Drug & supplement interaction

Wild Lettuce + Acetaminophen, Diphenhydramine

Acetaminophen, Diphenhydramine brand names: Tylenol PM, Tylenol PM Ex Strength.

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

Acetaminophen, Diphenhydramine falls into 2 drug categories that Wild Lettuce can interact with; the most serious is rated moderate. Theoretically, concomitant use with drugs with sedative effects might cause additive therapeutic effects and adverse effects.

Read the full interaction report
SeverityModerate
LikelihoodPossible
Interactions2
EvidenceD
What do Severity, Likelihood & Evidence mean?
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Interaction report

Wild Lettuce and Acetaminophen, Diphenhydramine

These two interact in 2 distinct ways. Each one is explained separately below.

Why Are There 2 Interactions?

Wild Lettuce interacts with whole categories of medication. Acetaminophen, Diphenhydramine falls into 2 of those categories, so it can interact with Wild Lettuce in 2 different ways. We’ve listed each one below — your overall risk is driven by the most serious of them (Moderate).

Moderate

CNS DEPRESSANTS

1 of 2

Why this applies to Acetaminophen, Diphenhydramine

Acetaminophen, Diphenhydramine falls under CNS DEPRESSANTS — the group Wild Lettuce interacts with.

Theoretically, concomitant use with drugs with sedative effects might cause additive therapeutic effects and adverse 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 thing to keep in mind with Tylenol PM: it already contains diphenhydramine, the same sleepy antihistamine found in Benadryl. Wild lettuce is traditionally used as a calming, sleep-promoting herb, so taking the two together could stack their sedating effects. This isn't about one changing how the other is broken down. It's simply two relaxing things added on top of each other.

In plain terms, you might feel extra drowsy, groggy, dizzy, or foggy-headed the next morning. I'll be honest, this concern is mostly theoretical and based on how these substances behave, not strong human studies. Still, it's worth a quick chat with your pharmacist before pairing them, especially if you drive or take other sleep aids.

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.
Moderate

ANTICHOLINERGIC DRUGS

2 of 2

Acetaminophen, Diphenhydramine also falls under ANTICHOLINERGIC DRUGS.

Studies report varying evidence on whether or not wild lettuce contains hyoscyamine, an anticholinergic drug. If it does, it appears to be in very low amounts. Nevertheless, there have been case reports of individuals consuming large amounts of wild lettuce experiencing anticholinergic-related side effects, such as constipation, dry mouth, dizziness, and sweating. Therefore, if you are already taking a drug with anticholinergic effects, you should be cautious about combining it with wild lettuce as the risk of side effects may be increased.
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 with a product like Tylenol PM: the diphenhydramine in it (that's the same ingredient as Benadryl) already has strong anticholinergic activity. That's what causes the classic dry mouth, blurry vision, constipation, drowsiness, and sometimes dizziness or trouble urinating. Wild lettuce may carry a tiny bit of an anticholinergic compound (hyoscyamine), though the evidence is mixed and shaky at best.

So the worry isn't really about how either one is broken down. It's simply that piling a possible anticholinergic herb on top of an already drying, sedating medicine could add up and make those side effects more noticeable. This is a low-quality, mostly theoretical concern tied to large amounts of wild lettuce, but since both also cause sleepiness, I'd run it by your pharmacist before pairing them, especially if you're older.

Contact Dr. Brian directly if you have additional questions on this interaction

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

Wild Lettuce Also Interacts With Other Medications

Wild Lettuce has 392 moderate known drug interactions in our database — the Acetaminophen, Diphenhydramine one above is among them. If you take anything else, check it against the full list below.

Moderate 392 No known interaction 2,438 (incl. Acetaminophen, Diphenhydramine)
Taking anything else?

Check Another of Your Medications Against Wild Lettuce

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

From our Q&A

Questions About Wild Lettuce or Acetaminophen, 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 Wild Lettuce or Acetaminophen, 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 Acetaminophen, Diphenhydramine

This page covers Wild Lettuce only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Acetaminophen, Diphenhydramine page lists 254 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), Asarabacca (major), Beer (major) and Gamma-hydroxybutyrate (ghb) (major).

By severity: 11 major · 204 moderate · 39 minor.

Open the Acetaminophen, Diphenhydramine interaction page

One more smart check

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

We hold 99 real supplement products containing Wild Lettuce, each one broken down to its full ingredient list — and combination products often carry several ingredients besides Wild Lettuce. Your product may carry other ingredients that interact with Acetaminophen, Diphenhydramine too, on top of Wild Lettuce — 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 Wild Lettuce and Acetaminophen, 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 Wild Lettuce
Steady interest

#1,149 of 1,452 supplements looked up here in the last 7 days

29 days ago today
Medication Acetaminophen, Diphenhydramine
Top 10%

#235 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 Wild Lettuce

What is Wild Lettuce?

Wild Lettuce
  • Insomnia and trouble sleeping
  • Anxiety and restlessness
  • Pain relief
  • Cough and respiratory symptoms
  • Muscle spasms

Wild lettuce is a traditional herb used mainly for sleep, anxiety, and pain, but solid human research supporting these uses is very limited. Because its safety is not well studied, it should be used cautiously, avoided in pregnancy and breastfeeding, and discussed with your pharmacist or doctor first.

Read the full Wild Lettuce monograph & all interactions
Keep checking

Other Drugs & Wild Lettuce

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

0Major
392Moderate
0Minor
2,437No known interaction
392 Moderate 2,437 No interaction
Moderate

392 interactions

Showing 60 of 392 moderate interactions — see all 392 on the Wild Lettuce page.

No interaction 2,437 drugs checked — show the list

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

Showing the 60 most looked-up of 2,437 medications checked with no known interaction — see the full Wild Lettuce list.

See the full Wild Lettuce interactions page
See every supplement checked against Acetaminophen, 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
Wild Lettuce monograph › Uses, safety, and every drug interaction in one place Acetaminophen, Diphenhydramine supplement interactions › Every supplement checked against Acetaminophen, Diphenhydramine, ranked by severity 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 Wild Lettuce and Acetaminophen, Diphenhydramine Together: Common Questions

Can you take Wild Lettuce with Acetaminophen, 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.
Why are there 2 interactions listed for Wild Lettuce and Acetaminophen, Diphenhydramine?
Acetaminophen, Diphenhydramine belongs to more than one drug category, and Wild Lettuce interacts with each of those categories a little differently. We list every one so nothing is missed — your overall risk is driven by the most serious of them.
How serious is the Wild Lettuce and Acetaminophen, 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 Acetaminophen, Diphenhydramine and Wild Lettuce?

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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.