The combined effects on performance and respiration of pentazocine (PZ) and amitriptyline (AMI) were evaluated in a double-blind cross-over study in 11 healthy students. After pretreatment for 1 week with AMI or placebo, on Day 8 the subjects received placebo or 50 mg p.o. AMI and 30 mg PZ or saline i.m. so that the final treatments were 1) placebo, 2) acute AMI 50 mg, 3) acute PZ, 4) subchronic AMI + acute PZ and 5) subchronic AMI. The subacute treatments were started at two-week intervals. Objective and subjective performance tests and respiratory function (minute volume, ETCO2) were measured. Parenteral PZ impaired sensory processing (digit symbol substitution, choice reactions) and extraocular muscle balance (Maddox wing) but left motor skills (tracking, tapping speed) unaffected. A single oral dose of AMI 50 mg affected both sensory and motor performance. The psychomotor effects of PZ were clearest at 1.5 h, and those of AMI at 3.5 h. Both drugs rendered the subjects drowsy, clumsy, and muzzy on visual analogue scales, but PZ also induced positive feelings, like contentedness and friendliness. PZ depressed respiration in terms of lowered minute volume and elevated ETCO2, and subchronic AMI increased this depression. The chemically assayed plasma concentrations of AMI and PZ were as expected; radioreceptor assay revealed low or negligible mu-opiate activity in plasma after PZ. The results suggest that AMI does not enhance the moderate psychomotor decrement produced by PZ. However, respiratory depression may be increased by their concomitant use.