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 |
Citations in the library
Cited by 5
- Transient entanglement in minimal open XXZ spin chains: a toy-model analogy for microtubule-inspired quantum biology Frontiers in Psychiatry August 11, 2026
- Optimized Oral Glutamatergic Augmentation in Refractory Home-Dominant Contamination Obsessive-Compulsive Disorder With Somatic, Affective, and Motivational Features: A Case Report of Incremental Functional Gains. Cureus June 1, 2026
- Rapid Symptom Reduction Following Intramuscular Ketamine in Refractory Obsessive–Compulsive Disorder: A Case Report Case Reports in Psychiatry 2026
- Differential Improvement in Obsessive Rumination and Fantasy Intrusions Versus Attachment-Related Emotional Dysregulation During Oral Glutamatergic Augmentation in a 16-Year-Old Adolescent. Cureus July 1, 2026
- Longitudinal Outcomes of Oral Glutamatergic Augmentation in Trauma-Related Dissociation: A Six-Month Case Study. Cureus May 1, 2026
Cites 6
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Dextromethorphan-bupropion (Auvelity) for the Treatment of Major Depressive Disorder Clinical Psychopharmacology and Neuroscience July 17, 2023
- Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression. Behavioural Brain Research June 6, 2011
and 1 more in the library