Drug & supplement interaction

L-citrulline + Macitentan, Tadalafil

Macitentan, Tadalafil brand name: Opsynvi.

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

Macitentan, Tadalafil falls into 2 drug categories that L-citrulline can interact with; the most serious is rated moderate. Theoretically, concomitant use of L-citrulline with antihypertensive drugs might have additive effects and increase the chance of hypotension.

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

L-citrulline and Macitentan, Tadalafil

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

Why Are There 2 Interactions?

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

Moderate

ANTIHYPERTENSIVE DRUGS

1 of 2

Why this applies to Macitentan, Tadalafil

Macitentan, Tadalafil falls under ANTIHYPERTENSIVE DRUGS — the group L-citrulline interacts with.

Theoretically, concomitant use of L-citrulline with antihypertensive drugs might have additive effects and increase the chance of hypotension.
L-citrulline is converted to L-arginine, which can increase nitric oxide and cause vasodilation. However, a meta-analysis of 5 small clinical studies suggests that taking L-citrulline 3-6 grams daily for 1-8 weeks does not lower blood pressure when compared with control.
Severity Moderate Likelihood Possible Evidence B

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

Opsynvi combines two medicines that both relax and widen your blood vessels. Macitentan blocks the effects of a vessel-tightening chemical, and tadalafil (the same ingredient as Cialis) boosts nitric oxide signaling to open vessels up. Since L-citrulline also nudges up nitric oxide, stacking it on top could add to that blood-pressure-lowering effect. You might notice more dizziness, lightheadedness when standing up, flushing, or headache.

Here's the reassuring part: this is mostly a theoretical concern, and a review of small studies found L-citrulline didn't actually drop blood pressure much. Still, because Opsynvi is already a strong vessel-relaxer, it's worth a quick chat with your pharmacist or doctor before adding it, rather than guessing.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Cheng JW, Balwin SN. L-arginine in the management of cardiovascular diseases. Ann Pharmacother 2001;35:755-64. PubMed
  2. Schwedhelm E, Maas R, Freese R, et al. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. Br J Clin Pharmacol 2008;65:51-9. PubMed
  3. Romero MJ, Platt DH, Caldwell RB, Caldwell RW. Therapeutic use of citrulline in cardiovascular disease. Cardiovasc Drug Rev 2006;24:275-90. PubMed
  4. Mirenayat MS, Moradi S, Mohammadi H, Rouhani MH. Effect of L-citrulline supplementation on blood pressure: a systematic review and meta-analysis of clinical trials. Curr Hypertens Rep. 2018;20(11):98. PubMed
Moderate

PHOSPHODIESTERASE-5 INHIBITORS

2 of 2

Macitentan, Tadalafil also falls under PHOSPHODIESTERASE-5 INHIBITORS.

Theoretically, concurrent use of phosphodiesterase-5 (PDE-5) inhibitors and L-citrulline might result in additive vasodilation.
L-citrulline is converted to L-arginine, which can increase nitric oxide and cause vasodilation. Theoretically, taking L-arginine with PDE-5 inhibitors might have additive vasodilatory and hypotensive effects. However, in studies evaluating the combined use of L-arginine and sildenafil for erectile dysfunction, hypotension was not reported.
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

Opsynvi combines two blood-pressure-lowering medicines: tadalafil, which relaxes blood vessels, and macitentan, which blocks a vessel-tightening hormone. L-citrulline works from a different angle, turning into L-arginine and boosting nitric oxide, which also widens blood vessels. So on paper, stacking them could add up to a little extra vasodilation.

What might that feel like? Possibly a bit more dizziness, lightheadedness, flushing, or a headache, especially when you stand up quickly. Honestly, this concern is theoretical, based on how the ingredients work rather than real reports of problems, and studies mixing L-arginine with similar drugs didn't show low blood pressure. Still, since Opsynvi already lowers your pressure, please check with your pharmacist or doctor before adding L-citrulline.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Cheng JW, Balwin SN. L-arginine in the management of cardiovascular diseases. Ann Pharmacother 2001;35:755-64. PubMed
  2. Schwedhelm E, Maas R, Freese R, et al. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. Br J Clin Pharmacol 2008;65:51-9. PubMed
  3. Romero MJ, Platt DH, Caldwell RB, Caldwell RW. Therapeutic use of citrulline in cardiovascular disease. Cardiovasc Drug Rev 2006;24:275-90. PubMed
  4. Xu Z, Liu C, Liu S, Zhou Z. Comparison of efficacy and safety of daily oral L-arginine and PDE5Is alone or combination in treating erectile dysfunction: A systematic review and meta-analysis of randomised controlled trials. Andrologia. 2021:e14007. 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

L-citrulline Also Interacts With Other Medications

L-citrulline has 177 moderate known drug interactions in our database — the Macitentan, Tadalafil one above is among them. If you take anything else, check it against the full list below.

Moderate 177 No known interaction 2,653 (incl. Macitentan, Tadalafil)
Taking anything else?

Check Another of Your Medications Against L-citrulline

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

From our Q&A

Questions About L-citrulline or Macitentan, Tadalafil

These are real questions from readers, answered by the pharmacists at HelloPharmacist — written by a person, not generated from a database. Each one covers L-citrulline or Macitentan, Tadalafil, 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 Macitentan, Tadalafil

This page covers L-citrulline only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Macitentan, Tadalafil page lists 264 supplements it has a documented interaction with, worst first, each one explained.

The most serious there right now: Activated Charcoal (major), American Hellebore (major), American Mistletoe (major), Beer (major) and Grapefruit (major).

By severity: 10 major · 215 moderate · 39 minor.

From our pharmacist’s overview on the Macitentan, Tadalafil page

“Opsynvi pairs macitentan and tadalafil to lower pressure in the lung arteries, so anything that drops blood pressure further or shifts how the body handles these drugs deserves genuine respect, and I would read this list carefully. Ten of the 264 ingredients rate major, and most of the rest fall into two camps: additive blood-pressure-…”

Reviewed by 2 · Jul 18, 2026

Open the Macitentan, Tadalafil interaction page

One more smart check

Taking L-citrulline as Part of a Dietary Supplement Product? Check It for Interactions

We hold 63 real supplement products containing L-citrulline, each one broken down to its full ingredient list — and combination products often carry several ingredients besides L-citrulline. Your product may carry other ingredients that interact with Macitentan, Tadalafil too, on top of L-citrulline — 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 L-citrulline and Macitentan, Tadalafil 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 L-citrulline
Top 25%

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

29 days ago today
Medication Macitentan, Tadalafil
Top 25%

#651 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 L-citrulline

What is L-citrulline?

L-citrulline
  • Exercise performance
  • Muscle soreness and fatigue
  • Blood flow and circulation
  • Erectile dysfunction
  • Blood pressure support

L-citrulline is an amino acid that the body turns into L-arginine to help make nitric oxide, which relaxes blood vessels and may improve blood flow. It is popular for exercise performance and circulation, but the evidence is mixed and most benefits are modest. It appears generally well tolerated, but talk to your pharmacist or doctor before starting, especially if you have a health condition or are pregnant.

Read the full L-citrulline monograph & all interactions
Keep checking

Other Drugs & L-citrulline

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

0Major
177Moderate
0Minor
2,652No known interaction
177 Moderate 2,652 No interaction
Moderate

177 interactions

Showing 60 of 177 moderate interactions — see all 177 on the L-citrulline page.

No interaction 2,652 drugs checked — show the list

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

Showing the 60 most looked-up of 2,652 medications checked with no known interaction — see the full L-citrulline list.

See the full L-citrulline interactions page
See every supplement checked against Macitentan, Tadalafil, 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
L-citrulline monograph › Uses, safety, and every drug interaction in one place Macitentan, Tadalafil supplement interactions › Every supplement checked against Macitentan, Tadalafil, 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 L-citrulline and Macitentan, Tadalafil Together: Common Questions

Can you take L-citrulline with Macitentan, Tadalafil?
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 L-citrulline and Macitentan, Tadalafil?
Macitentan, Tadalafil belongs to more than one drug category, and L-citrulline 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 L-citrulline and Macitentan, Tadalafil 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.