Hypnotic Activity of Melatonin

Abstract & Commentary

Synopsis: Timing is everything! Melatonin just may work if given at the right time.

Source: Stone BM, et al. Sleep 2000;23(5):663-669.

The purpose of this study was to establish the effect of melatonin on sleep. Stone and colleagues conducted two experiments. In the first experiment, varying doses (0.1-10 mg) of melatonin were administered to eight healthy volunteers at 23:30. Sleep time was from 23:30 to 07:30. Core body temperature, sleep structure, and dim light melatonin onsets (DMLO) were measured. This study was placebo-controlled, double-blinded, and included a crossover comparison with temazepam (20 mg). Melatonin had no significant effect on sleep compared with placebo, but temazepam resulted in classic benzodiazepine-induced changes of increased sleep efficiency, increased stage 2 sleep, and increased rapid eye movement (REM) sleep latency compared with placebo.

In the second experiment, varying doses of melatonin were administered at 18:00, and sleep time was from 18:00 to 24:00. Core body temperature, sleep structure, and DMLO were measured. This study was also placebo-controlled and double-blinded, and included a crossover comparison with temazepam (20 mg). In this study, all doses (range, 0.1-10 mg) increased total sleep time, sleep efficiency, and stage 2 sleep. There was an absence of dose response over the range of 0.5-10.0 mg. These changes were similar to those induced by temazepam.

Comment by Barbara A. Phillips, MD, MSPH & Carl Boethel, MD

Melatonin is a pineal hormone that is secreted during darkness. In people with normal sleep-wake schedules, melatonin levels begin to rise approximately two hours before sleep, and begin to decline prior to the termination of sleep. There is a strong correlation between the time course of endogenous melatonin production and sleep propensity.1 Further, daytime exogenous melatonin administration increases subjective sleepiness but impairs cognition.2 Because melatonin is a "food supplement" not regulated by the FDA, rigorous testing of safety, efficacy, and dose-response curves has not been done. It appears that the dose response curve may be flat, with effects noted at extremely low doses (< 1 mg), and little increase in toxicity at extremely high doses (> 1000 g). Because of these properties, melatonin has been recently touted in the lay press as a cure for insomnia and sleep disorders associated with abnormal daytime sleep schedules such as shift work and jet lag.

In this report, Stone et al produce evidence that melatonin given at 23:30 has no significant clinical effect on nocturnal sleep in healthy good sleepers. However, they found that melatonin given at 6 pm (presumably before endogenous levels begin to rise) has immediate hypnotic activity similar to 20 mg temazepam. This suggests that melatonin is unlikely to result in useful hypnotic activity in healthy people when taken around the normal time of sleep, but may be beneficial for sleep induction for "out-of-phase" sleeping.

Another finding of this study is that doses of melatonin above 0.5 mg did not further improve sleep. We have learned something useful about dosing melatonin.

This study’s findings may not be extrapolated to all populations. It is notable that Stone et al studied healthy young men, who had high baseline sleep efficiencies (92%) to begin with. But it strongly suggests that 0.5 mg of melatonin has an effect comparable to temazepam for sleep induction in the evening, which could be very beneficial to time zone travelers and shift workers. (Dr. Boethel is a Fellow in Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, Ky.) v

References

1. Dijk DJ, et al. Sleep Research 1995;24A:162.

2. Hughes RJ, Badia P. Sleep 1997;20:124-131.