Why Does Long-Term Benzodiazepine Use Cause Cognitive Impairment?

Benzodiazepines (sometimes called "benzos") are a class of psychoactive drugs that may be prescribed for conditions like anxiety, insomnia, and seizures. Benzodiazepines like diazepam (Valium, Ducene) and triazolam (Halcion) are widely used and considered to be effective, but are not safe as a long-term treatment. 

Scientists had already found that taking benzodiazepines for a long time can lead to physical dependence and cognitive impairment, particularly in older patients. But until recently, the cellular mechanism behind this effect wasn’t established, says Mario M. Dorostkar, PhD, from LMU's Center for Neuropathology and Prion Research and the German Center for Neurodegenerative Diseases (DZNE).

Dorostkar was one of the lead researchers on an animal study, published in Nature Neuroscience, which demonstrated that the active ingredient in benzodiazepines results in a loss of neural connections in the brain.

A Closer Look at the Study 

The scientists administered a daily sleep-inducing dose of the benzodiazepine diazepam to mice. After several weeks, they found that the mice had suffered synapse loss and cognitive impairment. When the diazepam treatment was stopped the effect persisted for some time, but was ultimately reversible.

It's all due to a specific protein, known as the mitochondrial 18 kDa translocator protein (TSPO). Benzodizepines bind to this protein on the surface of cell organelles of the microglia (the first immune cells to respond when something goes wrong in the brain). As the study authors explain, these cells are activated, which leads to the deterioration and recovery of synapses (connections between nerve cells).

The researchers believe that the study could have effects on how sleep disorders and anxiety are treated in people at risk of dementia. 

“Long-term use of benzodiazepines should be avoided, especially in elderly people,” Dorostkar says. “This has been recommended by organisations such as the American Geriatrics society, for several years. Currently, our lab is once more working on the initial question on what effects benzodiazepines have on the development of neurodegenerative diseases.”

Due to the effect of long-term benzodiazepine use on cognition, several alternatives are available. “These include drugs with different mechanisms of action as well as behavioural approaches, depending on the underlying condition,” says Dorostkar. He recommends that people currently taking benzodiazepines discuss whether alternatives can be considered with their prescribing physician. 

Alternatives to Medication for Anxiety and Insomnia 

While physicians may still prescribe benzodiazepine and other medications for anxiety and insomnia, other treatment options are available.

Cognitive behavioral therapy (CBT) is a form of talking therapy aimed at changing the way a person thinks and behaves, to help reduce symptoms of various mental health conditions, including anxiety disorders.

"CBT-i (cognitive behavioral therapy for insomnia) is a non-medication approach to treating insomnia," says psychotherapist Annie Miller, LCSW.

It helps to change thinking patterns and behaviors around sleep, with the cognitive piece focusing on beliefs and emotions around sleep and insomnia and the behavioral component helping to developing new habits through sleep scheduling and techniques that improve sleep drive, Miller explains.

CBT-i is a short-term therapy that typically takes about 6-8 sessions, and studies show that it can be up to 80 percent effective in reducing the symptoms of insomnia. One meta-analysis, published in Sleep Medicine Reviews, found that CBT-i had significant positive effects on insomnia severity, sleep efficiency, and sleep quality.

When it comes to more generalized anxiety, standard CBT can be very helpful, Miller says. Mindfulness can also be very beneficial when coping with anxiety.

"It is very important that people know therapeutic treatments are an option, as opposed to starting with medication," Miller says. "Therapy typically doesn't have any side effects and can provide more long-term results. Many physicians are now suggesting therapy before prescribing medications, particularly for sleep problems. CBT-i is now the first-line treatment for many providers."

An article published in Neurotherapeutics in 2019 advises doctors to be "very cautious" before prescribing benzodiazepines to older patients and recommends pursuing good sleep hygiene to alleviate the symptoms of anxiety or insomnia.

Per the Centers for Disease Control and Prevention (CDC), good sleep hygiene includes several steps. For starters, cut out (or cut back on) caffeinated beverages, particularly before bedtime, exercise regularly, adopt a consistent sleep routine (go to bed at the same time each night and get up at the same time each morning, including on the weekends), create a quiet, dark, relaxing sleeping space at a comfortable temperature, and remove TVs, smart phones, and other electronic devices from the bedroom.