A meta-analysis of scientific studies found that the risk of dementia increased 22% with every additional twenty daily doses of benzodiazepine medications that people took annually, according to a study in PLoS One.

Researchers from Chongqing Medical University in China analyzed six studies (involving 11,891 dementia cases and 45,391 participants) that provided risk estimates on the association of benzodiazepine use with dementia. They found that long-term benzodiazepine use was associated with about a 50% increase in risk of developing dementia. “The risk of dementia increased by 22% for every additional 20 defined daily dose per year,” they added.

The authors noted that early symptoms of dementia such as sleep disturbance, anxiety and depression can often begin ten years before people receive a diagnosis of dementia. For this reason, they stated, some researchers do not believe that benzodiazepines are causing dementia, but instead believe that people’s symptoms of dementia are motivating physicians to prescribe benzodiazepines.

The authors of the meta-analysis then put forth data and arguments to refute that perspective. Adjusting for the presence of symptoms of anxiety and depression did not change their findings, they noted. And comparing people who’d stopped taking benzodiazepines with people who were currently taking them also did not change their findings. Rates of developing dementia were about 50% higher for all of these different groups of past or present long-term users, the authors wrote, and the dose-response relationship they’d found persisted across all of the groups.

Such findings, they wrote, support arguments that there is “a causal relationship between benzodiazepine use and dementia.”

“Long-term benzodiazepine users have an increased risk of dementia compared with never users,” the researchers concluded. “However, findings from our study should be treated with caution due to limited studies and potential reverse causation. Large prospective cohort studies with long follow-up duration are warranted to confirm these findings.”

Zhong, GuoChao, Yi Wang, Yong Zhang, and Yong Zhao. “Association between Benzodiazepine Use and Dementia: A Meta-Analysis.” PLoS ONE 10, no. 5 (May 27, 2015): e0127836. doi:10.1371/journal.pone.0127836. (Full text)