Melatonin, a naturally occurring hormone produced by the pineal gland that regulates the sleep–wake cycle (circadian rhythm), was identified in the mid-20th century and later developed as a therapeutic agent for sleep disorders. Its clinical use expanded significantly in the 1990s after its role in circadian rhythm regulation became better understood. Melatonin, a chronobiotic agent, is primarily used to treat insomnia, jet lag, and circadian rhythm sleep–wake disorders. It acts by mimicking endogenous melatonin and signaling nighttime to the body, thereby promoting sleep initiation and regulating sleep timing. Over time, it has become widely available as both a prescription and over-the-counter supplement in many countries, with growing interest in its antioxidant and neuroprotective properties.
BRAND NAMES
Melatonex
Natrol Melatonin
MECHANISM OF ACTION
Melatonin acts by binding to specific G-protein–coupled receptors in the brain, mainly MT1 and MT2 receptors, located in the suprachiasmatic nucleus (SCN) of the hypothalamus, which is the body’s central circadian clock. Activation of MT1 receptors promotes sleepiness by inhibiting neuronal firing in wake-promoting pathways, while MT2 receptor activation helps regulate and reset circadian rhythm timing.
PHARMACOKINETICS
Absorption
Melatonin is rapidly absorbed after oral administration, with relatively high variability in bioavailability due to extensive first-pass hepatic metabolism. Peak plasma concentrations are typically reached within 30 to 60 minutes for immediate-release formulations.
Distribution
Melatonin has a relatively moderate volume of distribution, typically reported in the range of ~1 to 2 L/kg, indicating that it distributes into both plasma and body tissues.
Metabolism
Melatonin is extensively metabolized in the liver, primarily via the cytochrome P450 enzyme system, especially CYP1A2. It undergoes hydroxylation to form 6-hydroxymelatonin, which is then conjugated with sulfate or glucuronide to form water-soluble metabolites.
Elimination
Melatonin is eliminated primarily after hepatic metabolism, with its metabolites excreted mainly through the kidneys in urine. The major excreted metabolite is 6-sulfatoxymelatonin, which accounts for most of the eliminated dose.
PHARMACODYNAMICS
Melatonin exerts its pharmacological effects primarily through activation of MT1 and MT2 G-protein–coupled receptors located in the suprachiasmatic nucleus (SCN) of the hypothalamus, the central regulator of circadian rhythm. MT1 receptor activation promotes sleep initiation by inhibiting neuronal firing in wake-promoting pathways, while MT2 receptor activation helps reset and synchronize the circadian clock with the external light–dark cycle.
ADMINISTRATION
Melatonin is administered orally in immediate-release or controlled-/prolonged-release formulations, available as tablets, capsules, or liquid preparations. Immediate-release melatonin is typically taken 30–60 minutes before bedtime to aid sleep onset, while prolonged-release formulations are used for sleep maintenance throughout the night.
DOSAGE AND STRENGTH
Melatonin is available in a wide range of strengths depending on formulation and indication, commonly including 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, and 10 mg tablets or capsules. Controlled-release formulations are often available as 2 mg prolonged-release tablets (e.g., for sleep maintenance). For sleep-onset insomnia, a typical dose is 0.5–3 mg taken 30–60 minutes before bedtime.
DRUG INTERACTIONS
Melatonin can interact with several drug classes, mainly through additive sedative effects and CYP1A2-mediated metabolism. Concomitant use with central nervous system depressants such as benzodiazepines, barbiturates, opioids, antihistamines, and alcohol may increase drowsiness, sedation, and impaired psychomotor function.
FOOD INTERACTIONS
Food can influence the absorption of melatonin. High-fat meals may delay its absorption and reduce peak plasma levels, leading to a slower onset of its sleep-inducing effect. For faster and more predictable action, melatonin is often recommended to be taken on an empty stomach or at least 1–2 hours after a heavy meal.
CONTRAINDICATIONS
Melatonin is contraindicated in individuals with known hypersensitivity to melatonin or any component of the formulation. It should be used with caution or avoided in patients with autoimmune disorders due to its potential immunomodulatory effects. Caution is also advised in individuals with severe hepatic impairment, as metabolism may be reduced, leading to increased drug levels.
SIDE EFFECTS
Drowsiness or daytime sleepiness
Headache
Dizziness
Nausea
Fatigue
Vivid dreams or nightmares
Irritability
OVER DOSE
Melatonin overdose is generally not associated with severe toxicity, but excessive intake can lead to exaggerated pharmacological effects. Common symptoms include excessive drowsiness, fatigue, dizziness, headache, nausea, and confusion.
TOXICITY
Melatonin toxicity is generally low due to its short half-life and wide therapeutic margin, but excessive or prolonged use may lead to increased central nervous system effects such as excessive sedation, confusion, dizziness, and impaired alertness. High doses can also cause disturbances in circadian rhythm, leading to sleep disruption rather than improvement.
