This study is a 12-week, randomized-controlled trial of memantine hydrochloride (Namenda) for the treatment of social impairment in adolescents with autism spectrum disorder (ASD). The investigators will also conduct pre- and post-treatment neuroimaging (functional magnetic resonance imaging [fMRI] and hydrogen magnetic resonance spectroscopy [HMRS]) to assess neural functional deficits in adolescents with autism spectrum disorder compared to healthy volunteer adolescents. This pre- and post-neuroimaging will also be used to assess any effects of memantine therapy on neural function in adolescents with autism spectrum disorder. The investigators hypothesize that short-term memantine monotherapy will be safe, well-tolerated, and effective in improving the core symptoms of autism spectrum disorder in adolescents with autism spectrum disorder. Additionally, the investigators hypothesize that following memantine therapy, adolescents with autism spectrum disorder will exhibit a decrease in glutamate (Glu) concentration in the anterior cingulate cortex (ACC) and a change towards normalization in altered functional connectivity of the anterior cingulate cortex and medial temporal lobes, consistent with improvement in social impairments in autism spectrum disorder. The investigators hypothesize that compared to healthy volunteer participants, participants with autism spectrum disorder will significantly differ on neuroimaging measures at baseline but that following memantine therapy, the difference between autism spectrum disorder and healthy volunteer neuroimaging data will decrease.

INCLUSION CRITERIA

All Participants:

1. Male and female participants, ages 8-17 years (inclusive)

   Participants with Autism Spectrum Disorder:

2. Meets Diagnostic and Statistical Manual-5 autism spectrum disorder diagnostic criteria, as established by clinical diagnostic interview

3. At least moderate severity of social impairment, as measured by a total raw score of ≥85 on the parent/guardian-completed Social Responsiveness Scale, Second Edition (SRS-2) and a score of ≥4 on the clinician-administered Autism Spectrum Disorder Clinical Global Impression-Severity scale (ASD CGI-S)

Healthy Control Participants:

2. Age-, sex-, and IQ-matched with participants with autism spectrum disorder 3. No Axis I diagnoses, as established by the Kiddie Schedule for Affective Disorders and Schizophrenia-Epidemiological Version (K-SADS-E) and confirmed by clinical diagnostic interview 4. No significant traits of autism spectrum disorder, as measured by a total raw score of <60 on the parent/guardian-completed Social Responsiveness Scale, Second Edition

EXCLUSION CRITERIA

All Participants:

1. IQ ≤70 based, on the Wechsler Abbreviated Scale of Intelligence, Second Edition (WASI-II) Vocabulary and Matrix Reasoning subtests

2. Impaired communicative speech

3. Current treatment with the following medications, which are known to impact glutamate levels:

   1. Lamotrigine
   2. Amantadine
   3. N-acetylcysteine
   4. D-cycloserine

4. Current treatment with a psychotropic medication, not listed above, on a dose that has not been stable for at least 4 weeks prior to study baseline

5. Co-administration of drugs that compete with memantine for renal elimination using the same renal cationic system, including hydrochlorothiazide, triamterene, metformin, cimetidine, ranitidine, quinidine, and nicotine

6. Initiation of a new psychosocial intervention within 30 days prior to randomization

7. Participants who are pregnant and/or nursing

8. Participants with a history of non-febrile seizures without a clear and resolved etiology

9. Participants with a history of or a current liver or kidney disease

10. Clinically unstable psychiatric conditions or judged to be at serious suicidal risk

11. Participants who meet for alcohol or drug dependence or abuse on the Kiddie Schedule for Affective Disorders and Schizophrenia-Epidemiological Version. If the participant has a recent history of substance abuse, as an added precaution, there will be a 2-week washout period before initiating the trial. There are no known safety issues relating to memantine and recent history of substance abuse.

12. Serious, stable or unstable, systemic illness, including hepatic, renal, gastroenterological, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease

13. Participants with severe hepatic impairment (Liver Function Tests [LFTs] >3 times the Upper Limit of Normal [ULN])

14. Participants with genitourinary conditions that raise urine Power of Hydrogen (pH) (e.g., renal tubular acidosis, severe infection of the urinary tract)

15. Known hypersensitivity to memantine

16. Severe allergies or multiple adverse drug reactions

17. A non-responder or history of intolerance to memantine after treatment at adequate doses, as determined by the clinician

18. Investigator and his/her immediate family, defined as the Investigator's spouse, parent, child, grandparent, or grandchild.

Baseline Participants in the Memantine and Placebo groups completed the Week 0: Baseline study visit. Baseline Participants in the Control group completed the Week 100: Baseline Scan study visit. The Baseline assignment is different for the Control group because they received no intervention and so did not complete the Week 0: Baseline study visit.

12 Weeks

Adverse events were collected from participants in the memantine arm and the placebo arm systematically, via regular investigator assessment. At every study visit, study clinicians queried participants and their parent(s)/guardian(s) about any adverse events that may have occurred since the last study visit. Participants in the Control Group were excluded from this analysis because they did not receive study medication and adverse events were not monitored/assessed for the Control Group.