Low doses of the antidepressant mirtazapine or the neuroleptic quetiapine are often prescribed off-label for insomnia. However, studies on the effects on sleep and hangover effects the following day are scarce. In this randomised, double-blind, cross-over, placebo-controlled trial, the influence of 7.5 mg mirtazapine and 50 mg quetiapine on both normal sleep and sleep disturbed by acoustic stress (traffic noise) as a model for transient insomnia was assessed. Additionally, hangover effects on next-day alertness and cognitive functioning were examined. A total of 19 healthy men without sleep complaints completed three treatment sessions, each session consisting of three consecutive nights in one of the mirtazapine, quetiapine or placebo conditions. Sleep was assessed using polysomnography and the Leeds Sleep Evaluation Questionnaire. Daytime sleepiness and cognitive functioning were assessed using the Leeds Sleep Evaluation Questionnaire, Karolinska Sleepiness Scale, Digit Symbol Substitution Task, Psychomotor Vigilance Task and an addition task. Under acoustic stress, both mirtazapine and quetiapine increased total sleep time by half an hour and reduced the number of awakenings by 35-40% compared to placebo. While quetiapine specifically increased the duration of non-rapid eye movement sleep, stage N2, mirtazapine mainly increased deep sleep stage N3. Subjects reported that both mirtazapine and quetiapine eased getting to sleep and improved sleep quality. Both drugs caused daytime sleepiness and lessened sustained attention. These findings support the use of low doses of mirtazapine and quetiapine for the treatment of insomnia. Further prospective studies on the long-term effects regarding effectiveness and adverse effects are needed.