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Aging is often associated with some loss of cognitive function.[1] However, several prescription and over-the-counter medications also are associated with symptoms of cognitive impairment in older adults, such as confusion, memory loss, problems paying attention or difficulty thinking.[2] These symptoms are sometimes not recognized as drug induced but are either considered to be a normal part of aging or mistaken for symptoms of serious conditions such as Alzheimer’s disease and other types...
Aging is often associated with some loss of cognitive function.[1] However, several prescription and over-the-counter medications also are associated with symptoms of cognitive impairment in older adults, such as confusion, memory loss, problems paying attention or difficulty thinking.[2] These symptoms are sometimes not recognized as drug induced but are either considered to be a normal part of aging or mistaken for symptoms of serious conditions such as Alzheimer’s disease and other types of dementia.[3] Since drug-induced cognitive impairment often can be at least partially reversed if treatment is stopped,[4],[5] it is important to review all medications you are taking with your clinician if new symptoms of cognitive impairment occur.
Unfortunately, the cognitive safety of drugs studied in clinical trials is often ignored. For instance, an analysis of 803 study protocols registered in the United States between 2000 and 2022 found that only 6.5% of trials actively assessed whether the tested drug had any effect on cognitive function.[6]
The potential effects of many prescription and over-the-counter medications, such as antianxiety drugs, antidepressants, antipsychotics, antihistamines and pain medication, on cognitive function in older adults have long been established.[7] In particular, three classes of drugs have been repeatedly identified as problematic: anticholinergic drugs, benzodiazepines and Z-drugs, and proton pump inhibitors.[8],[9],[10]
Anticholinergic drugs
Anticholinergic drugs interfere with the neurotransmitter acetylcholine, which is responsible for transmitting some signals between nerve cells.[11],[12] These drugs are prescribed for asthma, Parkinson’s disease, certain psychiatric disorders, cardiovascular disease, allergies and other conditions.
Examples of anticholinergic drugs include antihistamines (such as cyproheptadine [generic only], diphenhydramine [BENADRYL and generics], and meclizine [ANTIVERT and generics]), tricyclic antidepressants (including doxepin [SILENOR and generics] and nortriptyline [PAMELOR and generics]), antipsychotics (such as olanzapine [ZYPREXA and generics]) and medications to treat overactive bladder (such as fesoterodine [TOVIAZ and generics], oxybutynin [generic only] and tolterodine [DETROL and generics]).
Blocking or impeding the effects of acetylcholine can result in serious problems, including memory loss, confusion and worsening of cognitive function, as well as dry mouth, blurred vision, constipation, urinary retention and other effects.[13] For instance, a systematic review of 26 observational studies found that the use of anticholinergic drugs — especially long-term use — was associated with an increased incidence of cognitive decline and dementia.[14] Moreover, taking several anticholinergic medications concomitantly (at the same time) may significantly increase these risks.
Benzodiazepines and Z-drugs
Benzodiazepines, such as alprazolam (XANAX and generics), chlordiazepoxide (LIBRIUM and generics) and diazepam (DIAZEPAM INTENSOL, VALIUM and generics), are sedative hypnotics that are used to treat insomnia or acute anxiety.[15],[16]
Another class of hypnotics, often called Z-drugs, are approved for short-term relief of insomnia and have similar but shorter-acting effects than benzodiazepines. They are called Z-drugs because the names of many of the first drugs in this class to be marketed begin with the letter “z.” This class includes eszopiclone (LUNESTA and generics), zaleplon (SONATA and generics) and zolpidem (AMBIEN, EDLUAR and generics).
Because of the serious risks associated with these drugs, including abuse and addiction, Public Citizen’s Health Research Group classifies all benzodiazepines (except for alprazolam, which can be used to treat panic disorder) and all Z-drugs as Do Not Use for people of any age. Moreover, in older adults, use of these drugs is associated with an increased risk of cognitive impairment, memory loss and delirium.[17] A systematic review of 10 observational studies found that use of benzodiazepines for more than 30 days was associated with a 1.8-fold increased risk of developing dementia compared with the dementia risk for people not taking benzodiazepines.[18]
Proton pump inhibitors
Proton pump inhibitors (PPIs) are a class of medications used to reduce the amount of acid the stomach produces; PPIs are one of the most commonly prescribed drug classes in the United States.[19] PPIs are available by prescription and over the counter and include esomeprazole (NEXIUM, NEXIUM 24HR and generics), omeprazole (PRILOSEC, PRILOSEC OTC and generics) and pantoprazole (PROTONIX and generics).
PPIs are associated with several serious adverse events, including micronutrient deficiencies, bone fractures and kidney injury. Public Citizen’s Health Research Group has designated all PPIs as Limited Use.
Adding to earlier studies,[20] a nationwide Danish cohort study published in 2024, which included almost 2 million adults between the ages of 60 and 75, found that those who had been prescribed PPIs anytime during the 15-year follow-up period had a higher risk of dementia than those who had never used PPIs.[21] Moreover, this risk was further increased for the youngest cohorts (60 to 69 years of age) who used PPIs over long periods.
Dangerous drug combinations
The risk of drug-induced mild cognitive decline and dementia increases substantially for people who take multiple drugs.[22] This is of particular concern because many older adults take medications with cognitive effects. For instance, one study based on data from a nationally representative survey found that the prevalence of older adults taking more than one medication with cognitive effects increased substantially between 2000 and 2016. About 9% of older adults took at least three such medications concomitantly, and almost half of the older adults in this study were taking at least one of these drugs for more than a year.[23]
The researchers also identified certain common drug combinations among those who were taking three or more drugs that are associated with a higher risk of drug-induced cognitive decline (see Table, below, for examples of such combinations).[24] Most of these combinations included a PPI and a statin, a class of drugs prescribed to lower high cholesterol. Although statins alone may not increase the risk of cognitive impairment,[25] in combination with other drugs (for example, benzodiazepines), they appear to increase the risk of drug-induced cognitive decline.[26]
Table: Examples of Common Combinations of Drugs With Cognitive Effects[27]
| Combinations of seizure drugs, statins and PPIs | ||
|---|---|---|
| gabapentin* (GRALISE, NEURONTIN and generics) | simvastatin (FLOLIPID, ZOCOR and generics) | omeprazole* (PRILOSEC, PRILOSEC OTC** and generics) |
| gabapentin* (GRALISE, NEURONTIN and generics) | simvastatin (FLOLIPID, ZOCOR and generics) | esomeprazole* (NEXIUM, NEXIUM 24HR** and generics) |
| Combinations of benzodiazepines or Z-drugs, statins and PPIs | ||
| alprazolam*** (XANAX and generics) | simvastatin (FLOLIPID, ZOCOR and generics) | omeprazole* (PRILOSEC, PRILOSEC OTC** and generics) |
| zolpidem****(AMBIEN, EDLUAR and generics) | atorvastatin (ATORVALIQ, LIPITOR and generics) | esomeprazole* (NEXIUM, NEXIUM 24HR** and generics) |
| Combinations of antidepressants, statins and PPIs | ||
| fluoxetine* (PROZAC and generics) | simvastatin (FLOLIPID, ZOCOR and generics) | pantoprazole* (PROTONIX and generics) |
| trazodone****(generics only) | simvastatin (FLOLIPID, ZOCOR and generics) | omeprazole* (PRILOSEC, PRILOSEC OTC** and generics) |
*Designated as Limited Use by Public Citizen’s Health Research Group
**Over-the-counter PPI brand names
***Designated as Do Not Use Except For Panic Disorder by Public Citizen’s Health Research Group
****Designated as Do Not Use by Public Citizen’s Health Research Group
What You Can Do
If you are an older adult, be aware of changes in your cognitive function, such as memory loss, because this could possibly be an early sign of dementia. If you regularly take prescription or over-the-counter medications, make sure to also speak with your clinician about whether one or a combination of these drugs are associated with cognitive decline. Do not stop taking a drug without talking with your clinician because some drugs can cause serious adverse effects when stopped suddenly.
Report all adverse events related to prescription and over-the-counter medicines, biologics, medical devices and combination products to the FDA’s MedWatch medical product safety reporting program by visiting www.fda.gov/MedWatch or by calling 800-FDA-1088.
References
[1] Do D, Schnittker J. Utilization of medications with cognitive impairment side effects and the implications for older adults’ cognitive function. Journal of Aging and Health. 2020 Oct;32(9):1165-1177.
[2] National Institute on Aging. Brain health: medications’ effects on older adults’ brain function. https://www.nia.nih.gov/sites/default/files/d7/MedAgeBrain-Brochure.pdf. Accessed September 26, 2024.
[3] Reimers A, Ljung H. Cognitive safety is largely ignored in clinical drug trials: a study of registered study protocols. Drug Safety. 2024;47(1):23-28.
[4] Chippa V, Roy K. Geriatric cognitive decline and polypharmacy. Updated April 16, 2023. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan.
[5] Drug-induced cognitive impairment: delirium and dementia. Worst Pills, Best Pills News. March 2009. https://www.worstpills.org/chapters/view/459. Accessed September 24, 2024.
[6] Reimers A, Ljung H. Cognitive safety is largely ignored in clinical drug trials: a study of registered study protocols. Drug Safety. 2024;47(1):23-28.
[7] National Institute on Aging. Brain health: medications’ effects on older adults’ brain function. https://www.nia.nih.gov/sites/default/files/d7/MedAgeBrain-Brochure.pdf. Accessed September 26, 2024.
[8] Drugs that can be dangerous for older adults. Worst Pills, Best Pills News. July 2024. https://www.worstpills.org/newsletters/view/1606. Accessed September 26, 2024.
[9] Pourhadi N, Janbek J, Jensen-Dahm C, et al. Proton pump inhibitors and dementia: A nationwide population-based study. Alzheimers Dement. 2024 Feb;20(2):837-845.
[10] Proton pump inhibitors linked to dementia in the elderly. Worst Pills, Best Pills News. August 2016. https://www.worstpills.org/newsletters/view/1049. Accessed September 26, 2024.
[11] Drugs that can be dangerous for older adults. Worst Pills, Best Pills News. July 2024. https://www.worstpills.org/newsletters/view/1606. Accessed September 26, 2024.
[12] Ghossein N, Kang M, Lakhkar AD. Anticholinergic Medications. [Updated 2023 May 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan.
[13] Chippa V, Roy K. Geriatric cognitive decline and polypharmacy. Updated April 16, 2023. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan.
[14] Pieper NT, Grossi CM, Chan WY, et al. Anticholinergic drugs and incident dementia, mild cognitive impairment and cognitive decline: a meta-analysis. Age Ageing. 2020 Oct 23;49(6):939-947.
[15] Drugs that can be dangerous for older adults. Worst Pills, Best Pills News. July 2024. https://www.worstpills.org/newsletters/view/1606. Accessed September 24, 2024.
[16] 2023 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023;71(7):2052-2081.
[17] National Institute on Aging. Brain health: medications’ effects on older adults’ brain function. https://www.nia.nih.gov/sites/default/files/d7/MedAgeBrain-Brochure.pdf. Accessed September 24, 2024.
[18] Islam MM, Iqbal U, Walther B, et al. Benzodiazepine use and risk of dementia in the elderly population: a systematic review and meta-analysis. Neuroepidemiology. 2017;47(3-4):181-91.
[19] Long-term risks with the use of proton pump inhibitors. Worst Pills, Best Pills News. February 2024. https://www.worstpills.org/newsletters/view/1579. Accessed September 26, 2022.
[20] Proton pump inhibitors linked to dementia in the elderly. Worst Pills, Best Pills News. August 2016. https://www.worstpills.org/newsletters/view/1049. Accessed September 24, 2024.
[21] Pourhadi N, Janbek J, Jensen-Dahm C, et al. Proton pump inhibitors and dementia: A nationwide population-based study. Alzheimers Dement. 2024 Feb;20(2):837-845.
[22] Chippa V, Roy K. Geriatric cognitive decline and polypharmacy. Updated April 16, 2023. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.
[23] Do D, Schnittker J. Utilization of medications with cognitive impairment side effects and the implications for older adults’ cognitive function. Journal of aging and health. 2020 Oct;32(9):1165-1177
[24] Ibid.
[25] Zhou Z, Ryan J, Ernst ME. Effect of statin therapy on cognitive decline and incident dementia in older adults. J Am Coll Cardiol. 2021 Jun 29;77(25):3145-3156.
[26] Islam MM, Iqbal U, Walther B, et al. Benzodiazepine use and risk of dementia in the elderly population: a systematic review and meta-analysis. Neuroepidemiology. 2017;47(3-4):181-91.
[27] Do D, Schnittker J. Utilization of medications with cognitive impairment side effects and the implications for older adults’ cognitive function. Journal of aging and health. 2020 Oct;32(9):1165-1177.
