The result of research to develop a nonaddictive cough suppressant produced dextromethorphan. It was FDA approved in 1954 but the pharmacology of this cough suppressant is complex. It functions as an uncompetitive NMDA-glutamate blocker (thin ketamine), sigma-1 stimulator, and serotonin reuptake inhibitor. It should start to become clear why there is renewed interest in this medication. 

Bupropion functions as a selective norepinephrine/dopmaine reuptake inhibitor. It’s currently used to treat depression, seasonal affective disorder, and nicotine dependence. Recent research suggests it acts as a potent inhibitor of cytochrome P450 2D6 (CYP2D6). Understanding the cytochrome P450 system is not a primary concern here but this enzyme metabolizes dextromethorphan. 

The combination of these two drugs dextromethorphan 45 mg and bupropion 105 mg two times per day is AXS-05. The proposed mechanism is prolongation of dextromethorphan activity by CYP2D6 inhibition with the added benefit of norepinephrine/dopamine reuptake inhibition. 

A phase-3 RCT of AXS-05 in patients with MDD outperformed placebo and improved depression scores over 6 weeks.