Dose- and Circadian- Dependent Melatonin Entrainment in Humans By Naila Ramji

Background Exogenous melatonin can entrain the free-running rhythm in blind people Exogenous melatonin can entrain the free-running rhythm in blind people Low doses (~0.5 mg) administered at the appropriate CT time (Phase Advance portion of melatonin PRC CT6-18) most effective Low doses (~0.5 mg) administered at the appropriate CT time (Phase Advance portion of melatonin PRC CT6-18) most effective Lockley et al, 2000; Hack et al, 2003 Lockley et al, 2000; Hack et al, 2003 Increasing doses of melatonin to induce a greater phase shift, but all relatively small doses (<1.0mg) Increasing doses of melatonin to induce a greater phase shift, but all relatively small doses (<1.0mg) Lewy et al, 2005 Lewy et al, 2005

Lack of Entrainment vs. Entrainment with Melatonin (Lockley et al, 2000)

The Problematic Case Assumptions: Assumptions: melatonin PRC sufficiently accurate melatonin PRC sufficiently accurate phase advance portion is the best time for all doses of melatonin to entrain phase advance portion is the best time for all doses of melatonin to entrain What about the subject with a tau very, very close to 24.0 hrs, who cannot entrain to LD cycle? What about the subject with a tau very, very close to 24.0 hrs, who cannot entrain to LD cycle?

Hypothesis Different doses of melatonin administered at different Circadian Times will result in multiple possibilities for entrainment in free-running blind human subjects

Method Free-running blind human subjects in a Field Study Free-running blind human subjects in a Field Study 10 melatonin dose groups: 10 melatonin dose groups: placebo=negative control placebo=negative control 3.0 mg 3.0 mg 2.5 mg 2.5 mg 2.0 mg 2.0 mg 1.5 mg 1.5 mg 1.0 mg 1.0 mg 0.8 mg 0.8 mg 0.6 mg 0.6 mg 0.5 mg 0.5 mg 0.4 mg 0.4 mg 0.3 mg 0.3 mg } } Higher Doses Lower Doses

For each dose group, subjects will be divided into different CT time groups (different PRC for different doses): For each dose group, subjects will be divided into different CT time groups (different PRC for different doses): CT4 CT4 CT8 CT8 CT12 CT12 CT16 CT16 CT20 CT20 CT24 CT24 } Phase Advance Times on Current Melatonin PRC

Subjects will take the melatonin at a given CT time on the first day and then at the same clock-hour afterwards, for 30 days Subjects will take the melatonin at a given CT time on the first day and then at the same clock-hour afterwards, for 30 days Sleep Diaries would be maintained during this time, and subjects would wear activity monitors as well Sleep Diaries would be maintained during this time, and subjects would wear activity monitors as well

Potential Results Entrainment might be possible during the delay phase, at certain doses Entrainment might be possible during the delay phase, at certain doses Individuals who may not have entrained during the advance portion at a lower dose, might entrain at a higher dose Individuals who may not have entrained during the advance portion at a lower dose, might entrain at a higher dose The results for the best phase advance / delay for each dose, should entrainment ensue, would also indicate the lower / upper limit of melatonin entrainment for that particular dose The results for the best phase advance / delay for each dose, should entrainment ensue, would also indicate the lower / upper limit of melatonin entrainment for that particular dose

Further Research Examining limits of entrainment for melatonin at different doses as compared to the LD limits of entrainment Examining limits of entrainment for melatonin at different doses as compared to the LD limits of entrainment Degree of inter-individual variability with regard to melatonin PRC and at different doses Degree of inter-individual variability with regard to melatonin PRC and at different doses

Sources & Acknowledgements Dr. Charles Czeisler and Josh Gooley for their guidance in figuring out how to go about this experiment. Hack et al. “The Effects of Low-Dose 0.5-mg Melatonin on the Free- Running Circadian Rhythms of Blind Subjects” in Journal of Biological Rhythms. Vol. 18, No. 5 (2003) Lewy et al. “Melatonoin Entrains Free-Running Blind People According to a Physiological Dose-Response Curve” in Chronobiology International. Vol. 22, No. 6 (2005) Lockley et al. “Melatonin Administration can Entrain the Free-running circadian system of blind subjects” in Journal of Endocrinology. Vol. 164, No. 1 (2000). 1-6