Melatonin as a Chronobiotic with Sleep-promoting Properties

Abstract

The use of exogenous melatonin (exo-MEL) as a sleep-promoting drug has been under extensive debate due to the lack of consistency of its described effects. In this study, we conduct a systematic and comprehensive review of the literature on the chronobiotic, sleep-inducing, and overall sleep-promoting properties of exo-MEL. To this aim, we first describe the possible pharmacological mechanisms involved in the sleep-promoting properties and then report the corresponding effects of exo-MEL administration on clinical outcomes in: a) healthy subjects, b) circadian rhythm sleep disorders, c) primary insomnia. Timing of administration and doses of exo-MEL received particular attention in this work. The exo-MEL pharmacological effects are hereby interpreted in view of changes in the physiological properties and rhythmicity of endogenous melatonin. Finally, we discuss some translational implications for the personalized use of exo-MEL in the clinical practice.

Keywords: Melatonin; chronobiotic; circadian rhythm sleep disorders; hypnotic; insomnia; sleep-inducing; sleep-promoting; soporific.

Fig. (1)

PRISMA Flow diagram of literature search and selection process.

Fig. (2)

Regulatory pathway of the pineal MEL. The initial step in the pineal MEL synthesis involves the intrinsically photosensitive retinal ganglion cells (ipRGCs), expressing the photopigment melanopsin in response to light exposition (particularly within frequencies of 460-500 nm (blue spectrum). It depolarizes the neurons sending action potentials to several brain targets, including the suprachiasmatic nucleus (SCN), which is reached through a monosynaptic pathway called the retinohypothalamic tract (RHT) [56]. The RHT stores both glutamate and pituitary adenylate cyclase-activating polypeptide (PACAP). The photic activation of the SCN induces the release of GABA inputs from the SCN to the paraventricular nucleus of the hypothalamus (PVN), blocking its glutamatergic activity and resulting in an inhibition of the melatonin synthesis. Instead, in the absence of light, with no inhibitory input from the SCN, the PVN is activated, inducing glutamatergic signals to the sympathetic preganglionic neurons of the intermediolateral nucleus (iml), from which cholinergic projections stimulate the postganglionic neurons located in the superior cervical ganglion (SCG). The SCG contains norepinephrine (NE) projections able to stimulate the pinealocytes, resulting in an activation of the MEL synthesis. As such, MEL is released immediately into circulation with a peak during the dark phase of the day [55, 61, 66]. MEL is produced for a longer time in winter when nights are long, than in summer when nights are short.

Fig. (3a)

Chronobiotic effect of exogenous melatonin. Studies evaluating the phase-shift effect of exo-MEL on the DLMO in healthy subjects. The results are expressed as the difference (Δ) between the DLMO phase shift induced by the placebo and that induced by exo-MEL. When the Δ phase-shift was not reported directly, the phase shift to exo-MEL reported by each study was corrected by subtracting the phase shift of the placebo condition. Each study Δ phase-shift was plotted against the time of the exo-MEL administration, discriminating by those studies that established the timing of administration based upon the clock-time (black triangles) and those that reported the timing of administration in relation to the baseline DLMO (red circles). Each study contributed one point to the PRC. The studies plotted are described in Appendix Table 1 and highlighted with an asterisk (*). The theoretical PRC of MEL was plotted based on From Eastman CI, Burgess HJ et al. (2009)[190]. Fig. (3b). Sleep-promoting effect of exogenous melatonin. Summary of the results reported by studies evaluating the exo-MEL effect as sleep-promoting as measured through the sleep onset latency (SOL) in healthy subjects. The results are expressed as the difference (Δ) between the SOL induced by the placebo and that induced by exo-MEL. Each study ΔSOL was plotted against the time of the exo-MEL administration. The exo-MEL posology was divided as dose less than 1mg (blue), dose between 1mg and 5 mg (green), a dose between 5 mg and 10mg (magenta), and dose greater than 10mg (red). Each study protocol was plotted separately so that studies using several timings of administration and different dosages were plotted differentially. The studies plotted are described in Appendix Table 2 and highlighted with an asterisk (*).

Fig. (4)

Summary of the results reported in studies evaluating the sleep-inducing and the sleep-promoting effect of exogenous melatonin in healthy subjects. Studies are organized as a function of the timing of administration (morning, afternoon, early evening, night). MEL+ refers to sleep episodes scheduled when endogenous melatonin levels were elevated, while MEL- refers to sleep episodes scheduled when endogenous melatonin levels were low to absent. Sleepiness refers to the acute effects of exo-MEL. Abbreviations: S: sleepiness; F: fatigue, SOL, sleep onset latency; TST, total sleep time; WASO, waking after sleep onset; SE, sleep efficiency; REM, rapid eye movements sleep; S1, Stage 1; S2, Stage 2; S3, Stage 3; S4, Stage 4, SWS, slow wave sleep; AW: awakenings; ss: sleep spindles; SOT: sleep onset time; SQ: sleep quality. Cells in blue indicate that exogenous melatonin had a significant effect on the evaluated variable, cells in red indicate the absence of melatonin-induced effect on the evaluated variable.