LiCl in vitro markedly inhibits forskolin-stimulated human platelet adenylate cyclase activity by competing competitively with Mg2+ for a site on the catalytic subunit. The sensitivity of platelet membrane adenylate cyclase to lithium inhibition for individual manic patients was determined by the Dixon plot procedure: marked individual differences in sensitivity to lithium were observed pretreatment (0.66 mM-3.15 mM LiCl). After 3 weeks of continuous treatment with lithium in vivo a significant decrease in adenylate cyclase affinity for lithium was observed (pretreatment average Ki = 1.38 +/- 0.92 mM vs. treatment average Ki = 2.98 +/- 1.35 mM LiCl, n = 10). The clinical implications of these findings relating to chronic lithium exposure are discussed.