Inositol is a simple polyol precursor in a second messenger system important in brain myo-insitol, the natural isomer, which has been found to be therapeutically effective in depression, panic disorder, and obsessive-compulsive disorder in double-blind controlled trials. Recently, epi-inositol, an unnatural stereoisomer of myo-inositol, was found to have effects similar to those of myo-inositol to reverse lithium-pilocarpine seizures. We measured the behavior of rats in an elevated plus maze model of anxiety after chronic treatment of 11 daily intraperitoneal injections of epi-inositol, myo-inositol, or control solution. Epi-inositol reduced anxiety levels of rats compared with controls, and its effect was stronger than that of myo- inositol. Lithium has been hypothesized to alleviate mania by reducing brain inositol levels. Inositol in brain derives from the second messenger cycle, from new synthesis, or from diet via transport across the blood brain barrier. Because the first two are inhibited by lithium, we propose that an inositol-free diet will augment lithium action in mania by enhancing restriction of inositol.