Previous research suggests that the noradrenergic system modulates certain types of cognitive flexibility. This study compared various doses of beta-adrenergic antagonists for their effect on cognitive flexibility in problem solving, and how task difficulty interacts with this effect, as well as the effect of beta-adrenergic antagonists on other tasks. Anagram task performance was compared in 72 subjects using a within-subject design for propranolol at 20 mg, 40 mg, 60 mg, and placebo in a double-blinded manner, and the effects of subject ability and task difficulty were examined. We also examined the effect of the 40 mg propranolol dose on a range of other tasks. Overall, more anagram problems were solved while on propranolol 40 mg than on placebo. Subjects least able to solve the problems benefited significantly from 40 mg of propranolol. Also, for all subjects the most difficult problems were solved more quickly with propranolol 40 mg than placebo. Benefits were also seen for word fluency and backward digit span. Therefore, noradrenergic modulation of cognitive flexibility is affected by how much difficulty the subject is encountering when searching for the solution, a pattern consistent with what might be expected in an effect on the search of the semantic and associative network.