Drug Interaction Report

Diphenhydramine Topical and Cannabidiol: Interaction Details

Name: Diphenhydramine Topical and Cannabidiol Interaction
Creator: Dr. Brian Staiger, PharmD, BCPS

A pharmacist-reviewed analysis of the Diphenhydramine Topical and Cannabidiol interaction: the documented clinical effects, severity rating, onset, mechanism, and management considerations, with cited references throughout.

AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature

Diphenhydramine Topical

Afterbite with Antihistamine Benadryl® Itch Stopping Gel Dermamycin

Cannabidiol

Epidiolex

Medically reviewed by

Dr. Brian Staiger, PharmD, BCPS

Updated Aug 8, 2026

Editorial policy · Data sources

Interaction severity

Major

Potentially serious — often needs a change or close monitoring.

Minor

Moderate

Major

Contraindicated

How we grade severity & evidence

Severity levels

Contraindicated: These should generally not be used together.
Major: Potentially serious — often needs a change or close monitoring.
Moderate: Can be significant — usually manageable with monitoring.
Minor: Usually limited clinical impact.

Evidence grades

Established: Well documented — supported by controlled studies or strong clinical data.
Probable: Good supporting evidence, though not definitively proven.
Suspected: Some evidence suggests this interaction, but it is not well established.
Possible: Limited or conflicting evidence; the interaction may occur.
Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.

Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.

Of 123 documented Diphenhydramine Topical interactions, 102 are rated major — including this one.

Worried about symptoms right now? Contact your pharmacist or prescriber, or call Poison Control at 1-800-222-1222 (US). Call 911 for an emergency.

Onset

unspecified

Evidence

theoretical

Severity

Major

What happens

Increased risk of CNS depression and an increased risk of sedation and somnolence

Interaction Deep Dive

Concomitant use of cannabidiol, which is a CNS depressant, with another CNS depressant may increase the risk of sedation and somnolence. Monitor for somnolence and sedation and advise patients not to drive or operate machinery until they have gained sufficient experience on cannabidiol¹.

Why it happens (mechanism)

Additive CNS depression

Common questions

Can I take Diphenhydramine Topical and Cannabidiol together?

Increased risk of CNS depression and an increased risk of sedation and somnolence Always confirm with your pharmacist or prescriber before making any change.

How serious is the Diphenhydramine Topical and Cannabidiol interaction?

It is rated major. Potentially serious — often needs a change or close monitoring.

How quickly could this interaction happen?

The documented onset is "unspecified". The timing of this interaction is not well characterized.

How strong is the evidence for this interaction?

The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.

From our Q&A

Real reader questions about these medications, each personally answered by our pharmacist:

Can You Take CBD (Cannabidiol) And Bupropion Together?

Questions for your pharmacist

Does my dose of Diphenhydramine Topical or Cannabidiol need adjusting while I take them together?
What symptoms should prompt me to call you or my prescriber right away?
Does the timing of my doses matter for this combination?
Is there a safer alternative to one of these medications for me?

References (1)

Product Information: EPIDIOLEX(R) oral solution, cannabidiol oral solution. Jazz Pharmaceuticals, Inc. (per FDA), Palo Alto, CA, 2025. DailyMed

Was this write-up helpful?

Diphenhydramine Topical

Keep reading about Diphenhydramine Topical

All Diphenhydramine Topical interactions (123) Diphenhydramine Topical drug information

Also serious with: Sodium Oxybate Tranylcypromine Isocarboxazid Calcium Oxybate

Cannabidiol

Keep reading about Cannabidiol

All Cannabidiol interactions (53)

Also serious with: Deuruxolitinib Erdafitinib Orlistat Dexlansoprazole

Check another combination

Our instant two-drug interaction checker is almost here.

Coming soon

The instant two-drug checker is on its way.

In the meantime, browse the directory below to look up any drug and see its documented interactions.

Still have questions about this combination?

Every question gets a real answer from a licensed pharmacist — free, and usually within a day.

Ask the pharmacist

A message from HelloPharmacist

About our interaction database: depth, not breadth

HelloPharmacist doesn't license one of the big commercial interaction databases, so what you'll find here is not a complete list of every known drug interaction. Instead, each entry is researched, analyzed, and written up individually — documented from the published literature, reviewed by a pharmacist, and cited so you can check every source yourself.

If a combination isn't listed here, it means we haven't documented it yet — never that it's safe. For screening a full medication list, we recommend pairing this site with a comprehensive tool like the Drugs.com Interaction Checker and, most importantly, a review by your own pharmacist. For a deep, plain-English, fully sourced explanation of a specific documented interaction — that's exactly what we built this for.

This information is for education, not a substitute for professional medical advice. Do not start, stop, or change any medication without talking to your pharmacist or prescriber.