What causes behavioral side effects in popular weight loss drugs?

By Dr. Sanchari Sinha Dutta, Ph.D.Reviewed by Danielle Ellis, B.Sc.Jan 23 2025

GLP1R gene variants link to cardiometabolic traits and behavioral changes, but findings suggest behavioral effects of GLP1RA are indirect

In a study published in Diabetes, Obesity, and Metabolism, researchers explored how GLP1R genetic variations influence mental ill-health and cardiometabolic traits, shedding light on GLP1RA's behavioral effects.

Background

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), commonly used for type 2 diabetes and obesity, are gaining attention for their potential effects beyond weight loss. Mental health disorders frequently overlap with metabolic diseases, with studies showing links between obesity, depression, and shared biological pathways.

Emerging evidence suggests GLP-1 RAs may impact mental health and behavior, including reducing addictive behaviors like smoking and alcohol misuse. While their metabolic benefits—such as improved blood glucose control, reduced body fat, and lower inflammation—are well-documented, behavioral effects remain unclear.

Research shows mixed outcomes: some studies report protective or neutral effects on mental health, while others suggest adverse outcomes. Further research is needed to clarify these findings and guide their use in patients with both metabolic and mental health conditions.

The study

Scientists analyzed common genetic variants in the GLP1R gene in 408,774 white British, 50,314 white European, 7,667 South Asian, 10,437 multiple ancestries, and 7,641 African-Caribbean individuals.

The study found consistent associations between variants in the GLP1R gene and cardiometabolic traits, including body mass index (BMI), blood pressure, and type 2 diabetes, across ancestries.

Significant associations were also observed between GLP1R variants and behavioral traits in all ancestries except South Asian ancestry. Specifically, these associations were observed for risk-taking behavior, mood instability, chronic pain, and anxiety. 

The trans-ancestry meta-analysis showed consistent effects of GLP1R on cardiometabolic traits across ancestries but inconsistent effects on behavioral traits.

Notably, the study found that GLP1R variants influencing the cardiometabolic traits were separate from those influencing the behavioral traits.

Seven lead variants showed associations with behavioral traits. However, none of these variants influenced the expression levels of GLP1R gene, suggesting that the effects of GLP1R variants on behavioral traits are unlikely to occur through GLP1R. 

The study could not find any significant positive or negative impact of GLP1RA on behavioral changes. These observations collectively suggest that GLP1RA, as obesity and diabetes medicine, is unlikely to induce depression or other serious mental health disorders through GLP1R.

“Whilst it is not possible to directly compare genetic findings to the effects of a drug, our results suggest that behavioral changes are unlikely to be a direct result of the GLPRAs. Exactly how these indirect effects are occurring is currently unclear,” said Rona J. Strawbridge, the corresponding author and scientist at the University of Glasgow, UK. 

Study significance

The study provides valuable insights into the genetic architecture of the GLP1R locus and its associations with both cardiometabolic and mental disorder traits.

The study findings indicate that GLP1R variants influence these traits across different ancestries without directly mediating behavioral changes through GLP1R. Given these observations, scientists suggest that GLP1RA therapies might be employed broadly in patients with type 2 diabetes and obesity without undue concern for augmenting mental health problems. 

However, scientists highlight the need for long-term randomized controlled trials and pharmaco-epidemiological datasets to more conclusively understand the mental health and behavioral impacts of GLP1RA.