Melatonin

Introduction Overview

Generic Name

melatonin

Brand Name

Various OTC brands (e.g., Natrol, Nature Made, Sundown Naturals)

Dosage Form

Oral tablets, capsules, liquid drops, chewable gummies, fast-dissolve tablets, time-release formulations

Drug Class

Minerals and electrolytes
Miscellaneous anxiolytics, sedatives and hypnotics
Nutraceutical products

Pharmacokinetics

Absorption:
Melatonin, when administered orally as a dietary supplement, exhibits rapid absorption from the gastrointestinal tract. Peak plasma concentrations are generally achieved within 20 to 60 minutes post-administration. Its bioavailability is subject to significant first-pass hepatic metabolism, which leads to variability among individuals. The immediate-release formulations lead to a quick increase in plasma melatonin levels, closely mimicking physiological night-time peaks. Conversely, time-release formulations aim to sustain plasma concentrations over several hours but may have lower peak concentrations. Factors influencing absorption include the formulation type (liquid, tablet, capsule), the presence of food (which may delay absorption), and the metabolic activity of the liver.

Distribution:
After absorption, melatonin is widely distributed throughout the body, crossing the blood-brain barrier and readily penetrating cerebrospinal fluid. Its lipophilic nature facilitates distribution into both central nervous system tissues and peripheral organs. Melatonin binds moderately to plasma proteins, primarily albumin, which influences free drug concentrations. It achieves peak levels in the brain, acting on melatonin receptors in the suprachiasmatic nucleus and other sleep-regulating brain areas. Distribution may be influenced by age, with older adults exhibiting lower endogenous production and possibly altered tissue uptake.

Metabolism:
Melatonin undergoes extensive hepatic metabolism primarily via cytochrome P450 enzymes, especially CYP1A2 and CYP2C19. It is converted primarily to 6-hydroxymelatonin and then conjugated to 6-sulfatoxymelatonin, which is excreted in urine. Genetic polymorphisms of CYP enzymes, concurrent medications, and lifestyle factors such as smoking can influence metabolic rate. Melatonin also displays non-hepatic metabolism pathways, although these are less significant. The short half-life (~30 to 60 minutes) is attributable to its rapid metabolism.

Elimination:
Elimination occurs mainly via renal excretion of the sulfate and glucuronide conjugates of melatonin metabolites. Urinary 6-sulfatoxymelatonin levels serve as a biomarker for endogenous melatonin production. The plasma half-life generally ranges from 30 to 50 minutes in healthy adults. Renal impairment has minimal impact on melatonin elimination due to low unchanged renal excretion. The pharmacokinetics may be altered in specific populations, such as older adults or those with liver dysfunction, potentially prolonging elimination times and enhancing effects or side effects.

Dosage Forms

Available Dosage Forms:
Melatonin supplements are commercially available in multiple oral formulations to accommodate various patient preferences and dosing regimens. These include:
- Oral immediate-release tablets (commonly 1 mg, 3 mg, 5 mg, up to 10 mg)
- Oral capsules (both immediate and time-release)
- Liquid drops with concentrations such as 1 mg/mL
- Chewable gummies, often available in 1 mg, 3 mg, or 5 mg doses marketed for both adults and children
- Fast-dissolving tablets designed for rapid absorption before bedtime
- Time-release formulations aiming at sustained melatonin plasma levels overnight

Dosages for Adults and Adolescents:
Dosing varies widely depending on the indication and patient sensitivity. Typical adult doses range from 0.5 mg to 5 mg taken orally about 30 minutes before bedtime. For jet lag, doses between 0.5 mg and 5 mg have shown efficacy, with some clinical evidence suggesting lower doses (0.5 to 1 mg) are nearly as effective as higher doses (5 mg) but with fewer side effects. For insomnia, doses commonly start at 0.5 mg and may be titrated up to 3-5 mg as needed, emphasizing the lowest effective dose. Shift work sleep disorder dosing typically is 1 mg to 3 mg administered 30 minutes before daytime sleep after night shifts. Delayed sleep-wake phase disorder dosing in adults ranges from 3 mg to 5 mg taken early evening, at least 1.5 hours before desired bedtime.

Specific Patient Populations:
Children and Adolescents: Dosing is more cautious due to limited long-term safety data. For pediatric delayed sleep-wake phase disorder, doses around 0.15 mg/kg administered 1.5 to 2 hours before bedtime have been recommended under medical supervision. Melatonin use in children with ADHD or autism spectrum disorder ranges from 3 mg to 5 mg short-term but should be guided by a healthcare provider. Older Adults: May have lower endogenous melatonin production and increased sensitivity; lower starting doses (e.g., 0.5 mg) are often recommended to minimize sedation or next-day drowsiness. Pregnant or Nursing Women: Safety data are limited; use is not generally recommended without medical consultation.

Clinically, the lowest effective dose is favored to minimize side effects such as daytime drowsiness, vivid dreams, or headache. Timed-release formulations should not be split, and caution is advised when using alcohol or medications with sedative effects concurrently.

Mechanism Of Action

Melatonin functions primarily as a hormone that regulates the sleep-wake cycle, also called the circadian rhythm, by acting on melatonin receptors located in various tissues throughout the body. The pineal gland endogenously synthesizes melatonin from serotonin in response to darkness, providing a biochemical signal to the suprachiasmatic nucleus (SCN) of the hypothalamus, the body's central circadian pacemaker.

At the molecular level, melatonin binds to high-affinity G protein-coupled receptors, primarily MT1 and MT2, which are abundant in the SCN and other brain areas involved in sleep regulation. Activation of MT1 receptors generally inhibits neuronal firing and promotes the onset of sleep, whereas MT2 receptors primarily contribute to phase shifting the circadian clock, enabling synchronization of biological rhythms to environmental light-dark cycles. This dual receptor activity underlies melatonin's ability to both promote sleep initiation and adjust circadian timing.

Additionally, melatonin exhibits antioxidant properties, reducing oxidative stress by scavenging free radicals and upregulating antioxidant enzymes. While this action is less relevant to sleep promotion, it suggests potential pleiotropic effects that may contribute to its investigational use in neurodegenerative diseases and aging.

Clinically, melatonin taken exogenously supplements endogenous hormone levels to facilitate sleep onset, especially in disorders characterized by impaired circadian signaling or delayed melatonin secretion, such as delayed sleep-wake phase disorder and non-24-hour sleep-wake disorder. Unlike traditional hypnotics that depress the central nervous system, melatonin's receptor-mediated effects align with physiological sleep mechanisms, offering a favorable side effect profile. Compared to prescription melatonin receptor agonists like ramelteon, dietary melatonin shows similar receptor affinity but a shorter half-life and variable pharmacokinetics, influencing dosing strategies. Research supports melatonin’s efficacy for jet lag and certain circadian rhythm disorders, although its effects on sleep maintenance and chronic insomnia remain less conclusive.

Pharmacological Actions

Regulation of circadian rhythms via MT1 and MT2 receptor activation in the suprachiasmatic nucleus
Promotion of sleep onset and reduction of sleep latency
Phase-shifting of the biological clock to synchronize internal rhythms with environmental light-dark cycles
Antioxidant activity through direct free radical scavenging and enhancement of antioxidant enzymes
Modulation of immune responses and potential anti-inflammatory effects
Influence on hormonal secretions including inhibition of gonadotropin-releasing hormone at high doses
Mild anxiolytic and sedative effects contributing to sleep facilitation
Neuroprotective properties suggested in experimental models of neurodegeneration
No significant respiratory depression or dependence associated with use
Minimal sedative hangover when used at appropriate doses

Therapeutic Or Clinical Uses

Treatment of jet lag to alleviate symptoms and expedite circadian adjustment
Short-term management of insomnia characterized by difficulty initiating sleep
Management of shift-work sleep disorder to improve daytime sleep quality
Treatment of delayed sleep-wake phase disorder, particularly in adolescents and young adults
Supportive therapy for non-24-hour sleep-wake disorder, especially in totally blind individuals
Adjunctive treatment in REM sleep behavior disorder
Investigational use for conditions including cancer adjunct therapy, heart failure symptom relief, IBS, fibromyalgia, bipolar disorder, migraine prophylaxis, COVID-19 supportive care, Alzheimer's disease, autism spectrum disorder, ADHD, seasonal affective disorder, Parkinson's disease, and preoperative anxiety
Potential to improve sleep quality in elderly patients with reduced endogenous melatonin production
Supplement to behavioral sleep interventions for various circadian rhythm sleep disorders
Use in pediatric sleep initiation difficulties under medical supervision

Side Or Adverse Effects

Daytime drowsiness and fatigue
Dizziness and weakness
Headache
Vivid dreams or nightmares
Nausea, gastrointestinal discomfort including diarrhea and stomach pain
Mood changes such as irritability, anxiety, or feelings of depression
Confusion or impaired cognitive function in sensitive individuals
Blood pressure fluctuations, either elevated or reduced
Joint or back pain
Elevated risk for seizures in predisposed patients
Potential hormonal effects including altered prolactin secretion
Bedwetting or increased urination in children
Agitation or restlessness
Possible rebound insomnia upon abrupt discontinuation of higher doses or prolonged use
Rare allergic reactions in susceptible individuals

Precautions

Use cautiously in individuals with diabetes or impaired glucose metabolism due to potential impact on blood sugar control
Avoid use or use with caution in patients with depression or mood disorders
Caution in patients with bleeding or clotting disorders and those on anticoagulant therapy like warfarin due to enhanced bleeding risk
Monitor blood pressure as melatonin can affect cardiovascular parameters
Avoid in patients with seizure disorders unless supervised by a healthcare provider
Use cautiously in elderly patients who may be more sensitive to sedative effects and risk of falls
Not recommended during pregnancy or breastfeeding without medical advice due to insufficient safety data
Avoid concurrent use with sedatives or tranquilizers unless advised by a doctor
Ensure accurate dosing in children to minimize risk of overdose or side effects
Avoid use in patients undergoing organ transplant or on immunosuppressive therapies without physician approval
Discontinue use if allergic reactions occur
Consider potential interactions with other CNS depressants
Avoid use in children without pediatrician consultation
Avoid alcohol and other CNS depressants concurrently
Adhere to recommended dosing to avoid hormonal disturbances

Warnings

Not approved by the FDA for therapeutic uses; sold as a dietary supplement without rigorous regulation
Potential for next-day drowsiness or impaired alertness; avoid driving or hazardous tasks until effects are known
Risk of inaccurate labeling and variable melatonin content in over-the-counter products; prefer USP-verified brands
High doses (>5 mg) not shown to offer improved efficacy and may increase the incidence of side effects
Use in children carries risks of overdose and unknown long-term hormonal effects; use under medical supervision only
Overdose reports have risen, particularly in children who accidentally ingest melatonin; keep supplements out of reach
Avoid use with alcohol, caffeine, and tobacco as they may interfere with melatonin’s effectiveness
Possible interaction with warfarin that can increase bleeding risk; consult healthcare provider before use
Use caution when combined with medications that cause drowsiness or dizziness
Avoid melatonin use if allergic to melatonin or formulation components
Sudden discontinuation after prolonged use at high doses may result in rebound insomnia
Limited safety data in pregnancy and breastfeeding; use only if clearly needed and prescribed
Blue light exposure at night can counteract melatonin’s endogenous and exogenous effects
May alter reproductive hormones at very high doses, affecting fertility and menstrual cycles
Potential for impaired physical or mental performance howsoever mild in sensitive individuals

Contraindication

Known hypersensitivity or allergy to melatonin or any ingredient in the formulation
Use in patients with uncontrolled epilepsy or seizure disorders unless directed and supervised by a physician
Concurrent use in patients on warfarin or other anticoagulants without medical supervision due to risk of bleeding
Use in pregnant or breastfeeding women without medical advice due to unknown safety
Avoid use in children younger than 3 years old except under pediatric specialist direction
Use contraindicated during use of immune suppressants or in organ transplant patients without physician approval
Known severe hepatic impairment due to altered metabolism and clearance
Use in patients with autoimmune disorders may require caution
Contraindicated concomitantly with medications known to adversely interact or potentiate sedation without monitoring
Not to be used as a replacement therapy for serious underlying sleep disorders diagnosed by a healthcare provider

Drug Interactions

Warfarin: Melatonin may increase anticoagulant effect and bleeding risk
Alcohol: Enhances CNS depression, may increase drowsiness and impair coordination
Caffeine: May interfere with melatonin’s efficacy and increase unexpected drowsiness via enzyme interactions
Tobacco: Can alter melatonin metabolism and reduce effectiveness
Diazepam and other benzodiazepines: Additive sedative effects may occur
Gabapentin: Combined CNS depressant effects may enhance drowsiness
Codeine: Potential additive sedation and respiratory depression
Aripiprazole: Possible pharmacodynamic interactions affecting sedation and metabolism
Ketamine: Unknown interaction but may alter sedation levels
Trazodone: Combined sedative effects may potentiate drowsiness
Echinacea: Potential metabolic interactions via cytochrome P450 enzymes
Sedatives and tranquilizers: Additive sedation and respiratory depression risks
Medications affecting CYP1A2 enzyme (e.g., fluvoxamine) may alter melatonin metabolism
Medications altering hepatic enzyme activity may affect melatonin levels and effects
Medications causing drowsiness or impaired cognition when combined with melatonin increase fall or accident risk

Preparations Of The Drug

Immediate-release oral tablets typically in strengths of 1 mg, 3 mg, 5 mg, and 10 mg
Timed-release (extended-release) oral tablets designed for sustained melatonin delivery overnight
Oral capsules containing powdered melatonin in various doses, immediate or timed-release
Liquid drop formulations for flexible dosing, commonly 1 mg/mL concentration
Chewable gummy tablets with flavored formulations in 1 mg to 5 mg doses, often marketed for children or adults
Fast-dissolve or orally disintegrating tablets for rapid absorption and convenience
Natural melatonin products derived from animal pineal glands exist but are not recommended due to contamination risks; synthetic laboratory-made melatonin preferred
USP-verified preparation options provide assurance of purity and dose accuracy
Formulations formulated specifically for pediatric use with lower doses and flavor masking
Combination products including melatonin with other herbal ingredients occasionally available but require caution
Packaging designed to maintain stability and protect from moisture and light; store in cool dry place
Over-the-counter availability varies by region; in the U.S., no prescription required but products vary widely in quality
Formulations may be marketed with sleep hygiene guidance and dosing instructions emphasizing low starting doses