Cognitive Consequences of Benzodiazepine Use: Is it Worth Losing Our Mind Over?

Benzodiazepines are a commonly prescribed class of medications used to manage conditions such as anxiety, insomnia, alcohol withdrawal, muscle spasms, and seizures. Due to the potential for dependence, withdrawal and long-term adverse effects (AEs), they’re only intended for short term use.

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However, benzodiazepines are frequently used to manage disease states long-term despite labeling recommending that the duration of use of these medications be limited to a maximum of 2-4 weeks.¹ In a meta-analysis of 13 studies, the average duration of benzodiazepine use was 9.9 years, with some patients using benzodiazepines for as long as 34 years, which is much longer than the recommended duration.² This is concerning because as health care professionals, it is our responsibility to provide care that is not only effective, but safe for patients. The safety and efficacy of long-term benzodiazepine use beyond the recommended timeframe is not well understood.³

One of the primary concerns of long-term benzodiazepine use is their impact on cognitive function. There is still much that is unknown about long-term use of benzodiazepines leading to cognitive impairment, but they are still widely used.⁴

Some prescribers believe that cognitive impairment resulting from benzodiazepine use is only a transient effect related to peak plasma levels and time since last dose;² however, a multitude of studies have shown otherwise. Several studies have shown that long-term use of benzodiazepines can cause impairment in numerous dimensions of cognitive function.²

In current long-term users, benzodiazepines have been shown to cause impairment in the domains of motor coordination, psychomotor speed, verbal reasoning and learning, executive function, sensory processing, episodic memory, and concentration.^2,5 They have also been shown to cause decreased IQ, processing speed, and visuospatial and visuomotor abilities. They can also result in delayed response time and an altered perception of self, environment, and relationships in addition to causing deficits in expressive language, working memory, visuoconstruction, and divided attention.^2,6

In a meta-analysis that included 13 studies in which the average length of benzodiazepine use was 10 years, cognitive impairment was found in all domains studied, including sensory processing, visuospatial abilities, and motor performance.² Another study analyzing the impact of long-term benzodiazepine use on cognition found that about 21% of subjects had cognitive impairment in all domains studied.⁵ All of these studies further corroborate the detrimental impact benzodiazepines can have on patients’ cognitive abilities.

In addition, multiple studies have implicated inappropriate use of benzodiazepines as a risk factor for dementia-related illnesses. In a meta-analysis including both clinical and observational studies, Ettcheto et al. supported that the long term us of benzodiazepines—especially in elderly patients—increases the risk of Alzheimer disease and dementia.⁷ The increased risk of dementia was determined to be further compounded when patients take high cumulative doses.⁷

Another study by Islam et al. concluded that long-term exposure to benzodiazepines increases the risk of dementia by as much as 78% compared to those who do not use benzodiazepines.⁸ The exact mechanism by which benzodiazepines increase the risk of dementia disorders is unknown; however, some proposed ways in which they may lead to dementia include preventing the ability to create new memories by inhibiting brain activity and synaptic plasticity, decreasing metabolic activity in the brain, and encouraging the formation of neurofibrillary tangles.⁷

Although a variety of studies have found that benzodiazepines can potentially lead to dementia, other studies have presented conflicting evidence that long-term use does not lead to an increased risk for Alzheimer disease or dementia.^7,9 One study even found that benzodiazepines may have a beneficial impact on preventing these diseases; however, this could be because disease states treated by benzodiazepines, including insomnia and anxiety, are implicated in dementia and benzodiazepines help manage these disease states.⁹

A major hindrance to our current knowledge in this area is that a majority of studies are observational—meaning that a causal relationship can’t be determined.⁸ Once again, this means more research is needed in this area to further the knowledge on the relationship between benzodiazepine use and dementia risk.

As previously mentioned, the effects of long-term benzodiazepine use are not well understood, and many prescribers believe that the pernicious effects of benzodiazepines on cognition are temporary. However, studies also demonstrate that cognitive dysfunction attributed to benzodiazepines are long lasting and can persist for extended periods after discontinuation.

Fortunately, previous long-term benzodiazepine users experience some degree of improvement in cognitive abilities.⁴ On the other hand, this improvement is not always enough to allow previous users to return to baseline levels of functioning.

One study supported that although patients improve after cessation of benzodiazepines, they never improve to the level of cognitive function of controls who have not used benzodiazepines.² Impairments have been found to persist in domains, including speed of processing, working memory, and divided and sustained attention.⁶

In a study following previous benzodiazepine users for 6 months after withdrawal, it was observed that they continued to show dysfunction in multiple cognitive domains compared to controls. Another study followed previous benzodiazepine users and saw impairments in cognitive function even at 10 months post discontinuation.⁶

These studies support continued impairment at 6 and 10 months after discontinuation of benzodiazepines but it is unknown whether or when cognitive function will return to baseline levels.⁵ A potential confounding factor in whether patients return to normal cognitive function is that benzodiazepines are often used to manage mental health disorders, which can lead to some degree of cognitive impairment. If patients discontinue treatment, it’s possible that symptoms of these diseases may return; however, in studies comparing cognitive function in previous benzodiazepine users to controls and anxious controls, previous benzodiazepine users still performed worse in multiple cognitive categories.^4,6

Knowing that using benzodiazepines beyond the recommended duration can have such detrimental lasting effects on patients, it’s important that providers take the time to educate themselves to make the best decisions for patient health. Many patients trust their providers to make decisions in their best interest, so it is crucial that providers ensure that when benzodiazepines are used as a means of treatment, they are the best available option based on a thorough risk benefit assessment.

It is also essential that prior to being prescribed benzodiazepines, patients are educated on the potential harms so they can be involved in making a decision they feel most comfortable with. In addition, this is yet another opportunity to further involve pharmacists as members of the health care team.

Pharmacists truly are the medication experts, so they can play an integral role in helping with patient care decisions, such as determining whether there are better alternatives, whether a medication is the best choice for a patient, and finding ways to minimize the risk of certain AEs.

Some important things to be aware of—and for providers to consider—regarding the reduction of harm to patients caused by long-term benzodiazepine use are risk factors. Certain patient populations are at a higher risk of experiencing lasting AEs on cognition, including those taking higher doses, elderly patients, and those using benzodiazepines concomitantly with drugs, alcohol, or anticholinergic psychotropic medications.²

Concerning age as a risk factor, older patients are at a higher risk of experiencing reduced recovery of cognition after discontinuation of benzodiazepines.⁶ This is because as patients get older, they have fewer neurons and receptors to which benzodiazepines can bind—meaning more receptors are occupied at the same dose, which makes them more susceptible to the AEs of benzodiazepines.³

Pharmacokinetic properties of benzodiazepines also play a role in the probability of patients experiencing cognitive dysfunction after withdrawal from long-term benzodiazepine use. For example, agents with shorter half-lives tend to have a lower risk of cognitive impairment, whereas those with intermediate to long half-lives have an increased risk.⁶

Another potential risk factor for experiencing cognitive impairment after long-term benzodiazepine use is sex, however, there is conflicting evidence on whether males or females are at a higher risk. One study stated that males were at an increased risk, however, another supported that women are at a higher risk.

In one study, women were found to have a significantly lower compound cognitive score than men, and sex was determined to be an important predictor of cognitive dysfunction.⁵ Women were found to have a worse cognitive function performance; however, it was determined to be due to state anxiety and when this was accounted for, sex was no longer found to be a predictor of worse cognitive function. Instead, it was determined that state anxiety itself was the predictor.⁵

This conflicting evidence on sex as a risk factor further goes to show that more research is needed to increase our knowledge on the long-term effects of benzodiazepines not only on cognition, but on overall health. It is important for providers to assess for these risk factors prior to prescribing benzodiazepines to patients because those with an increased risk may not be the best candidates for benzodiazepines, especially in the long term, and it may be an important time to consider alternatives.

Due to inadequate knowledge on the impact of long-term benzodiazepine use on cognition, health care professionals must educate themselves on the potentially harmful AEs of benzodiazepines because we are entrusted with making quality health care decisions for patients. This is even more important because labeling for the recommended duration of use of benzodiazepines was only recently updated, so disseminating this information to providers is crucial.

Once again, this is also a call to further involve pharmacists in the health care team because their expertise in the safe and effective use of medications can not only save lives, but improve their quality.

References

1. Kennedy KM, O'Riordan J. Prescribing benzodiazepines in general practice. Br J Gen Pract. 2019 Mar;69(680):152-153. doi: 10.3399/bjgp19X701753. PMID: 30819759; PMCID: PMC6400612.

2. Stewart SA. The effects of benzodiazepines on cognition. J Clin Psychiatry. 2005;66 Suppl 2:9-13. PMID: 15762814.

3. Lader M. Benzodiazepine harm: how can it be reduced? Br J Clin Pharmacol. 2014 Feb;77(2):295-301. doi: 10.1111/j.1365-2125.2012.04418.x. PMID: 22882333; PMCID: PMC4014015.

4. Barker MJ, Greenwood KM, Jackson M, Crowe SF. An evaluation of persisting cognitive effects after withdrawal from long-term benzodiazepine use. J Int Neuropsychol Soc. 2005 May;11(3):281-9. doi: 10.1017/S1355617705050332. PMID: 15892904.

5. Zetsen SPG, Schellekens AFA, Paling EP, Kan CC, Kessels RPC. Cognitive Functioning in Long-Term Benzodiazepine Users. Eur Addict Res. 2022;28(5):377-381. doi: 10.1159/000525988. Epub 2022 Aug 30. PMID: 36041417.

6. Crowe SF, Stranks EK. The Residual Medium and Long-term Cognitive Effects of Benzodiazepine Use: An Updated Meta-analysis. Arch Clin Neuropsychol. 2018 Nov 1;33(7):901-911. doi: 10.1093/arclin/acx120. PMID: 29244060.

7. Ettcheto M, Olloquequi J, Sánchez-López E, Busquets O, Cano A, Manzine PR, Beas-Zarate C, Castro-Torres RD, García ML, Bulló M, Auladell C, Folch J, Camins A. Benzodiazepines and Related Drugs as a Risk Factor in Alzheimer's Disease Dementia. Front Aging Neurosci. 2020 Jan 8;11:344. doi: 10.3389/fnagi.2019.00344. PMID: 31969812; PMCID: PMC6960222.

8. Islam MM, Iqbal U, Walther B, Atique S, Dubey NK, Nguyen PA, Poly TN, Masud JH, Li YJ, Shabbir SA. Benzodiazepine Use and Risk of Dementia in the Elderly Population: A Systematic Review and Meta-Analysis. Neuroepidemiology. 2016;47(3-4):181-191. doi: 10.1159/000454881. Epub 2016 Dec 24. PMID: 28013304.

9. Pariente A, de Gage SB, Moore N, Bégaud B. The Benzodiazepine-Dementia Disorders Link: Current State of Knowledge. CNS Drugs. 2016 Jan;30(1):1-7. doi: 10.1007/s40263-015-0305-4. PMID: 26715389.