Adults with attention-deficit/hyperactivity disorder (ADHD) frequently experience residual symptoms such as cognitive fatigue, brain fog, and reduced motivation despite optimized stimulant therapy. Emerging evidence points to disrupted dopamine-glutamate coupling and insufficient synaptic pruning as contributors to these persistent deficits, suggesting a potential role for glutamatergic modulation inspired by ketamine's rapid neuroplastic effects. This report describes a 25-year-old man with childhood-onset ADHD who, despite trials of high-dose methylphenidate (up to 72 mg) and lisdexamfetamine (up to 80 mg), continued to report daytime lethargy, mental sluggishness, irritability, and oversleeping while on moderate-dose extended-release methylphenidate (Concerta 36-54 mg daily). After several weeks of monotherapy yielding incomplete benefit, low-dose dextromethorphan (DXM, 30 mg as needed) and piracetam (600 mg as needed) were introduced on a pro re nata (PRN, as-needed) basis, primarily on workdays with higher cognitive demands. Within one week, the patient reported a marked and reproducible shift: elimination of afternoon tiredness, clearer thinking, reduced irritability, enhanced processing speed, and restored functional drive, with symptoms reverting on days the adjuncts were withheld. No significant adverse effects were noted. This single-case observation suggests that low-dose dextromethorphan, through brief N-methyl-D-aspartate modulation, combined with piracetam’s α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) potentiation, may enhance methylphenidate’s modest glutamate release, potentially promoting an AMPA-favorable plasticity state that could help mitigate pruning-related network inefficiencies often seen in adult ADHD. Carefully designed controlled studies are needed to better understand efficacy, optimal dosing, and long-term safety of such combinations (preliminary observation only).
Ngo Cheung (2026) studied this question.