Melatonin beyond chronobiology: integrating pharmacokinetics, dose-exposure forecasting, and clinical evidence

Abstract

Melatonin is established as a regulator of circadian timing and sleep, while a wider range of receptor-dependent and receptor-independent biological effects has generated interest in additional therapeutic applications. This review critically examines whether those proposed effects can be interpreted within an exposure-based pharmacological framework. We integrate recent preclinical and clinical evidence with the pharmacokinetics of oral and intravenous melatonin and with ordinary differential equation (ODE)-based dose-exposure forecasting. Oral melatonin is rapidly absorbed but undergoes extensive first-pass metabolism and shows substantial interindividual variability, whereas intravenous administration produces higher and more predictable systemic concentrations. These pharmacokinetic differences do not imply therapeutic superiority of the intravenous route. Rather, they highlight the need to distinguish established chronobiotic uses from investigational high-exposure pharmacology. Clinical evidence is most coherent for sleep and circadian outcomes; evidence for perioperative, analgesic, cardiovascular, renal, anti-inflammatory, neuroprotective, and other non-circadian applications is more heterogeneous and frequently lacks pharmacokinetic-pharmacodynamic measurements. The modelling presented here is therefore hypothesis-generating and is intended to relate dose to exposure, not to provide validated treatment recommendations. Future studies should prospectively link administered dose, timing, formulation, achieved concentration, target engagement, and clinically meaningful outcomes. Melatonin is best established as a chronobiotic agent; proposed non-circadian effects require indication-specific interpretation rather than extrapolation from biological pleiotropy. Oral and intravenous melatonin should be viewed as pharmacokinetically distinct routes, not as a therapeutic hierarchy: oral administration has the stronger clinical evidence base, whereas intravenous administration remains investigational and mainly illustrates the consequences of controlled high systemic exposure. Future studies should link dose, formulation, route, timing, achieved exposure, target engagement, and clinical outcome instead of treating nominal melatonin dose as a transferable measure across indications.