The possibility that a disorder of brain alpha 2-adrenoceptor sensitivity might contribute to the etiology of panic disorder was examined using a challenge paradigm with the alpha 2-adrenoceptor agonist clonidine. The cardiovascular, psychological, and endocrine actions of 1.5-microgram/kg clonidine hydrochloride given intravenously were assessed in 16 patients and compared with age- and sex-matched controls. Patients with panic disorder showed an increased fall in blood pressure and decreased sedative and endocrine responses as compared with controls. These results suggest that there may be subsensitivity of some, and supersensitivity of other, brain alpha 2-adrenoceptors in panic disorder. In view of the increased cardiovascular responses seen in the present study and other reports of increased responses to the alpha 2-adrenoceptor antagonist yohimbine, there may exist an increased lability (decreased damping) of cardiovascular control mechanisms in panic disorder. Such a dysfunction could contribute to the symptoms of panic attacks, such as dizziness, palpitations, and faintness.