Antihistamines and Dementia Risk: What You Need to Know About Long-Term Use

For decades, millions of older adults have reached for over-the-counter sleep aids like Benadryl to help them fall asleep. It’s cheap, easy to find, and works-fast. But what if that nightly pill could be quietly increasing the risk of memory loss and dementia? The answer isn’t simple, but the evidence is growing harder to ignore.

Why Some Antihistamines Are a Problem

Not all antihistamines are the same. There are two main types: first-generation and second-generation. First-generation ones-like diphenhydramine (Benadryl), doxylamine (Unisom), and chlorpheniramine-are the ones that make you drowsy. That’s because they cross the blood-brain barrier and block acetylcholine, a key brain chemical involved in memory and learning. This effect is called anticholinergic activity.

Second-generation antihistamines-like loratadine (Claritin), cetirizine (Zyrtec), and fexofenadine (Allegra)-were designed to avoid this. They don’t cross into the brain easily, thanks to special transporters that push them back out. That means they relieve allergies without making you sleepy or messing with your memory.

The difference isn’t small. Preclinical studies show first-gen antihistamines bind to brain receptors with 100 to 1,000 times more strength than second-gen ones. That’s why the American Geriatrics Society’s 2023 Beers Criteria lists first-generation antihistamines as drugs to avoid in adults over 65. They give them the highest warning level: “Avoid,” with strong evidence backing it up.

What the Research Actually Shows

A major 2015 study in JAMA Internal Medicine tracked over 3,400 people over 65 for 10 years. It found a link between long-term use of anticholinergic drugs and higher dementia risk. But here’s the twist: when researchers looked specifically at antihistamines, the risk wasn’t there. The real culprits were antidepressants, bladder medications, and drugs for Parkinson’s.

That same study was followed up in 2019 with a larger group. Again, antihistamines showed no significant increase in dementia risk-even with more than 1,095 cumulative doses. The hazard ratio? Exactly 1.00. No increased risk.

But not all studies agree. A 2021 meta-analysis grouped all anticholinergic drugs together and found a 46% higher dementia risk. The problem? That study didn’t separate antihistamines from stronger drugs like oxybutynin or amitriptyline. When you mix apples and oranges, the result is misleading.

A 2022 study of nearly 9,000 older adults found that those taking first-gen antihistamines had a higher rate of dementia (3.83%) compared to those taking second-gen (1.0%). But when they adjusted for age, health conditions, and other medications, the difference vanished. The adjusted hazard ratio was 1.029-statistically meaningless.

Even more telling: a 2023 analysis from the UK Biobank found no link between antihistamine use and dementia when researchers accounted for sleep disorders. That suggests the real issue might not be the drug itself, but the reason people take it-chronic insomnia, which is itself a known risk factor for cognitive decline.

Why the Confusion? The Science Isn’t Settled

The truth is, the data is messy. Studies use different methods, different definitions of “long-term,” different ways to measure dementia, and different populations. One study might count anyone who took Benadryl once a week for a year as “exposed.” Another might only count daily use over three years. The variation is so high that meta-analyses show I² statistics over 75%, meaning the studies barely agree with each other.

Some experts, like Dr. Shelley Gray from the University of Washington, say the strongest links are with drugs that have much higher anticholinergic power than antihistamines. Others, like Dr. Malaz Boustani, warn that even weak effects can add up over time-especially in people with multiple health problems, taking five or more medications.

The European Medicines Agency acknowledges the inconsistency. Their 2022 report says there’s no clear proof antihistamines cause dementia-but they still recommend updating patient labels to mention “potential long-term cognitive effects with prolonged use.” That’s not a warning. It’s a heads-up.

What People Are Really Using-and Why

Despite the warnings, first-generation antihistamines are still everywhere. In 2022, they made up 62% of the $874 million over-the-counter sleep aid market. That’s over half a billion dollars in sales.

Why? Because alternatives aren’t easy to access. Cognitive behavioral therapy for insomnia (CBT-I) is proven to work better than pills-70% to 80% success rate in older adults. But finding a therapist? The average wait time is over eight weeks. Medicare pays only $85 to $120 per session. Most people can’t afford that.

A 2022 survey by the National Council on Aging found that 42% of adults over 65 use OTC antihistamines for sleep. And 78% had no idea these drugs have anticholinergic effects. On Reddit, a geriatric care manager reported that 83% of her clients over 70 were taking diphenhydramine nightly-no doctor’s order, no warning.

“I used to give my mom Benadryl every night,” wrote one user on AgingCare.com. “Now she has dementia. I can’t help but wonder.”

What Should You Do?

If you’re over 65 and taking diphenhydramine, doxylamine, or chlorpheniramine regularly-especially for sleep-talk to your doctor. Don’t stop cold turkey. Sudden withdrawal can cause rebound insomnia or anxiety. But do ask: Is this still necessary?

Ask about alternatives:

• Second-generation antihistamines: Loratadine, cetirizine, fexofenadine. No drowsiness. No brain effects.
• Low-dose doxepin (Silenor): FDA-approved for insomnia. Anticholinergic burden score of 1-very low.
• Cognitive behavioral therapy for insomnia (CBT-I): Gold standard. Not easy to get, but worth the wait.
• Good sleep hygiene: Dark room, no screens before bed, consistent schedule. Simple, free, and effective.

The Anticholinergic Cognitive Burden Scale (ACB) rates diphenhydramine as level 3-the highest risk. Fexofenadine? Level 0. That’s a clear signal: not all antihistamines are created equal.

What’s Next?

The FDA is currently reviewing all anticholinergic medications for dementia risk. Results are expected in early 2024. Meanwhile, the American Geriatrics Society is updating its Beers Criteria in June 2024. Expect more specific guidance-maybe even a list of which antihistamines are safe and which aren’t.

The market is already shifting. Sales of first-gen antihistamines dropped 24% between 2015 and 2022. Second-gen sales rose 18%. More pharmacies are putting warning stickers on Benadryl bottles. More doctors are asking patients: “Why are you taking this?”

The message isn’t: “Stop all antihistamines.” It’s: “Know what you’re taking. Ask if it’s really needed. And don’t assume OTC means safe for long-term use.”

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