Taking Xanax (alprazolam) with Benadryl (diphenhydramine) increases CNS depression, causing excessive drowsiness, impaired coordination, slowed reaction time, and difficulty thinking clearly. In higher doses, the combination can cause dangerous levels of sedation and respiratory depression.
How This Interaction Works (Mechanism)
Alprazolam enhances GABA-A receptor activity, producing sedation and anxiolysis. Diphenhydramine blocks H1 histamine receptors in the brain, which also produces sedation (this is the mechanism behind its use as a sleep aid). Additionally, diphenhydramine has anticholinergic properties that can cause confusion, dry mouth, and urinary retention. The combination of GABAergic and antihistaminic sedation is additive and can impair consciousness significantly.
Source: Beers Criteria for Potentially Inappropriate Medication Use in Older Adults, 2023
Avoid taking Benadryl with Xanax unless directed by your doctor. If you need an antihistamine for allergies while taking Xanax, consider a non-sedating option like cetirizine (Zyrtec) or loratadine (Claritin), which do not cross the blood-brain barrier significantly. If you must take both, do not drive or operate machinery. Elderly patients are at particularly high risk for falls and confusion with this combination.
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Sources and standards behind this page
What a drug interaction does, and how strongly it is supported, is documented in public labeling and federal safety references rather than in any one summary, and the sources below are the primary ones. They are linked so a reader can check a claim without taking this page's word for it.
- DailyMed carries the current FDA labeling for every marketed drug product, including the warnings and drug interaction sections.
- Drugs@FDA is the federal database of approved drug products and their approval documents.
- FDA: Drug interactions, what you should know explains how drug-drug, drug-food and drug-condition interactions are described on labels.
- FDA Drug Safety Communications publishes the agency's safety alerts and label changes as they are issued.
- FDA MedWatch is the program for reporting and reviewing adverse events, including suspected interactions.
- openFDA provides public access to FDA labeling and adverse event data.
- MedlinePlus drug information is the National Library of Medicine's consumer reference for what a medicine is and how it is taken.
- NIAAA: Harmful interactions documents which medicines interact with alcohol and how.
- NCCIH: Herb-drug interactions summarises the evidence on interactions between herbal products and medicines.
- National Library of Medicine maintains the drug and health databases the sources above draw on.
This page describes how this interaction works and where it is documented. It is not medical advice: a prescriber or pharmacist decides what applies to a particular patient and medication.
Frequently Asked Questions
Xanax and Benadryl have a moderate interaction that requires caution. While some patients may take both under medical supervision, the combination can cause adverse effects. Talk to your doctor before combining these medications, and do not adjust doses on your own.
Taking Xanax (alprazolam) with Benadryl (diphenhydramine) increases CNS depression, causing excessive drowsiness, impaired coordination, slowed reaction time, and difficulty thinking clearly. In higher doses, the combination can cause dangerous levels of sedation and respiratory depression.
Yes. Anytime you are taking multiple medications, supplements, or substances, you should inform your doctor and pharmacist. They can evaluate your specific risk factors (age, kidney function, other medications, medical conditions) and determine whether the Xanax and Benadryl combination is safe for you, or whether adjustments are needed.
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