Generic Name

Melatonin

Mechanism

Melatonin is a neurohormone synthesized from serotonin in the pineal gland. Its principal actions include:
• Binding to high‑affinity MT₁ and MT₂ G‑protein–coupled receptors in the suprachiasmatic nucleus (SCN) and other brainstem structures.
• Modulating circadian phase: MT₁ activation enhances GABAergic inhibition, while MT₂ influences photic entrainment, ultimately resetting the internal clock.
• Regulation of sleep‑wake architecture: Promotes sleep onset, increases slow‑wave sleep, and reduces nocturnal arousals.
• Indirect antioxidant and anti‑inflammatory effects: By scavenging free radicals and attenuating pro‑inflammatory cytokines, it supports neuronal health.

These actions make melatonin a potent chronobiotic that restores sleep continuity in disorders of circadian rhythm.

Pharmacokinetics

• Absorption: Rapid oral absorption; peak plasma concentration (T_max) 30–60 min.
• Bioavailability: Low first‑pass metabolism; ~15–35 % depending on formulation.
• Distribution: Lipid‑soluble; crosses blood‑brain barrier.
• Metabolism: Primarily hydroxylated by CYP1A2 and conjugated via UGT1A1 to 6-hydroxymelatonin.
• Elimination: Renal excretion of metabolites; half‑life 20–45 min (short).
• Drug interactions: CYP1A2 inhibitors (e.g., fluvoxamine) increase plasma exposure; warfarin synergy reported but clinically insignificant.

Indications

• Insomnia with sleep‑onset delay or poor sleep quality.
• Circadian rhythm sleep‑wake disorders: jet lag, shift‑work sleep disorder, delayed sleep phase syndrome.
• Sleep disturbances in neurodegenerative disorders: Parkinson’s disease, Alzheimer’s disease.
• Seasonal affective disorder (SAD): as adjunct for sleep problems.
• Pediatric use: circadian‑related sleep problems; limited data, use under supervision.

Contraindications

• Contraindicated in patients with uncontrolled bleeding disorders or severe hepatic impairment due to rare but documented bleeding risk.
• Warnings:
• Potentially synergistic effect with anticoagulants (e.g., warfarin, rivaroxaban).
• Possible endocrine interference: reports of reduced LH/FSH in high doses; caution in hormone‑sensitive cancers.
• Psychogenic reactions: rare episodes of hallucinations or psychosis in susceptible individuals.
• Caution in:
• Patients with autoimmune disorders (possible immune modulation).
• Pregnant/nursing patients: data scarce; use only if benefit outweighs risk.

Dosing

• No routine titration; adjust based on subjective sleep latency and sleep quality.
• Avoid concurrent use of sedating CNS agents unless clinically indicated.

Adverse Effects

• Common:
• Drowsiness, mild headache, dizziness, nausea.
• Light‑headedness on rapid standing.
• Serious (rare):
• Hemorrhagic events (bleeding gums, epistaxis).
• Severe allergic reactions (urticaria, angioedema).
• Neuropsychiatric events (mania, psychosis) in predisposed individuals.
• Withdrawal: No tolerance or dependence noted; abrupt discontinuation generally well tolerated.

Monitoring

• Sleep diaries: latency, total sleep time, awakenings.
• Adverse reaction log: especially bleeding signs or mood changes.
• Laboratory: monitor coagulation profile if concurrently on anticoagulants.
• Hormonal panels: in patients on long‑term therapy or with endocrine disease.

Clinical Pearls

• Melatonin is not a hypnotic: It re‑establishes circadian alignment, so it may take several days to notice marked improvement.
• Sustained‑release vs. immediate‑release: For jet lag, use sustained‑release to cover early morning light. For insomnia, immediate‑release maximizes onset.
• Dose–response plateau: Increasing above 5 mg does not enhance efficacy and may increase adverse events.
• Timing is critical: Administering too early can shift circadian phase further from desired time, worsening sleep quality.
• Use with caution in children: Start ≤2 mg, monitor hormone levels, involve pediatric sleep specialist.
• Potential synergy with CBT‑I: Combining melatonin with cognitive‑behavioral therapy for insomnia (CBT‑I) yields superior outcomes versus monotherapy.
• Seasonal variations: Daylight savings and changes in nocturnal light exposure can alter endogenous melatonin production—adjust supplemental dose accordingly.

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• *References:*

[1] Reiter R.J. et al. “Melatonin: biology, health and disease.” *Int J Mol Sci*, 2021.

[2] Brainard G.C. et al. “The circadian clock, sleep and melatonin.” *Curr Opin Pharmacol*, 2022.

[3] Figueiredo D. et al. “Efficacy of melatonin in jet lag.” *Sleep Med Rev*, 2020.

[4] Choi Y. et al. “Melatonin in neurodegenerative disorders.” *Neurotherapeutics*, 2023.