Melatonin - Drug Monograph

Introduction

Melatonin is an endogenous neurohormone primarily synthesized and secreted by the pineal gland. It plays a crucial role in regulating circadian rhythms and sleep-wake cycles. While available as an over-the-counter dietary supplement in many countries, it is also prescribed as a medication for specific sleep disorders in various formulations.

Mechanism of Action

Melatonin exerts its effects primarily through activation of MT₁ and MT₂ G-protein-coupled receptors in the suprachiasmatic nucleus of the hypothalamus. MT₁ receptors promote sleepiness, while MT₂ receptors help phase-shift circadian rhythms. Melatonin also functions as a powerful antioxidant, scavenging free radicals and reducing oxidative stress. Its secretion is inhibited by light and stimulated by darkness, making it a key regulator of the body's internal clock.

Indications

• Treatment of non-24-hour sleep-wake disorder in blind individuals
• Jet lag disorder

• Insomnia (sleep onset and maintenance)
• Delayed sleep-wake phase disorder
• Sleep disturbances in shift workers
• Preoperative anxiety reduction
• Adjunctive treatment in neurodegenerative disorders

Dosage and Administration

• Adults: 0.5-5 mg orally 30-60 minutes before bedtime
• Extended-release formulations: 2 mg once daily

• Elderly: Start with lower doses (0.5-1 mg) due to increased sensitivity
• Hepatic impairment: Use with caution; consider reduced dosing
• Renal impairment: No specific dosage adjustment required
• Pediatrics: Limited data; consult specialist for appropriate dosing

• Take on empty stomach for optimal absorption
• Consistent timing relative to desired sleep time is crucial
• For jet lag: 0.5-5 mg at bedtime for several days after arrival

Pharmacokinetics

Contraindications

• Hypersensitivity to melatonin or any component of the formulation
• Autoimmune diseases (theoretical risk of exacerbation)
• Use in pregnant women without medical supervision

Warnings and Precautions

• May cause daytime drowsiness; caution when operating machinery
• Use with caution in patients with depression or hepatic impairment
• May affect glucose tolerance; monitor in diabetic patients
• Potential for hormone-sensitive condition exacerbation (theoretical)
• Long-term safety data beyond 3 months is limited

Drug Interactions

• Fluvoxamine: Increases melatonin levels 17-fold via CYP1A2 inhibition
• Other CYP1A2 inhibitors: Ciprofloxacin, estrogens
• Anticoagulants: Theoretical increased bleeding risk
• Antihypertensives: Additive hypotensive effects
• CNS depressants: Additive sedative effects (benzodiazepines, alcohol)
• Immunosuppressants: Theoretical interaction

Adverse Effects

• Headache
• Dizziness
• Nausea
• Daytime drowsiness
• Transient depression

• Vivid dreams or nightmares
• Hypothermia
• Reduced blood pressure
• Irritability
• Hormonal effects (theoretical)

• Seizures (case reports)
• Autoimmune reactions (theoretical)
• Severe allergic reactions

Monitoring Parameters

• Sleep patterns and quality assessment
• Daytime alertness and cognitive function
• Mood changes, particularly in those with depression history
• Blood pressure in hypertensive patients
• Glucose levels in diabetic patients
• Adverse effects profile at follow-up visits

Patient Education

• Take consistently at the same time each night
• Avoid driving or operating machinery after ingestion
• Do not combine with alcohol or other sedating substances
• Report persistent drowsiness, mood changes, or unusual dreams
• Not intended for long-term use without medical supervision
• Store in light-resistant container as melatonin is photosensitive
• Inform healthcare providers of all supplement use

References

1. Zisapel N. New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation. Br J Pharmacol. 2018;175(16):3190-3199. 2. Auld F, Maschauer EL, Morrison I, Skene DJ, Riha RL. Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders. Sleep Med Rev. 2017;34:10-22. 3. Costello RB, Lentino CV, Boyd CC, et al. The effectiveness of melatonin for promoting healthy sleep: a rapid evidence assessment of the literature. Nutr J. 2014;13:106. 4. Ferracioli-Oda E, Qawasmi A, Bloch MH. Meta-analysis: melatonin for the treatment of primary sleep disorders. PLoS One. 2013;8(5):e63773. 5. Brzezinski A, Vangel MG, Wurtman RJ, et al. Effects of exogenous melatonin on sleep: a meta-analysis. Sleep Med Rev. 2005;9(1):41-50. 6. FDA prescribing information for melatonin formulations. 7. European Medicines Agency assessment reports on melatonin-containing medicinal products.