Exploring a Pruning–Plasticity–Aging Hypothesis for Substance Use Disorders: Rationale for Investigating the Cheung Glutamatergic Regimen Combined With N-Acetylcysteine and Exploratory Aging Modulators

Substance use disorders (SUDs) remain undertreated, and existing pharmacotherapies address only part of the underlying biology. Recent pathway-level transcriptomic analyses by Cheung have proposed a neurodevelopmental model in which genetic liability for SUDs involves disrupted synaptic pruning, reduced adult synaptic plasticity, and altered cellular aging. This short report explores whether the Cheung Glutamatergic Regimen—an oral combination of dextromethorphan, a CYP2D6-inhibiting antidepressant, and piracetam—might be studied alongside N-acetylcysteine and exploratory low-dose lithium or metformin to engage multiple axes of this framework. Evidence for each component is reviewed, practical safety considerations are discussed, and a research agenda is outlined. The proposal remains speculative and is intended as a hypothesis for future investigation rather than clinical guidance.