Efficacy of dextromethorphan for the treatment of depression: a systematic review of preclinical and clinical trials
Amna Majeed, Jiaqi Xiong, Kayla M Teopiz, Jason Ng, Roger Ho, Joshua D. Rosenblat, Lee Phan, Bing Cao, Roger S McIntyre
Expert Opinion on Emerging Drugs January 2, 2021 DOI: 10.1080/14728214.2021.1898588 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Interventions | Dextromethorphan Bupropion |
| Topics | Anxiety Depression Serotonin |
| Keywords | Bupropion Antidepressant Dextromethorphan Monoamine neurotransmitter Pharmacology Depression economics Bipolar disorder Oncology Mood Smoking cessation |
| Citations | 48 |
| Key findings | Dextromethorphan combined with bupropion is a safe, well tolerated, and efficacious treatment option in adults with major depressive disorder, with replicated and relatively rapid onset efficacy. |
Abstract
INTRODUCTION: The large percentage of adults with major depressive disorder (MDD) insufficiently responding and/or tolerating conventional monoamine-based antidepressants invites the need for mechanistically novel treatments. Convergent evidence implicates glutamatergic signaling as a potential therapeutic target in MDD. AREAS COVERED: The synthesis herein of preclinical and clinical studies indicates that dextromethorphan (DXM) is well tolerated and exhibits clinically significant antidepressant effects; DXM combined with bupropion has demonstrated replicated and relatively rapid onset efficacy in adults with MDD. DXM efficacy has been preliminarily reported in adults with bipolar depression. The combination of DXM and bupropion represents a pharmacokinetic and pharmacodynamic synergy which may account for the rapidity of action in MDD. EXPERT OPINION: The combination of DXM and bupropion is a safe, well tolerated and efficacious treatment option in adults with MDD. Priority questions are whether DXM/bupropion is uniquely effective across discrete domains of psychopathology (e.g. anhedonia, reward processing, general cognitive systems) and/or whether it is able to significantly improve patient-reported outcomes (e.g. quality of life, psychosocial functioning). The availability of ketamine/esketamine and DXM/bupropion instantiates the relevance of glutamate as a treatment target in MDD. Studies in bipolar depression with DXM/bupropion are warranted as well as in MDD with suicidality.
Comparable studies
Other narrative reviews on depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synaptic Dysfunction in Depression: Potential Therapeutic Targets | 2012 | Review | |
| Mindfulness-Based Cognitive Therapy for Depression: A New Approach to Preventing Relapse | 2003 | Review | |
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. General population | 2019 | Integrative review | |
| Sudarshan Kriya Yogic Breathing in the Treatment of Stress, Anxiety, and Depression: Part II—Clinical Applications and Guidelines | 2005 | Review |
Citations in the library
Cited by 22
- Ketamine and serotonergic psychedelics: An update on the mechanisms and biosignatures underlying rapid-acting antidepressant treatment Neuropharmacology January 13, 2023
- Glutamatergic Modulators for Major Depression from Theory to Clinical Use. CNS Drugs November 1, 2024
- Clinical specificity profile for novel rapid acting antidepressant drugs. International Clinical Psychopharmacology September 1, 2023
- Psychedelics for the Treatment of Psychiatric Disorders: Interpreting and Translating Available Evidence and Guidance for Future Research. American Journal of Psychiatry 2025
- The Use of Ketamine for the Treatment of Anhedonia in Depression. CNS Drugs August 1, 2024
and 17 more in the library
Cites 11
- Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective Psychiatry and Clinical Neurosciences June 19, 2019
- The effect of intravenous, intranasal, and oral ketamine in mood disorders: A meta-analysis. Journal of Affective Disorders November 1, 2020
- Oral Ketamine for Depression The Journal of Clinical Psychiatry April 15, 2019
- Dextromethorphan in Cough Syrup: The Poor Man's Psychosis. Psychopharmacology Bulletin August 12, 2025
- Dextromethorphan/Bupropion: A Novel Oral NMDA (N-methyl-d-aspartate) Receptor Antagonist with Multimodal Activity CNS Spectrums September 30, 2019
and 6 more in the library