This study was designed to evaluate the efficacy and safety of a dietary herbal supplement containing citrus aurantium and phenylephrine in the treatment of obesity. Two pilot studies enrolled healthy subjects with body mass indexes 25-40 kg/m(2) to similar 8-week weight loss programs. Safety was assessed by physical examination and laboratory tests at screening and 8 weeks. The first pilot study randomized eight subjects to citrus aurantium (herbal phenylephrine) or placebo. Body composition by DEXA scan, waist circumference, and resting metabolic rate (RMR) were measured at baseline and 8 weeks. Food intake and appetite ratings were measured at baseline and week 2. The second pilot study randomized 20 subjects to two 2-hour RMR tests a week apart after phenylephrine (20 mg) or placebo followed by phenylephrine (20 mg) three times a day for 8 weeks. In the first pilot study, the citrus aurantium group gained 1.13 +/- 0.27 (mean +/- SEM) kg compared with 0.09 +/- 0.28 kg in the placebo group (P < .04). RMR at baseline rose more in the citrus aurantium group, 144.5 +/- 15.7 kcal/24 hours, than the placebo group, 23.8 +/- 28.3 kcal/24 hours (P < .002), but not at 8 weeks. DEXA, waist circumference, food intake, and hunger ratings were not different. In the second pilot study, the phenylephrine group lost 0.8 +/- 3.4 kg in 8 weeks (not significant), and RMR increased more in the phenylephrine group (111.5 +/- 32.6 vs. 37.4 +/- 22.7 kcal/24 hours, P = .02). There were no significant safety issues in either study. Although no toxicity was seen, these pilot studies suggest phenylephrine is not efficacious for weight loss.