The excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG), the urinary metabolite which may best reflect brain norepinephrine, was measured in eight depressed patients on a longitudinal basis during the administration of placebo, d- and 1-amphetamine (30 mg/day), lithium carbonate (0.9 - 2.1 g/day), and d- and 1-amphetamine together with lithium. d-Amphetamine significantly decreased MHPG excretion. No significant change in MHPG was observed during administration of 1-amphetamine or when d- or 1-amphetamine was given together with lithium carbonate. Six patients responded with behavioral activation and euphoria to d-amphetamine, and these patients tended to have lower base line MHPG values in comparison to the nonresponders. Reductions in MHPG excretion during amphetamine administration were greatest in the patients with minimal behavioral responses to the drug, while some of the patients demonstrating more marked stimulant effects had elevated levels of MHPG during the amphetamine administration period. Variable changes, including elevated levels of MHPG in the responders, might represent the contribution of amphetamine-related changes in clinical state, including increased physical activity and (in two of the responding patients) the development of hypomania.