AbstractTen healthy female volunteers received single doses of amitriptyline 50 mg (AMI); mianserin 20 mg (MIA); trazodone 50 mg (TRA); paroxetine 30 mg (PAR) and placebo (PLA), with or without a ‘social’ dose of alcohol (ALC) in a double‐blind, balanced crossover study where each subject acted as her own control.Psychomotor activity related to car handling ability was measured on a battery of tests at 1.5 and 4 h following study drug. The tests included tracking accuracy (RMS) and latency of response to a peripheral stimulus (RT) as measures of sensorimotor co‐ordination; the Maddox Wing test (MW) for the balance of extraocular muscles; critical flicker fusion threshold (CFF) for overall levels of CNS activity; choice reaction time (CRT) for psychomotor performance and the latency of brake reaction time (BRT) measured in a driving simulator. Subjective ratings of sedation were measured on line analogue ratings scales (VARS) and the Leeds Sleep Evaluation Questionnaire (LSEQ).When compared to PLA on objective tests, AMI significantly impaired RMS, RT, MW and CFF at 4 h post‐drug and AMI + ALC similarly impaired the same measures and BRT. MIA produced a significant impairment of RT, MW, CFF and CRT at both 1.5 and 4 h. MIA + ALC further impaired RMS at 1.5 and 4 h and BRT at 4 h. TRA showed a detrimental activity on CFF at 1.5 h and CFF, RT, MW and BRT at 4 h. TRA + ALC produced a greater effect than TRA alone at 1.5 h and significantly impaired RT, MW, TRT, BRT. There were no significant effects of TRA + ALC at 4 h. PAR alone had no measurable effect on any of the test measures at either 1.5 or 4 h after treatment. PAR + ALC impaired RT at 1.5 and 4 h but had no effect on any other measures at either test times. Indeed, compared to PLA, CFF levels were significantly improved at 4 h following both PAR and PAR + ALC and improvements in RRT were also measured 4 h after taking PAR.Subjective measures (VARS) compared to placebo, show AMI at 4 h and AMI + ALC at 1.5 and 4 h, both MIA and MIA + ALC after 1.5 and 4 h, TRA + ALC after 1.5 h and PAR + ALC at 4 h to have significant sedative activity.In this placebo‐controlled study, acute doses of AMI 50 mg, MIA 20 mg and TRA 50 mg alone and with alcohol showed evidence both of significant impairment of psychomotor skills related to vehicle handling and of perceived sedation at 1.5 and / or 4 h following treatment. Under identical circumstances PAR 30 mg produced no detrimental effect on any of the test measures, there was an impairment with PAR + ALC of one component of a divided attention task and on a subjective measurement