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Medications That Should Never Be Combined with Benadryl

Cartoon of two hands one holding a blue pill and one holding a red pill

Benadryl is the brand name of the generic medication diphenhydramine. This common over-the-counter antihistamine is one of the staple products of many households’ medicine cabinets. Benadryl is commonly used to treat hay fever, seasonal allergies, year-round allergies, the common cold, minor throat irritation, motion sickness, and insomnia. 

Benadryl is very effective in relieving sneezing, runny nose, and itchy, watery eyes. However, taking Benadryl with certain other medications can result in potentially dangerous drug interactions. 

Even though this article talks about Benadryl, a medicine cabinet essential, this information focuses on interactions to watch out for. Please keep in mind that this list is not all-inclusive since these interactions occur with very commonly-used drugs.

What is Benadryl?

Benadryl is a widely available over-the-counter antihistamine that contains the generic medication diphenhydramine. You can get this medication in the following dosage forms:

  • Diphenhydramine hydrochloride tablet
  • Diphenhydramine hydrochloride capsule
  • Diphenhydramine hydrochloride liquid-filled capsule
  • Diphenhydramine hydrochloride solution

Generic diphenhydramine is available under brand names such as Benadryl, Childrens Benadryl Allergy, Aler-Dryl, Diphenhist, Nytol, Pediacare Children’s Allergy, Benadryl Allergy Ultratab, Childrens Benadryl Chewables tablets, and Siladryl

Diphenhydramine is also present in many combination medications such as Advil PM (ibuprofen / diphenhydramine), Aleve PM (naproxen / diphenhydramine), Motrin PM (ibuprofen / diphenhydramine), and others. Benadryl Itch Relief contains diphenhydramine in different dosage forms, such as zinc acetate solution, zinc acetate cream, or zinc acetate spray, to relieve skin symptoms related to allergic reactions. 

What are Benadryl interactions?

Taking Benadryl with certain other drugs can lead to possible interactions. This can increase the risk of side effects, some of which can be mild and go away naturally, though there is also the possibility of serious adverse effects and health complications. That’s why it’s important to tell your doctor or healthcare professional about all medications and health conditions, such as high blood pressure, before starting treatment. If there are known interactions between Benadryl and your other medications, a licensed healthcare professional can give you another treatment option for your medical conditions.

Which Medications Does Benadryl Interact With?  

The following medications or substances, including others not listed, can have drug interactions with Benadryl. If you have other medical conditions and are taking medications for them, or even if you only take OTC products like a multivitamin or supplements, you should ask your pharmacist or healthcare professional if Benedryl is right for you when:

  • It is the first time you plan to take Benadryl
  • You have been taking Benadryl and are prescribed a new medication.

Doing this would prevent possible side effects and ensure that this new drug combination does not cause harm if you have other underlying conditions. Also, it is good to keep in mind that for any given drug, different people may react differently, so promptly getting medical care is necessary when you experience severe side effects, such as an allergic reaction.

Remember that some medications can interact with certain foods and even lab tests. People can interact differently based on factors like age and underlying health status. Below are the common interactions to watch out for.


Alcohol alone is a CNS depressant; taken together with Benadryl, it can increase the sedating effect of Benadryl, thus worsening drowsiness. So if you drink alcohol while taking Benadryl, you will feel extremely sleepy. Drinking alcohol while on Benadryl can also lead to other side effects like dizziness, confusion, and slowed breathing rate. These effects can impair your alertness and ability to focus, putting you at risk of accidents.

Blood pressure medications

There is no known drug interaction between Benadryl and medications prescribed for high blood pressure. However, Benadryl can increase the side effects of metoprolol succinate (Toprol XL) and metoprolol tartrate (Lopressor), which can lead to low blood pressure, dizziness, and slow heart rate.

As mentioned above, Benadryl is an ingredient of many OTC cough and cold products. Benadryl doesn’t raise blood pressure by itself. These products contain decongestants such as pseudoephedrine that can increase blood pressure.

Other antihistamines

Taking Benadryl along with other antihistamines can increase the risk of side effects. This includes drugs like meclizine (Antivert), loratadine (Claritin), cetirizine (Zyrtec), hydroxyzine (Vistaril), and promethazine (Promethegan). Also, taking other diphenhydramine-containing products can lead to more severe side effects like dizziness, drowsiness, confusion, and inability to concentrate.


Tricyclic antidepressants (TCAs), an older antidepressant class, and trazodone (Desyrel) have sedating effects.  Drug interactions between Benadryl and these specific antidepressants can increase the risk of side effects like drowsiness and reduced alertness. 

Sleeping medicines

Taking Benadryl with sedative-hypnotics (sleep aids) like eszopiclone (Lunesta), zolpidem (Ambien), or suvorexant (Belsomra) can increase the risk of side effects like extreme drowsiness, confusion, and difficulty concentrating. Prescription sleep medications and OTC sleep aids, such as melatonin and Unisom, should not be combined with Benadryl. An interesting fact to keep in mind is that, except for melatonin, the active ingredients in most OTC sleeping pills are antihistamines like Benadryl. 

Bowel disease medications

Certain medications used to treat bowel diseases, such as irritable bowel syndrome with diarrhea (IBS-D), can cause constipation as a side effect. In some rare cases, Benadryl can interact with these medications for IBS-D and worsen constipation. However, this is rare and only happens if you take high doses of Benadryl regularly over a long period.

Seizure medications

Certain medications used to treat seizures, such as zonisamide (Zonegran), can lead to increased body temperature and decreased sweating. Though not common, Benadryl interactions can worsen these side effects and may lead to heat stroke. Your healthcare professional will tell you to exercise caution, especially during vigorous exercise in warm weather, if you are on this combination of drugs.

Cannabis products

The use of cannabis and Benadryl together can lead to side effects like dizziness, drowsiness, confusion, and difficulty concentrating. These effects may be especially severe in elderly individuals who may also experience impaired judgment and coordination.

Wrapping up

In addition to drug interactions with the medicines listed above, other drugs may also interact with Benadryl. If you take medications for certain medical conditions, give your healthcare professional a complete list of your other drugs. Your doctor or pharmacist will make sure that all your medications are appropriate and that no known drug interactions exist. If Benadryl is not an appropriate option, your care team can discuss other alternative therapy that is safe and effective for you. 


  1. https://medlineplus.gov/druginfo/meds/a682539.html
  2. https://www.ncbi.nlm.nih.gov/books/NBK526010/
  3. https://www.pdr.net/drug-summary/Diphenhydramine-Hydrochloride-diphenhydramine-hydrochloride-1140.941
  4. https://link.springer.com/article/10.1007/BF00625799
  5. https://pubmed.ncbi.nlm.nih.gov/10824625/
  6. https://meridian.allenpress.com/mhc/article/4/3/118/37078/An-overview-of-clinically-significant-drug