The trial, led by Dr. Gagan Joshi and colleagues from the Alan and Lorraine Bressler Clinical and Research Program for Autism Spectrum Disorder at Massachusetts General Hospital, investigated whether memantine could enhance social functioning in children and adolescents with ASD.
The 12-week, double-blind, placebo-controlled study enrolled 42 participants between the ages of 8 and 17 years. All participants had ASD without intellectual disability (IQ ≥ 85). Using proton magnetic resonance spectroscopy (¹H-MRS), researchers also measured glutamate levels in the pregenual anterior cingulate cortex (pgACC), a brain region previously linked with social and cognitive functions.
Key findings of the study were as follows:
- Of the 42 youths enrolled, 35 were included in the efficacy analysis, with 16 receiving memantine and 19 receiving a placebo.
- At trial completion, 56.2% of participants in the memantine group met the response criteria, compared to 21% in the placebo group.
- The odds ratio of response was 4.8, showing a significantly higher likelihood of social improvement with memantine treatment.
- Memantine was well tolerated, with no significant difference in adverse events between the memantine and placebo groups.
- Youths with ASD had significantly higher pgACC glutamate levels compared with healthy controls (95.5 IU vs 76.6 IU).
- Elevated glutamate levels were found in over half of the ASD participants, defined as at least one standard deviation above healthy controls.
- In this subgroup, 80% of those treated with memantine showed improvement, compared with 20% in the placebo group.
- pgACC glutamate levels strongly predicted treatment response, indicating their potential as a biomarker for identifying likely responders to memantine.
The authors emphasized that while these results are promising, larger and more rigorous studies are required before memantine can be considered a standard therapy for ASD. They also highlighted the importance of further validating pgACC glutamate as a biomarker to personalize treatment strategies for autism.
"The clinical trial demonstrated that memantine may be a safe and effective intervention for addressing social impairments in youths with ASD without intellectual disability. The association between elevated pgACC glutamate levels and better treatment outcomes points toward the possibility of biomarker-guided treatment in the future," the authors concluded.
Reference:
Joshi G, Gönenc A, DiSalvo M, et al. Memantine to Treat Social Impairment in Youths With Autism Spectrum Disorder: A Randomized Clinical Trial. JAMA Netw Open. 2025;8(10):e2534927. doi:10.1001/jamanetworkopen.2025.34927
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