Submitted:
04 December 2025
Posted:
09 December 2025
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Abstract
Ketamine’s ability to lift mood and spur new synapse growth has put glutamate biology at the center of modern neurotherapeutics. Yet the drug’s intravenous route, monitoring requirements, and dissociative effects make it a poor candidate for long-term prevention of Alzheimer’s disease (AD).Here we advance a testable hypothesis: an all-oral “synaptogenic stack” could mimic ketamine’s downstream benefits—namely, the rise in brain-derived neurotrophic factor (BDNF) and the activation of mTOR—while avoiding its toxicities.The stack combines three inexpensive agents that have decades of human use. First, dextromethorphan, kept in circulation with a small dose of a CYP2D6 inhibitor, provides gentle NMDA antagonism. Second, piracetam acts as a positive modulator of AMPA receptors, boosting fast excitatory transmission. Third, oral L-glutamine replenishes presynaptic glutamate stores and buffers against excitotoxic spill-over. Working in concert, these drugs should reduce extrasynaptic NMDA stress, enhance AMPA throughput, and preserve dendritic spine density in the ageing brain.If this mechanism proves sound, the regimen offers a low-cost, scalable way to delay the clinical onset of AD, particularly in people who already show prodromal biomarkers or genetic risk. Prospective trials are needed to evaluate safety, target engagement, and long-term cognitive outcomes.
Keywords:
Alzheimer’ s disease
; preclinical AD
; synaptic dysfunction
; glutamate
; NMDA receptor
; extrasynaptic NMDA
; AMPA receptor
; neuroplasticity
; dextromethorphan
; piracetam
; L-glutamine
; CYP2D6 inhibition
; Glutamatergic Regimen
; disease prevention
; synaptogenesis
; BDNF
; mTOR
; ketamine-like mechanism
; cognitive reserve
; APOE4
; primary prevention
Background
Alzheimer's disease (AD) is now viewed less as a sudden loss of memory and more as a very long slide into synaptic failure that can start 20 or 30 years before a diagnosis [1,2]. In the earliest phase, two things go wrong with glutamate signalling. First, extrasynaptic NMDA receptors—especially those that carry the NR2B sub-unit—become hyperactive. At the same time AMPA receptors, which should sit in the synapse and pass the fast excitatory message, are pulled inside the neuron and degraded [3,4,5,6] Together these shifts set off calcium overload, oxidative stress, loss of long-term potentiation, spine shrinkage and, finally, cell death [7]. Drugs on the market today arrive late in that process and work on only half of the problem—for example, memantine mostly calms the rogue NMDA channels [8]. A better preventive approach would dampen toxic NMDA activity, rescue AMPA traffic and spark new synapse growth while the network is still salvageable.
The Cheung Glutamatergic Regimen
Cheung's four-part oral stack was first built for stubborn mood and anxiety illnesses, yet its design maps neatly onto those early AD defects [9,10,11]. The plan is simple and inexpensive: dextromethorphan (DXM) at 30–120 mg a day; a low dose of a strong CYP2D6 blocker such as fluoxetine, paroxetine or high-dose duloxetine to keep DXM in the blood; piracetam 1.6 g a day to nudge AMPA receptors; and supplementary oral l-glutamine to refill presynaptic stores and curb excitotoxicity. Together, these agents reproduce the "NMDA-to-AMPA flip" that underlies ketamine's burst of plasticity [12,13,14].
Mechanistic Alignment with Early AD Pathophysiology
Selective dampening of extrasynaptic NMDA noise is the first pillar. Like low-dose ketamine or memantine, high but steady DXM blocks open NMDA channels in a voltage-dependent way and shows a clear preference for NR2B-rich receptors [8]. Because soluble Aβ forces exactly these receptors to the cell surface and even drives damaging metabotropic signals without ion flow ([15,7], DXM held in circulation by a CYP2D6 inhibitor [11] could blunt calcium overload and tau mis-chief long before plaques appear.
The second pillar is keeping AMPA receptors where they belong. Aβ promotes rapid tagging and internalisation of GluA1/GluA2 receptors, a change that tracks closely with memory loss [4,5,6]. Piracetam reverses that trend: work in aged and amyloid-exposed systems shows more surface AMPA receptors, stronger currents and better LTP after treatment [16,17]. By preserving fast transmission, piracetam may protect dendritic spines through the long pre-clinical window.
Third, presynaptic glutamate stores need topping up. Stress and early amyloid lesions drain vesicular glutamate and weaken release probability [18,19]. Oral l-glutamine quickly restores the glutamate–glutamine cycle, normalises excitatory postsynaptic currents and sharpens cognition in stressed or amyloid-bearing animals [18,19]. Curiously, when extracellular glutamate soars under inflammatory pressure, high-dose glutamine can actually bring it down [20,19], providing a two-way safety net against excitotoxicity.
Finally, the pairing of an NMDA brake with an AMPA accelerator triggers a well-studied plasticity cascade: BDNF release and mTOR-dependent spine formation [12,21]. Because BDNF/TrkB signalling falters early in AD, repeated activation through the Cheung stack could hold synaptic density steady in people at risk [9].
Emerging Clinical Signals Relevant to Cognition and Neuroprotection
Case reports already hint at brisk cognitive gains with the full or partial regimen. Patients describe clearer thinking, faster processing and stronger working memory within weeks—improvements that mirror the subtle executive losses seen years before an AD diagnosis [22,23,24,25]. One young man with schizoaffective disorder said the stack "cleared decades of mental sludge" after everything else had failed [23]. Although anecdotal, such stories match the known importance of healthy AMPA throughput for high-order cognition.
Feasibility for Long-Term Prevention
All four ingredients are off-patent, cheap (well under two dollars a day), taken by mouth and backed by decades of safety data. Side-effects tend to be mild—occasional insomnia, jitters or stomach upset—and usually ease with dose adjustment [9,11]. Because many clinicians already prescribe the stack off-label, it is uniquely positioned for pragmatic prevention trials in APOE-ε4 carriers, people with subjective cognitive decline or biomarker-positive preclinical AD.
Conclusions
The earliest biology of Alzheimer's looks like a tilt from a balanced NMDA–AMPA partnership toward runaway extrasynaptic NMDA activity and dwindling AMPA support. The Cheung Glutamatergic Regimen addresses both faults at once: sustained DXM plus a CYP2D6 blocker reins in toxic NMDA signalling; piracetam revives AMPA strength; glutamine refuels presynaptic stores and cushions against spill-over damage. Given its low cost, oral delivery and growing clinical experience, the regimen deserves fast-tracked trials as a primary or secondary preventive for Alzheimer's disease.
Conflict of Interest and Source of Funding Statement
None declared.
Funding Declaration
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Ethics Declaration
Not applicable.
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