In a recent preclinical study, researchers at McGill University found that metformin (an FDA-approved treatment for type 2 diabetes) improved behavior and memory in a mouse model of Phelan-McDermid syndrome. One key gene involved in Phelan-McDermid syndrome, SHANK3, helps control how brain cells communicate. When SHANK3 is not working properly, these communication pathways can become overactive or signaling may be unbalanced. The researchers studied mice that lacked SHANK3 (called SHANK3 knockout mice) to understand these effects.
Metformin is a type of drug called a “biguanide” that lowers blood sugar by reducing sugar production in the liver. Interestingly, it also affects brain pathways that are important for learning, memory, and behavior. In male SHANK3 knockout mice, metformin signaling pathway activity in the brain, as well as performance on common experimental tasks testing behavior and memory.
What else do we know?
Similar effects were seen in Fragile X syndrome, another rare genetic disorder affecting learning and behavior. In the mouse model of Fragile X syndrome, metformin improved performance on tasks of social communication and behavior. In the recent first randomized, double-blind, placebo-controlled trial of metformin in children with Fragile X syndrome (ages 2-16 years), improvements on measures of hyperactivity and sleep were reported for children on metformin compared to placebo. However, metformin did not improve learning, social communication, or repetitive behaviors. Long-term effects were not studied in this clinical trial.
What are some limitations?
All studies have limitations. Metformin was only tested in male SHANK3 knockout mice. It was not tested in female SHANK3 knockout mice, so it is not known whether similar benefits would be observed across both sexes. Additionally, metformin was given to SHANK3 knockout mice at birth, so future pre-clinical studies are needed in juvenile mice so that findings would be more similar to a human clinical trial.
Looking ahead
Metformin is considered a safe, widely available, FDA-approved medication and has shown potential benefit in individuals with another genetic disorder affecting learning and behavior. Thus, metformin is important to continue to study in mouse models of Phelan-McDermid syndrome to replicate and extend these new findings. Because a common side effect of metformin includes GI upset (which may exacerbate existing issues in individuals with Phelan-McDermid syndrome), it also may be important for researchers to determine whether there is a drug similar to metformin that has fewer side effects.
Ultimately, this study is an important first step in the drug development pathway to eventually testing its effects in individuals with Phelan-McDermid syndrome in a clinical trial. We will continue to follow updates closely!
Click here to read the full publication
Fragile X syndrome mouse study: https://pubmed.ncbi.nlm.nih.gov/28504725/
Fragile X clinical trial: https://link.springer.com/article/10.1186/s13229-025-00691-z