Association between dextromethorphan/bupropion with diabetes mellitus and hyperglycemia: reports to the Food and Drug Administration Adverse Event Reporting System (FAERS).

Dextromethorphan/bupropion (DXM/BUP) is the first orally administered antidepressant combining dextromethorphan, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist, and bupropion, a CYP2D6 inhibitor and antidepressant. DXM/BUP was approved by the United States Food and Drug Administration for Major Depressive Disorder (MDD) in adults in August 2022. Given that select psychotropic agents prescribed for MDD may alter glucose and insulin homeostasis, we investigated whether DXM/BUP was associated with disproportionate reporting of diabetes mellitus or hyperglycemia. Disproportionality analyses were conducted using reporting odds ratios (RORs), with DXM/BUP and comparator agents evaluated relative to a reference agent (acetaminophen). Data were obtained from the Food and Drug Administration Adverse Event Reporting System (FAERS) from the year of approval to April 26, 2026. A sensitivity analysis was performed on a restricted dataset from January 1, 2022, to April 30, 2026. Statistical significance was defined as a 95% confidence interval (CI) excluding 1.0. DXM/BUP was not associated with disproportionate reporting of diabetes mellitus (ROR = 0.33, 95% CI [0.07, 1.65], p = 0.18) or hyperglycemia (ROR = 0.10, 95% CI [0.01, 1.67], p = 0.11) relative to acetaminophen. Findings from the restricted 2022-2026 analysis were directionally consistent with the primary analysis. Given the sparse number of reports and wide CIs, these findings should be interpreted as preliminary and underpowered, rather than evidence of metabolic neutrality. Continued pharmacovigilance and prospective investigation are needed to further characterize the metabolic profile of DXM/BUP.