Divergent Importance of Chronobiological Considerations in High- and Low-dose Melatonin Therapies.

Rüdiger Hardeland

doi:10.3390/diseases9010018

Abstract

Melatonin has been used preclinically and clinically for different purposes. Some applications are related to readjustment of circadian oscillators, others use doses that exceed the saturation of melatonin receptors MT1 and MT2 and are unsuitable for chronobiological purposes. Conditions are outlined for appropriately applying melatonin as a chronobiotic or for protective actions at elevated levels. Circadian readjustments require doses in the lower mg range, according to receptor affinities. However, this needs consideration of the phase response curve, which contains a silent zone, a delay part, a transition point and an advance part. Notably, the dim light melatonin onset (DLMO) is found in the silent zone. In this specific phase, melatonin can induce sleep onset, but does not shift the circadian master clock. Although sleep onset is also under circadian control, sleep and circadian susceptibility are dissociated at this point. Other limits of soporific effects concern dose, duration of action and poor individual responses. The use of high melatonin doses, up to several hundred mg, for purposes of antioxidative and anti-inflammatory protection, especially in sepsis and viral diseases, have to be seen in the context of melatonin’s tissue levels, its formation in mitochondria, and detoxification of free radicals.

Highlights

Melatonin has been tested as a protective drug against numerous diseases and disorders, both preclinically and clinically
CaM-mediated effects of melatonin may participate in circadian changes of various cell functions, no evidence exists for a role in phase resetting of circadian oscillators
Melatonin can be used for different purposes, over a remarkably broad spectrum of doses

Summary

Introduction

Melatonin has been tested as a protective drug against numerous diseases and disorders, both preclinically and clinically. Circulating melatonin had been assumed to be the major source of chronobiotic effects, but more recent evidence indicates that melatonin release into the third ventricle, from where this agent gets direct access the adjacent SCN, may be even more important [23,24] These chronobiological considerations have, disregarded an important fact, namely, that melatonin is not exclusively formed in the pineal gland, and in other, presumably all organs [25,26]. The fact that melatonin is synthesized in many places within the body, at much higher quantities than in the pineal gland, sheds light on the necessity of defining melatonin’s physiological role in a way exceeding the chronobiotic aspects This is the more important as circadian variations of tissue melatonin are either much smaller than in those in pineal and circulation or even almost absent [25,30,31].

Basis of Chronobiotic Treatment

Tissue and Organellar Melatonin

The Rationale for Chronobiotic and Nonchronobiotic Treatments

Conclusions