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Sunday, August 17, 2025

Melatonin


Overview

Melatonin is an endogenous indoleamine hormone produced by the pineal gland in response to darkness. It plays a central role in regulating the circadian rhythm, sleep–wake cycle, seasonal rhythms, and other physiological processes. Synthetic melatonin is widely available as an over-the-counter supplement in many countries, though in others it is classified as a prescription-only medicine.

Therapeutically, melatonin is used to treat insomnia, circadian rhythm sleep disorders, jet lag, and sleep disturbances in neurological conditions such as autism spectrum disorder and attention-deficit/hyperactivity disorder (ADHD). It has also been studied in other conditions, including anxiety, cancer adjuvant therapy, and migraine prophylaxis, though evidence is mixed.

Pharmacological Class and Formulations

  • Class: Neurohormone; chronobiotic and hypnotic agent

  • ATC Code: N05CH01

  • Formulations:

    • Immediate-release tablets/capsules (0.5 mg, 1 mg, 3 mg, 5 mg, 10 mg)

    • Prolonged-release tablets (2 mg, 5 mg)

    • Oral solutions (liquid, drops)

    • Sublingual tablets, gummies, sprays (varies by region and regulation)

Mechanism of Action

  • Receptors: Melatonin acts on MT1 and MT2 G-protein coupled receptors in the suprachiasmatic nucleus (SCN) of the hypothalamus.

  • Effects:

    • MT1 activation: promotes sleep onset.

    • MT2 activation: phase-shifts circadian rhythm.

  • Other roles: antioxidant activity, immune modulation, regulation of reproductive and metabolic functions.

Pharmacokinetics

  • Absorption: Rapid after oral administration; peak plasma concentrations within 20–60 minutes.

  • Bioavailability: Low (~10–15%) due to first-pass metabolism.

  • Metabolism: Extensively metabolized in the liver by CYP1A2 to 6-hydroxymelatonin, conjugated with sulfate/glucuronide.

  • Elimination: Renal excretion as metabolites.

  • Half-life: Short, ~30–50 minutes (immediate-release); prolonged-release forms extend activity up to 6–8 hours.

Clinical Indications

Approved / Common Uses

  1. Insomnia

    • Particularly effective in sleep-onset insomnia in older adults and children with neurodevelopmental disorders.

  2. Circadian rhythm sleep disorders

    • Delayed sleep phase disorder

    • Non-24-hour sleep-wake disorder (especially in blind individuals)

    • Shift work disorder

    • Jet lag

Off-label / Investigational Uses

  • Anxiety (perioperative, generalized)

  • Migraine prophylaxis

  • Cancer adjuvant therapy (studied in some malignancies)

  • COVID-19 (investigational for antioxidant/anti-inflammatory properties)

Contraindications

  • Known hypersensitivity to melatonin or excipients.

  • Rare: autoimmune diseases (due to immunomodulatory effects, though evidence is limited).

Precautions

  • Elderly: Safe and effective, especially prolonged-release 2 mg formulation approved for insomnia in adults ≥55 years.

  • Children: Used in ASD and ADHD-associated insomnia under specialist supervision.

  • Liver impairment: Avoid in severe hepatic impairment due to altered metabolism.

  • Drug interactions: Metabolized by CYP1A2 → caution with inhibitors (fluvoxamine, ciprofloxacin) and inducers (smoking, carbamazepine).

  • Driving/machinery: May cause drowsiness, dizziness.

Adverse Effects

Common

  • Daytime drowsiness

  • Headache

  • Dizziness

  • Nausea

Less Common

  • Irritability, vivid dreams

  • Abdominal pain

  • Mood changes

Rare but Serious

  • Allergic reactions (very rare)

  • Interaction-related toxicity if combined with other sedatives or CYP1A2 inhibitors

Drug Interactions

  • CYP1A2 inhibitors (fluvoxamine, ciprofloxacin): increase melatonin exposure.

  • CYP inducers (smoking, carbamazepine, rifampin): reduce efficacy.

  • CNS depressants (alcohol, benzodiazepines, zolpidem): additive sedation.

  • Anticoagulants (warfarin): possible increased bleeding risk (monitor INR).

  • Immunosuppressants: theoretical antagonism due to melatonin’s immunomodulatory effects.

Dosage

Adults

  • Insomnia:

    • Immediate-release: 1–5 mg orally, 30–60 min before bedtime.

    • Prolonged-release (licensed in many countries for ≥55 years): 2 mg at bedtime, up to 13 weeks; can be extended under supervision.

  • Circadian rhythm disorders:

    • Delayed sleep phase: 0.5–3 mg, 1–3 hours before desired bedtime.

    • Jet lag: 0.5–5 mg at local bedtime at destination, usually for 2–5 days.

    • Shift work: 1–3 mg before sleep following night shift.

Children

  • Neurodevelopmental disorders (ASD, ADHD):

    • 1–3 mg 30–60 min before bedtime, titrated up to 6–9 mg if needed.

    • Use prolonged-release in children ≥2 years (where approved).

Monitoring

  • Monitor efficacy via sleep diaries or actigraphy.

  • Check for excessive daytime sleepiness or behavioral changes.

  • In long-term use: periodic reassessment of necessity and dose.

Patient Counseling Points

  • Take melatonin 30–60 minutes before desired sleep time.

  • Avoid alcohol and caffeine near bedtime.

  • Keep a regular sleep schedule and optimize sleep hygiene.

  • Do not drive or operate machinery after taking melatonin.

  • Report persistent headaches, mood changes, or unusual sleep behaviors.




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