Drug & supplement interaction

Caffeine + Aspirin, Diphenhydramine, Phenylpropanolamine

Aspirin, Diphenhydramine, Phenylpropanolamine brand name: Alka Seltzer Plus Night Time Effervescent.

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

Aspirin, Diphenhydramine, Phenylpropanolamine falls into 3 drug categories that Caffeine can interact with; the most serious is rated moderate. Theoretically, caffeine may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.

Read the full interaction report
SeverityModerate
LikelihoodPossible
Interactions3
EvidenceD
What do Severity, Likelihood & Evidence mean?
Know someone taking this? Share
Facebook Post Reddit Email
On this page
Interaction report

Caffeine and Aspirin, Diphenhydramine, Phenylpropanolamine

These two interact in 3 distinct ways. Each one is explained separately below.

Why Are There 3 Interactions?

Caffeine interacts with whole categories of medication. Aspirin, Diphenhydramine, Phenylpropanolamine falls into 3 of those categories, so it can interact with Caffeine in 3 different ways. We’ve listed each one below — your overall risk is driven by the most serious of them (Moderate).

Moderate

ANTICOAGULANT/ANTIPLATELET DRUGS

1 of 3

Why this applies to Aspirin, Diphenhydramine, Phenylpropanolamine

Aspirin, Diphenhydramine, Phenylpropanolamine falls under ANTICOAGULANT/ANTIPLATELET DRUGS — the group Caffeine interacts with.

Theoretically, caffeine may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.
Caffeine is reported to have antiplatelet activity. Theoretically, it might increase the risk of bleeding when used concomitantly with these agents; however, this interaction has not been reported in humans.
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

This combo product (Alka Seltzer Plus Night Time) contains aspirin, which thins the blood a little by keeping platelets from clumping together. The note on file says caffeine has been shown in lab studies to have its own mild antiplatelet (blood-thinning) effect. So on paper, pairing caffeine with the aspirin in this product could add up to a slightly higher chance of bleeding or bruising.

Here is the honest part: this concern comes only from test-tube and animal research, and it has never actually been reported in real people. For most folks, the caffeine in a normal cup or two of coffee is very unlikely to matter. If you take aspirin regularly, drink a lot of caffeine, or notice easy bruising, unusual bleeding, or stomach upset, check in with your pharmacist or doctor.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Ali M, Afzal M. A potent inhibitor of thrombin stimulated platelet thromboxane formation from unprocessed tea. Prostaglandins Leukot Med 1987;27:9-13. PubMed
  2. Ardlie NG, Glew G, Schultz BG, Schwartz CJ. Inhibition and reversal of platelet aggregation by methyl xanthines. Thromb Diath Haemorrh 1967;18:670-3. DOI
Moderate

STIMULANT DRUGS

2 of 3

Aspirin, Diphenhydramine, Phenylpropanolamine also falls under STIMULANT DRUGS.

Theoretically, concomitant use might increase stimulant adverse effects.
Due to the central nervous system (CNS) stimulant effects of caffeine, concomitant use with stimulant drugs can increase the risk of adverse effects.
Severity Moderate Likelihood Probable Evidence C

Interaction 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..

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

This combination product has three ingredients, but the one that matters here is phenylpropanolamine, a decongestant that works like a stimulant. Caffeine is also a stimulant, so stacking them together can pile on the same kind of effects. You might feel more jittery, notice your heart racing or pounding, feel anxious, or have trouble settling down to sleep, which is a bit ironic for a night-time product.

To be fair, this concern is based on expert opinion rather than hard studies, so it's more of a sensible caution than a guarantee. A normal cup of coffee with this medicine probably won't cause much, but several cups or energy drinks could push things. If you tend to be caffeine-sensitive or have heart concerns, run it by your pharmacist or doctor first.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Institute of Medicine. Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations. Washington, DC: National Academy Press, 2001. Available at: http://books.nap.edu/books/0309082587/html/index.html. DOI
Moderate

PHENYLPROPANOLAMINE

3 of 3

Aspirin, Diphenhydramine, Phenylpropanolamine also falls under PHENYLPROPANOLAMINE.

Theoretically, phenylpropanolamine might increase the risk of hypertension, as well as the levels and adverse effects of caffeine.
Concomitant use of phenylpropanolamine and caffeine might cause an additive increase in blood pressure. Phenylpropanolamine also seems to increase caffeine serum levels.
Severity Moderate Likelihood Probable Evidence B

Interaction 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..

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

This combo product contains phenylpropanolamine, a decongestant that works by tightening blood vessels. When you pair it with caffeine, two things can happen. First, both can nudge your blood pressure up, and the effect can add together. Second, phenylpropanolamine seems to slow how fast your body clears caffeine, so caffeine levels can run higher than usual. That means a normal cup or two of coffee might hit harder, leaving you feeling jittery, with a racing or pounding heart, restlessness, or trouble sleeping.

The evidence here is moderate and partly theoretical, so for most healthy folks it is not an emergency. But if you have high blood pressure, heart issues, or anxiety, go easy on caffeine while taking this, and check with your pharmacist or doctor first.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Brown NJ, Ryder D, Branch RA. A pharmacodynamic interaction between caffeine and phenylpropanolamine. Clin Pharmacol Ther 1991;50:363-71. PubMed
  2. Lake CR, Rosenberg DB, Gallant S, et al. Phenylpropanolamine increases plasma caffeine levels. Clin Pharmacol Ther 1990;47:675-85. 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

Caffeine Also Interacts With Other Medications

Caffeine has 8 major, 482 moderate, 164 minor known drug interactions in our database — the Aspirin, Diphenhydramine, Phenylpropanolamine one above is among them. If you take anything else, check it against the full list below.

Major 8 Moderate 482 Minor 164 No known interaction 2,176 (incl. Aspirin, Diphenhydramine, Phenylpropanolamine)
Taking anything else?

Check Another of Your Medications Against Caffeine

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

From our Q&A

Questions About Caffeine or Aspirin, Diphenhydramine, Phenylpropanolamine

These are real questions from readers, answered by the pharmacists at HelloPharmacist — written by a person, not generated from a database. Each one covers Caffeine or Aspirin, Diphenhydramine, Phenylpropanolamine, 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 Aspirin, Diphenhydramine, Phenylpropanolamine

This page covers Caffeine only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Aspirin, Diphenhydramine, Phenylpropanolamine page lists 361 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 Danshen (major).

By severity: 17 major · 308 moderate · 36 minor.

From our pharmacist’s overview on the Aspirin, Diphenhydramine, Phenylpropanolamine page

“A cold remedy used for a few nights can still collide with supplements taken daily, and Alka Seltzer Plus Night Time (aspirin, diphenhydramine, phenylpropanolamine) is one to treat with genuine care. Its three ingredients thin the blood, sedate, and stimulate all at once, which is why 361 supplements and herbs are on file here.”

Reviewed by 2 · Jul 18, 2026

Open the Aspirin, Diphenhydramine, Phenylpropanolamine interaction page

One more smart check

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

We hold 6,775 real supplement products containing Caffeine, each one broken down to its full ingredient list — and combination products often carry several ingredients besides Caffeine. Your product may carry other ingredients that interact with Aspirin, Diphenhydramine, Phenylpropanolamine too, on top of Caffeine — 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 Caffeine and Aspirin, Diphenhydramine, Phenylpropanolamine 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 Caffeine
Top 5%

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

29 days ago today
Medication Aspirin, Diphenhydramine, Phenylpropanolamine
Top 10%

#249 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 Caffeine

What is Caffeine?

  • Mental alertness and reducing fatigue
  • Improving athletic performance
  • Headache and migraine relief
  • Boosting focus and concentration
  • Weight loss aid

Caffeine is a natural stimulant found in coffee, tea, and many other plants and products. In moderate amounts it can boost alertness and reduce tiredness for most healthy adults, but too much can cause jitteriness, a racing heart, and sleep problems. Pregnant women and people with heart conditions or anxiety should be especially careful and check with a doctor or pharmacist.

Read the full Caffeine monograph & all interactions
Keep checking

Other Drugs & Caffeine

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

8Major
482Moderate
164Minor
2,175No known interaction
8 Major 482 Moderate 164 Minor 2,175 No interaction
Major

8 interactions

Moderate

482 interactions

Showing 60 of 482 moderate interactions — see all 482 on the Caffeine page.

Minor

164 interactions

Showing 60 of 164 minor interactions — see all 164 on the Caffeine page.

No interaction 2,175 drugs checked — show the list

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

Showing the 60 most looked-up of 2,175 medications checked with no known interaction — see the full Caffeine list.

See the full Caffeine interactions page
See every supplement checked against Aspirin, Diphenhydramine, Phenylpropanolamine, 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
Caffeine monograph › Uses, safety, and every drug interaction in one place Aspirin, Diphenhydramine, Phenylpropanolamine supplement interactions › Every supplement checked against Aspirin, Diphenhydramine, Phenylpropanolamine, 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 Caffeine and Aspirin, Diphenhydramine, Phenylpropanolamine Together: Common Questions

Can you take Caffeine with Aspirin, Diphenhydramine, Phenylpropanolamine?
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 3 interactions listed for Caffeine and Aspirin, Diphenhydramine, Phenylpropanolamine?
Aspirin, Diphenhydramine, Phenylpropanolamine belongs to more than one drug category, and Caffeine 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 Caffeine and Aspirin, Diphenhydramine, Phenylpropanolamine 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 Aspirin, Diphenhydramine, Phenylpropanolamine and Caffeine?

Our pharmacists answer your medication & supplement questions — free.

Ask a pharmacist

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.