What is the current consensus on using diphenhydramine in adults at risk for cognitive decline, such as older patients or those with mild cognitive impairment or early dementia?

Diphenhydramine and Cognitive Decline: Current Consensus

Diphenhydramine should be avoided in older adults and those at risk for cognitive decline due to strong evidence linking its anticholinergic properties to increased dementia risk, accelerated cognitive decline, and delirium. 1

Guideline Recommendations

The 2020 Canadian Consensus Conference on Dementia provides the strongest directive: exposure to medications with highly anticholinergic properties (including diphenhydramine) should be minimized in older persons, with alternative medications used instead (Grade 1B, 100% consensus). 1

• The Mayo Clinic 2021 polypharmacy guidelines specifically identify diphenhydramine and hydroxyzine as old antihistamines that cause CNS impairment including delirium, slowed comprehension, sedation, and falls in older adults. 1

• The 2019 AAAAI guidelines on mast cell disorders explicitly warn that cognitive decline has been reported for H1 blockers with anticholinergic effects, particularly in elderly populations. 1

• Multiple guideline sources recommend avoiding diphenhydramine in adults ≥65 years due to significant cognitive impairment, delirium, and dementia risk. 2

Evidence of Harm

The relationship between diphenhydramine and cognitive decline shows a dose-response pattern, meaning higher cumulative exposure increases risk:

• A 2020 systematic review demonstrates moderate to strong risk of dementia with anticholinergic use across multiple study designs, particularly with cumulative burden and high-level anticholinergics. 3

• A 2001 prospective cohort study of 426 hospitalized older patients found diphenhydramine exposure increased risk for delirium symptoms (RR 1.7), inattention (RR 3.0), disorganized speech (RR 5.5), and altered consciousness (RR 3.1), with clear dose-response relationships. 4

• A 2020 meta-analysis found anticholinergic use associated with incident dementia (OR 1.20) for any use, with long-term use showing even higher risk (OR 1.50). 5

• A 2025 expert opinion paper concludes diphenhydramine has reached the end of its life cycle and represents a public health hazard, recommending it should no longer be widely prescribed or available over-the-counter. 6

Clinical Algorithm for Management

When encountering patients using diphenhydramine:

1. Immediately discontinue diphenhydramine in all older adults (≥65 years) and those with cognitive impairment, MCI, or dementia. 1, 2

2. Substitute with second-generation antihistamines (fexofenadine, cetirizine) for allergic conditions, which lack anticholinergic effects and do not cross the blood-brain barrier. 1, 6

3. Screen for cognitive impairment using validated tools (Mini-Mental State Examination or Montreal Cognitive Assessment) in adults ≥65 years annually. 1, 7

4. Review all medications for anticholinergic burden systematically, as cumulative effects from multiple anticholinergic medications significantly increase adverse outcomes. 2, 8

5. Monitor for improvement in cognitive function 2-4 weeks after discontinuation, as anticholinergic cognitive effects can be reversed with medication changes. 8

High-Risk Populations Requiring Absolute Avoidance

Diphenhydramine must be avoided in:

• Adults ≥65 years of age 1, 2
• Patients with existing cognitive impairment, MCI, or dementia 7, 2
• Patients with diabetes (who have higher baseline cognitive decline risk) 1, 2
• Patients with dementia risk factors 2
• Patients with narrow-angle glaucoma 2

Common Pitfalls to Avoid

Do not assume over-the-counter availability means safety - diphenhydramine remains available in over 300 formulations despite its problematic therapeutic ratio. 6

Do not use diphenhydramine for sleep in older adults - the sedating effects come with unacceptable cognitive risks, and safer alternatives exist. 1, 2

Do not overlook cumulative anticholinergic burden - approximately one-third of independent living older adults take multiple medications with anticholinergic properties that may be unnecessary. 2

Do not continue diphenhydramine "because it's been working" - the cognitive effects are cumulative and may not be immediately apparent, but long-term use significantly increases dementia risk (OR 1.50). 5