A Mathematical Model of the Circadian Phase-Shifting Effects of Exogenous Melatonin

Melatonin is endogenously produced and released in humans during nighttime darkness and is suppressed by ocular light exposure. Exogenous melatonin is used to induce circadian phase shifts and sleep. The circadian phase-shifting ability of a stimulus (e.g., melatonin or light) relative to its timing may be displayed as a phase response curve (PRC). Published PRCs to exogenous melatonin show a transition from phase advances to delays approximately 1 h after dim light melatonin onset. A previously developed mathematical model simulates endogenous production and clearance of melatonin as a function of circadian phase, light-induced suppression, and resetting of circadian phase by light. We extend this model to include the pharmacokinetics of oral exogenous melatonin and phase-shifting effects via melatonin receptors in the suprachiasmatic nucleus of the mammalian hypothalamus. Model parameters are fit using 2 data sets: (1) blood melatonin concentration following a 0.3- or 5.0-mg dose, and (2) a PRC to a 3.0-mg dose of melatonin. After fitting to the 3.0-mg PRC, the model correctly predicts that, by comparison, the 0.5-mg PRC is slightly decreased in amplitude and shifted to a later circadian phase. This model also reproduces blood concentration profiles of various melatonin preparations that differ only in absorption rate and percentage degradation by first-pass hepatic metabolism. This model can simulate experimental protocols using oral melatonin, with potential application to guide dose size and timing to optimally shift and entrain circadian rhythms.