Purpose: The aim of the review was to provide an overview of studies investigating the pharmacokinetics of exogenous melatonin in humans and if possible, to provide recommendations for clinical use.

Methods: The review was conducted in accordance to PRISMA guidelines. A systematic literature search was performed in PubMed and Embase databases. The pharmacokinetic variables included maximal plasma/serum concentration (Cmax), time to maximal plasma/serum concentration (Tmax), elimination half-life (T1/2), area-under-the-curve plasma/serum concentrations (AUC), clearance (Cl), volume of distribution (VD), and bioavailability.

Results: The literature search identified 392 records. Twenty-two studies were included in the review. Melatonin dosages varied between 0.3 and 100 mg and were administered either orally or intravenously. Cmax ranged from 72.1 (10 ml/h; 0.02 mg, IV) to 101,163 pg/ml (100 mg, oral). Tmax ranged between 15 (2 mg) and 210 min (10 mg). T1/2 ranged from 28 (0.005 mg, IV) to 126 min (4 mg, oral), whereas AUC ranged between 5400 (0.005 mg, IV) and 6.56 × 10(10) pg/ml × min (1 mg, oral). Cl ranged from 0.97 (0.005 mg, IV) to 132.50 L/min (6 mg, oral), whereas VD ranged between 35 (0.005 mg, IV) and 1602 L (4 mg, oral). Bioavailability of oral melatonin ranged from 9 to 33%. Pharmacokinetics was affected by age, caffeine, smoking, oral contraceptives, feeding status, and fluvoxamine. Critically ill patients displayed accelerated absorption and compromised elimination.

Conclusions: Despite methodological differences between the included studies, Tmax was approximately 50 min following oral immediate-release formulations of melatonin. T1/2 was 45 min in both administration routes. Cmax, AUC, Cl, and VD varied extensively between studies. Bioavailability of oral melatonin was approximately 15%.