Abuse liability of dextromethorphan and its combinatory formulation dextromethorphan/bupropion: a pharmacologic perspective.

Abstract

Dextromethorphan/Buproprion (DXM/BUP) has received breakthrough FDA approval in August 2022 as a rapid-acting antidepressant. DXM/BUP is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist, with bupropion (BUP), a norepinephrine/dopamine reuptake inhibitor and cytochrome P450 2D6 (CYP2D6) inhibitor. As DXM/BUP moves closer to widespread clinical use for MDD, examining whether the combination does or does not carry meaningful abuse liability is essential given that DXM alone has long been misused, likely attributed to its metabolism into the psychoactive metabolite DXO. We discuss the pharmacodynamics and pharmacokinetics of DXM and its primary active metabolite, dextrorphan (DXO). We then highlight the abuse potential of DXM when administered alone. Additionally, we present preclinical, clinical, and pharmacovigilance findings that support the reduced abuse liability of DXM/BUP. The formulation demonstrates clinically meaningful improvement within one week of its initiation. Given its safety and efficacy, alongside its novelty, this glutamatergic modulator represents a promising candidate for approval across global jurisdictions and regions. Future research should examine DXM/BUP's potential efficacy in bipolar depression and trauma-associated MDD, populations exhibiting refractory responses to conventional antidepressants and in need of an alternative, mechanistically distinct therapeutic.