Does Diphenhydramine (Benadryl) Lead to Dementia?
Yes, diphenhydramine use is associated with increased dementia risk and should be avoided in older adults, particularly with chronic or high-dose use. 1, 2
Evidence from Guidelines
The American Geriatrics Society (AGS) 2019 Beers Criteria explicitly recommends avoiding diphenhydramine in older adults due to its highly anticholinergic properties, which increase risk of cognitive impairment, confusion, and delirium. 1 The AGS classifies diphenhydramine as having "high anticholinergic properties" that should be avoided in older adults due to substantial CNS effects. 1
Diphenhydramine is classified as a strongly anticholinergic medication that causes broad muscarinic receptor blockade, resulting in negative effects on cognition in addition to vision, urination, and constipation problems. 2 Patients taking anticholinergic drugs like diphenhydramine experience "anticholinergic burden" that adversely affects cognition, functional status, and activities of daily living scores. 2
The AGS postoperative delirium guideline specifically identifies diphenhydramine among medications that induce delirium and should be avoided in older surgical patients. 1 Studies have directly identified diphenhydramine use with increased delirium risk. 1
Mechanism and Dose-Response Relationship
The link between diphenhydramine and dementia operates through its anticholinergic properties. Anticholinergic medications block acetylcholine receptors in the brain, and chronic blockade is associated with cognitive decline. 1, 2
A dose-response relationship exists between antihistamine use and dementia risk. Recent research on H1 antihistamines (the class including diphenhydramine) demonstrates escalating dementia risk with increasing cumulative dosage. 3 First-generation antihistamines like diphenhydramine show higher dementia risk compared to second-generation antihistamines. 3
In hospitalized older patients, diphenhydramine exposure increases risk of:
- Any delirium symptoms (RR 1.7) 4
- Inattention (RR 3.0) 4
- Disorganized speech (RR 5.5) 4
- Altered consciousness (RR 3.1) 4
These effects demonstrate a dose-response relationship, with 24% of diphenhydramine doses administered inappropriately in older patients. 4
Clinical Implications
For sleep disturbances: Avoid diphenhydramine entirely. The sleep medicine guideline notes that commonly used over-the-counter antihistamines have very high rates of side effects, including cognitive impairment and daytime somnolence. 1 Consider melatonin or behavioral interventions instead. 1
For allergic reactions: When diphenhydramine is medically necessary (such as severe allergic or transfusion reactions), short-term use may be justified, but chronic use should be avoided. 1
For patients already taking diphenhydramine: Discontinue if possible and switch to non-anticholinergic alternatives. The AGS recommends avoiding all medications with high anticholinergic properties in older adults. 1
Common Pitfalls to Avoid
Do not assume over-the-counter status means safety. Diphenhydramine's widespread availability as an OTC sleep aid does not negate its significant cognitive risks in older adults. 1, 4
Do not use diphenhydramine for chronic insomnia. There is virtually no evidence-based data to support its efficacy for sleep in older adults, while risks are substantial. 1
Recognize cumulative anticholinergic burden. Patients often take multiple medications with anticholinergic properties. Diphenhydramine adds significantly to this burden and should be eliminated first given its strong anticholinergic effects. 2, 5