OBJECTIVES: To assess the effect of acute changes in serotonin (5-HT) synthesis using the acute tryptophan depletion (ATD) paradigm on gastrointestinal (GI) and mood symptoms in irritable bowel syndrome (IBS).METHODS: In a randomized double-blind crossover study, 29 subjects (18 patients with ROME II defined IBS and 11 age-matched controls) were studied under ATD and acute tryptophan increase (ATI) conditions. GI symptoms, mood and anxiety ratings, as well as plasma tryptophan concentrations were measured.RESULTS: Total (and free) plasma tryptophan concentrations decreased on the ATD day in patients (73% [82%]) and controls (73% [80%]), and increased on the ATI day in patients (59% [143%]) and controls (61% [381%]). Compared with the ATD day, IBS patients reported more GI symptoms on the ATI day at +210 (p < 0.001) and at +270 (p < 0.05) min post drink. IBS patients also reported less anxiety on the ATI day compared with the ATD day at +270 min (p < 0.001). ATD and ATI did not affect these ratings in control participants. IBS patients had a lower mood compared with controls (p < 0.05), but this did not differ between the ATI and ATD days in either group.CONCLUSIONS: IBS patients' GI and anxiety responses to changes in tryptophan load differ from controls. This suggests a difference in serotonergic functioning between these two groups and provides evidence to support the hypothesis that 5-HT dysfunction is involved in IBS.