The melatonin rhythm reflects the phase of all other endogenous circadian rhythms, including those of Cortisol, temperature, and sleep propensity (see above). As mentioned earlier, another use of melatonin is to give it exogenously in order to cause phase shifts.13 Inspired by animal studies,86 these effects were most conclusively demonstrated by entraining free-running blind people (blind free-runners [BFRs]) with a daily dose of melatonin.87 Although

an early subject showed apparent entrainment to a dose of about 7 mg,88-90 entrainment of BFRs was conclusively demonstrated using a dose of 10 mg.87,91 Only one of seven Inhibitors,research,lifescience,medical BFRs failed to entrain to the 1.0-mg dose; this BFR had the longest tau (24.9 h). Although the melatonin PRC was experimentally determined

in sighted people, it appears to apply to blind people as well. Currently, more is known about the phaseadvance zone of the melatonin PRC: for at least the second half of the advance zone, the earlier melatonin is given, Inhibitors,research,lifescience,medical the greater the magnitude of the phase-advance shift. When melatonin is given daily to a free-running blind person, the melatonin PRC will continue to drift later Inhibitors,research,lifescience,medical and later until exogenous melatonin is hitting the point on the melatonin PRC that will produce a phase advance equal to the daily drift (this is called the entrainment point on the melatonin PRC and will vary between

individuals, depending in part on the intrinsic tau). Then, the endogenous pacemaker will lock on to the daily melatonin dose. For example, if a BFR’s intrinsic circadian Inhibitors,research,lifescience,medical PS341 period, or tau, is 24.4 h, the melatonin dose will Inhibitors,research,lifescience,medical stop the pacemaker from drifting later when it is stimulating that part of the melatonin PRC when it produces a phase advance of 0.4 h. Thus, entrainment occurs and the pacemaker now functionally has a tau of 24.0 h. The finding that low doses of melatonin may be more effective than high doses, leading to the idea of avoiding spillover, is illustrated in the treatment of the one BFR who failed to entrain to the 10-mg dose (recall that he had the longest tau, 24.9 h, in that study). Despite repeat treatment with 9 to 10 mg melatonin for 83 days and 20 mg melatonin for 60 days (Figure 3),92 he failed to entrain, although his tau did shorten to 24.36 and 24.58 h, respectively He was finally Oxymatrine entrained with 0.5 mg melatonin.92 Figure 3. A totally blind subject with free-running circadian rhythms during four trials of oral melatonin administration. Each data point represents an assessment of circadian phase as determined by successive measurements of the time that endogenous plasma melatonin … The melatonin PRC might explain why a lower dose of melatonin is more effective than higher doses (Figure 4).