June 2, 2023: Why is the combination of Dextromethorphan/Bupropion an antidepressant?


June 2, 2023

Why is the combination of Dextromethorphan/Bupropion an antidepressant?

An 18-year-old male on medications for ADHD and an antidepressant (AD) presented as hypertensive, tachycardia, and agitated with altered mental status. He had been increasing the amount of his antidepressant as it said on the internet that his AD would get him “high.” What is the relatively new AD that he was taking?

Answer Dextromethorphan (DM)/Bupropion (Auvelity)

This is one of the most interesting drugs I have met.

The FDA approved this extended-release-fixed-dose combination for the treatment of major depressive disorder (MDD) in August 2022.

DM is rapidly absorbed from the GI tract and undergoes first-pass metabolism primarily by CYP2D6. This rapid metabolism prevents the DM plasma concentration needed for therapeutic effects to be maintained. Bupropion inhibits CYP2D6 and prevents the metabolism of DM. Therefore, the concentration of DM is increased, and the action is prolonged.

DM is an analog of the opiate levorphanol, but it does not have analgesic activity. DM blocks the NMDA receptor. Why the antagonism of NMDA causes an antidepressant effect is unclear. Ketamine was one of the first NMDA receptor antagonists used to treat MDD, but it must be administered parenterally. (Efficacy of ketamine treatment is variable.) DM is the first oral NMDA receptor antagonist

Other actions of DM include sigma-1 receptor agonism, and inhibition of both the serotonin and norepi reuptake transporters (increases serotonin and norepi in the synapse). As DM has serotonergic actions, concomitant use of other serotonergic drugs may cause a serotonin syndrome.

Antidepressant actions of Bupropion may be related to noradrenergic and/or dopaminergic (blocks reuptake of dopamine) mechanisms. There is a lot that is unclear.

It is an expensive medicine that costs $1000 for a month's supply. Third-line AD treatment must have failed for insurance to pay for this drug.


1. Keam S. Dextromethorphan/Bupropion: First Approval. CNS Drugs (2022) 36:1229-1238

2. Kabir Y, Hashmi M, Asghar A. Rapid-acting oral drug (Auvelity) for major depressive disorder Annals of Medicine and Surgery 82 (2022) 104629

Question submitted by Donna Seger MD

Comment: Remember, in overdose, bupropion (Wellbutrin) can cause seizures. ds  

I am interested in any questions you would like addressed in the Question of the Week. Please email me with any suggestions at donna.seger@vumc.org.


Professor Emeritus
Department of Medicine






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