shown to couple to Gq/11​ proteins and to increase potassium conductance through inwardly rectifying channels.[15]
• MT2 Signaling: The MT2 receptor also couples to Gi​ proteins to inhibit adenylyl cyclase and decrease cAMP formation. In addition, it distinctively inhibits the enzyme guanylyl cyclase, leading to a reduction in cyclic guanosine monophosphate (cGMP) levels. MT2 activation can also stimulate the Protein Kinase C (PKC) pathway and modulate intracellular ion flux.[5]

3.1.2. Functional Specialization and Receptor Oligomerization

A growing body of evidence from knockout mouse models and receptor localization studies indicates a functional specialization between the two receptor subtypes. MT1 receptor activation appears to be primarily responsible for the acute sleep-promoting effects of melatonin, including the inhibition of neuronal firing in the SCN and the regulation of REM sleep.[16] In contrast, MT2 receptor activation is more critically linked to the phase-shifting of the circadian clock and the promotion of non-REM (NREM) sleep.[16] This functional divergence is supported by their differential localization in brain regions associated with these sleep stages; for example, MT2 receptors are located in the NREM-associated reticular thalamus, while MT1 receptors are found in REM-associated areas like the locus coeruleus.[20] This specialization suggests that developing receptor-selective agonists could offer more targeted therapies for specific sleep pathologies than the non-selective melatonin.

Adding another layer of complexity, melatonin receptors can form protein complexes. MT1 and MT2 can form homodimers (MT1/MT1, MT2/MT2) and heterodimers (MT1/MT2) with each other, which can alter the pharmacological and signaling properties of the individual receptors.[15] Furthermore, they can form hetero-oligomers with other unrelated GPCRs, such as the serotonin 5-HT2C receptor. This interaction is particularly noteworthy; in an MT2/5-HT2C heteromer, the binding of melatonin to the MT2 receptor can cause a conformational change that

transactivates the associated 5-HT2C receptor, inducing Gq signaling—a pathway not typically engaged by MT2 alone.[20] This molecular crosstalk provides a physical basis for the interplay between the melatoninergic and serotonergic systems and helps to explain the therapeutic mechanism of the antidepressant drug agomelatine, which combines MT1/MT2 agonism with 5-HT2C antagonism.[15]

Table 2: Comparative Analysis of MT1 and MT2 Receptor Signaling Pathways

Feature	MT1 Receptor	MT2 Receptor
Primary G-Protein Coupling	Gi​ (inhibitory), Gq/11​	Gi​ (inhibitory)
Effect on Adenylyl Cyclase/cAMP	Inhibition (↓ cAMP)	Inhibition (↓ cAMP)
Effect on Guanylyl Cyclase/cGMP	No primary effect reported	Inhibition (↓ cGMP)
Effect on PLC/PKC	Can activate	Can activate (increases PKC)
Primary CNS Location	Suprachiasmatic Nucleus (SCN), Pars Tuberalis	Retina, Reticular Thalamus
Implicated Sleep Function	Sleep promotion, REM sleep regulation	NREM sleep promotion
Implicated Circadian Function	Inhibition of SCN firing, entrainment	Phase-shifting of the circadian clock

3.2. Receptor-Independent Mechanisms: A Potent Antioxidant and Free Radical Scavenger

Separate from its receptor-mediated actions, melatonin is a highly effective antioxidant that acts directly as a chemical scavenger.[1] Its electron-rich aromatic indole ring allows it to readily donate an electron to neutralize free radicals, functioning as a terminal or "suicidal" antioxidant in the process.[10]

A remarkable feature of this activity is the generation of an "antioxidant cascade." When melatonin scavenges a reactive species, the resulting metabolites—including cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), and N1-acetyl-5-methoxykynuramine (AMK)—are themselves potent free radical scavengers.[1] This cascade effect means that a single molecule of melatonin can ultimately be responsible for neutralizing multiple free radicals, making it exceptionally efficient compared to antioxidants that are consumed after a single reaction.

Additionally, melatonin has been reported to chelate transition metals like iron and copper. By binding these metals, it prevents their participation in the Fenton and Haber-Weiss reactions, which generate the extremely cytotoxic hydroxyl radical (∙OH), thereby averting one of the most damaging forms of oxidative stress.[14] This combination of direct scavenging, a cascading antioxidant effect, and metal chelation, all occurring within a molecule that preferentially accumulates at the site of highest oxidative stress (the mitochondria), explains why melatonin is regarded as an uncommonly powerful endogenous protector.[1]

Section 4: Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The clinical utility and safety profile of exogenously administered melatonin are profoundly influenced by its pharmacokinetic properties. This section analyzes the absorption, distribution, metabolism, and excretion (ADME) of melatonin, with a particular focus on the critical impact of pharmaceutical formulation and the potential for drug interactions arising from its metabolic pathway.

4.1. Absorption and Bioavailability

Following oral administration, melatonin is subject to rapid absorption but also extensive first-pass metabolism, which results in low and highly variable bioavailability.

• Absorption: Immediate-release (IR) formulations are absorbed quickly from the gastrointestinal tract. The time to reach maximum plasma concentration (Tmax​) is typically short, with a systematic review of multiple studies concluding an average Tmax​ of approximately 50 minutes, though values can range from 15 to 90 minutes depending on the dose and individual factors.[12]
• Bioavailability: The absolute oral bioavailability of melatonin is generally low and exhibits significant inter-individual variability, with reported values ranging from 9% to 33%.[21] A consensus estimate places the average bioavailability at around 15%.[21] This low value is a direct consequence of extensive presystemic (first-pass) metabolism in the liver.
• Impact of Formulation: The pharmacokinetic profile of melatonin is fundamentally mismatched for its primary use in sleep maintenance due to its short half-life. This "pharmacokinetic problem" has been the single greatest driver of innovation in melatonin delivery systems. Different formulations are designed to overcome this limitation and achieve distinct therapeutic goals:
• Immediate-Release (IR): These formulations provide a rapid peak in plasma concentration, which is suitable for addressing sleep-onset insomnia. However, due to rapid clearance, the effect is transient and often insufficient to maintain sleep throughout a typical 7- to 9-hour night.[7]
• Extended/Controlled-Release (ER/CR): Formulations such as the prescription product Circadin are engineered to release melatonin slowly over several hours. This technology aims to mimic the natural, sustained "mesa wave" profile of endogenous melatonin secretion.[7] Compared to IR formulations, ER products exhibit a delayed Tmax​ (e.g., 1.6 hours vs 0.6 hours) and a longer apparent elimination half-life (e.g., 1.6 hours vs 1.0 hour), providing more sustained plasma concentrations intended for sleep maintenance.[12]
• Novel Delivery Systems: More advanced formulations seek to optimize this profile further. "Surge-sustained" products combine an immediate-release component for rapid sleep onset with a controlled-release component for maintenance, with one study showing elevated melatonin levels for an average of 10 hours.[8] Another innovative approach involves a continuous-release and absorption (CRA) tablet that incorporates an acidic excipient. This maintains an acidic microenvironment within the tablet matrix as it transits the gastrointestinal tract, overcoming the pH-dependent solubility limitation of melatonin and allowing for continuous dissolution and absorption for up to 7 hours.[7]

4.2. Distribution

Once absorbed into the systemic circulation, melatonin is distributed widely throughout the body. Its amphiphilic nature allows it to readily cross morphophysiological barriers, including the blood-brain barrier and the placenta, gaining access to both aqueous and lipid environments.[9] It has been detected in various body fluids, including saliva, urine, cerebrospinal fluid (CSF), and amniotic fluid.[9] The apparent volume of distribution (

Vd​) is large and variable, with reported values ranging from 35 L to as high as 1602 L, indicating extensive distribution into tissues outside of the plasma compartment.[21]

4.3. Hepatic Metabolism

Melatonin is extensively and rapidly metabolized, primarily in the liver. This metabolic pathway is the "Achilles' heel" of its safety profile, as it is the source of numerous clinically significant drug interactions.

• Primary Pathway: Approximately 90% of a dose of melatonin undergoes hepatic metabolism via hydroxylation to form the principal metabolite, 6-hydroxymelatonin.[8]
• CYP450 Isozymes: This hydroxylation step is predominantly mediated by the cytochrome P450 isoenzyme CYP1A2. The isozymes CYP2C19 and, to a lesser extent, CYP2C9 also play a minor role in its metabolism.[23] The central role of CYP1A2 makes melatonin highly susceptible to interactions with other drugs or substances that inhibit or induce this enzyme.
• Conjugation and Metabolites: Following hydroxylation, 6-hydroxymelatonin is rapidly conjugated with either sulfuric acid or glucuronic acid to form water-soluble metabolites that can be readily excreted by the kidneys.[8] At least 14 distinct metabolites have been identified in animal models.[5]

4.4. Elimination

• Elimination Half-Life: Reflecting its rapid metabolism, melatonin has a short elimination half-life (t1/2​). For IR formulations, the average t1/2​ is consistently reported to be around 45 to 60 minutes.[12]
• Route of Excretion: The water-soluble conjugated metabolites of melatonin are primarily eliminated via the kidneys. Studies using radiolabeled melatonin in mice found that approximately 70% of the dose was recovered in the urine and 15% in the feces within 48 hours.[8]
• Factors Affecting Pharmacokinetics: A systematic review confirmed that the pharmacokinetics of melatonin can be significantly influenced by several factors, including age, co-administration of fluvoxamine, feeding status, and lifestyle factors such as caffeine consumption (which increases melatonin levels by inhibiting CYP1A2) and tobacco smoking (which decreases melatonin levels by inducing CYP1A2).[21]

Table 3: Pharmacokinetic Parameters of Immediate-Release vs. Extended-Release Melatonin Formulations

Pharmacokinetic Parameter	Immediate-Release (IR)	Extended-Release (ER/CR)	Source(s)
Tmax​ (Time to Peak)	15–90 min (avg. ~50 min)	1.5–2.1 hours	12
Cmax​ (Peak Concentration)	High and sharp peak	Lower and broader peak	7
t1/2​ (Elimination Half-Life)	~45–60 minutes	~1.6–2.1 hours (apparent)	8
Bioavailability	~15% (highly variable)	Similar to IR (formulation affects release, not first-pass)	21
Primary Clinical Utility	Sleep onset difficulties	Sleep maintenance difficulties	7

Section 5: Clinical Applications and Therapeutic Efficacy

This section critically evaluates the evidence supporting the use of melatonin across a spectrum of conditions. A clear hierarchy of evidence exists: its efficacy is strongest for disorders directly involving circadian rhythm disruption, becomes more controversial for general insomnia, and remains largely investigational for its many off-label applications.

5.1. Established Uses in Circadian Rhythm Sleep-Wake Disorders

Melatonin is most effective when used to correct a primary problem with the body's internal timing, reflecting its core physiological function as a chronobiotic.

• Delayed Sleep-Wake Phase Disorder (DSWPD): There is robust evidence and strong guideline support for the use of melatonin in DSWPD, a condition where an individual's sleep period is significantly delayed relative to the conventional sleep-wake cycle. The American Academy of Sleep Medicine (AASM) recommends melatonin as a treatment for adults with this disorder.[25] Clinical studies show that appropriately timed administration can advance sleep onset by approximately 34 to 40 minutes.[26] The completion of a Phase 3 clinical trial (NCT03715465) further solidifies its role in this indication.[28]
• Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD): This disorder, characterized by a circadian rhythm that is not entrained to the 24-hour day, is most common in totally blind individuals who lack the photic cues necessary to reset their internal clock. Melatonin is considered a highly effective treatment, with multiple guidelines and authorities endorsing its use to entrain the sleep-wake cycle in this population.[23]
• Jet Lag: Melatonin is widely used and supported by research for alleviating the symptoms of jet lag, particularly when traveling eastward across multiple time zones.[26] While it may not significantly shorten the time it takes to fall asleep, it has been shown to improve daytime alertness and reduce subjective feelings of fatigue.[23]
• Shift Work Disorder: The evidence for melatonin in managing sleep problems associated with shift work is more tentative. Some data suggest it may help increase total sleep time during the day for those who work at night, but its overall utility in this complex disorder is less established.[26]

5.2. Management of Primary Insomnia

The use of melatonin for primary insomnia, where there is no underlying medical or circadian cause, is one of its most common yet controversial applications. The evidence for its efficacy is modest, and clinical guidelines are conflicting.

• Efficacy: Multiple meta-analyses have concluded that melatonin has only a small effect on sleep parameters in individuals with primary insomnia. It has been shown to reduce sleep onset latency by a statistically significant but clinically modest margin of approximately 7 to 12 minutes and has a minimal effect on increasing total sleep time.[23] Its hypnotic effect is generally considered weak.[30]
• Guideline Discrepancies: This modest efficacy has led to divergent recommendations from professional bodies. The American Academy of Family Physicians (AAFP) recognizes melatonin as a first-line pharmacological therapy for insomnia, likely reflecting its widespread use and favorable short-term safety profile compared to traditional hypnotics.[25] In stark contrast, the AASM and the American College of Physicians do not recommend melatonin for the treatment of chronic insomnia, citing the low quality of evidence and poor efficacy.[26] The 2023 European Insomnia Guideline takes a more nuanced position, recommending prescription prolonged-release melatonin for short-term (up to 3 months) use in patients aged 55 or older, but specifically recommending against the use of fast-release or over-the-counter melatonin for insomnia.[27]
• Regulatory Context: This discrepancy in guidelines may be influenced by the differing regulatory status of melatonin. In the European Union, where it is a regulated prescription drug, its indication is narrow and evidence-based (prolonged-release formulation for patients >55).[27] In the United States, its availability as an unregulated supplement has led to broader use, and some guidelines may pragmatically reflect this clinical reality.

5.3. Investigational and Off-Label Uses: A Review of Emerging Evidence

The discovery of melatonin's potent antioxidant, anti-inflammatory, and neuroprotective properties has spurred a vast amount of research into its potential use for a wide range of conditions far removed from sleep.

• Neuroprotection: Melatonin is being actively investigated as a neuroprotective agent.
• Alzheimer's Disease (AD): Preclinical models show that melatonin can reduce the pathological hallmarks of AD, such as beta-amyloid (Aβ) deposition and tau hyperphosphorylation.[32] A major clinical trial (NCT00000171) was initiated to evaluate its efficacy for sleep disturbances in AD patients.[33] However, its use in this population is cautioned against by the AASM due to safety concerns in individuals with dementia.[26]
• Other Neurodegenerative Disorders: Its antioxidant and anti-inflammatory properties form the basis for its investigation in Parkinson's disease and for mitigating damage following traumatic brain injury.[9]
• Oncology: High doses of melatonin, typically used as an adjunctive therapy alongside conventional treatments like chemotherapy, have shown promise in some studies for reducing tumor size and improving survival rates.[23] Its proposed anticancer mechanisms are multifaceted, including epigenetic regulation, modulation of the immune microenvironment, and inhibition of critical cancer signaling pathways like PI3K/AKT.[11]
• Pain Syndromes and Migraine: Evidence suggests a potential role for melatonin in the prophylaxis of migraine headaches in both adults and children, and for reducing pain in conditions such as temporomandibular disorders (TMD).[23] A clinical trial investigating melatonin for chronic back pain (The MOCHA Trial, NCT06476392) is currently underway.[35]
• Psychiatric Disorders: The link between the melatoninergic system and mood is evidenced by the melatonin receptor agonist, agomelatine, which is an approved antidepressant in Europe.[15] Clinical trials have also explored melatonin's role in managing sleep and circadian disruptions associated with psychotic disorders (NCT03826563) and schizophrenia (NCT00512070).[36]
• Metabolic and Cardiovascular Health: Investigational uses include the regulation of glucose metabolism, with some studies suggesting it can suppress hepatic gluconeogenesis.[25] Completed trials have examined its effects in the context of obesity.[39] Controlled-release formulations have also been shown to lower blood pressure in some individuals with hypertension.[23]
• Pre-procedural Anxiety: Multiple studies support the use of melatonin to reduce anxiety before surgery, with evidence suggesting it may be as effective as the standard anxiolytic, midazolam.[23]

Table 4: Summary of Clinical Evidence for Key Therapeutic Indications

Indication	Level of Evidence/Guideline Support	Key Findings	Representative Source(s)
DSWPD	Strong; Recommended by AASM	Advances sleep onset by ~34-40 minutes.	25
N24SWD (in the blind)	Strong; Recommended by AASM	Effective for entraining sleep-wake cycles.	25
Jet Lag	Moderate-Strong; Widely supported	Improves daytime alertness and reduces fatigue.	26
Primary Insomnia (>55, EU)	Guideline-supported (EU); Approved	Prolonged-release form improves sleep quality.	27
Primary Insomnia (General, US)	Controversial; Not recommended by AASM	Modest effect on sleep latency (~7-12 min).	23
Pre-Surgical Anxiety	Moderate; Strong evidence from review	Reduces pre-operative anxiety; may be as effective as midazolam.	26
Migraine Prophylaxis	Moderate; Possibly effective	Can prevent migraines in adults and children.	23
Neurodegenerative Disease	Investigational; Preclinical evidence	Reduces pathological markers in animal models of AD/PD.	32
Cancer (Adjunctive)	Investigational; Preliminary evidence	May reduce tumor size and improve survival rates.	23

Section 6: Safety Profile, Adverse Effects, and Drug Interactions

While often perceived as a benign natural supplement, melatonin is a potent neurohormone with a distinct side effect profile and a wide range of clinically significant interactions. The statement "melatonin is safe" is a significant oversimplification that fails to account for risks in specific populations and those on concomitant medications.

6.1. Common and Serious Adverse Reactions

• General Safety Profile: Melatonin is generally considered safe for short-term use in healthy adults.[23] Unlike many prescription hypnotics, it is not associated with dependence, tolerance (loss of response after repeated use), or a significant "hangover" effect.[40]
• Common Side Effects: The most frequently reported adverse effects are generally mild and transient. They include headache, dizziness, nausea, and daytime drowsiness or sleepiness.[23]
• Other Reported Side Effects: A range of other less common side effects have been noted, including vivid dreams or nightmares, stomach cramps, irritability, short-term feelings of depression, and confusion or disorientation.[40]
• Serious (Rare) Adverse Reactions: Although rare, serious adverse events can occur.
• Hypersensitivity Reactions: Rare cases of serious allergic reactions, including anaphylaxis and angioedema involving the tongue or glottis, have been reported. Such reactions can be life-threatening and require immediate medical intervention.[43]
• Neuropsychiatric Effects: In line with warnings for other hypnotic agents, melatonin receptor agonists have been associated with worsening of depression, including suicidal ideation. The emergence of abnormal thinking, behavioral changes, and complex sleep behaviors like "sleep-driving" (driving while not fully awake) have also been reported.[23]
• Other Serious Effects: Rare reports include changes to eyesight (blurred vision), fainting (syncope), and vertigo, all of which warrant immediate medical consultation.[43]

6.2. Contraindications and High-Risk Populations

The use of melatonin is contraindicated or requires significant caution in several specific populations due to potential risks.

• Pregnancy and Breastfeeding: Melatonin is considered possibly unsafe. Due to its hormonal nature, there are concerns it could interfere with conception by having effects similar to birth control. There is insufficient data on its safety during pregnancy and lactation, and therefore its use should be avoided.[23]
• Autoimmune Conditions: Individuals with autoimmune diseases such as rheumatoid arthritis or lupus should use melatonin with caution, as it can stimulate immune system activity, potentially exacerbating the condition.[23]
• Bleeding Disorders: Melatonin may inhibit platelet aggregation and slow blood clotting, which could increase the risk of bleeding in individuals with pre-existing bleeding disorders.[23]
• Depression: While the agonist agomelatine is an antidepressant, melatonin itself may worsen symptoms of depression in some individuals.[23]
• Seizure Disorders: There is a concern that melatonin may lower the seizure threshold, potentially increasing the risk of seizures in susceptible individuals.[23]
• Dementia: The AASM explicitly recommends against the use of melatonin in people with dementia due to safety concerns and lack of proven benefit.[26]
• Hepatic and Renal Impairment: Patients with significant liver or kidney problems should use melatonin with caution, as their ability to metabolize and clear the drug may be compromised, leading to higher exposure and increased risk of side effects.[25]
• Transplant Recipients: Melatonin's immune-stimulating properties may counteract the effects of immunosuppressant medications used to prevent organ rejection.[23]

6.3. Clinically Significant Drug and Food Interactions

Melatonin is subject to numerous drug and food interactions, primarily arising from its metabolism via CYP1A2 and its own pharmacodynamic effects.

• Pharmacokinetic Interactions (Metabolism-Based):
• CYP1A2 Inhibitors (Increase Melatonin Levels):
• Fluvoxamine (Luvox): This potent CYP1A2 inhibitor dramatically increases melatonin exposure. Co-administration has been shown to increase melatonin's area-under-the-curve (AUC) by 17-fold and its peak concentration (Cmax​) by 12-fold, a clinically critical interaction that significantly elevates the risk of adverse effects.[23]
• Caffeine: A common dietary substance and moderate CYP1A2 inhibitor. Co-administration of 200 mg of caffeine (equivalent to a large cup of coffee) can more than double the AUC and Cmax​ of melatonin.[47]
• Oral Contraceptives: Products containing ethinyl estradiol can inhibit CYP1A2, leading to a 4- to 5-fold increase in melatonin concentrations.[24]
• CYP1A2 Inducers (Decrease Melatonin Levels):
• Tobacco Smoking: The hydrocarbons in tobacco smoke are potent inducers of CYP1A2. Smoking significantly accelerates the metabolism of melatonin, reducing its blood levels and potentially rendering a standard dose ineffective.[47]
• Pharmacodynamic Interactions (Additive or Antagonistic Effects):
• CNS Depressants: Co-administration with other central nervous system depressants, including alcohol, benzodiazepines, barbiturates, and opioids, can lead to additive sedative effects, resulting in excessive drowsiness and impairment. Alcohol consumption should be avoided.[50]
• Anticoagulant/Antiplatelet Drugs: Melatonin may have its own antiplatelet effects. When taken with drugs like warfarin, aspirin, or clopidogrel, there is a theoretical increased risk of bruising and bleeding.[23]
• Antihypertensive Drugs: The interaction with blood pressure medications is complex and appears contradictory. While there is a general warning for additive hypotensive effects (risk of blood pressure going too low) [23], there is also specific evidence that melatonin can antagonize and decrease the effectiveness of the calcium channel blocker nifedipine, potentially leading to a loss of blood pressure control.[50] This highlights a critical ambiguity that requires careful patient monitoring.
• Antidiabetic Drugs: Melatonin may lower blood glucose levels, which could increase the risk of hypoglycemia when taken with insulin or oral antidiabetic agents.[23]
• Anticonvulsants: By potentially lowering the seizure threshold, melatonin may decrease the efficacy of medications used to prevent seizures.[23]

Table 5: Clinically Significant Pharmacokinetic and Pharmacodynamic Interactions

Interacting Agent/Class	Mechanism of Interaction	Clinical Consequence	Management Recommendation	Source(s)
Fluvoxamine (Luvox)	Potent CYP1A2 Inhibition	Dramatically increased melatonin levels (17x AUC) and risk of toxicity.	Avoid combination.	23
Caffeine	Moderate CYP1A2 Inhibition	Increased melatonin levels (~2x AUC) and potential for side effects.	Monitor for increased drowsiness; consider dose adjustment.	47
Tobacco Smoking	CYP1A2 Induction	Decreased melatonin levels and potential loss of efficacy.	Dose may need to be increased in smokers.	47
CNS Depressants (Alcohol, etc.)	Pharmacodynamic (Additive Sedation)	Excessive drowsiness, impairment, respiratory depression.	Avoid concomitant use, especially alcohol.	50
Anticoagulants (Warfarin, etc.)	Pharmacodynamic (Antiplatelet Effect)	Potential for increased risk of bleeding.	Use with caution; monitor for signs of bleeding.	23
Nifedipine	Pharmacodynamic (Antagonism)	Decreased antihypertensive effect of nifedipine.	Monitor blood pressure closely; may require alternative sleep aid.	50
Antidiabetic Drugs	Pharmacodynamic (Hypoglycemia)	Potential for additive blood sugar lowering effects.	Monitor blood glucose closely.	23
Anticonvulsants	Pharmacodynamic (Lowers Seizure Threshold)	Potential to decrease efficacy of anticonvulsant medication.	Avoid use in patients with seizure disorders.	23
Immunosuppressants	Pharmacodynamic (Immune Stimulation)	Potential to antagonize the effects of immunosuppressive therapy.	Avoid use in transplant recipients.	23

Section 7: Use in Special Populations: Pediatrics and Geriatrics

The use of melatonin at the extremes of the age spectrum requires special consideration due to unique physiological characteristics, differing risk-benefit profiles, and a general lack of long-term safety data.

7.1. Pediatric Use: Efficacy, Dosing, and Long-Term Safety Considerations

The use of melatonin in children represents a significant public health paradox: a hormonally active substance with unknown long-term developmental effects is being used with increasing frequency, a trend driven by its availability as an unregulated supplement and the high prevalence of sleep problems, particularly in children with neurodevelopmental disorders.

• Efficacy and Off-Label Use: Melatonin is widely used off-label for sleep difficulties in children, especially those with conditions like Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD), where sleep-onset insomnia is a common and challenging comorbidity.[41] Clinical studies, though often small, have shown that melatonin can be effective in this population, reducing the time it takes to fall asleep by approximately 20 minutes and increasing total sleep duration.[26]
• Dosing: Dosing in children must be approached with caution and always under the supervision of a pediatrician. The principle is to start with the lowest possible dose (e.g., 0.5 mg to 1 mg) and titrate upwards only if necessary. General ranges cited in literature are 1–3 mg for school-aged children and up to 5–10 mg for adolescents, but these are not official recommendations.[52]
• Major Safety Concerns:

1. Unknown Long-Term Effects: The most significant concern is the profound lack of data on the long-term safety of melatonin use in children.[41]
2. Hormonal Interference: As a hormone that plays a role in the reproductive axis, there is a theoretical concern that exogenous melatonin administration could interfere with the timing of puberty and other aspects of hormonal development. While animal studies have shown antigonadal effects, such effects have not been conclusively demonstrated in human trials. Nevertheless, given this potential risk, experts advise extreme caution.[26]
3. Overdose Risk and Product Quality: The unregulated nature of melatonin supplements in the U.S. poses a direct risk to children. The availability of palatable, flavored gummy formulations, often in containers without child-resistant caps, has been linked to a dramatic 530% increase in calls to poison control centers for pediatric melatonin ingestions between 2012 and 2021.[41] While most cases are not life-threatening, some have required hospitalization, and fatalities have been reported.[57]

• Professional Guidance: Major pediatric bodies, such as the American Academy of Pediatrics, strongly urge parents to consult a physician before giving melatonin to a child. They emphasize that behavioral interventions (e.g., establishing good sleep hygiene) should always be the first-line approach, and melatonin should be considered a short-term tool for specific problems, not a routine sleep solution.[52] In countries like the UK, melatonin use in children is restricted and requires a specialist recommendation.[46]

7.2. Geriatric Use: Pharmacokinetic Alterations and Clinical Guidelines

For the geriatric population, melatonin presents as a double-edged sword. Older adults are a logical target population due to the natural age-related decline in endogenous melatonin production, yet they are simultaneously the population most vulnerable to its key adverse effects due to age-related changes in pharmacokinetics and a higher prevalence of comorbidities.

• Rationale and Efficacy: The decline in nocturnal melatonin secretion with age is thought to contribute to the high incidence of insomnia in the elderly.[1] This provides a clear "replacement therapy" rationale for its use. In the EU, a 2 mg prolonged-release formulation (Circadin) is specifically approved for the short-term treatment of primary insomnia in adults aged 55 and over, with studies showing modest improvements in sleep latency and subjective sleep quality.[31]
• Pharmacokinetic Considerations: The metabolism and clearance of melatonin may be slower in older adults. This can lead to a longer apparent half-life, meaning the drug may remain active in their system for a longer period. This increases the risk of carryover effects, such as next-day drowsiness, which can impair cognitive function and increase the risk of falls.[8]
• Safety and Contraindications: The risk of common side effects like dizziness and confusion is heightened in the elderly and can have more severe consequences, such as falls.[40] A critical safety warning comes from the AASM, which specifically recommends against the use of melatonin in people with dementia, a condition highly prevalent in the geriatric population.[26] Furthermore, caution is required in those with hepatic or renal impairment, which are more common with age.[46] The decision to use melatonin in an older adult therefore requires a careful and individualized risk-benefit analysis, weighing the modest potential sleep benefits against significant safety concerns.

Section 8: Global Regulatory Landscape: A Tale of Two Systems

The global regulatory status of melatonin is sharply divided, creating a "tale of two systems" that profoundly impacts public health, product quality, and clinical practice. This dichotomy—its classification as a tightly controlled prescription medicine in the European Union and other regions versus its status as a largely unregulated dietary supplement in the United States—is arguably the most critical factor explaining the controversies surrounding its use.

8.1. The United States: An Unregulated Dietary Supplement

In the United States, melatonin is regulated under the Dietary Supplement Health and Education Act of 1994 (DSHEA).[26] This framework classifies it as a dietary supplement, not a drug.

• Regulatory Status: The U.S. Food and Drug Administration (FDA) has not approved melatonin for any medical use and does not subject it to the same rigorous standards of safety, efficacy, and manufacturing quality as prescription or over-the-counter drugs.[25] While the FDA regulates the supplement industry through mechanisms like facility inspections and compliance with Good Manufacturing Practices (GMPs), the system is fundamentally less stringent than for pharmaceuticals.[60] Notably, the FDA has determined that melatonin is not Generally Recognized as Safe (GRAS) for use as an additive in conventional foods and has issued warning letters to companies marketing melatonin-laced products like brownies and beverages.[61]
• Consequences of Lack of Regulation: This regulatory gap has created a "Wild West" market with documented public health risks:

1. Dosage Inaccuracy: There is no federal mandate for companies to verify that the amount of melatonin in a product matches the label claim. A landmark 2017 study published in the Journal of Clinical Sleep Medicine found that the actual melatonin content in 31 commercially available supplements ranged from 83% less to 478% more than the labeled amount.[26] This extreme variability makes consistent and safe dosing impossible for consumers and clinicians.
2. Purity and Contamination: The same study found that over a quarter (26%) of the tested supplements were contaminated with serotonin, a potent neurotransmitter and prescription drug. The presence of such undeclared active substances can lead to unexpected and potentially serious drug interactions and adverse effects.[26]

• Industry Response: In an implicit acknowledgment of this regulatory failure, industry trade groups like the Council for Responsible Nutrition (CRN) have established voluntary guidelines for their members. These guidelines recommend a maximum serving size of 10 mg per day, specific label advisories, and the use of child-deterrent packaging for flavored, chewable forms.[64] However, the voluntary nature of these recommendations means they are not universally adopted and are not a substitute for mandatory federal oversight.

8.2. The European Union and Other Regions: A Prescription Medication

In stark contrast to the U.S., melatonin is classified as a prescription-only medicine (POM) in the European Union, the United Kingdom, Australia, and many other nations.[27]

• Regulatory Status: As a medicinal product, melatonin is subject to rigorous oversight by national and regional health authorities, such as the European Medicines Agency (EMA) and the UK's Medicines and Healthcare products Regulatory Agency (MHRA).[31] This process requires manufacturers to submit comprehensive data on quality, safety, and efficacy from clinical trials to gain marketing authorization.
• Approved Products and Indications: This stringent process has resulted in narrow, evidence-based indications.
• Circadin and Melatonin Neurim: These are brands of a 2 mg prolonged-release melatonin formulation that received marketing authorization from the EMA in 2007. They are approved for the short-term (up to 13 weeks) treatment of primary insomnia in patients aged 55 years and over.[27]
• Slenyto: A pediatric formulation of melatonin is also available by prescription in Europe for the treatment of insomnia in children and adolescents with certain neurodevelopmental disorders.[43]
• Implications of Regulation: This system ensures that when a patient in Europe receives a prescription for melatonin, the product has a verified dose, is free from contaminants, and is being used for an indication for which there is a demonstrated, albeit modest, benefit.

Table 6: Comparative Overview of Melatonin's Regulatory Status in the US and EU

Regulatory Aspect	United States	European Union
Classification	Dietary Supplement	Prescription-Only Medicine (POM)
Regulatory Body	FDA (under DSHEA)	EMA and National Agencies
Approval for Medical Use	No; not approved for any indication.	Yes; for specific indications.
Quality/Purity Control	Limited; no federal requirement to test for purity or contaminants.	Rigorous; required for marketing authorization.
Dosage Accuracy	Not guaranteed; wide variations found in commercial products.	Guaranteed; must meet pharmaceutical standards.
Availability	Over-the-counter (OTC)	Prescription only.
Approved Indications	None (marketed for sleep support, jet lag, etc.)	Primary insomnia (in patients >55); some pediatric insomnia.

Section 9: Conclusion and Future Directions

9.1. Synthesis of Melatonin's Role in Medicine

Melatonin has emerged from its initial identity as a simple "sleep hormone" to be recognized as a truly pleiotropic molecule with profound and diverse physiological roles. Its function as a master chronobiotic, signaling darkness to the body and entraining circadian rhythms, is well-established and forms the basis of its most effective clinical applications. Concurrently, its powerful, multi-mechanistic antioxidant and anti-inflammatory properties, particularly its role as a mitochondria-targeted protector, have opened a vast frontier of therapeutic investigation.

This dual identity is reflected in the hierarchy of clinical evidence for its use. Its utility is strongest and best supported by clinical guidelines for correcting frank circadian rhythm disorders, such as DSWPD and N24SWD in the blind. Its efficacy for general primary insomnia is modest and highly controversial, with conflicting recommendations from major professional bodies. For its myriad investigational uses in neurodegeneration, cancer, and pain, the evidence remains largely preclinical or preliminary, though promising.

The therapeutic potential of melatonin is significantly modulated by two critical factors. First, its challenging pharmacokinetics—specifically its short elimination half-life and extensive first-pass metabolism—necessitate advanced drug delivery technologies to achieve a clinically useful profile for sleep maintenance. Second, and most critically, its clinical application and public safety are profoundly impacted by a stark global regulatory dichotomy. The system in the United States, which treats melatonin as an unregulated dietary supplement, has led to a marketplace fraught with issues of dosage inaccuracy and contamination, posing tangible risks to consumers. This stands in sharp contrast to the European model, where its classification as a prescription medicine ensures product quality and restricts its use to evidence-based indications.

9.2. Unanswered Questions and Avenues for Future Research

To resolve the existing controversies and fully realize the therapeutic potential of melatonin, several key areas of research must be prioritized.

• Long-Term Safety Studies: The most pressing need is for well-designed, long-term, prospective safety studies, particularly in pediatric populations. The widespread off-label use in children, coupled with legitimate concerns about potential interference with hormonal development, makes this an urgent public health priority.[56]
• Rigorous Clinical Trials for Off-Label Uses: The promising preclinical data for melatonin in neuroprotection, adjunctive cancer therapy, and inflammatory conditions must be translated into robust, large-scale, placebo-controlled clinical trials. Such studies are essential to move these applications from the realm of speculation to that of evidence-based medicine.[14]
• Drug Delivery Innovation: Continued research and development of novel drug delivery systems are crucial. Formulations that can more precisely and reliably mimic the endogenous nocturnal profile of melatonin secretion hold the potential to significantly improve its efficacy for sleep maintenance disorders.[7]
• Development of Receptor-Selective Agonists: Given the functional specialization of the MT1 and MT2 receptors, the development of receptor-selective agonists represents a logical and promising path forward. Such compounds could offer more targeted therapies with improved efficacy and potentially fewer side effects for specific sleep architecture disturbances, circadian disorders, and mood disorders.[15]
• Call for Regulatory Re-evaluation: There is a compelling case for regulatory bodies, particularly the U.S. FDA, to re-evaluate the regulatory status of melatonin. Classifying melatonin as a drug, or at a minimum, enforcing stricter quality control standards for supplements, would be a critical step toward protecting public safety by ensuring that consumers have access to products with accurate dosages and verified purity.[63] This regulatory harmonization would help bridge the current gap between its scientific potential and its safe clinical use.

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