Drug & supplement interaction

Caffeine + Promethazine, Pseudoephedrine

Promethazine, Pseudoephedrine brand name: Phenergan D.

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

Promethazine, Pseudoephedrine falls into 2 drug categories that Caffeine can interact with; the most serious is rated moderate. Theoretically, concomitant use might increase stimulant adverse effects.

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

Caffeine and Promethazine, Pseudoephedrine

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

Why Are There 2 Interactions?

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

Moderate

STIMULANT DRUGS

1 of 2

Why this applies to Promethazine, Pseudoephedrine

Promethazine, Pseudoephedrine falls under STIMULANT DRUGS — the group Caffeine interacts with.

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

Phenergan D is a combo: promethazine (an antihistamine that usually makes you drowsy) plus pseudoephedrine, which is a decongestant and a mild stimulant. Caffeine is also a stimulant, so the concern here is mostly about the pseudoephedrine side. Stacking two stimulants together can add up.

In real life that might mean a faster or pounding heartbeat, feeling jittery or wired, higher blood pressure, or trouble sleeping. This is based on expert opinion rather than hard studies, so it is more of a heads-up than a red alert. A morning cup of coffee probably will not be a big deal for most people, but loading up on energy drinks or pre-workout supplements is where I'd be cautious. If you have heart issues or high blood pressure, please 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
Minor

PHENOTHIAZINES

2 of 2

Promethazine, Pseudoephedrine also falls under PHENOTHIAZINES.

Theoretically, phenothiazines might increase the levels and adverse effects of caffeine.
Phenothiazines, including perazine, chlorpromazine, levomepromazine, and thioridazine, can reduce the metabolism of caffeine by inhibiting cytochrome P450 1A2 (CYP1A2).
Severity Minor 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 gist for Phenergan D, which pairs promethazine (an antihistamine) with pseudoephedrine (a decongestant). The promethazine part can mildly slow down a liver enzyme called CYP1A2, and that enzyme is the one your body uses to clear caffeine. If caffeine breaks down a little slower, it can hang around longer than usual.

So in theory, your coffee or energy drink might hit harder. That could mean more jitteriness, a faster heartbeat, or trouble sleeping, which can stack with the pseudoephedrine, since that decongestant is already a bit of a stimulant. Keep in mind this is a minor interaction based only on lab data, so for most people it's not a big deal. If you notice you feel wired, just ease up on the caffeine and check with your pharmacist.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Wojcikowski, J. and Daniel, W. A. Perazine at therapeutic drug concentrations inhibits human cytochrome P450 isoenzyme 1A2 (CYP1A2) and caffeine metabolism--an in vitro study. Pharmacol Rep. 2009;61(5):851-858. PubMed
  2. Daniel, W. A., Syrek, M., Rylko, Z., and Kot, M. Effects of phenothiazine neuroleptics on the rate of caffeine demethylation and hydroxylation in the rat liver. Pol.J Pharmacol 2001;53(6):615-621.

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 Promethazine, Pseudoephedrine 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. Promethazine, Pseudoephedrine)
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 Promethazine, Pseudoephedrine

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 Promethazine, Pseudoephedrine, 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 Promethazine, Pseudoephedrine

This page covers Caffeine only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Promethazine, Pseudoephedrine page lists 116 supplements it has a documented interaction with, worst first, each one explained.

The most serious there right now: Activated Charcoal (major), Ephedra (major), Henbane (major), Peyote (major) and Rauvolfia Vomitoria (major).

By severity: 7 major · 93 moderate · 16 minor.

From our pharmacist’s overview on the Promethazine, Pseudoephedrine page

“Phenergan D combines a sedating antihistamine, promethazine, with the decongestant stimulant pseudoephedrine, and its supplement list pulls hard in both directions, so this is one to treat with genuine care. The biggest cluster, from everyday caffeine sources like coffee and cola nut up to ephedra, stacks extra stimulation on the pseud…”

Reviewed by 2 · Jul 18, 2026

Open the Promethazine, Pseudoephedrine 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 Promethazine, Pseudoephedrine 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 Promethazine, Pseudoephedrine 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%

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

29 days ago today
Medication Promethazine, Pseudoephedrine
Steady interest

#1,797 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 Promethazine, Pseudoephedrine, 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 Promethazine, Pseudoephedrine supplement interactions › Every supplement checked against Promethazine, Pseudoephedrine, 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 Promethazine, Pseudoephedrine Together: Common Questions

Can you take Caffeine with Promethazine, Pseudoephedrine?
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 Caffeine and Promethazine, Pseudoephedrine?
Promethazine, Pseudoephedrine 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 Promethazine, Pseudoephedrine 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

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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.