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The effects of bupropion on blood pressure and heart rate were evaluated in a double-blind, placebo-controlled study of community volunteers with untreated mild (stage 1) hypertension (systolic blood pressure [SBP], 140-159 mm Hg, and/or diastolic blood pressure, 90-99 mm Hg). Three hundred subjects were randomly assigned (1:1:1:1) to 4 weeks of placebo or bupropion sustained release (SR) 150, 300, or 400 mg/d. Mean clinical blood pressures decreased from baseline to the end of protocol in all groups (n = 296): −6.53, −6.46, −4.20, −4.87 mm Hg for SBP; and −2.36, −2.27, −1.95, −1.55 mm Hg for diastolic blood pressure, for each group, respectively. Although decreases in mean clinical blood pressure were observed in all groups, the reduction in SBP was less on bupropion SR 300 mg/d than on placebo (−4.20 vs −6.53 mm Hg, respectively; Δ = 2.33, P = 0.020). Neither mean 24-hour ambulatory blood pressure measurements nor the proportion of subjects with clinically significant increases in blood pressure differed between any bupropion SR dose and placebo. Mean heart rate increases were small but statistically significant at 400 mg/d versus placebo (2.28 vs −0.64 beats/min; Δ = 2.92, P = 0.004). Although only minor effects on blood pressure were observed in this trial, an infrequent association of bupropion therapy and treatment-emergent hypertension cannot be ruled out.