In other words, a lower dose will have less “spillover” and might thus be more effective than a higher dose. Figure 4. Pharmacokinetic data from two different melatonin doses (0.5 and 10 mg) in relation to the endogenous melatonin profile and the melatonin phase response curve (PRC). The 0.5 mg dose and the endogenous melatonin profile are data from the subject in this … The efficacy of low doses means that melatonin can be administered well before sleep without causing daytime or evening sleepiness. This is important

because the treatment goal Inhibitors,research,lifescience,medical is not only entrainment, but also entrainment at the optimal phase. Indeed, in the original study of 10 mg,87 successfully 5FU entrained BFRs had MOs occurring after sleep onset, often much later (Figure 5).93 In other words, the MO occurred at the same time each night, but later than normal. As in animal studies, the greater the pretreatment free-running tau, the later entrainment occurs relative Inhibitors,research,lifescience,medical to the time of the entraining stimulus. In our entrained BFRs, their sleep disorders had improved with treatment, but our subjects still had trouble falling asleep and getting up in the morning. About 30% of people become sleepy on melatonin, Inhibitors,research,lifescience,medical and this side effect appears to be dose-related and is troublesome at doses greater than 1 mg, certainly at 10 mg. Now that 0.5 mg has been shown to be an effective

dose with minimal soporific side effects, it can be administered earlier than bedtime (which is when the 10 mg was originally given, in order to make use of this side effect). Melatonin Inhibitors,research,lifescience,medical can be given earlier in the evening, so that the MO occurs 2 h before desired sleep time, thus resulting in optimal sleep quality. Figure 5. Pretreatment tau predicts phase angle of entrainment Inhibitors,research,lifescience,medical (PAE). PAE is the interval (in hours) between the time of the bedtime 10 mg melatonin dose and the entrained melatonin onset (MO) of the endogenous melatonin profile. This figure is an updated version … When shifting the clock time of exogenous melatonin administration, the endogenous MO can be reset to any time. Shifting the clock time of administration earlier

should be done gradually, so as not to cross over the break point on the melatonin PRC. The clock time of administration can over also be shifted later, which can be done in 1 day without loss of entrainment. In either case, the pacemaker will shift with the time of the melatonin dose. In blind people who appear to be entrained (or at least have a tau virtually indistinguishable from 24.0 h) to a behaviorally related zeitgeber or to ambient light (perhaps in some blind people who are not bilaterally enucleated), MOs can be reset earlier or later with a daily dose of melatonin, so that the MO occurs 14 h after waketime. Several years ago, we also proposed that the abscissa and ordinate of Figure 5 could be reversed.