Drug & supplement interaction

St. John's Wort + Levomilnacipran

Levomilnacipran brand name: Fetzima.

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

Levomilnacipran falls into 2 drug categories that St. John's Wort can interact with; the most serious is rated major. St. John's wort increases the metabolism and reduces the levels of CYP3A4 substrates.

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

St. John's Wort and Levomilnacipran

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

Why Are There 2 Interactions?

St. John's Wort interacts with whole categories of medication. Levomilnacipran falls into 2 of those categories, so it can interact with St. John's Wort in 2 different ways. We’ve listed each one below — your overall risk is driven by the most serious of them (Major).

Major

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES

1 of 2

Why this applies to Levomilnacipran

Levomilnacipran falls under CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES — the group St. John's Wort interacts with.

St. John's wort increases the metabolism and reduces the levels of CYP3A4 substrates.
St. John's wort induces CYP3A4 enzymes and increases metabolism of CYP3A4 substrates. Clinically significant interactions have been reported with St. John's wort products containing hyperforin 1 mg or more.
Severity Major 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

Here's the thing with pairing St. John's wort and Fetzima (levomilnacipran). Your liver uses an enzyme called CYP3A4 to help break down Fetzima, and St. John's wort speeds that enzyme up. The likely result is that your body clears the medication faster, so you may end up with lower levels than your doctor intended. That can mean your depression symptoms creep back or your medication just doesn't seem to work as well.

There's also a second concern. Both products nudge serotonin upward, so combining them could raise the risk of too much serotonin, which can cause agitation, a racing heart, sweating, or shakiness. Please don't start or stop either one on your own. Loop in your pharmacist or prescriber first so they can guide you safely.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Henderson L, Yue QY, Bergquist C, et al. St John's wort (Hypericum perforatum): drug interactions and clinical outcomes. Br J Clin Pharmacol 2002;54:349-56..
  2. Markowitz JS, Donovan JL, DeVane CL, et al. Effect of St. John's wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. JAMA 2003;290:1500-4.. PubMed
  3. Gurley BJ, Gardner SF, Hubbard MA, et al. Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans. Clin Pharmacol Ther 2002;72:276-87.. PubMed
  4. Foster BC, Vandenhoek S, Hana J, et al. In vitro inhibition of human cytochrome P450-mediated metabolism of marker substrates by natural products. Phytomedicine 2003;10:334-42.. PubMed
  5. Komoroski BJ, Zhang S, Cai H, et al. Induction and inhibition of cytochromes P450 by the St. John's wort constituent hyperforin in human hepatocyte cultures. Drug Metab Dispos 2004;32:512-8. PubMed
  6. Smith M, Lin KM, and Zheng YP. PIII-89 an open trial of nifedipine-herb interactions: Nifedipine with St. John's wort, ginseng or ginkgo biloba. Clin Pharm Ther 2001;69:P86.
  7. Kawaguchi, A., Ohmori, M., Tsuruoka, S., Nishiki, K., Harada, K., Miyamori, I., Yano, R., Nakamura, T., Masada, M., and Fujimura, A. Drug interaction between St John's Wort and quazepam. Br.J.Clin Pharmacol. 2004;58(4):403-410. PubMed
  8. Dresser, G. K., Schwarz, U. I., Wilkinson, G. R., and Kim, R. B. Coordinate induction of both cytochrome P4503A and MDR1 by St John's wort in healthy subjects. Clin Pharmacol Ther 2003;73(1):41-50. PubMed
  9. Patel, J., Buddha, B., Dey, S., Pal, D., and Mitra, A. K. In vitro interaction of the HIV protease inhibitor ritonavir with herbal constituents: changes in P-gp and CYP3A4 activity. Am.J.Ther. 2004;11(4):262-277. PubMed
  10. Izzo, A. A. and Ernst, E. Interactions between herbal medicines and prescribed drugs: an updated systematic review. Drugs 2009;69(13):1777-1798. PubMed
  11. Chrubasik-Hausmann S, Vlachojannis J, McLachlan AJ. Understanding drug interactions with St John's wort (Hypericum perforatum L.): impact of hyperforin content. J Pharm Pharmacol. 2018.
  12. Haron MH, Dale O, Martin K, et al. Evaluation of the Herb-Drug Interaction Potential of Commonly Used Botanicals on the US Market with Regard to PXR- and AhR-Mediated Influences on CYP3A4 and CYP1A2. J Diet Suppl 2022. PubMed
  13. Pochet S, Lechon AS, Lescrainier C, et al. Herb-anticancer drug interactions in real life based on VigiBase, the WHO global database. Sci Rep 2022;12(1):14178. PubMed
  14. Gümüs KS, Teegelbekkers A, Sauter M, et al. Effect of Tacrolimus Formulation (Prolonged-Release vs Immediate-Release) on Its Susceptibility to Drug-Drug Interactions with St. John's Wort. Clin Pharmacol Drug Dev 2024. PubMed
Moderate

SEROTONERGIC DRUGS

2 of 2

Levomilnacipran also falls under SEROTONERGIC DRUGS.

Theoretically, St. John's wort might inhibit reuptake and increase levels of serotonin, resulting in additive effects with serotonergic drugs.
Concomitant use of serotonergic drugs with St. John's wort can lead to increased adverse effects and increase the risk of serotonergic side effects, including serotonin syndrome and cerebral vasoconstriction disorders.
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 this pair. Levomilnacipran (Fetzima) is an SNRI, so it already raises serotonin in your brain. St. John's wort is thought to nudge serotonin up too. Stack the two together and you can get too much serotonin activity, which is the real concern here.

That can show up as agitation, a racing heart, sweating, shivering, tremor, or diarrhea. In rare, more serious cases this becomes serotonin syndrome, which is a medical emergency. This warning is based on how both work in theory rather than on lots of hard cases, but the overlap is real enough that I wouldn't combine them on your own. Please check with your pharmacist or doctor before adding St. John's wort.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Miller LG. Herbal Medicinals: Selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med 1998;158:2200-11.
  2. Gordon JB. SSRIs and St. John's Wort: possible toxicity? Am Fam Physician 1998;57:950, 953.
  3. Beckman SE, Sommi RW, Switzer J. Consumer use of St. John's wort: A survey of effectiveness, safety, and tolerability. Pharmacotherapy 2000;20:568-74.
  4. Singhal AB, Caviness VS, Begleiter AF, et al. Cerebral vasoconstriction and stroke after use of serotonergic drugs. Neurology 2002;58:130-3. PubMed
  5. Sarris J, Ravindran A, Yatham LN, et al. Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety T

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

St. John's Wort Also Interacts With Other Medications

St. John's Wort has 754 major, 388 moderate known drug interactions in our database — the Levomilnacipran one above is among them. If you take anything else, check it against the full list below.

Major 754 Moderate 388 No known interaction 1,688 (incl. Levomilnacipran)
Taking anything else?

Check Another of Your Medications Against St. John's Wort

Covers the 2,830 medications we’ve checked against St. John's Wort. Pick one to open its full report.

From our Q&A

Questions About St. John's Wort or Levomilnacipran

These are real questions from readers, answered by the pharmacists at HelloPharmacist — written by a person, not generated from a database. Each one covers St. John's Wort or Levomilnacipran, 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 Levomilnacipran

This page covers St. John's Wort only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Levomilnacipran page lists 156 supplements it has a documented interaction with, worst first, each one explained.

The most serious there right now: Activated Charcoal (major), Grapefruit (major), Lithium (major), 5-htp (moderate) and Acacia Rigidula (moderate).

By severity: 4 major · 110 moderate · 42 minor.

From our pharmacist’s overview on the Levomilnacipran page

“For levomilnacipran (Fetzima), an antidepressant, this list deserves real attention. Four of its 156 interacting ingredients rate major, and those are the ones to learn first: grapefruit and St.”

Reviewed by 2 · Jul 18, 2026

Open the Levomilnacipran interaction page

One more smart check

Taking St. John's Wort as Part of a Dietary Supplement Product? Check It for Interactions

We hold 1,159 real supplement products containing St. John's Wort, each one broken down to its full ingredient list — and combination products often carry several ingredients besides St. John's Wort. Your product may carry other ingredients that interact with Levomilnacipran too, on top of St. John's Wort — 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 St. John's Wort and Levomilnacipran 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 St. John's Wort
Top 25%

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

29 days ago today
Medication Levomilnacipran
Top half

#1,347 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 St. John's Wort

What is St. John's Wort?

St. John's Wort
  • Mild to moderate depression
  • Anxiety and stress
  • Sleep problems
  • Menopausal symptoms
  • Wound healing (topical)

St. John's wort is a well-studied herb most often used for mild to moderate depression, and some research suggests it may help with this. However, it has many serious interactions with prescription medicines and is not safe for everyone, so always talk to your pharmacist or doctor before taking it.

Read the full St. John's Wort monograph & all interactions
Medication

About Levomilnacipran

What Is Levomilnacipran Used For?

Brand name: Fetzima

Fetzima (levomilnacipran) is approved to treat major depressive disorder (MDD) in adults. It is taken as a once-daily extended-release capsule.

It is important to know that Fetzima is not approved for fibromyalgia — its safety and effectiveness for that condition have not been established. It is also not approved for use in children or teens.

See full Levomilnacipran drug information
Keep checking

Other Drugs & St. John's Wort

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

754Major
388Moderate
0Minor
1,687No known interaction
754 Major 388 Moderate 1,687 No interaction
Major

754 interactions

Showing 60 of 754 major interactions — see all 754 on the St. John's Wort page.

Moderate

388 interactions

Showing 60 of 388 moderate interactions — see all 388 on the St. John's Wort page.

No interaction 1,687 drugs checked — show the list

We also checked St. John's Wort against these medications and found no known interaction in our sources. Open any page to confirm.

Showing the 60 most looked-up of 1,687 medications checked with no known interaction — see the full St. John's Wort list.

See the full St. John's Wort interactions page
See every supplement checked against Levomilnacipran, 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
St. John's Wort monograph › Uses, safety, and every drug interaction in one place Levomilnacipran supplement interactions › Every supplement checked against Levomilnacipran, ranked by severity Levomilnacipran 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 St. John's Wort and Levomilnacipran Together: Common Questions

Can you take St. John's Wort with Levomilnacipran?
This is rated a major interaction, so the combination is best avoided unless your doctor or pharmacist has specifically told you otherwise. Read the full details on this page and confirm with your pharmacist before combining them.
Why are there 2 interactions listed for St. John's Wort and Levomilnacipran?
Levomilnacipran belongs to more than one drug category, and St. John's Wort 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 St. John's Wort and Levomilnacipran interaction?
We rate it Major. This is a clinically significant combination that is generally best avoided, or used only under the direct supervision of your physician or pharmacist.

Written and reviewed by the HelloPharmacist editorial staff. Our editorial policy

Still Have a Question About Levomilnacipran and St. John's Wort?

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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.