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 seems harmless. But what if taking it every night for years could quietly raise your risk of memory problems? That’s the growing concern behind antihistamines and dementia risk - especially when it comes to first-generation drugs like diphenhydramine and doxylamine.

How Antihistamines Affect the Brain

Not all antihistamines are the same. First-generation ones - such as diphenhydramine (Benadryl), doxylamine (Unisom), and chlorpheniramine - cross the blood-brain barrier. Once inside, they block acetylcholine, a key brain chemical needed for memory, attention, and learning. This is called anticholinergic activity. It’s why these drugs make you drowsy. But over time, constantly reducing acetylcholine may interfere with how brain cells communicate, potentially contributing to cognitive decline.

Second-generation antihistamines - like loratadine (Claritin), cetirizine (Zyrtec), and fexofenadine (Allegra) - were designed to avoid this. They don’t cross into the brain easily because of special transporters that push them out. As a result, their anticholinergic effect is 100 to 1,000 times weaker. For someone needing daily allergy relief, switching to one of these is a simple, low-risk change.

What the Research Actually Shows

A 2015 study in JAMA Internal Medicine that tracked over 3,400 adults aged 65+ for 10 years sparked widespread concern. It found a link between long-term use of anticholinergic drugs and higher dementia risk. But here’s the twist: when researchers looked at antihistamines alone, the risk wasn’t clear. Other drugs - like certain antidepressants, bladder medications, and Parkinson’s drugs - showed stronger associations. In fact, a 2019 follow-up study found no significant dementia risk tied specifically to antihistamine use (hazard ratio of 1.00).

A 2022 study of nearly 9,000 older adults showed higher dementia rates among those using first-gen antihistamines (3.83%) compared to second-gen users (1.0%). But even that difference wasn’t statistically significant after adjusting for other factors. That means the data doesn’t prove one caused the other. It just shows they sometimes happen together.

Why the confusion? Many studies group all anticholinergics together. When you mix drugs with strong brain effects (like oxybutynin for overactive bladder) with mild ones (like Claritin), the signal gets blurred. Also, people who take these meds often have other health issues - chronic allergies, insomnia, depression - that themselves may raise dementia risk. So is it the drug, or the underlying condition?

Expert Guidelines Are Clearer Than the Science

Despite mixed evidence, medical organizations are acting cautiously. The American Geriatrics Society’s 2023 Beers Criteria, a trusted guide for prescribing in older adults, says: avoid first-generation antihistamines in people 65 and older. They give diphenhydramine the highest warning level (Level A) - meaning the risk is well-documented and the recommendation is strong.

The Anticholinergic Cognitive Burden Scale (ACB) rates diphenhydramine as a 3 - the worst possible score. Fexofenadine and loratadine? Score 0. That’s why doctors are increasingly switching patients off Benadryl for sleep or allergies. The American Academy of Neurology recommends reviewing all medications every six months and choosing alternatives whenever possible.

Meanwhile, the European Medicines Agency updated patient leaflets in 2022 to include a note about “potential long-term cognitive effects with prolonged use.” The FDA, however, still only requires OTC labels to say “may cause drowsiness.” There’s a gap between what experts know and what consumers see on the bottle.

Who’s Most at Risk?

Not everyone who takes Benadryl will develop dementia. But some people are more vulnerable:

• Those over 70
• People taking multiple anticholinergic drugs (e.g., Benadryl + a bladder med + an antidepressant)
• Individuals with mild cognitive impairment or early memory complaints
• Those using these drugs daily for more than three years

A 2022 survey by the National Council on Aging found that 42% of adults 65+ use OTC antihistamines for sleep. Shockingly, 78% didn’t know they had anticholinergic properties. Many think it’s just a “sleep aid,” not a brain-altering drug.

On Reddit, a geriatric care manager with over 2,000 karma shared that 83% of her clients over 70 were taking diphenhydramine nightly - often prescribed by their doctor years ago and never re-evaluated. One user wrote: “My mother’s doctor gave her Benadryl for sleep for 15 years. Now she has dementia. I can’t help but wonder.”

What to Do Instead

If you or a loved one is using diphenhydramine for sleep or allergies, here’s what to consider:

For allergies: Switch to loratadine, cetirizine, or fexofenadine. They work just as well without the brain fog. No prescription needed.

For sleep: Benadryl isn’t meant for long-term insomnia. It disrupts sleep architecture, leading to poor-quality rest. Better options:

• Cognitive Behavioral Therapy for Insomnia (CBT-I): Proven effective in 70-80% of older adults. It teaches better sleep habits without drugs.
• Low-dose doxepin (Silenor): A prescription sleep aid with minimal anticholinergic activity (ACB score of 1).
• Non-drug strategies: Reduce screen time before bed, keep a consistent sleep schedule, avoid caffeine after noon, and get sunlight in the morning.

CBT-I works better than pills for long-term results - but access is limited. Average wait time for a therapist is over eight weeks, and Medicare only covers $85-$120 per session. Still, it’s a safer investment than years of daily anticholinergics.

The Bigger Picture: Why This Matters

The global market for first-gen antihistamines dropped 24% between 2015 and 2022. Sales of second-gen versions rose 18% in the same period. That’s not coincidence. As awareness grows, people are switching. Pharmaceutical companies are responding with newer, safer alternatives.

The NIH is funding a major 10-year study called ABCO, tracking 5,000 older adults to get clearer answers. Early data from the UK Biobank suggests that when researchers account for underlying sleep disorders, the link between antihistamines and dementia disappears. That’s a big clue - maybe the problem isn’t the drug, but the reason people take it.

Still, the American Geriatrics Society doesn’t wait for perfect data. They act on what’s known now. And what’s known is that first-gen antihistamines carry a real, avoidable risk - especially in older adults.

Final Takeaway

If you’re over 65 and taking Benadryl, Unisom, or any OTC sleep aid with diphenhydramine or doxylamine as the active ingredient - pause. Ask yourself: Why am I taking this? How long have I been taking it? Is there a safer option?

Switching to a second-generation antihistamine for allergies is easy. Finding a better solution for sleep takes more effort - but it’s worth it. Your brain will thank you.