Tricyclic antidepressants (TCAs) were introduced almost 50 years ago. Whilst there is no doubt that TCAs are effective in treating depression. they are also more cardiotoxic when taken in overdose than other antidepressant groups. Lofepramine is a more recently introduced modified TCA, which in animals and man has low toxicity when compared to older TCAs. Paradoxically, lofepramine is extensively metabolised to desipramine, which has considerable toxicity, both experimentally and in overdose. The toxicity of such compounds is attributed, in part, to a membrane stabilising effect (MSA) on cell membranes. This MSA causes gross effects to the cell structure and in turn. normal cell activity. The aim of this study was to compare the MSA of lofepramine with that of desipramine and amitriptyline in order to see if this might help to explain the low toxicity of lofepramine. The local anaesthetic agent lignocaine was also studied for comparison. Each compound was enclosed in a beta-cyclodextrin to increase its solubility in aqueous medium, The extent of MSA was determined as a measure of the effect on the swimming speed of the protozoan Tetrahymena pyriformis using a video image analysis system. The IC50 for the various drugs were then correlated with their respective octanol-water partition coefficient values (Pow). Amitriptyline had an IC50 of 1.26+/-0.29 mM, desipramine 75.99+/-14.40 mM, while lofepramine had an IC50 of 357.40+/-25.00 mM. Lignocame had an IC50 of 85.73+/-18.30 mM. There was also a significant correlation between the IC50 values and the Pow values. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.