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Melatonergic Sleep Promotion: Fundamental Chronobiological Issues Concerning Sleep Onset and Maintenance, Dose and Duration of Action

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Abstract

Purpose

This review summarizes the conditions under which sleep promotion by melatonin or other melatonergic drugs can be successfully achieved or not. Importantly, the chronobiological rules are outlined which have to be followed in cases in which an etiology of circadian deviations is responsible for sleep difficulties.

Dose and Duration of Action

Sleep initiation is already possible with low doses (below 1 mg) of immediate-release melatonin. Prolonged actions have only caused moderate improvements of sleep maintenance. At elevated doses, melatonin may occasionally cause sleep fragmentation in some patients. Low doses (below 1 mg) of short-acting melatonin are also suitable for entraining and readjusting circadian rhythms, because circadian oscillators are particularly sensitive to nonparametric synchronizing signals.

Phase Response Curve

Successful entrainment of circadian rhythms is only possible if the phase response curve (PRC) is considered, which consists of phases of a silent zone with poor resetting, a delay and an advance part. Notably, the dim light melatonin onset (DLMO) is still in the silent zone.

Conclusions

For purposes of melatonergic treatment, the knowledge of synchronization-sensitive phases within the circadian cycle is helpful in correcting circadian rhythm sleep disorders, otherwise poorly entrainable rhythms, e.g., in blind people, and mood disorders with circadian etiology. The disregard of the PRC leads to false conclusions on inefficacy of melatonin or other melatonergic drugs. Correcting actions by melatonin should not be inhibited by other drugs. For instance, attempts of shortening a circadian oscillation by well-timed melatonin should not be counteracted by period-lengthening drugs, such as lithium.

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Authors and Affiliations

  1. Johann Friedrich Blumenbach Institute of Zoology and Anthropology, University of Göttingen, Bürgerstr. 50, 37073, Göttingen, Germany

    Rüdiger Hardeland

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Hardeland, R. Melatonergic Sleep Promotion: Fundamental Chronobiological Issues Concerning Sleep Onset and Maintenance, Dose and Duration of Action. Sleep Vigilance 2, 5–11 (2018). https://doi.org/10.1007/s41782-017-0014-9

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