1 Introduction
During evening hours, serum melatonin levels start to rise, reaching peak concentration around 2–4 am, after which melatonin levels decline again until reaching low daytime levels [1]. In healthy subjects, the average peak of melatonin in serum at night reaches values around 60 pg/ml, gradually declining to levels as low as\10 pg/ml during daytime [1, 2]. It is known that melatonin levels decline in aging adults [3, 4], as melatonin is subject both to altered hormone regulation due to changes in renal and hepatic clearance and to changes in body composition [5].
As melatonin levels decrease with age, their secretion patterns also alter [4, 7]. It is assumed that older adults are prone to develop disorders that are related to an altered circadian rhythm, such as sleeping disorders [8, 9], disorders of cognitive functioning [10–12], and delirium [13–15]. These previous investigations have shown that administration of exogenous melatonin had beneficial effects. Melatonin mainly synchronizes the sleep–wake cycle by advancing the oscillatory activity of the major circadian pacemaker and restores the circadian secretion pattern and endogenous levels of melatonin [16].
Efficacy of administered melatonin in adults appears to be dependent on the magnitude of the dose and the time of administration [17]. The appropriate timing of exogenous melatonin is widely investigated by its phase response curve (PRC) [18–22]. In this response curve, dim light melatonin onset (DLMO), the time of day when melatonin in dim light conditions starts to rise, can be used to determine the phase shift in disorders related to altered melatonin levels and altered circadian rhythm [23–25]. It is supposed that melatonin administered in the afternoon or early evening, prior to the normal onset of nocturnal melatonin production, can restore disorders related to an altered circadian rhythm [16].
While adequate timing of melatonin administration is investigated, the effective dose of melatonin, especially in older adults, remains unclear [25]. Many studies have investigated pharmacokinetics in younger adults [16, 17, 26– 30], but only a few have studied older adults [5, 31].
4 Discussion
First, we found an elevation of endogenous melatonin after exogenous administration compared with placebo in a dose-dependent manner.
In younger adults, it is amply proven that low exogenous doses of melatonin, even above 0.3 mg, produce supra-physiological levels [16, 20–22, 26–30, 35] as well as in older adults [33].
Second, we also demonstrated that higher doses of exogenous melatonin cause prolongation of elevated melatonin levels. Gooneratne et al. [5] showed that a higher dose in a 75 % sustained-release formulation (4 mg) compared with a lower dose (0.4 mg) caused significant prolongation of elevated melatonin levels lasting throughout the morning hours and during the day.
This implies that a higher maximum dose carries the risk of prolongation of supra-physiological levels in older adults throughout the next day. This might cause problems with side effects like drowsiness, somnolence, or unsteady feeling when waking up, despite melatonin’s low toxicity [30, 33, 36, 42].
Exogenous melatonin had a positive effect on sleep parameters [5, 31, 35, 37, 40, 44]. Some studies showed that with higher doses and prolongation of supra-physiological levels, melatonin loses its effectiveness on sleep parameters, and with lower doses it can regain its effectiveness [25, 31, 44, 47]. In addition to this, higher doses are more influential on body temperature [35].
5 Conclusion
The best applicable dosage for melatonin for older adults still cannot be adequately determined, as endogenous melatonin levels are subject to altered pharmacokinetics and -dynamics. This causes higher intra-individual variability, higher maximum concentrations by a greater and more variable increment, and, thereby, the risk of prolonged and elevated endogenous melatonin levels after exogenous melatonin administration in older adults.
Therefore, we advise the use of the lowest possible dose of immediate-release formulation melatonin in older adults, varying from 0.3 mg (which is already effective) to a maximum of 1 or 2 mg, preferably 1 h before bedtime to best mimic the normal physiological circadian rhythm of melatonin and to avoid prolonged, supra-physiological blood levels.
Referência :
(1) Drugs Aging. 2014 Jun;31(6):441-51.
