1. The effects of amitriptyline, protriptyline, protriptyline, and a chemically related potential antidepressant, BW247, on performance tests and subjective ratings were studied. 2. Two groups of twelve healthy subjects received drugs and lactose dummy in identical capsules at weekly intervals according to a balanced design, under double-blind conditions, and with standarized tests and environment. 3. Amitriptyline produced the most marked effects, with significant (P less than 0.05) impairment in auditory vigilance after 6.25 mg. Auditory reaction time, tapping rate, arithmetic, and digit symbol substitutions were impaired by amitriptyline 12.5 and 25 mg and all doses produced increased ratings of mental sedation. The effects began 1.5 h after drug and lasted approximately 5 h. 4. Nortriptyline produced fewer effects which were later in onset. Tapping at 1.8 h and auditory vigilance at 3.5 to 4.5 h were impaired by nortriptyline 25 mg whereas reaction time was prolonged by both doses at 5 h. No change in rating of mental sedation occurred. 5. No significant change in performance or subjective ratings followed protriptyline 10 mg or BW247, 12.5 and 25 mg. 6. The findings are discussed in relation to the presence of secondary and tertiary amines on the side chain of the compounds, and their relative abilities to block neuronal uptake of noradrenaline and 5-hydroxytryptamine.