Daily use of diabetes drug metformin eases hyperactivity in fragile X boys
Still, small trial testing medication's effectiveness failed to meet main goal
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Six months of daily treatment with the diabetes medication metformin was significantly better than a placebo at easing hyperactivity and sleep problems in boys with fragile X syndrome, according to the results of a small clinical trial.
However, while those given metformin showed greater overall behavioral improvement than those on the placebo, these differences did not reach statistical significance. Thus, the single-center study failed to meet its main goal.
The researchers noted that the oral medication was generally well tolerated by the children in the study.
“Although the primary [goal] was not met, these secondary findings support further investigation of metformin for targeted behavioral domains in individuals with [fragile X],” the researchers wrote. The team added that larger and longer studies will be needed to confirm the therapy’s benefits and better evaluate its impact on behavioral issues.
The study, “Effects of Metformin on children with Fragile X Syndrome: a randomized, double-blind, placebo-controlled trial,” was published in the journal Molecular Autism.
A neurodevelopmental disorder fragile X is caused by mutations in the FMR1 gene that impair the production of a protein called FMRP. This protein helps in the proper development of synapses, or the sites of near-contact between nerve cells where electrical signals are relayed for communication.
A loss or shortage of the FMRP protein disrupts normal communication between nerve cells in the brain. As a result, nerve cells fire electrical signals more readily than usual, which leads to fragile X symptoms such as learning difficulties, developmental delays, anxiety, sleep problems, and hyperactive or autistic behaviors. Symptoms are often more severe in boys.
“Currently, the primary treatment of FRX involves behavioral interventions and symptomatic management,” the researchers wrote, adding that “despite extensive research,” no targeted therapy has proven effective or been approved for the condition.
Metformin, used for type 2 diabetes, also affects pathways in fragile X
Metformin, a widely used medication for type 2 diabetes, has drawn interest because it affects biological pathways that are overactive in fragile X.
“By attenuating the hyperactivity of these pathways, metformin is predicted to restore synaptic protein [balance] and rebalance excitatory-inhibitory dynamics, ultimately leading to functional improvements in neural circuits across multiple brain regions,” the researchers wrote.
Studies in animal models have shown that metformin can improve social behaviors and reduce repetitive actions, and clinical reports have hinted at possible benefits in a small number of adults and young children with fragile X.
Now, a research team in China conducted a Phase 4 clinical trial (NCT05120505) to assess metformin’s safety and effectiveness. It involved 34 children, all boys and ranging in ages from 2 to 16, who had genetically confirmed fragile X. All were enrolled at a single Chinese hospital between November 2021 and January 2025.
The children were randomly assigned to receive either weight-adjusted oral metformin or a placebo, once daily for six months. A total of 30 participants, 15 in each group, completed the study. Their mean age was 5.6 years at the time of study entry.
The trial’s main goal was to determine whether metformin would improve overall behavior after six months, measured using the Aberrant Behavior Checklist (ABC), a 58-item questionnaire covering five behavioral domains. It failed to reach that endpoint.
Clear benefits seen for hyperactivity behaviors in boys in trial
The results showed that boys who received metformin had a larger overall reduction in ABC scores than those given the placebo (by 16 vs. four points), suggesting greater improvement of behavioral issues. However, this difference failed to reach statistical significance, which had been the primary endpoint.
Still, one specific behavioral domain did show a clear benefit. On the ABC hyperactivity subscale, scores dropped by a mean of 7.86 points in children given metformin compared with 0.8 points in those on placebo. This reflected significantly greater reductions in behaviors such as restlessness, impulsivity, or difficulty sitting still with the therapy, according to the researchers.
Score changes on ABC subscales assessing irritability and repetitive behaviors also tended to favor metformin, but the group differences did not reach statistical significance.
The study provides foundational clinical evidence to support further investigation of metformin in larger, long-term trials incorporating objective biomarkers. … Given its established safety and accessibility, metformin represents a promising candidate for improving quality of life in individuals with [fragile X].
Metformin was also associated with significantly greater total score reductions in the Children’s Sleep Habits Questionnaire, a caregiver survey that assesses sleep problems in children over the prior month.
In addition, scores in the bedtime resistance domain — reflecting trouble settling down at night — were unchanged in the metformin group and increased (worsened) by about two points in the placebo group; a statistically significant difference. Other sleep domains also favored metformin, but group differences failed to reach statistical significance.
There were no significant differences between the two groups in terms of changes in measures of cognitive development, autism-related symptoms, or repetitive behaviors.
Metformin was generally safe and well tolerated. The overall rate of adverse events was similar in both groups, with the most commonly reported in the metformin group being mild increases in blood lactate levels (26.7%) and temporary loss of appetite (13.3%). Lactate is a substance the body naturally produces during energy use, and levels can rise during illness, stress, or with certain medications.
Overall, the researchers acknowledged that the study’s small size may have limited its ability to detect subtle changes and that the relatively short treatment period may not have captured longer-term effects. In addition, many outcomes relied on caregiver or clinician reports, which can introduce subjectivity, the team noted.
“The study provides foundational clinical evidence to support further investigation of metformin in larger, long-term trials incorporating objective biomarkers,” the researchers wrote. “Given its established safety and accessibility, metformin represents a promising candidate for improving quality of life in individuals with [fragile X].”
