The calcium receptor (CaR) plays a central role in calcium (Ca) sensing by the parathyroid gland and other organs, including the brain. Chronic lithium (Li) therapy causes a significant alteration in Ca-sensing by the CaR-expressing parathyroid chief cells through an unknown mechanism, shifting the PTH set-point (the level of Ca that half-maximally suppresses PTH secretion) to the eight. Ca is known to stimulate ACTH levels in normal subjects, and baseline ACTH levels are increased in patients with bipolar disorder. Because the stimulation of ACTH secretion by Ca likely involves the CaR, the aim of this study was to investigate the effects of Li on Ca-induced changes in ACTH levels, using Ca and citrate infusions in seven Li-treated patients and seven controls. During the Ca infusion, increments in serum-ionized Ca concentration (Cai) were accompanied by increments in ACTH levels that were significantly greater in the Li-treated group, P =3D 0.014, by ANOVAlso, cortisol levels increased significantly in the Li-treated, but not the control group, during the Ca infusion, P < 0.0001. There was a statistically significant shift in the midpoint of the Cai/ACTH curve, to the right, in the Li-treated group, compared with the controls (P =3D 0.042), that was largely caused by an effect of Li on Cai. However, for comparable levels of Cai, there were no significant differences in the levels of ACTH between the two groups. Therefore, within the physiological range of Ca, there was no effect of Li on Cai-induced change in ACTH levels