Antidepressants are used in irritable bowel syndrome (IBS) and may have effects on the gut independent of improving mood. We have investigated the actions of a tricyclic antidepressant on small intestinal motor function in eight healthy volunteers and in six patients with diarrhea-predominant IBS. Fasting ambulatory motility was recorded from six small intestinal sites for 16-18 hr while on no drug (baseline) and while taking imipramine for five days. Orocecal transit time (OCTT) was measured by lactulose hydrogen breath test, during baseline and imipramine administration. Imipramine did not alter migrating motor complex periodicity, but slowed jejunal phase III propagation velocity in controls from 7.5 +/- 1.1 to 3.6 +/- 0.5 cm/min (P < 0.01) and in IBS from 7.8 +/- 0.6 to 4.4 +/- 0.5 cm/min (P < 0.0001). Phase III duration at each site was increased, and total recorded phase III was greater during imipramine than baseline studies. Imipramine increased the amplitude of phase III contractions. There was no effect of imipramine on non-phase-III motility index or discrete clustered contractions. Imipramine, prolonged OCTT from 73 +/- 6 min to 97 +/- 8 min in controls (P < 0.05) and from 61 +/- 9 min to 89 +/- 8 min in IBS (P < 0.05). Although OCTT was shorter in the IBS group, no motility differences were seen between controls and IBS. This demonstration that a tricylic antidepressant can modify small intestinal motor function in health and in IBS supports the view that these drugs may have therapeutic actions in IBS unrelated to mood improvement.