The Effects of Low-Dose 0.5-mg Melatonin on the Free-Running Circadian Rhythms of Blind Subjects

Abstract

Exogenous melatonin (0.5-10 mg) has been shown to entrain the freerunning circadian rhythms of some blind subjects. The aim of this study was to assess further the entraining effects of a daily dose of 0.5 mg melatonin on the cortisol rhythm and its acute effects on subjective sleep in blind subjects with free-running 6-sulphatoxymelatonin (aMT6s) rhythms (circadian period [τ] 24.23-24.95 h). Ten subjects (9 males) were studied, aged 32 to 65 years, with no conscious light perception (NPL). In a placebo-controlled, single-blind design, subjects received 0.5 mg melatonin or placebo p.o. daily at 2100 h (treatment duration 26-81 days depending on individuals' circadian period). Subjective sleep was assessed from daily sleep and nap diaries. Urinary cortisol and aMT6s were assessed for 24 to 48 h weekly and measured by radioimmunoassay. Seven subjects exhibited an entrained or shortened cortisol period during melatonin treatment. Of these, 4 subjects entrained with a period indistinguishable from 24 h, 2 subjects continued to free run for up to 25 days during melatonin treatment before their cortisol rhythm became entrained, and 1 subject appeared to exhibit a shortened cortisol period throughout melatonin treatment. The subjects who entrained within 7 days did so when melatonin treatment commenced in the phase advance portion of the melatonin PRC (CT6-18). When melatonin treatment ceased, cortisol and aMT6s rhythms free ran at a similar period to before treatment. Three subjects failed to entrain with initial melatonin treatment commencing in the phase delay portion of the PRC. During melatonin treatment, there was a significant increase in nighttime sleep duration and a reduction in the number and duration of daytime naps. The positive effect of melatonin on sleep may be partly due to its acute soporific properties. The findings demonstrate that a daily dose of 0.5 mg melatonin is effective at entraining the free-running circadian systems in most of the blind subjects studied, and that circadian time (CT) of administration of melatonin may be important in determining whether a subject entrains to melatonin treatment. Optimal treatment with melatonin for this non-24-h sleep disorder should correct the underlying circadian disorder (to entrain the sleep-wake cycle) in addition to improving sleep acutely.

Paracrine Regulation of Thyroid-Hormone Synthesis by C Cells

“…This indoleamine has the capacity to resynchronize circadian rhythms [188][189][190] and regulate sleep-wake-cycles [191]. Besides playing an important role as a transmitter of photoperiodic information, melatonin has wellcharacterized antioxidant capacities, either, directly as a free-radical neutralizer or, indirectly by enhancing the activity or the expression of antioxidant enzymes [192,193].…”

Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders

“…Two of these trials [54,55] were eligible for meta-analysis. There was no overall significant difference between the effects of melatonin and placebo on sleep onset latency in blind patients (total mean difference = -3.17 minutes, 95% CI: -11.88-5.54).…”

“…Only subjective measures were used by Hack et al [54] to assess sleep parameters with a small sample size (n=10). The use of daily diary reporting measures increased the likelihood of bias due to inaccurate reporting and therefore PSG or wrist M A N U S C R I P T…”

“…One study used adolescents and young adults (aged 16-25) [69,70] Three studies [54,55,58] highlighted the use of melatonin in phase advancement and entrainment of circadian rhythm in patients who are blind. Two of these trials [54,55] were eligible for meta-analysis.…”

Increasing positive sleep behaviors in young children who are blind : the significance of auditory sleep association stimuli.

“…Numerous studies of adults who are blind and have circadian rhythm disorders found these individuals have an inappropriate secretion of evening melatonin (too low) and cortisol (too high) to induce nighttime sleep, maintain the duration of sleep throughout the night, and reduce daytime napping (Hack, Lockley, Arendt, & Skene, 2003;Lewy, Emens, Lefler, Yuhas, & Jackman, 2005;Lockley, Arendt, & Skene, 2007;Sack, Brandes, Kendall, & Lewy, 2000;Skene, Lockley, & Arendt, 1999). Thus, one potential chronobiotic for persons who are blind or visually impaired is exogenous melatonin.…”