Aside from inducing and maintaining sleep, hypnotic medications also impact sleep stages. Historically, the barbiturates were REM suppressants, while the benzodiazepines were Stage 3–4 (SWS) suppressants. The newer benzodiazepine receptor agonists like zolpidem increase stage 2 and latency to REM. Previous research, however, was conducted utilizing bedtime dosing. Across the night, there are dramatic changes in sleep stages, with the first half being primarily enriched with SWS, and the last half with REM sleep. A buffered zolpidem sublingual formulation (ZST) is approved to be taken in the middle of the night (MOTN) by patients with MOTN insomnia (and at least 4h of bedtime remaining). The question then arises regarding possible sleep stage effects following MOTN ZST dosing taking pharmacologic and circadian influences into consideration.A double-blind, placebo-controlled 3- way cross-over sleep laboratory polysomnography study conducted with 1.75 and 3.5mg buffered zolpidem tartrate sublingual tablets (ZST) demonstrated efficacy, compared to placebo, on latency to persistent sleep (LPS) when administered to patients with primary insomnia whose chief complaint was MOTN awakenings with difficulty returning to sleep. 58 Female and 24 male patients were randomized. Patients were dosed with 3.5mg, 1.75mg or placebo 4h after lights out, kept awake for 30min, then returned to bed for 4h. Sleep stages were scored centrally by standardized criteria in 30s epochs for 4h predose and 4h postdose. The mean of each sleep parameter was calculated from the postdose periods of the 2 treatment nights. Subjective ratings of sleep quality and morning alertness were also obtained.LPS, total sleep time, and sleep efficiency all improved significantly postdose with both ZST doses compared to placebo. Postdose, there was a dose-dependent change in NREM sleep. The percent of light stage 1 decreased, while the % and minutes of deeper stages 2 and 3–4 increased. While REM sleep minutes were stable, % REM declined with a minor dose- dependent increase in REM latency. The overall improvements in sleep quality and daytime alertness reported by patients on mornings post ZST dosing may be related to the differential effects in NREM sleep stages.In summary, sleep after MOTN dosing with ZST included all sleep stages, including SWS typically not observed in the latter half of the night. These findings may relate to the improved ratings of sleep quality and alertness.Funding was provided by Transcept Pharmaceuticals, Inc. and Purdue Pharma LP.