Anticholinergic Burden Calculator
Calculate your risk from medications that affect memory and cognitive function. Based on the University of Washington's ACB scoring system.
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ACB Score Key: 0-1 = Low risk, 2 = Moderate risk, 3+ = High risk (especially dangerous)
Combining antihistamines with other sedating drugs isn’t just a bad idea-it can land you in the hospital. Millions of people reach for over-the-counter diphenhydramine (Benadryl) for allergies, colds, or sleep, often without realizing how dangerously it mixes with common prescriptions and even alcohol. The truth is, these interactions aren’t rare or theoretical. They’re happening every day, especially in older adults, and the consequences can be life-threatening.
Why First-Generation Antihistamines Are Riskier Than You Think
Not all antihistamines are created equal. The ones you find on the shelf-diphenhydramine, hydroxyzine, promethazine-are first-generation drugs. They were designed decades ago to block histamine, but they don’t stop there. They also cross into your brain and mess with other receptors, especially acetylcholine. This is why they make you drowsy, dry your mouth, and blur your vision. On the Anticholinergic Cognitive Burden (ACB) scale, diphenhydramine scores a 3-the highest level of risk. That means even a single dose can impair memory, balance, and reaction time.When you add another sedating drug on top-like a benzodiazepine (Xanax, lorazepam), an opioid (oxycodone, hydrocodone), or even sleep aids like zolpidem-the effects don’t just add up. They multiply. A 2013 study showed diphenhydramine boosted the sedative power of lorazepam by 37% in objective tests. In real life, that means slower breathing, confusion, falls, or worse. The CDC reports that combining first-gen antihistamines with opioids increases the risk of respiratory depression from 1.5% to nearly 9%. That’s a six-fold jump.
Second-Generation Antihistamines: The Safer Alternative
The good news? There’s a better option. Second-generation antihistamines like loratadine (Claritin), cetirizine (Zyrtec), and fexofenadine (Allegra) were developed to avoid the brain. Thanks to special transporters in the blood-brain barrier, they stay out of your central nervous system. That’s why they’re called "non-drowsy."Studies show 97% of people taking loratadine report no drowsiness, compared to 68% with diphenhydramine. And when tested alongside benzodiazepines, second-gen antihistamines like bilastine showed no increase in sedation at all. That’s not marketing-it’s science. These drugs also have ACB scores of 0 or 1, meaning minimal anticholinergic activity. For most people, especially those on multiple medications, switching to a second-generation antihistamine is the single safest change you can make.
But don’t assume "non-drowsy" means "no risk." Cetirizine still has an ACB score of 1. If you’re taking it with a strong opioid or an antidepressant like amitriptyline, you’re still stacking sedative effects. Always check with your pharmacist or doctor before mixing any meds.
Hidden Dangers: Cimetidine and the Cytochrome System
Most people don’t realize that some antihistamines aren’t even H1 blockers. Cimetidine (Tagamet), used for heartburn, is an H2 blocker-but it’s a powerful inhibitor of liver enzymes. Specifically, it shuts down CYP1A2, CYP2D6, and CYP3A4, the same enzymes that break down dozens of common drugs. When cimetidine blocks these, other medications build up in your bloodstream like traffic on a highway with no exits.This isn’t hypothetical. A patient on warfarin who starts cimetidine can see their INR spike dangerously high. Someone taking codeine might turn it into too much morphine, leading to overdose. Even antidepressants, antifungals, and statins can become toxic when combined with cimetidine. The FDA now requires stronger warnings on cimetidine labels, but many patients still take it without knowing the risks. If you’re on any prescription meds and use Tagamet, talk to your doctor about switching to famotidine (Pepcid), which doesn’t interfere with liver enzymes.
Who’s Most at Risk? The Elderly and Polypharmacy Patients
The biggest danger zone? Older adults. As we age, our kidneys and liver slow down. First-generation antihistamines like diphenhydramine clear 50-70% slower in people over 65. That means the drug lingers longer, building up over days. Combine that with other meds-blood pressure pills, painkillers, sleep aids-and you’ve got a perfect storm.The American Geriatrics Society has listed diphenhydramine and hydroxyzine on its Beers Criteria since 2012-and updated it again in 2024 to include hydroxyzine for dementia patients. Why? Because studies show that using these drugs in older adults increases delirium risk by 54% and raises dementia risk by 54% over time. A 2021 JAMA Internal Medicine study found that just one month of diphenhydramine use in seniors with multiple meds was linked to measurable cognitive decline.
And it’s not just pills. Many seniors take OTC sleep aids, cold remedies, or even topical creams containing antihistamines. These add up. The average Medicare beneficiary takes 7.8 prescription drugs. One of those might be a benzodiazepine. Another might be an opioid. Add in Benadryl for allergies, and you’ve got a triple threat.
Real Stories: What Happens When People Mix These Drugs
Reddit threads, pharmacy forums, and drug review sites are full of warnings. One user on r/Pharmacy described taking 50mg of diphenhydramine with 1mg of Xanax and nearly stopping breathing. Over 400 people upvoted the post. Another shared that after combining Benadryl with alcohol, they had a blackout and woke up in the ER with low oxygen levels.GoodRx users gave diphenhydramine a 1.8 out of 5 stars for safety, with 63% of negative reviews citing "dangerous drowsiness with other meds." WebMD reports that 41% of people taking diphenhydramine with opioids experienced severe dizziness requiring medical care. In contrast, Allegra (fexofenadine) holds a 4.3-star rating on Amazon with over 18,000 reviews-many praising "no drowsiness, even with my other meds."
These aren’t outliers. They’re predictable outcomes. The CDC says antihistamines contribute to nearly 15% of the 2.1 million annual emergency visits for CNS depressant interactions. That’s tens of thousands of hospitalizations every year-many preventable.
What to Do: A Practical Safety Plan
If you’re taking any sedating medication-whether it’s prescribed or bought over the counter-here’s what to do:- Check your meds. Look at every pill in your cabinet. If it’s diphenhydramine, hydroxyzine, promethazine, or cimetidine, write it down.
- Know your ACB score. Use the University of Washington’s free Anticholinergic Burden Calculator. Add up the scores of all your meds. If your total is 3 or higher, you’re at increased risk for confusion, falls, and cognitive decline.
- Switch to second-gen. Replace diphenhydramine with loratadine, cetirizine, or fexofenadine. Even if you’re using it for sleep, try melatonin or a non-antihistamine option.
- Ask about alternatives. If you’re on cimetidine, ask your doctor about switching to famotidine. If you’re on a benzodiazepine, ask if a non-sedating option is possible.
- Use free tools. The Institute for Safe Medication Practices offers a free online Antihistamine Interaction Checker. Pharmacies often have free interaction checkers too.
Don’t wait for a bad reaction. If you’re over 65, taking more than three medications, or have a history of falls or memory issues, the safest choice is to avoid first-generation antihistamines entirely.
What’s Changing in 2025?
The tide is turning. Since 2018, sales of first-generation antihistamines have dropped 12.7% per year. Second-gen drugs now make up 83% of the U.S. OTC antihistamine market. The FDA now requires bold warnings on diphenhydramine packaging: "May cause severe drowsiness when combined with alcohol, opioids, or sleep medications."Health systems like Kaiser Permanente have added automated alerts in their electronic records. When a doctor tries to prescribe diphenhydramine to someone already on an opioid, the system pops up a red flag. Between 2020 and 2022, that reduced adverse events by 34%.
Research is moving toward even safer options. Newer antihistamines like levocetirizine (Xyzal) and bilastine (Bilaxten) are designed to be ultra-selective-hitting only the H1 receptor and nothing else. A 2023 study showed bilastine didn’t increase sedation even at double the normal dose when mixed with lorazepam. The future of antihistamines isn’t just non-drowsy-it’s interaction-free.
For now, the message is clear: if you’re taking anything that makes you sleepy, skip the old-school antihistamines. They’re not worth the risk.
Can I take Benadryl with my anxiety medication?
No, combining diphenhydramine (Benadryl) with benzodiazepines like Xanax, Ativan, or Klonopin is dangerous. Both drugs slow down your central nervous system. Together, they can cause extreme drowsiness, confusion, slowed breathing, or even respiratory failure. Even small doses can be risky, especially for older adults. Switch to a second-generation antihistamine like loratadine or fexofenadine instead.
Is Zyrtec safer than Benadryl?
Yes, cetirizine (Zyrtec) is significantly safer than diphenhydramine (Benadryl) when combined with other medications. Zyrtec is a second-generation antihistamine with minimal brain penetration and an ACB score of 1, compared to Benadryl’s score of 3. While Zyrtec can still cause mild drowsiness in some people, it doesn’t amplify the effects of opioids, benzodiazepines, or sleep aids the way Benadryl does. It’s the recommended first-line choice for allergy relief in people taking multiple drugs.
Can I drink alcohol with antihistamines?
Never mix alcohol with first-generation antihistamines like diphenhydramine or promethazine. Even one drink can cause dangerous drowsiness, dizziness, impaired coordination, or slowed breathing. Over 1,200 user reports on BuzzRx describe blackouts and hospital visits after combining just 25mg of Benadryl with one standard drink. Second-generation antihistamines like fexofenadine are safer, but alcohol still increases drowsiness and lowers your reaction time. The safest choice is to avoid alcohol entirely while taking any antihistamine.
Are all "non-drowsy" antihistamines safe?
Most are, but not all. Loratadine, fexofenadine, and bilastine have very low interaction risks. Cetirizine (Zyrtec) has a slightly higher chance of causing drowsiness and an ACB score of 1, so use caution if you’re on other sedatives. Always check the active ingredient. Some "non-drowsy" cold medicines still contain diphenhydramine. Read labels carefully and avoid anything that lists diphenhydramine, hydroxyzine, or promethazine.
What should I do if I’ve been taking Benadryl with other meds?
Don’t stop abruptly if you’re using it for sleep or chronic symptoms-talk to your doctor or pharmacist first. But start by replacing diphenhydramine with a second-generation antihistamine like loratadine or fexofenadine. Review all your medications with a pharmacist using the Anticholinergic Burden Calculator. If you’ve experienced dizziness, confusion, or memory lapses, mention it. Many people don’t realize these symptoms are drug-related. Your health is worth the switch.
Final Thoughts: Your Meds Are a Team
Your medications don’t work in isolation. They talk to each other-sometimes quietly, sometimes loudly. A pill you think is harmless, like Benadryl, can turn a safe opioid into a danger. A sleep aid you take once a week can make your blood pressure med act like a double dose. The more meds you take, the more important it is to look at the whole picture.Second-generation antihistamines are the new standard for a reason. They work just as well for allergies, without the brain fog, the falls, or the ER visits. If you’re still using first-gen antihistamines, especially with other sedating drugs, it’s time to change. Talk to your doctor. Ask your pharmacist. Your future self will thank you.
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