Therapeutic Efficacy and Safety of Memantine for Children and Adults With ADHD With a Focus on Glutamate-Dopamine Regulation: A Systematic Review

Objective: Pharmacotherapy plays a crucial role in treating attention-deficit/ hyperactivity disorder (ADHD). However, current medications for ADHD have limitations and potential adverse effects. Glutamate, a neurotransmitter that directly and indirectly modulates dopamine neurotransmission, is considered a new therapeutic target for ADHD. We conducted a systematic review to determine the efficacy and safety of memantine, an uncompetitive N-methyl D-aspartate (NMDA) receptor antagonist, in both pediatric and adult patients with ADHD. Data Sources: We searched PubMed, EMBASE, PsycINFO, and Cochrane Library for articles on memantine use in ADHD patients published up to August 31, 2023, using terms related to ADHD and memantine. Study Selection: Studies selected according to PRISMA guidelines. We included both randomized and nonrandomized trials for a comprehensive review. We excluded non-English publications, review articles, and studies without full text. Data Extraction: Two authors extracted data using the data extraction form designed for this review. Independent authors conducted a risk of bias assessment using risk of bias 2 (RoB 2) and Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I). Results: Six studies met the inclusion criteria, 3 on pediatric populations, and 3 on adults. Three studies were conducted in the United States (2 in adults) and 3 in Iran (1 in adults). Memantine showed potential benefits in managing ADHD symptoms and had a favorable safety profile. However, most studies involved small patient groups at single institutions, and their quality was low. Conclusions: Memantine has the potential to be a relatively safe alternative or adjunctive treatment for ADHD, but more refined studies with larger populations are needed. J Clin Psychiatry 2025;86(1):24r15507. Author affiliations are listed at the end of this article.