Drug & supplement interaction

St. John's Wort + Segesterone Acetate, Ethinyl Estradiol

Segesterone Acetate, Ethinyl Estradiol brand name: Annovera.

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

Segesterone Acetate, Ethinyl Estradiol falls into 4 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
Interactions4
EvidenceB
What do Severity, Likelihood & Evidence mean?
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Interaction report

St. John's Wort and Segesterone Acetate, Ethinyl Estradiol

These two interact in 4 distinct ways. Each one is explained separately below.

Why Are There 4 Interactions?

St. John's Wort interacts with whole categories of medication. Segesterone Acetate, Ethinyl Estradiol falls into 4 of those categories, so it can interact with St. John's Wort in 4 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 4

Why this applies to Segesterone Acetate, Ethinyl Estradiol

Segesterone Acetate, Ethinyl Estradiol 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 concern with combining St. John's wort and Annovera (the segesterone and ethinyl estradiol vaginal ring). St. John's wort revs up a liver enzyme called CYP3A4, which is the same system that clears the hormones in your birth control. When that enzyme works faster, your hormone levels can drop lower than intended. The real-world worry isn't a side effect, it's that your birth control may simply stop doing its job, leaving you at risk for an unplanned pregnancy. You might also notice breakthrough spotting or bleeding as a clue that hormone levels are off.

This isn't just theory, real interactions have been reported with hormonal contraceptives. Please don't stop either product on your own. Talk with your pharmacist or doctor so they can help you pick a reliable plan, which may include a backup method.

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
Major

P-GLYCOPROTEIN SUBSTRATES

2 of 4

Segesterone Acetate, Ethinyl Estradiol also falls under P-GLYCOPROTEIN SUBSTRATES.

St. John's wort decreases the levels and clinical effects of P-glycoprotein substrates.
St. John's wort induces P-glycoprotein. P-glycoprotein is a carrier mechanism responsible for transporting drugs and other substances across cell membranes. When P-glycoprotein is induced in the gastrointestinal (GI) tract, it can prevent the absorption of some medications. In addition, induction of p-glycoprotein can decrease entry of drugs into the central nervous system (CNS) and decrease access to other sites of action.
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

Annovera is your birth control ring, and it slowly releases two hormones (segesterone and ethinyl estradiol) to prevent pregnancy. The concern here is that St. John's wort speeds up how quickly your body processes and clears these hormones. The result is lower hormone levels, which means your ring may not work as well at stopping ovulation.

In plain terms, mixing the two can raise your risk of an unintended pregnancy, and some women also notice breakthrough bleeding or spotting when hormone levels dip. This is a well-recognized, serious interaction, not just a theory. If you want or need to take St. John's wort, please talk with your pharmacist or doctor first. They may suggest a different birth control approach or backup protection.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Johne A, Brockmoller J, Bauer S, et al. Pharmacokinetic interaction of digoxin with an herbal extract from St John's wort (Hypericum perforatum). Clin Pharmacol Ther 1999;66:338-45.
  2. Durr D, Stieger B, Kullak-Ublick GA, et al. St. John's Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4. Clin Pharmacol Ther 2000;68:598-604. PubMed
  3. Hennessy M, Kelleher D, Spiers JP, et al. St Johns wort increases expression of P-glycoprotein: implications for drug interactions. Br J Clin Pharmacol 2002;53:75-82.
  4. Kim RB. Drugs as P-glycoprotein substrates, inhibitors, and inducers. Drug Metab Rev 2002;34:47-54. PubMed
Major

CONTRACEPTIVE DRUGS

3 of 4

Segesterone Acetate, Ethinyl Estradiol also falls under CONTRACEPTIVE DRUGS.

St. John's wort increases the clearance of contraceptive drugs and reduces their clinical effects.
Females taking St. John's wort and oral contraceptives concurrently should use an additional or alternative form of birth control. St. John's wort can decrease norethindrone and ethinyl estradiol levels by 13% to 15%, resulting in breakthrough bleeding, irregular menstrual bleeding, or unplanned pregnancy. Bleeding irregularities usually occur within a week of starting St. John's wort and regular cycles usually return when St. John's wort is discontinued. Unplanned pregnancy has occurred with concurrent use of oral contraceptives and St. John's wort extract. St. John's wort is thought to induce the cytochrome P450 1A2 (CYP1A2), 2C9 (CYP2C9), and 3A4 (CYP3A4) enzymes, which are responsible for metabolism of progestins and estrogens in contraceptives.
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

Annovera is a vaginal ring that slowly releases two hormones, segesterone acetate and ethinyl estradiol, to prevent pregnancy. Here's the catch: St. John's wort speeds up the liver enzymes (mainly CYP3A4) that break these hormones down. That means your body clears them faster, so the hormone levels drop and the ring may not protect you as well as it should.

In real life, this can show up as spotting or breakthrough bleeding, irregular periods, and most importantly a higher chance of an unplanned pregnancy. This isn't just theory, real pregnancies have happened with this combination. Please don't stop either one on your own. Talk with your pharmacist or doctor, and in the meantime consider a backup method like condoms.

Contact Dr. Brian directly if you have additional questions on this interaction
References
  1. Yue QY, Bergquist C, Gerden B. Safety of St. John's wort (Hypericum perforatum). Lancet 2000;355:576-7. PubMed
  2. Gorski JC, Hamman MA, Wang Z, et al. The effect of St. John's wort on the efficacy of oral contraceptives (abstract MPI-80). Clin Pharmacol Ther 2001;71:P25.
  3. 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..
  4. Schwarz UI, Buschel B, Kirch W. Unwanted pregnancy on self-medication with St John's wort despite hormonal contraception. Br J Clin Pharmacol 2003;55:112-3. PubMed
  5. Pfrunder A, Schiesser M, Gerber S, et al. Interaction of St John's wort with low-dose oral contraceptive therapy: a randomized controlled trial. Br J Clin Pharmacol 2003;56:683-90. PubMed
  6. Hall SD, Wang Z, Huang SM, et al. The interaction between St John's wort and an oral contraceptive. Clin Pharmacol Ther 2003;74:525-35. PubMed
  7. Murphy PA, Kern SE, Stanczyk FZ, Westhoff CL. Interaction of St. John's Wort with oral contraceptives: effects on the pharmacokinetics of norethindrone and ethinyl estradiol, ovarian activity and breakthrough bleeding. Contraception 2005;71:402-8. PubMed
Moderate

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES

4 of 4

Segesterone Acetate, Ethinyl Estradiol also falls under CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES.

St. John's wort may increase the metabolism and reduce the levels of CYP1A2 substrates.
Clinical and in vitro research shows that St. John's wort induces CYP1A2, but to a lesser extent than CYP3A4.
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

Annovera is a vaginal ring that releases two hormones (segesterone acetate and ethinyl estradiol) to prevent pregnancy. St. John's wort is one of the better-known herbs for nudging your liver to clear hormones faster. The file here points to it speeding up CYP1A2, but the bigger worry with any birth control is that St. John's wort also strongly revs up CYP3A4, which breaks down these very hormones. The end result is lower hormone levels in your body.

Why that matters: weaker hormone levels can mean breakthrough bleeding or spotting and, more importantly, a real risk of the ring not working, meaning unintended pregnancy. This is a well-recognized concern, so please talk with your pharmacist or doctor before mixing the two.

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. 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
  3. Van Strater, A. C. and Bogers, J. P. Interaction of St John's wort (Hypericum perforatum) with clozapine. Int.Clin.Psychopharmacol. 2012;27(2):121-124. PubMed
  4. 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

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 Segesterone Acetate, Ethinyl Estradiol 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. Segesterone Acetate, Ethinyl Estradiol)
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 Segesterone Acetate, Ethinyl Estradiol

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 Segesterone Acetate, Ethinyl Estradiol, 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 Segesterone Acetate, Ethinyl Estradiol

This page covers St. John's Wort only. If you take other supplements — a multivitamin, a sleep aid, something for joints — the Segesterone Acetate, Ethinyl Estradiol page lists 229 supplements it has a documented interaction with, worst first, each one explained.

The most serious there right now: Beer (major), Grapefruit (major), Siberian Cocklebur (major), Wine (major) and Acacia Rigidula (moderate).

By severity: 5 major · 193 moderate · 31 minor.

From our pharmacist’s overview on the Segesterone Acetate, Ethinyl Estradiol page

“St. John's wort is the interaction I would explain first to anyone using Annovera (segesterone acetate with ethinyl estradiol, a vaginal ring for birth control).”

Reviewed by 2 · Jul 18, 2026

Open the Segesterone Acetate, Ethinyl Estradiol 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 Segesterone Acetate, Ethinyl Estradiol 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 Segesterone Acetate, Ethinyl Estradiol 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%

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

29 days ago today
Medication Segesterone Acetate, Ethinyl Estradiol
Top 25%

#363 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
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 Segesterone Acetate, Ethinyl Estradiol, 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 Segesterone Acetate, Ethinyl Estradiol supplement interactions › Every supplement checked against Segesterone Acetate, Ethinyl Estradiol, 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 St. John's Wort and Segesterone Acetate, Ethinyl Estradiol Together: Common Questions

Can you take St. John's Wort with Segesterone Acetate, Ethinyl Estradiol?
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 4 interactions listed for St. John's Wort and Segesterone Acetate, Ethinyl Estradiol?
Segesterone Acetate, Ethinyl Estradiol 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 Segesterone Acetate, Ethinyl Estradiol 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 Segesterone Acetate, Ethinyl Estradiol 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.