Which medications are associated with cognitive impairment?

Medications That Cause Cognitive Impairment

The most important medications that cause cognitive impairment in older adults are anticholinergics, benzodiazepines, antipsychotics, and opioids, and these should be discontinued whenever possible. 1

High-Risk Medication Classes

Anticholinergics

Anticholinergics are among the most problematic medications for cognition, causing broad muscarinic receptor blockade that leads to:

• Delirium and slowed comprehension
• Impaired vision and sedation
• Increased fall risk 2

Common culprits include:

• First-generation antihistamines: diphenhydramine, hydroxyzine, chlorpheniramine 3, 2
• Muscle relaxants: cyclobenzaprine, metaxalone 2
• Overactive bladder medications: oxybutynin 2
• Cyproheptadine: has extended anticholinergic properties 3

The cognitive decline associated with anticholinergics is particularly concerning in elderly populations and worsens with cumulative use 3, 4. Recent research confirms that antidepressants with anticholinergic properties are specifically associated with cognitive decline in older adults without baseline cognitive impairment 4.

Benzodiazepines

Benzodiazepines cause significant cognitive harm through multiple mechanisms:

• Sedation and cognitive impairment
• Anterograde amnesia
• Impaired motor performance and increased falls
• Daytime sleepiness
• Physiologic dependence 5

All benzodiazepines are problematic, but long-acting agents like diazepam are particularly dangerous 2. Evidence shows cumulative benzodiazepine use is associated with cognitive decline 4. These medications should be avoided in older patients and those with existing cognitive impairment 6.

Benzodiazepine-like agents (zolpidem, zaleplon, eszopiclone) share similar risks despite shorter half-lives 5.

Antipsychotics

Both typical and atypical antipsychotics cause cognitive impairment:

• Worsen cognitive function in dementia
• Cause sedation and anticholinergic effects
• Associated with increased mortality (FDA black box warning) 2, 5

Specific agents to avoid:

• Typical: chlorpromazine, haloperidol 2
• Atypical: quetiapine, risperidone, olanzapine 2

Antipsychotic polypharmacy is associated with sedation, hypersalivation, and cognitive impairment 7. Recent evidence confirms antipsychotic use is associated with cognitive decline in older adults 4.

Opioids

Opioids cause cognitive impairment through:

• Sedation and anticholinergic properties
• Direct cognitive impairment
• Increased fall risk
• Morphine, oxycodone, and codeine are particularly problematic 2

Tramadol has mixed opioid and serotonin/norepinephrine reuptake inhibitor mechanisms, carrying risk of cognitive effects and seizures 8.

Other High-Risk Medications

NSAIDs (particularly indomethacin): Associated with cognitive effects, though mechanisms differ from centrally-acting drugs 2

Cannabinoids (nabilone, dronabinol): Cause ataxia, cognitive effects, sedation, dizziness, somnolence, and dysphoria 8

Muscle relaxants:

• Baclofen and tizanidine: Monitor for cognitive effects, sedation, and muscle weakness 8
• Clonazepam: Sedation and memory impairment 8

Over-the-counter antihistamines: Very high rates of cognitive impairment, daytime somnolence, and anticholinergic responses 5

Trazodone: Widely used off-label as a hypnotic despite virtually no evidence-based data supporting efficacy in older adults, with significant risks including orthostatic hypotension 5

Medications With Mixed or Context-Dependent Evidence

Antihypertensives

The evidence is nuanced:

• Some antihypertensives (e.g., amlodipine) show negative associations with cognitive scores in large population studies 9
• However, among hypertensive patients specifically, antihypertensive use may be associated with better cognitive performance longitudinally 10
• The class of antihypertensive may matter: medications that stimulate angiotensin II type 2 and 4 receptors (thiazides, dihydropyridine calcium channel blockers, ARBs) may have lower risk of cognitive impairment compared to those that inhibit these receptors (ACE inhibitors, beta-blockers) 11
• Overall, no specific antihypertensive drug class has been proven more effective than others in lowering dementia risk 12

Antidiabetics

Cross-sectional data shows antidiabetic use associated with poorer cognition, but this likely reflects underlying disease severity rather than drug toxicity, as longitudinal evidence is limited 10

Proton Pump Inhibitors

Surprisingly, PPIs like omeprazole show negative associations with cognitive performance in large studies 9, though causality remains unclear.

Cancer Treatments

Chemotherapy, immunotherapy (including CAR-T cells), hormone therapy, and targeted therapies all cause cognitive impairment through diverse mechanisms including cytokine release syndrome and blood-brain barrier disruption 13.

Clinical Approach

Use established deprescribing criteria:

• STOPP/START criteria
• Beers criteria 1

Priority actions:

1. Systematically review all medications in patients with cognitive impairment 14
2. Discontinue anticholinergics, benzodiazepines, antipsychotics, and opioids whenever possible 1
3. Assess for drug-drug and drug-disease interactions 1
4. Consider that polypharmacy itself (≥6 medications) may contribute to cognitive decline 15

Important caveat: The 2025 Lancet guideline emphasizes that medications should be reviewed as part of a comprehensive approach addressing nutrition, physical activity, mood, sensory impairments, and falls risk 1. However, medication review and deprescribing remain fundamental interventions with direct impact on cognitive outcomes.