Corticosteroid feedback effects on ACTH secretion in man can be manipulated by neuroactive drugs. In patients without endogenous corticosteroids (primary adrenocortical insufficiency) differential and integral feedback effects can be differentiated. When in these patients brain norepinephrine receptor activity was increased by desipramine, the normally negative differential feedback mechanism was converted into a positive one (paradoxical ACTH response). The pre-existing paradoxical ACTH response of patients with Cushing's disease after adrenalectomy was abolished after depletion of norepinephrine granules by means of reserpine.