We examined how lithium's demonstrated effects on various cellular processes in human brain would be reflected in the (31)P magnetic resonance spectra of living human beings with respect to brain high-energy phosphate metabolites. Eight healthy volunteers received a baseline (31)P magnetic resonance spectroscopy (MRS) scan, after which they received lithium carbonate, 900 mg/day, for 14 days. Follow-up MRS scans were obtained on day 7 and on day 14. We detected a lithium-induced decrease in alpha-, beta-, gamma- and total nucleoside triphosphate NTP levels with chronic administration of lithium. On day 7, significant decreases were noted in gamma-NTP (14%) and total NTP (11%) levels. There was a trend for a decrease in beta-NTP (11%) levels. On day 14, significant decreases were noted in alpha-NTP (7%) and total NTP (8%) levels. There was a trend for a decrease in beta-NTP (16%) levels. Lithium caused a 25% reduction in inorganic phosphate (P(i)) levels on day 14. The theoretical relevance of the lithium-induced alterations on brain high-energy phosphates to the lithium-induced modifications of neuroplasticity is discussed.