The "GI Cocktail" is a mixture of medications often given in the Emergency Department (ED) for dyspepsia symptoms. Several combinations are used, but the most effective has not yet been determined. This study compared three combinations commonly given for dyspepsia. The study was a prospective, randomized, double-blinded trial comparing antacid (group 1); antacid + Donnatal (group 2); antacid + Donnatal + viscous lidocaine (group 3) for acute treatment of dyspepsia in the ED. Patients were randomly assigned to receive one of the three medication combinations. Patients rated their discomfort on a Visual Analog Scale (VAS) immediately before receiving the medication and 30 min later. Change in VAS was the primary study endpoint. A 13-mm difference in VAS was considered clinically significant. VAS change in the three groups was compared using multivariable regression, controlling for pretreatment VAS, study drug, previous antacid use, and gastrointestinal (GI) history. One hundred twenty patients were enrolled between July and December 2000. One hundred thirteen subjects (113) completed the protocol: Group 1 (N = 38); Group 2 (N = 37); Group 3 (N = 38). There was no statistically significant difference between the groups in terms of age, gender, GI history, previous antacid use, or initial degree of pain. Group 1 had a 25 +/- 27 mm mean (+/- SD), decrease in pain; Group 2, 23 +/- 22 mm decrease; and Group 3, 24 +/- 26 mm decrease. There was no statistically significant difference in pain relief between the three groups on univariate analysis or multivariable regression. In conclusion, the addition of Donnatal or Donnatal + lidocaine to an antacid did not relieve dyspepsia better than plain antacid. The "GI Cocktail" concoction may not be necessary.