Arbaclofen May Benefit Some Patients With Autism

Study results suggest continued study of arbaclofen for autism spectrum disorder.

Researchers have conducted a randomized, placebo-controlled, phase 2 study to examine the effects of arbaclofen on patients with autism spectrum disorder (ASD).

While arbaclofen did not appear to improve the primary outcome of the parent-rated Aberrant Behavior Checklist Social Withdrawal/Lethargy subscale, secondary analyses revealed improvements in the clinician-rated Clinical Global Impression of Severity (CGI-S) and in the Vineland Adaptive Behavior Scales II Socialization domain, suggesting that arbaclofen may have potential to improve symptoms in a subset of children with autism, but that further studies are needed.

“Several lines of emerging data point to an imbalance between neuronal excitation and inhibition in at least a subgroup of individuals with autism spectrum disorder (ASD), including in those with fragile X syndrome (FXS), one of the most common genetic syndromes within ASD,” wrote Jeremy Veenstra-VanderWeele, MD, from Columbia University, New York Presbyterian Hospital, and New York State Psychiatric Institute and colleagues.

Previous studies have shown a potential benefit of arbaclofen in autism, including:

  • GABA-B agonists improving brain and behavioral phenotypes, including social behavior, in animal models of FXS and ASD
  • The GABA-B agonist arbaclofen improving social avoidance in FXS in a phase 2 randomized, placebo-controlled, crossover trial
  • Similar benefits of arbaclofen on ASD suggested from a pilot open label trial

This exploratory, phase 2 trial with a randomized, double-blind, placebo-controlled, multi-site design was conducted at 25 sites in the United States between June 2011 and September 2012 ( identifier NCT01288716). The researchers recruited participants 5-21 years old who met DSM-IV-TR criteria for Autistic Disorder, Asperger’s Disorder, or PDD-NOS, based on clinician interview with caregivers and direct assessment of ASD symptoms on the Autism Diagnostic Observation Schedule.

Reasons for exclusion included a known genetic disorder associated with ASD, such as Rett syndrome, tuberous sclerosis, and fragile X syndrome.

Patients receiving arbaclofen started with 5 mg twice-daily, and could be increased every 7 days to 10 mg twice-daily, 10 mg 3 times daily, and 15 mg 3 times daily. Dosage was capped at 10 mg 3 times daily for patients 12 years and younger, and could be reduced in all participants depending on side effects experienced. Participants were evaluated at 2, 4, 8, and 12 weeks, and arbaclofen was tapered after 12 weeks over 28 days.

The researchers found no difference between arbaclofen and placebo in the primary outcome of the Aberrant Behavior Checklist Social Withdrawal/Lethargy subscale (ABC-SW/L). “Improvement in ABC-SW/L scores were observed in both the arbaclofen and the placebo groups, similar to previous studies that found substantial placebo effects in ASD,” the authors noted.2 The researchers also noted that due to the adverse events in the experimental group, future studies would benefit from a scale assessing lethargy as well as social symptoms in order to assess the potential benefits of arbaclofen.

The researchers did find a nominally significant difference in CGI-S scores in the 13% of patients who showed a shift in 2 or more points in the arbaclofen group. “This result suggests that there was a clinically meaningful change in global ASD symptoms in this subset of children, but planned analyses of other outcome measures did not show statistically significant differences that clarify what specific symptoms are improving in the overall group,” the authors wrote.

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The researchers concluded that their results suggest continued study of arbaclofen for ASD.

“We should not expect to see immediate success in this effort to find new treatments that benefit every child within this heterogeneous spectrum. We can, however, use our results to refine our approach to testing medications that could provide specific benefits to subgroups of children that may share common, underlying neurobiology.”

Limitations and Disclosures

  • The primary outcome was not significant. Additional analyses were conducted to examine whether future studies could have potential, but the nominally significant findings in these additional analyses could potentially be a false positive.
  • The nominally significant CGI-S finding is not matched by a significant change in the CGI-I, and did not clearly identify symptoms that improved in patients who took arbaclofen.
  • Analysis of VABS Socialization represents a posthoc analysis that only generated a hypothesis which must be confirmed in future studies.
  • The stronger effect of arbaclofen in patients with higher IQ or greater communication function requires replication in future studies to interpret.
  • Future research would benefit from testing arbaclofen in a subgroup of patients who are identified either with a biomarker that defines E:I imbalance, or by a cluster of genetic findings.

Disclosures: Jeremy Veenstra-VanderWeele, MD, received research funding from Seaside Therapeutics to conduct this study. He has consulted or served on advisory boards for Roche, Novartis, and SynapDx; has received research funding from Roche Pharmaceuticals, Novartis, SynapDx, and Forest; and has received stipends for editorial work from Springer and Wiley. Edwin H. Cook Jr, MD, consulted with and received research funding from Seaside Therapeutics to conduct this study. Bryan H. King, MD, consulted with and received research funding from Seaside Therapeutics to conduct this study. He has also consulted with Roche; has served on the Scientific Advisory Board of Confluence Therapeutics; and has received research funding from Roche and Novartis. Peter Zarevics, Maryann Cherubini, Karen Walton-Bowen, MSc, Paul P. Wang, MD, and Randall L. Carpenter, MD, were employees of Seaside Therapeutics at the time of the study. Mark F. Bear, PhD, and Randall L. Carpenter, MD, were co-founders of Seaside Therapeutics.

This study was funded by Seaside Therapeutics, which is no longer in business.


1. Veenstra-VanderWeele J, Cook EH, King BH, et al. Arbaclofen in children and adolescents with Autism Spectrum Disorder: a randomized, controlled, phase 2 trial. Neuropsychopharmacology. 2016; doi:10.1038/npp.2016.237.

2. Masi A, Lampit A, Glozier N, Hickie IB, Guastella AJ. Predictors of placebo response in pharmacological and dietary supplement treatment trials in pediatric autism spectrum disorder: a meta-analysis. Transl Psychiatry. 2016;5:e640. doi:10.1038/tp.2015.143.