Melatonin administration can entrain the free-running circadian system of blind subjects

Abstract

Although melatonin treatment has been shown to phase shift human circadian rhythms, it still remains ambiguous as to whether exogenous melatonin can entrain a free-running circadian system. We have studied seven blind male subjects with no light perception who exhibited free-running urinary 6-sulphatoxymelatonin (aMT6s) and cortisol rhythms.In a single-blind design, five subjects received placebo or 5 mg melatonin p.o. daily at 2100 h for a full circadian cycle (35-71 days). The remaining two subjects also received melatonin (35-62 days) but not placebo. Urinary aMT6s and cortisol (n=7) and core body temperature (n=1) were used as phase markers to assess the effects of melatonin on the circadian system. During melatonin treatment, four of the seven free-running subjects exhibited a shortening of their cortisol circadian period (tau). Three of these had taus which were statistically indistinguishable from entrainment. In contrast, the remaining three subjects continued to free-run during the melatonin treatment at a similar tau as prior to and following treatment. The efficacy of melatonin to entrain the free-running cortisol rhythms appeared to be dependent on the circadian phase at which the melatonin treatment commenced.These results show for the first time that daily melatonin administration can entrain free-running circadian rhythms in some blind subjects assessed using reliable physiological markers of the circadian system.

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

“…This finding confirms and extends a previous report of entrainment of 3 free-running blind people with 0.5 mg melatonin (Lewy et al, 2001a). In agreement with our previous study with 5 mg melatonin (Lockley et al, 2000), entrainment was more likely when melatonin treatment was started in the phase advance portion of the melatonin PRC (CT6-18). When 0.5 mg melatonin 424 JOURNAL OF BIOLOGICAL RHYTHMS / October 2003 was started in the phase delay region of the PRC, some individuals did not exhibit changes in phase or period during melatonin administration and continued to free run, again in agreement with the 5-mg studies (Lockley et al, 2000).…”

“…The methods used to determine the characteristics of urinary aMT6s and cortisol rhythms have been detailed elsewhere (Lockley et al, 1997a;Skene et al, 1999;Lockley et al, 2000). Briefly, acrophase times for aMT6s (ng/h) and cortisol (nmol/h) were determined by cosinor analysis (Nelson et al, 1979) using a program written by Dr. D. S. Minors, University of Manchester, United Kingdom.…”

“…Later attempts to correct sleep disorders in freerunning blind subjects resulted in an apparent improvement in sleep with either no entrainment or a shortening of the period of endogenous circadian rhythms (Sack et al, 1991;Lapierre and Dumont, 1995;Jan and O'Donnell, 1996;Arendt et al, 1997;Palm et al, 1997;. In contrast, several recent studies have reexamined the ability of melatonin to entrain free-running rhythms in totally blind people and found that entrainment could be achieved following daily oral melatonin treatment with 5-mg (Lockley et al, 2000), 10-mg (Sack et al, 2000), or 0.5-mg doses (Lewy et al, 2001a). An individual with a period as long as 24.9 h (Lewy et al, 2002) has been shown to entrain using such a regime.…”

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

“…[32] Timed melatonin also successfully entrained rhythms in blind individuals. [33,34] Primary Insomnia 2. Non-benzodiazepine agonists and MT1/MT2 receptor agonists are safer for long term use than traditional benzodiazepines.…”

“…Participants unsuitable (n= 5) [26][27][28][29][30] Insufficient data for analysis (n= 2) [31,32] Inappropriate method and data collection (n= 4) [33][34][35][36] No clear comparison group (n= 4) [37][38][39][40] Number of studies included in review (n=13) [41][42][43][44][45][46][47][48][49][50][51][52] Publications handpicked (screening reference list) (n= 2) …”