Benzodiazepines, such as Valium and Xanax, are common medications used to treat anxiety, trouble sleeping, and seizures. They are known to be effective when used for a short period. However, doctors and scientists have long been concerned about what happens when people take these drugs for months or years.
Over time, some patients report problems like worsening inflammation or developing new health issues. Until now, the reasons behind these side effects weren’t well understood.
A new study, led by researchers at Virginia Commonwealth University and Columbia University, has uncovered important details about how benzodiazepines may affect the body after long-term use. Their findings were published in the journal Proceedings of the National Academy of Sciences and offer a new explanation that could help scientists design safer medicines in the future.
Benzodiazepines work by attaching to special proteins in the brain called GABAA receptors, which help calm brain activity. But these drugs also strongly attach to another protein in the body called HsTSPO1.
This protein lives on the outer membrane of mitochondria, which are the energy-making parts of cells. Scientists have long believed HsTSPO1 might be linked to side effects seen with benzodiazepines, but they didn’t fully understand what it does.
Some researchers had guessed that HsTSPO1 helped move cholesterol across cell membranes to help make hormones. But the VCU and Columbia team, led by Dr. Youzhong Guo and Dr. Wayne Hendrickson, had a different theory. They believed the protein might be acting as an enzyme, similar to how it works in bacteria.
The big challenge was that HsTSPO1 is a membrane protein, which means it lives in the fatty outer layers of cells. These types of proteins are hard to study because they lose their shape and function when removed from their natural environment. Most research methods use detergents to extract the proteins, but this can damage them.
To solve this, the team created a new method that doesn’t use detergents. Instead, they used special polymers to gently remove HsTSPO1 from cells while keeping its natural structure intact. This method let them observe the protein in conditions that closely resemble its real environment in the body.
Using this new method, the scientists discovered that HsTSPO1 acts as an enzyme that breaks down a substance called protoporphyrin IX, which is found in red blood cells. When HsTSPO1 breaks it down, it creates a new molecule the researchers named bilindigin.
This new molecule appears to help control levels of reactive oxygen species (ROS)—highly active chemicals that can damage cells and cause inflammation if they aren’t kept in check.
Here’s where it gets interesting: when benzodiazepines bind to HsTSPO1, they seem to block its ability to control ROS. This could lead to higher levels of these damaging chemicals, possibly causing the inflammatory side effects seen with long-term benzodiazepine use.
Inflammation linked to ROS can play a role in many serious diseases, including Alzheimer’s, arthritis, cancer, and multiple sclerosis.
This breakthrough could have a big impact. First, it helps explain why some people may develop health issues after taking benzodiazepines for a long time. Second, it offers a new target for drug companies looking to design better medicines—both safer benzodiazepines and entirely new treatments for diseases linked to inflammation.
The researchers believe that HsTSPO1 could be a powerful new target for drugs that aim to reduce inflammation. Since this protein exists in all forms of life—from bacteria to humans—it’s likely to play a very important and basic role in how cells manage stress and damage.
Dr. Guo says that now that we understand how HsTSPO1 works, we can start designing medications that avoid interfering with it—or even use it to treat diseases more effectively. While benzodiazepines remain useful drugs, this discovery opens the door to improving their safety and expanding treatments for a wide range of chronic illnesses.
In summary, this study sheds new light on why long-term benzodiazepine use might lead to side effects like inflammation. The protein HsTSPO1, which these drugs bind to, plays a key role in managing harmful molecules in the body.
By interfering with this process, benzodiazepines may unintentionally increase inflammation. With this new understanding, scientists can now explore ways to build better drugs and even treat other inflammation-related diseases more effectively.
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The research findings can be found in PNAS.
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