DXM, CYP2D6-inhibiting antidepressants, piracetam, and glutamine: proposing a ketamine-class antidepressant regimen with existing drugs.
Frontiers in Psychiatry 2026 DOI: 10.3389/fpsyt.2026.1751605 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Interventions | dextromethorphan CYP2D6 inhibitor piracetam L-glutamine |
| Topics | Depression Ketamine Esketamine |
| Keywords | Cyp2d6-inhibiting antidepressants Dxm Glutamatergic Glutamine Piracetam |
| Citations | 6 |
| Key points | Proposes that a four-component oral regimen may approximate ketamine's full plasticity cascade for rapid antidepressant effects, but remains untested in humans. |
Abstract
Rapid-acting antidepressants show that mood can lift within hours when glutamatergic circuits shift from an "NMDA-dominant" to an "AMPA-dominant" state. Intravenous ketamine achieves this flip but is hampered by dissociation and logistics, while dextromethorphan + bupropion (Auvelity®) primarily supplies the initial NMDA blockade and yields slower, less durable benefit. We hypothesize that a fully oral, low-cost, four-component regimen may be able to approximate ketamine's full plasticity cascade (1) dextromethorphan (DXM) for NMDA antagonism; (2) a potent CYP2D6 inhibitor (fluoxetine, paroxetine, or high-dose duloxetine) to prolong DXM exposure; (3) piracetam as an AMPA positive allosteric modulator; and (4) micronized L-glutamine to restore presynaptic glutamate pools and buffer against excitotoxicity. Preclinical evidence supports mechanistic synergy along the same axis, but the full combination remains untested in humans. This hypothesis warrants formal preclinical and clinical evaluation.
Comparable studies
Other theoretical and historical papers on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| An Integrative Approach to Ketamine Therapy May Enhance Multiple Dimensions of Efficacy: Improving Therapeutic Outcomes With Treatment Resistant Depression. | 2021 | Theoretical or philosophical paper | |
| Arketamine for cognitive impairment in psychiatric disorders | 2023 | Theoretical or philosophical paper | |
| The Montreal model: an integrative biomedical-psychedelic approach to ketamine for severe treatment-resistant depression | 2023 | Theoretical or philosophical paper | |
| Ketamine in Bipolar Disorder: A Review | 2020 | Theoretical or philosophical paper | |
| Rethinking the role of TRKB in the action of antidepressants and psychedelics. | 2024 | Theoretical or philosophical paper |