Drug & supplement interaction

Sassafras + Diphenhydramine

Diphenhydramine brand names: Benadryl, Dormin, Allerdryl, Valdrene, Sleep-Ettes D, and others.

Moderate Interaction
Medically reviewed by · Updated September 2026
The bottom line Moderate

Sassafras has a moderate interaction with Diphenhydramine. Theoretically, concomitant use of sassafras with drugs with sedative properties may cause additive sedative effects.

Read the full interaction report
SeverityModerate
LikelihoodPossible
EvidenceD
What do Severity, Likelihood & Evidence mean?
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Interaction report

Sassafras and Diphenhydramine

Here is the interaction we found between these two, with the evidence behind it.

Moderate

CNS DEPRESSANTS

Why this applies to Diphenhydramine

Diphenhydramine falls under CNS DEPRESSANTS — the group Sassafras interacts with.

Theoretically, concomitant use of sassafras with drugs with sedative properties may cause additive sedative effects.
Severity Moderate Likelihood Possible Evidence D

Interaction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.

Dr. Brian Staiger, PharmD, BCPS
Dr. Brian Staiger explains PharmD, Clinical Pharmacist

Here's the simple version: Benadryl (diphenhydramine) already makes most people drowsy. That's actually why some folks use it for sleep. Sassafras may add its own mild sedating effect on top of that. So if you took them together, you could feel sleepier, foggier, or more 'out of it' than usual, with possible dizziness, grogginess, or slowed reactions. That matters most before driving or operating anything that needs your full attention.

I want to be straight with you, though: this concern is theoretical, based on how these things work rather than real-world reports. My bigger worry with sassafras isn't the sleepiness at all. It contains safrole, which has been linked to liver damage and cancer in animal studies, so internal use generally isn't recommended. Please run any sassafras product past your pharmacist or doctor first.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Brinker F. Herb Contraindications and Drug Interactions. 2nd ed. Sandy, OR: Eclectic Medical Publications, 1998.

What These Ratings Mean

Every interaction above is graded three ways — here’s the key to each label.

Severity how clinically significant the interaction is
Major

Clinically significant. Avoid the combination, or use only under close professional supervision.

Moderate

Usually worth avoiding or managing — may need monitoring, a dose change, or timing apart.

Minor

Generally not serious. Be aware of it and mention it to your pharmacist.

Likelihood how strong the evidence is that the interaction actually happens in people
  • LikelyWell-controlled human studies have demonstrated the likely existence of this interaction.
  • ProbableInteraction has not been documented in well-controlled studies, however, the interaction has been demonstrated in some small human studies or in controlled animal studies in conjunction with multiple case reports.
  • PossibleInteraction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists.
  • UnlikelyInteraction has been demonstrated in animal or in lab research but has been shown not to occur in humans.
Evidence the quality of the studies behind the rating (graded A–D)
  • AHigh-quality meta-analysis (quantitative systematic review).
  • BCase-control study.
  • CConsensus.
  • DAnecdotal evidence.

These ratings are for information only. Never start, stop, or otherwise change your therapy before speaking with your provider.

Keep it in perspective

Sassafras Also Interacts With Other Medications

Sassafras has 274 moderate known drug interactions in our database — the Diphenhydramine one above is one of them. If you take anything else, check it against the full list below.

Moderate 274 No known interaction 2,556 (incl. Diphenhydramine)
Taking anything else?

Check Another of Your Medications Against Sassafras

Covers the 2,830 medications we’ve checked against Sassafras. Pick one to open its full report.

From our Q&A

Questions About Sassafras or Diphenhydramine

These are real questions from readers, answered by the pharmacists at HelloPharmacist — written by a person, not generated from a database. Each one covers Sassafras or Diphenhydramine, not necessarily both, but if one is close to what you were about to ask it will usually go further than a database entry can:

Not quite your question? Ask our pharmacists directly — it is free, there is no account required, and answers usually come back within 24 hours.

Everything else you take

See Every Supplement That Interacts With Diphenhydramine

This page covers Sassafras only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Diphenhydramine page lists 147 supplements it has a documented interaction with, worst first, each one explained.

The most serious there right now: 1,4-butanediol (major), Activated Charcoal (major), Beer (major), Gamma-hydroxybutyrate (ghb) (major) and Henbane (major).

By severity: 9 major · 119 moderate · 19 minor.

From our pharmacist’s overview on the Diphenhydramine page

“Diphenhydramine (Benadryl, Simply Sleep) is sedating by design, and most of the 147 supplements and herbal ingredients on this list lean into that. Seventy-eight are sedating substances themselves, alcohol and kava the standouts, and stacking them can slow breathing and reflexes well beyond ordinary drowsiness.”

Reviewed by 2 · Jul 18, 2026

Open the Diphenhydramine interaction page

One more smart check

Taking Sassafras as Part of a Dietary Supplement Product? Check It for Interactions

We hold 11 real supplement products containing Sassafras, each one broken down to its full ingredient list — and combination products often carry several ingredients besides Sassafras. Your product may carry other ingredients that interact with Diphenhydramine too, on top of Sassafras — and those would not show on this page. Find your product and we’ll check every ingredient on its label:

How much people look this up

Where Sassafras and Diphenhydramine Sit Against Everything Else

Out of every supplement and medication people look up on HelloPharmacist, here is where these two land this week — and which way each has been moving.

Supplement Sassafras
Steady interest

#727 of 1,452 supplements looked up here in the last 7 days

29 days ago today
Medication Diphenhydramine
Top half

#738 of 2,830 medications looked up here in the last 7 days

29 days ago today

Position among everything looked up on this site, not a measure of how commonly either one is used or how important it is. A supplement can climb this list because of a news story. It counts every request to the page, automated ones included, and nothing here identifies anyone.

Supplement

About Sassafras

What is Sassafras?

  • Digestive complaints
  • Cold and flu symptoms
  • Joint and muscle aches
  • Skin conditions (topical folk use)
  • As a flavoring agent (traditional root beer)

Sassafras is an aromatic North American tree whose root bark and oil were once popular in teas and as a flavoring, but it contains safrole, a compound the FDA has banned in foods because it can cause cancer and liver damage. There is no good evidence it safely treats any health condition, and most experts recommend avoiding internal use. If you want the flavor, choose products that are labeled safrole-free.

Read the full Sassafras monograph & all interactions
Medication

About Diphenhydramine

What Is Diphenhydramine Used For?

Brand names: Benadryl, Dormin, Allerdryl, Valdrene, Sleep-Ettes D, Simply Sleep, Sominex, Diphenhydramine, Compoz, Sleep Aid, Benadryl cream, Benadryl spray, Dermamycin cream, Ziradryl, Nytol

Diphenhydramine temporarily relieves symptoms of hay fever, other upper respiratory allergies, and the common cold — including runny nose, sneezing, itchy or watery eyes, and itching of the nose or throat.

After Bite Xtra gel is formulated for topical use and is approved to temporarily relieve pain and itching from minor burns, minor cuts and scrapes, insect bites, minor skin irritations, and rashes from poison ivy, poison oak, and poison sumac.

See full Diphenhydramine drug information
Keep checking

Other Drugs & Sassafras

Browse every other medication we’ve checked against Sassafras — both the ones with a known interaction and the ones without. Select any drug for the full detail.

0Major
274Moderate
0Minor
2,555No known interaction
274 Moderate 2,555 No interaction
Moderate

274 interactions

Showing 60 of 274 moderate interactions — see all 274 on the Sassafras page.

No interaction 2,555 drugs checked — show the list

We also checked Sassafras against these medications and found no known interaction in our sources. Open any page to confirm.

Showing the 60 most looked-up of 2,555 medications checked with no known interaction — see the full Sassafras list.

See the full Sassafras interactions page
See every supplement checked against Diphenhydramine, ranked by severity
Sources

Sources & How We Checked

Interaction details are evidence-graded and sourced from the Natural Medicines database. The medication overview comes from MedlinePlus.

Content is written and reviewed by licensed HelloPharmacist pharmacists. See our data sources and editorial standards for how this information is built and checked.

Parts of this content are provided by the Therapeutic Research Center, LLC.

DISCLAIMER: Currently this does not check for drug-drug interactions. This is not an all-inclusive comprehensive list of potential interactions and is for informational purposes only. Not all interactions are known or well-reported in the scientific literature, and new interactions are continually being reported. Input is needed from a qualified healthcare provider including a pharmacist before starting any therapy. Application of clinical judgment is necessary.

© 2021 Therapeutic Research Center, LLC

Keep exploring
Sassafras monograph › Uses, safety, and every drug interaction in one place Diphenhydramine supplement interactions › Every supplement checked against Diphenhydramine, ranked by severity Diphenhydramine drug information › The full plain-English guide to this medication Supplement interaction checker › Check any supplement or product against your medications Browse medications A–Z › Every drug we've checked against herbs & supplements Ask a pharmacist › Free, personal answer from our licensed team
Pharmacist Counseling Corner

Taking Sassafras and Diphenhydramine Together: Common Questions

Can you take Sassafras with Diphenhydramine?
There is a moderate interaction, so it may be acceptable with monitoring or timing changes — but check with your pharmacist first. Read the full details on this page and confirm with your pharmacist before combining them.
How serious is the Sassafras and Diphenhydramine interaction?
We rate it Moderate. This combination may require monitoring, a dose adjustment, or separating the times you take each one. Consult your pharmacist before using them together.

Written and reviewed by the HelloPharmacist editorial staff. Our editorial policy

Still Have a Question About Diphenhydramine and Sassafras?

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This information is for education only and is not a substitute for professional medical advice. Always check with your pharmacist or doctor before starting, stopping, or combining supplements and medications.