Electrocardiographic and haemodynamic changes have been compared in anesthetized cats and in conscious dogs after high doses of amitriptyline given as conventional tablets or as a sustained release form. Plasma or serum levels of amitriptyline and nortriptyline were determined. In anaesthetized cats tablets caused marked ECG changes in all 6 animals combined with pronounced acidosis in 3 of the animals. The sustained release form caused no electrocardiographic changes in 4 animals and moderate disturbances in 2 animals, without acidosis in any of the 6 cats. Almost identical haemodynamic changes were seen in both groups. The plasma levels did not indicate poorer absorption from one preparation than from the other. In conscious dogs tablets caused marked clinical signs including restlessness, sedation and convulsions (2 dogs). Pronounced electrocardiographic changes were seen in all 4 dogs. Bundle branch block developed in 3 dogs. The sustained release preparation caused slight to moderate sedation and no convulsions. Pronounced electrocardiographic changes without bundle branch block were seen in one dog. Moderate changes were seen in the remaining dogs. Acidosis was most pronounced after the tablets. The serum drug levels clearly show that the absorption is much slower after administration of the sustained release preparation than after tablet administration and that somewhat lower amounts of drug are absorbed from the sustained release preparation than from tablets. It is evident from the present studies, that administration of high doses of amitryptyline as a sustained release preparation causes less toxic manifestations than given as conventional tablets. Part of the explanation may be that less amitryptyline is absorbed from the sustained release preparation than from tablets because of the high dose (dogs), but the main reason is most likely that the absorption from the sustained release preparation is much slower than the absorption from tablets.