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

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.

Melatonin, Its Metabolites and Their Interference with Reactive Nitrogen Compounds

“…In terms of quantity and often also of concentration, its amounts exceed the circulating levels, sometimes by far. Moreover, exogenous melatonin can be administered at even higher doses to attain therapeutic concentrations [ 4 , 266 , 267 ]. Based on these conditions, melatonin appears as a highly suitable compound for counteracting pathologies associated with detrimental elevations of RNS.…”

“…Melatonin is mostly perceived as a highly pleiotropic regulator molecule that controls or modulates numerous physiological processes [ 1 , 2 ]. Originally discovered as a hormone of the pineal gland, it is now known to be produced in, perhaps, all tissues of the body [ 3 , 4 ]. Differences between pineal and extrapineal melatonin, concerning chronobiotic and nonchronobiotic actions, higher amounts produced in extrapineal sites with low rates of release have been extensively summarized elsewhere [ 1 , 4 ].…”

“…Originally discovered as a hormone of the pineal gland, it is now known to be produced in, perhaps, all tissues of the body [ 3 , 4 ]. Differences between pineal and extrapineal melatonin, concerning chronobiotic and nonchronobiotic actions, higher amounts produced in extrapineal sites with low rates of release have been extensively summarized elsewhere [ 1 , 4 ]. Mitochondrial synthesis of melatonin [ 4 , 5 , 6 ] has, again, changed our understanding of this molecule, which exceeds by far the earlier chronobiological conceptions.…”

“…Differences between pineal and extrapineal melatonin, concerning chronobiotic and nonchronobiotic actions, higher amounts produced in extrapineal sites with low rates of release have been extensively summarized elsewhere [ 1 , 4 ]. Mitochondrial synthesis of melatonin [ 4 , 5 , 6 ] has, again, changed our understanding of this molecule, which exceeds by far the earlier chronobiological conceptions. This view is well in accordance with the previously identified bacterial origin of this molecule [ 7 ].…”

Impact of Pharmacotherapy on Insomnia in Patients with Alzheimer’s Disease

“…Current perspectives on melatonin dosing suggest that lower doses (generally < 5 mg) are more effective for circadian phase shifting, whereas sedative/hypnotic effects, if any, may only be apparent at higher doses [90]. However, the several randomized placebo-controlled studies that do exist on melatonin and sleep parameters in patients with AD failed to show significant benefit from melatonin therapy (across a relatively wide range of dosages of 1.5-10 mg) on nocturnal characteristics outside of occasional nonsignificant trends [86,[91][92][93].…”