Study objectives: Pharmacologic enhancement of daytime sleep may help sustain optimal cognitive performance. At effective doses, zolpidem induces sleep but also impairs performance. Combining melatonin with low-dose zolpidem may promote daytime sleep without exacerbating performance impairments seen with high-dose zolpidem alone.
Design and methods: Following an 8-hour undisturbed nighttime sleep period, 80 subjects (50 men, 30 women) were administered oral zolpidem 0, 5, 10, or 20 mg at 10:00 am (n = 20 per group) and then oral melatonin 0 or 5 mg at 10:30 am (thus, n = 10 per drug combination) in a double-blind randomized fashion. Subjects napped from 10:00 am to 11:30 am, at which time they were awakened and cognitive tests administered (Restricted Reminding, Paired-Associates, and Psychomotor Vigilance). A second nap ensued from 12:45 pm to 4:00 pm, followed immediately by further testing.
Results: Melatonin 5 mg plus zolpidem 0 mg enhanced daytime sleep (P < .05) with no memory or performance impairment (P > .05). Zolpidem 20 mg plus melatonin 0 mg also enhanced daytime sleep (albeit nonsignificantly), but memory and vigilance were impaired (P < .05). Melatonin's sleep-promoting effects were not evident until the second nap.
Conclusions: No advantages to administering melatonin plus zolpidem "cocktails" were evident. Unlike zolpidem, melatonin 5 mg alone improved daytime sleep without impairing memory and vigilance. Functional coupling of sleep-inducing and memory-impairing effects may be specific to benzodiazepine-receptor agonists such as zolpidem, suggesting potential advantages to using melatonin in the operational environment. That melatonin's sleep-promoting effects were delayed for several hours presents a practical consideration that may limit melatonin's usefulness when daytime sleep periods cannot be reliably anticipated or planned in advance.