Melatonin Receptor Agonists

Melatonin receptor agonists (melatonin, ramelteon, tasimelteon, and agomelatine as an antidepressant) act on circadian timing and sleep onset. They treat insomnia, delayed sleep phase, jet lag and shift work sleep disorder, and are used in children with neurodevelopmental conditions. They carry little dependence or withdrawal risk.

Mechanism. They act as agonists at the MT1 and MT2 receptors in the suprachiasmatic nucleus. MT1 promotes sleep onset and MT2 shifts the circadian phase. Agomelatine is also a 5-HT2C antagonist.

Pharmacokinetics. Melatonin has a half-life of 40 to 60 minutes (prolonged-release forms give a longer profile). Ramelteon half-life is 1 to 2.6 hours. Hepatic metabolism by CYP1A2.

Differences. Melatonin is a hormone and supplement with variable product content in unregulated markets; regulated prolonged-release products are preferred. Ramelteon is licensed for sleep-onset insomnia in some regions only.

• Insomnia in adults over 55: prolonged-release melatonin 2 mg.
• Delayed sleep phase and jet lag: low dose (0.5 to 3 mg) at the target bedtime, with timed light exposure.
• Children with attention deficit hyperactivity disorder or autism and sleep onset problems: 1 to 5 mg, increased every 1 to 2 weeks to a maximum of 10 mg, under specialist care.
• Rapid eye movement sleep behaviour disorder: 3 to 12 mg at bedtime.
• Delirium prevention: evidence is mixed.
• Avoid use in severe liver impairment.

Special groups. Pregnancy: avoid. Breastfeeding: avoid. Children: specialist use, with review at 3 to 6 months. Older adults: first-line hypnotic option. Kidney impairment: no adjustment. Liver impairment: avoid. Regional: melatonin is frequently sold as an unregulated supplement, with content that differs from the label.

Adverse effects. Headache, dizziness, daytime sleepiness, nausea, vivid dreams, and mood changes. Ramelteon: raised prolactin and reduced testosterone with long use.

Contraindications. Ramelteon with fluvoxamine, and severe liver impairment.

Interactions. Fluvoxamine raises melatonin levels about 17-fold, so avoid it. Ciprofloxacin and oestrogens raise levels, and smoking and carbamazepine lower them. Alcohol adds to drowsiness.

Monitoring. Sleep diary, daytime function, and review of the need after 3 months.

Referral and escalation. Persistent insomnia after 4 weeks, daytime sleepiness suggesting sleep apnoea, or unexplained mood change.