This parallel-arm, phase I study investigated the potential cytochrome P450 (CYP)3A induction effect of NBI-1065845 (TAK-653), an investigational α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiator in phase II development for major depressive disorder. The midazolam treatment arm received the sensitive CYP3A substrate midazolam on Day 1, followed by NBI-1065845 alone on Days 5-13; on Day 14, NBI-1065845 was administered with midazolam, then NBI-1065845 alone on Day 15. The oral contraceptive treatment arm received ethinyl estradiol-levonorgestrel on Day 1, then NBI-1065845 alone on Days 5-13; on Day 14, NBI-1065845 was administered with ethinyl estradiol-levonorgestrel, then NBI-1065845 alone on Days 15-17. Blood samples were collected for pharmacokinetic analyses. The midazolam treatment arm comprised 14 men and 4 women, of whom 16 completed the study. Sixteen of the 17 healthy women completed the oral contraceptive treatment arm. After multiple daily doses of NBI-1065845, the geometric mean ratios (GMRs) (90% confidence interval) for maximum observed concentration were: midazolam, 0.94 (0.79-1.13); ethinyl estradiol, 1.00 (0.87-1.15); and levonorgestrel, 0.99 (0.87-1.13). For area under the plasma concentration-time curve (AUC) from time 0 to infinity, the GMRs were as follows: midazolam, 0.88 (0.78-0.98); and ethinyl estradiol, 1.01 (0.88-1.15). For levonorgestrel, the GMR for AUC from time 0 to the last quantifiable concentration was 0.87 (0.78-0.96). These findings indicate that NBI-1065845 is not a CYP3A inducer and support its administration with CYP3A substrates. NBI-1065845 was generally well tolerated, with no new safety signals observed after coadministration of midazolam, ethinyl estradiol, or levonorgestrel.