Alzheimer’s Disease Medication Shows Promise for Improving Social Impairment in Some Youth with Autism

A clinical trial of 42 intellectually capable individuals with autism spectrum disorder found that participants tolerated the drug memantine well and showed significant improvements in social functioning

Mass General Brigham researchers identified a potential biomarker that could help pinpoint those who are likely to respond well to treatment

Some people with autism spectrum disorder (ASD) have abnormal levels of glutamate in the brain. New research led by Mass General Brigham focused on this neuron-activating chemical, suggesting that a glutamate-modulating drug called memantine may improve social functioning in youth with ASD who do not have intellectual disabilities. The randomized clinical trial of 42 participants also found that participants with elevated glutamate in a specific brain region responded more favorably to treatment, which could help identify individuals most likely to benefit from treatment. Results are published in JAMA Network Open.

“If you have elevated blood glucose, we prescribe antidiabetic medications to decrease blood sugar levels. In the same way, we looked to see if glutamate modulators could improve social functioning in autism for individuals with abnormally high brain glutamate levels,” said corresponding author Gagan Joshi, MD, director of the Bressler Program for Autism Spectrum Disorder at Massachusetts General Hospital a founding member of the Mass General Brigham healthcare system. “We saw that patients who responded to memantine became more socially engaged.”

ASD affects more than 2% of all children and is characterized by difficulties in social interactions and communication. Prior research evaluating the effects of glutamate-modulating treatments on symptoms of autism have reported mixed results. These studies include memantine, a drug currently approved for treating moderate to severe Alzheimer’s disease. The researchers hypothesized that negative findings could be due to the use of lower drug doses and the inclusion of a broader range of participants with intellectual difficulties. A preliminary study that employed optimal doses of memantine in adults with ASD demonstrated promising results.

In this federally funded study, researchers built on these results. The team performed a 12-week, randomized, controlled trial involving ASD participants without intellectual disability between the ages of 8 and 18. Of the cohort of 42 participants, 33 completed the trial, with 16 participants receiving memantine and 17 receiving placebo. In addition, 37 of the participants with ASD as well as an additional 16 healthy controls underwent scanning to evaluate the pregenual anterior cingulate cortex (pgACC), a glutamate-rich brain region responsible for social processing and emotional awareness.

Memantine treatment was associated with a significantly higher rate of improvement in social behaviors (56%) compared to placebo (21%) and was generally well tolerated, although some participants reported mild side effects such as headaches. Furthermore, participants with ASD had elevated glutamate levels in the pgACC when compared to healthy controls. Among individuals with ASD, 54% had high levels of pgACC glutamate, while the remaining 46% had medium levels.

The investigators determined that treatment response varied based on pgACC glutamate activity. All memantine responders had high glutamate levels, and 80% of participants with abnormally elevated glutamate levels responded favorably to memantine. These results suggest that pgACC glutamate measurement could serve as a biomarker to identify patients who will benefit from memantine treatment.

Further research is needed to establish whether high glutamate levels can predict treatment responses to other glutamate modulators.

 “In our study, participants who responded to memantine showed improvements in social competence and a reduction in autism symptom severity, although they continued to experience milder features of autism,” said Joshi. “Larger clinical trials could help assess memantine responses in broader populations with ASD.”

Authorship: In addition to Joshi, Mass General Brigham authors include Atilla Gönenc, Maura DiSalvo, Tolga Atilla Ceranoglu, Mai Uchida, Christopher J. McDougle, and Janet Wozniak. Additional authors include Stephen V. Faraone and Amy M. Yule.

Disclosures: Joshi reports receiving support from the National Institute of Mental Health (NIMH) of the National Institutes of Health (NIH) under Award Number K23MH100450; research support from the Demarest Lloyd, Jr. Foundation as a primary investigator for investigator-initiated studies and Genentech and F. Hoffmann-La Roche Ltd. as a site PI for multi-site trials; speaker’s honorariums from the American Academy of Child and Adolescent Psychiatry, American Physician Institute, Asian College of Neuro-psychopharmacology, Hackensack Meridian Health, University of Colorado-Colorado Springs, Kennedy Krieger Institute, New York University, and Neuroimmune Institute; unpaid consultant for EuMentis Therapeutics; royalties from a licensed method for treating autism spectrum disorder through Mass General Brigham Innovation. Additional author disclosures can be found in the paper.

Funding: This work is funded by the National Institute of Mental Health of the National Institutes of Health under award number (K23MH100450).

Paper cited: Joshi G et al. “Efficacy of Memantine in Youth with Autism Spectrum Disorder” JAMA Network Open DOI: 10.1001/jamanetworkopen.2025.34927