Drug & supplement interaction

Rue + 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

Rue has a moderate interaction with Diphenhydramine. Theoretically, rue might increase the risk for phototoxicity when used with photosensitizing drugs.

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

Rue and Diphenhydramine

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

Moderate

PHOTOSENSITIZING DRUGS

Why this applies to Diphenhydramine

Diphenhydramine falls under PHOTOSENSITIZING DRUGS — the group Rue interacts with.

Theoretically, rue might increase the risk for phototoxicity when used with photosensitizing drugs.
Rue contains photosensitizing furanocoumarins and psoralens and has been associated with multiple reports of phototoxic reactions. There is also one case report of an increased phototoxic response to psoralen and ultraviolet A (PUVA) therapy associated with ingestion of rue.
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 thing to know about pairing rue with diphenhydramine (Benadryl): this isn't about how your body breaks the medicine down. Instead, both rue and diphenhydramine can make your skin more sensitive to sunlight. Rue carries natural compounds called furanocoumarins and psoralens that are linked to phototoxic reactions, basically an exaggerated sunburn. Diphenhydramine is already known to occasionally cause sun sensitivity on its own.

So used together, you could theoretically be a bit more likely to burn quickly, get a rash, or develop red, irritated skin after time outdoors. I'll be honest, though, this is based on weak, anecdotal evidence, not strong studies. If you do use both, simple sun protection (sunscreen, hat, covering up) goes a long way. Please check with your pharmacist or doctor first.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Puig L. Pharmacodynamic interaction with phototoxic plants during PUVA therapy. Br J Dermatol 1997;136:973-4. PubMed
  2. Radotra I, Gardiner S, Barnes D. A phytophototoxic injury at a burns unit: the ungraceful after-effects of the "common rue" plant. J Burn Care Res. 2018;39(6):1064-6. PubMed
  3. Avallone G, Mastorino L, Agostini A, et al. Ruta graveolens phytophotodermatitis. Dermatol Online J 2021;27(7). PubMed

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

Rue Also Interacts With Other Medications

Rue has 334 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 334 No known interaction 2,496 (incl. Diphenhydramine)
Taking anything else?

Check Another of Your Medications Against Rue

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

From our Q&A

Questions About Rue 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 Rue 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 Rue 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 Rue as Part of a Dietary Supplement Product? Check It for Interactions

We hold 47 real supplement products containing Rue, each one broken down to its full ingredient list — and combination products often carry several ingredients besides Rue. Your product may carry other ingredients that interact with Diphenhydramine too, on top of Rue — 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 Rue 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 Rue
Steady interest

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

29 days ago today
Medication Diphenhydramine
Top half

#756 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 Rue

What is Rue?

Rue
  • Menstrual cramps
  • Digestive upset
  • Muscle spasms and pain
  • Headache
  • Insect repellent (topical)
  • Traditional folk remedy

Rue is a strong-smelling herb from southern Europe with a long history in folk medicine, but there is very little reliable human research to support its health uses. It can be toxic in larger amounts and is considered unsafe during pregnancy, so most people should avoid it or use it only under professional guidance.

Read the full Rue 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 & Rue

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

0Major
334Moderate
0Minor
2,495No known interaction
334 Moderate 2,495 No interaction
Moderate

334 interactions

Showing 60 of 334 moderate interactions — see all 334 on the Rue page.

No interaction 2,495 drugs checked — show the list

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

Showing the 60 most looked-up of 2,495 medications checked with no known interaction — see the full Rue list.

See the full Rue 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
Rue 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 Rue and Diphenhydramine Together: Common Questions

Can you take Rue 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 Rue 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 Rue?

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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.