Methylphenidate plus Piracetam: A Two-Drug, AMPA-Centric Alternative Replicating Ketamine’s Neuroplastic Signature

Rapid-acting antidepressant research has moved therapeutic attention from monoamines to glutamatergic neuroplasticity. Intravenous ketamine and the oral "Cheung Glutamatergic Regimen" (dextromethorphan, a CYP2D6 inhibitor, piracetam, glutamine) rely on NMDA-receptor antagonism to unleash glutamate and drive AMPA throughput, but the price is polypharmacy and demanding pharmacokinetics. I advance a counterproposal: pair methylphenidate (MPH) with the AMPA-positive allosteric modulator piracetam. Evidence indicates that MPH elicits a brief, prefrontal-selective rise in extracellular glutamate; piracetam can magnify this impulse and may recreate the "AMPA-dominant" plasticity state linked to ketamine-like efficacy.The safety of the combination is weighed against the excitotoxic risks posed by amphetamine stimulants, and clinical vignettes of executive-function recovery and "brain-fog" relief are reviewed.