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

Many older adults reach for over-the-counter antihistamines like Benadryl to help with allergies, colds, or sleep. It’s cheap, easy to find, and works quickly. But what happens when you take it night after night, year after year? A growing body of research suggests that long-term use of certain antihistamines might be linked to higher dementia risk - not because they cause dementia directly, but because of how they affect the brain.

Not All Antihistamines Are the Same

There are two main types of antihistamines: first-generation and second-generation. The difference isn’t just about brand names - it’s about what they do inside your brain.

First-generation antihistamines like diphenhydramine (Benadryl), doxylamine (Unisom), and chlorpheniramine cross the blood-brain barrier easily. Once there, they block acetylcholine, a key chemical your brain uses for memory, focus, and learning. This is called anticholinergic activity. That’s why these drugs make you drowsy - they’re slowing down brain activity.

Second-generation antihistamines like loratadine (Claritin), cetirizine (Zyrtec), and fexofenadine (Allegra) were designed differently. They don’t cross into the brain as easily. Thanks to special transporters that push them back out, their anticholinergic effect is 100 to 1,000 times weaker. They relieve allergies without the foggy feeling.

The American Geriatrics Society’s 2023 Beers Criteria, a trusted guide for safe prescribing in older adults, says first-generation antihistamines should be avoided entirely in people over 65. That’s a Level A recommendation - the strongest possible warning. Yet, millions still take them daily.

What the Studies Actually Show

The biggest fear comes from a 2015 study in JAMA Internal Medicine that followed over 3,400 people aged 65+ for 10 years. It found that people who took strong anticholinergic drugs - including some antihistamines - had a higher chance of developing dementia. But here’s the catch: when researchers looked at antihistamines alone, the link disappeared.

A follow-up study in 2019 looked at different drug classes. Antidepressants, bladder medications, and Parkinson’s drugs showed clear increases in dementia risk. But antihistamines? No significant rise. The hazard ratio was exactly 1.00 - meaning no increased risk.

Another study in 2022 tracked nearly 9,000 older adults. It found 3.8% of those using first-gen antihistamines developed dementia, compared to 1% of those using second-gen. At first glance, that looks scary. But after adjusting for age, health conditions, and other medications, the difference wasn’t statistically significant. The numbers were too close to call it a true effect.

Even more confusing? A 2021 meta-analysis that grouped all anticholinergic drugs together claimed a 46% higher dementia risk. But when you break it down, that number was mostly driven by antidepressants and bladder meds - not allergy pills.

The European Medicines Agency says the evidence on antihistamines is inconsistent. The FDA hasn’t added dementia warnings to OTC labels, even though they did for prescription anticholinergics in 2021. Meanwhile, the UK Biobank study published in October 2023 found no link between antihistamine use and dementia once they accounted for underlying sleep disorders - suggesting that people who take these drugs for sleep might already be at higher risk due to poor sleep quality, not the drug itself.

Why the Confusion? It’s Not Just About the Drug

One big problem in this research is that people who take first-gen antihistamines long-term often have other health issues. They’re more likely to have chronic allergies, insomnia, anxiety, or urinary problems - all conditions linked to higher dementia risk. It’s hard to tell if the drug is the cause, or if it’s just a sign of other underlying problems.

Also, most studies rely on prescription records or self-reported use. Many people take diphenhydramine for sleep without telling their doctor. They buy it off the shelf. That makes tracking true exposure tricky.

And then there’s the Anticholinergic Cognitive Burden Scale (ACB). This tool rates drugs based on how strongly they block acetylcholine. Diphenhydramine scores a 3 - the highest. Fexofenadine? A 0. That’s why experts say: if you need an antihistamine, choose the ones with a score of 0 or 1.

Real People, Real Concerns

Behind the numbers are real stories. On Reddit, a geriatric care manager wrote that 83% of her clients over 70 take Benadryl every night to sleep. Most don’t know it’s an anticholinergic. On AgingCare.com, a daughter wrote: “My mother’s doctor prescribed Benadryl for years. Now she has dementia. I can’t help but wonder.”

These aren’t just fears. They’re valid concerns. Even if science hasn’t proven a direct link, the pattern is troubling enough that experts recommend caution. Why take a risk when safer options exist?

What Should You Do?

If you or someone you care for is taking diphenhydramine or doxylamine regularly - especially for sleep - here’s what to consider:

1. Switch to second-generation antihistamines. Loratadine, cetirizine, and fexofenadine work just as well for allergies and don’t affect the brain the same way.
2. Don’t use antihistamines for sleep. They’re not designed for long-term use as sleep aids. They disrupt natural sleep cycles and can cause next-day grogginess, falls, and confusion.
3. Ask about CBT-I. Cognitive Behavioral Therapy for Insomnia is the gold standard for chronic sleep problems in older adults. Studies show it works in 70-80% of cases. The downside? Therapists are hard to find, and insurance doesn’t always cover it. But it’s safer than any pill.
4. Review all meds every six months. Many older adults take 5+ medications. A pharmacist or doctor can check for hidden anticholinergic burden using the ACB scale.
5. Look for alternatives to OTC sleep aids. Melatonin, magnesium, or low-dose doxepin (Silenor) are better options with minimal anticholinergic effects.

The Choosing Wisely campaign, led by the American Board of Internal Medicine, specifically advises against using diphenhydramine for chronic insomnia in older adults. That’s not a suggestion - it’s a clear clinical guideline.

The Bigger Picture

Sales of first-generation antihistamines have dropped 24% since 2015. Second-generation ones have surged. Why? Because awareness is growing. Pharmacies now stock more Claritin and Zyrtec than Benadryl. Drug labels are changing. The FDA is reviewing all anticholinergic medications - with results expected in 2024.

The American Geriatrics Society’s 2024 Beers Criteria update, due in June, is expected to tighten these recommendations even further. We’re moving away from blanket warnings and toward drug-specific guidance. That’s progress.

But change takes time. Millions still sleep with Benadryl. Many don’t know the risks. And for those who do, finding a safe, effective alternative can be hard.

The truth? If you’re using a first-generation antihistamine long-term, you’re not alone - but you might be taking a risk you don’t need to. The science isn’t 100% settled, but the safest choice is clear: switch to a second-generation option. Your brain will thank you.