Preprints.org
November 28, 2025
Ngo Cheung
6 citations
preprint
An oral glutamatergic regimen combining dextromethorphan, a CYP2D6 inhibitor, piracetam, and l-glutamine shows promise for treating refractory mood and anxiety disorders, with case reports and small open series describing sudden, occasionally dramatic recoveries in depression, PTSD, chronic pain, and functional somatic syndromes. However, the pharmacokinetics require careful handling because the CYP2D6 blocker that maintains dextromethorphan levels can also push the drug or co-prescribed psychotropics into toxic territory, limiting the regimen's accessibility despite its potential to bring rapid-acting biology to outpatient clinics.
Preprints.org
November 25, 2025
Ngo Cheung
6 citations
preprint
Rapid-acting antidepressants can lift mood within hours by shifting glutamatergic circuits from an NMDA-dominant to an AMPA-dominant state. Intravenous ketamine achieves this but has dissociative side effects and logistical challenges; the oral combination dextromethorphan + bupropion (Auvelity) only provides initial NMDA blockade, yielding slower, less durable benefit. A proposed fully oral, low-cost, four-component regimen aims to replicate ketamine's plasticity cascade: dextromethorphan for fast NMDA antagonism, a strong CYP2D6 inhibitor to prolong DXM exposure, the AMPA positive allosteric modulator piracetam to amplify downstream glutamate burst, and micronized L-glutamine to restore presynaptic glutamate pools and buffer against excitotoxicity. Preclinical evidence suggests each element synergizes along the same mechanistic axis, potentially democratizing ketamine-level efficacy with inexpensive medications.
Frontiers in psychiatry
January 1, 2026
Ngo Cheung
4 citations
Rapid-acting antidepressants can lift mood within hours by shifting glutamatergic circuits from an NMDA-dominant to an AMPA-dominant state. Intravenous ketamine achieves this but causes dissociation and logistical challenges, while dextromethorphan plus bupropion (Auvelity) provides slower, less durable benefit. The authors hypothesize that a fully oral, low-cost, four-component regimen—dextromethorphan for NMDA antagonism, a potent CYP2D6 inhibitor to prolong DXM exposure, piracetam as an AMPA positive allosteric modulator, and micronized L-glutamine to restore presynaptic glutamate pools—may approximate ketamine's full plasticity cascade. Preclinical evidence supports mechanistic synergy, but the combination remains untested in humans, warranting formal evaluation.
Zenodo (CERN European Organization for Nuclear Research)
January 19, 2026
Ngo Cheung
1 citation
Antidepressants that target different brain pathways—glutamatergic (ketamine-like), monoaminergic (SSRI-like), and GABAergic (neurosteroid-like)—vary in how quickly they work, how long effects last, and the risk of triggering mania, especially in people with bipolar disorder. A computer model simulating depression showed that while all three restored normal performance initially, the ketamine-like approach rebuilt neural connections, leading to better resilience under extreme stress and no manic relapse after stopping treatment. The neurosteroid-like approach worked rapidly but caused relapse in 88.3% of cases when discontinued. The SSRI-like method was slowest, showed the highest risk of mania, and led to 95.0% relapse after cessation. These results suggest that selecting antidepressants based on their mechanism could improve safety and long-term outcomes.
Zenodo (CERN European Organization for Nuclear Research)
January 14, 2026
Ngo Cheung
1 citation
A computational model of major depressive disorder shows that excessive synaptic pruning during development leaves neural networks brittle, reducing accuracy under noise to about 32% when 95% of connections are removed. A single regrowth cycle that restores half the lost weights, followed by extended consolidation (15–20 epochs of fine-tuning), returns accuracy to roughly 97% and eliminates relapse losses from a second pruning challenge. Repeated smaller regrowth cycles further reduce residual sparsity below 1%, lift extreme-stress accuracy 9–11 points beyond single repair, and provide strong protection against relapse. These simulations suggest that lasting stability depends on both the duration and repetition of plasticity, explaining the clinical advantage of maintenance or multi-dose ketamine protocols.
Preprints.org
December 22, 2025
Ngo Cheung
1 citation
preprint
Obsessive-compulsive disorder remains treatment-resistant in 40–60% of patients despite optimized serotonin-reuptake inhibitor therapy and antipsychotic augmentation. Emerging evidence points to glutamatergic dysregulation in cortico-striato-thalamo-cortical circuits as a core driver of rigid, maladaptive synaptic patterns. The Cheung Glutamatergic Regimen—a fully oral, low-cost combination of dextromethorphan, a CYP2D6 inhibitor, piracetam, and optional L-glutamine—aims to replicate the rapid neuroplastic cascade triggered by intravenous ketamine.
Preprints.org
December 2, 2025
Ngo Cheung
1 citation
preprint
A 48-year-old man with treatment-resistant depression experienced dramatic mood improvement and elimination of suicidal thoughts after a single dose of intranasal esketamine, but the high cost (HK $6,000 per session) forced him to stop treatment. Over two years, his condition evolved into severe obsessive-compulsive disorder with violent intrusive images. In 2025, he was switched to an oral regimen designed to mimic ketamine's mechanism: dextromethorphan 120 mg/day, fluoxetine 20–40 mg/day, and piracetam 1.2 g/day. Within four weeks, intrusive imagery became sporadic, his PHQ-9 score dropped from 17 to 5–6, suicidal ideation disappeared, and he returned to full work productivity. Gains persisted for over eight months at a monthly cost of HK $400–600, less than one-tenth the cost of maintenance esketamine.
Cureus
June 1, 2026
Hoi Ki Cheung, Ngo Cheung
A 26-year-old woman with severe contamination-focused obsessive-compulsive disorder (OCD) that persisted despite standard treatments showed meaningful improvement after a glutamatergic augmentation strategy using dextromethorphan, piracetam, and L-glutamine, combined with CYP2D6-inhibiting antidepressants. Over nine months, bathing time decreased from about 1.5 hours to about 30 minutes, and ritual preoccupation reduced by 20-30%. Mood, energy, motivation, and daily functioning improved, and passive suicidal ideation resolved temporarily. Residual cleaning symptoms remained at home. The case is hypothesis-generating and not evidence of regimen-specific efficacy; larger controlled studies are needed.
Frontiers in psychiatry
January 1, 2026
Ngo Cheung
Four patients with hard-to-treat trauma-spectrum disorders—somatic PTSD, acute bereavement-related PTSD, trauma-linked adolescent depression, and complex PTSD with bipolar II, ADHD, and borderline features—showed clinically meaningful symptom improvement within days to weeks after starting an inexpensive oral protocol centered on dextromethorphan potentiated by fluoxetine, with optional piracetam or bupropion. Reductions in intrusive memories, rumination, somatic pain, and functional disability were noted; no episodes of dissociation, hypertension, or mania were clinically documented during follow-up, though structured screening for hypomania and serotonergic toxicity was not performed. The findings are hypothesis-generating and suggest further controlled investigation of oral NMDA-AMPA modulators for trauma-related conditions.