Can I take St John's Wort with Pioglitazone?

The short answer

No clinical study of St John's wort with pioglitazone was found, so an interaction is possible but unproven. Pioglitazone is cleared mainly by the liver enzyme CYP2C8, and its label warns that CYP2C8 inducers, using rifampin as the example, can cut pioglitazone exposure by about half; St John's wort is not named. St John's wort induces CYP3A4, the lesser pioglitazone pathway, and lowers levels of many medicines when the product contains enough hyperforin. In the closest comparison available, 2 weeks of St John's wort did not change blood levels or the glucose response of repaglinide, a diabetes drug cleared by the same CYP2C8 and CYP3A4 pathways, while it lowered gliclazide exposure by a third. If you use St John's wort with pioglitazone, tell the prescriber, keep to one product and dose, and watch glucose readings when starting or stopping the herb.

What this answer covers

St John's wort (Hypericum perforatum) extracts, capsules and teas taken with pioglitazone tablets. Hyperforin content, which drives the enzyme induction, varies widely between products and is often not stated on the label.

Supplement or preparation: St John's wort
Medication ingredient: pioglitazone

What the label says

The ACTOS label states that pioglitazone is metabolized by CYP2C8 and to a lesser degree CYP3A4, and that a CYP2C8 inducer may significantly decrease pioglitazone exposure; its example is rifampin, which lowered the exposure of a single 30 mg dose by 54 percent after 5 days. The label advises that if a CYP2C8 inducer is started or stopped, diabetes treatment may need adjusting based on clinical response without exceeding 45 mg daily. St John's wort is not mentioned.

What St John's wort does to drug clearance

After about 2 weeks of regular use, St John's wort induces CYP3A4 and the transporter P-glycoprotein, and reviews also attribute interactions to CYP2C9 and CYP1A2 induction. In a probe study, 2 weeks of St John's wort more than halved the exposure to oral midazolam, a CYP3A4 drug. Federal consumer guidance lists many medicines it weakens, including birth control pills, cyclosporine, digoxin and warfarin. Whether it induces CYP2C8, pioglitazone's main pathway, has not been measured directly in people in any source found.

The closest studies used other diabetes drugs

Repaglinide is cleared by CYP2C8 and CYP3A4, the same enzymes as pioglitazone. In 15 healthy volunteers, 14 days of St John's wort 325 mg three times daily did not change repaglinide levels, half-life, or its glucose and insulin effects. By contrast, 15 days of St John's wort lowered exposure to gliclazide, a sulfonylurea cleared by CYP2C9, to about two-thirds of baseline, although glucose and insulin responses did not change. Neither drug is pioglitazone, and both were given as single doses to healthy people.

Product strength matters

The inducing effect comes mainly from hyperforin. A low-hyperforin extract (Ze 117) produced no interaction with probe drugs for CYP3A4, CYP2C9, CYP2C19, CYP1A2, CYP2B6 or P-glycoprotein in 20 volunteers, and a systematic review calls the degree of induction unpredictable because constituent amounts vary between preparations. Two products with the same milligram strength can therefore behave differently, and the effect can change if you switch brands.

What was searched and not found

Searches of Europe PMC for pioglitazone, rosiglitazone or thiazolidinediones together with Hypericum, St John's wort or hyperforin, and for St John's wort with CYP2C8, returned no clinical study or case report of the combination. No source reports a change in pioglitazone levels or glucose control from St John's wort, in either direction.

Practical approach

Tell the prescriber before combining the two and when starting, stopping or changing a St John's wort product. Ask whether glucose checks or diabetes treatment need to change; do not adjust pioglitazone yourself. The concern is possible enzyme induction affecting drug exposure. No source found demonstrates a pioglitazone absorption change, and the absence of exact-pair data does not show that the combination is free of interaction.

Evidence and practical considerations

Absorption & effectiveness

St John's wort could lower pioglitazone exposure through enzyme induction, but no clinical study of the pair was found; the label's inducer warning is written for rifampin, St John's wort has documented CYP3A4 rather than CYP2C8 induction, and the closest comparator (repaglinide, a CYP2C8 and CYP3A4 substrate) was unaffected, while gliclazide exposure fell by a third. The effect, if any, depends on hyperforin content.

Exact scope: St John's wort products containing hyperforin. One low-hyperforin extract, Ze 117, showed no clinically relevant interactions with the tested probe drugs; CYP2C8 and pioglitazone were not tested. with Pioglitazone tablets (ACTOS and generics), usually 15 to 45 mg daily; cleared mainly by CYP2C8 with a lesser CYP3A4 contribution, with active metabolites M-III and M-IV. For combination tablets, this answer covers only the pioglitazone component; other active ingredients require separate assessment.
Medication form and route: oral medication; oral supplement
Timing or duration: Induction develops over about 2 weeks of regular use and would be expected to wear off after stopping; no pioglitazone-specific timing data

What remains uncertain

Mechanism-based; no exact-pair pharmacokinetic or clinical data; comparator drugs differ in enzyme dependence; single-dose studies in healthy volunteers.

Factors that may matter: Hyperforin content and product; Duration of St John's wort use (induction takes about 2 weeks); Pioglitazone dose; Other CYP2C8 inhibitors or inducers.

Research conclusion: insufficient evidence · Evidence assessment: very low

Read the supporting source summaries

Source 1: current product label

dailymed.nlm.nih.gov · Source check Sep 22, 2026

Population: People prescribed pioglitazone

Pioglitazone is metabolized by CYP2C8 and, to a lesser degree, CYP3A4. An inducer of CYP2C8 (the label's example is rifampin) may significantly decrease pioglitazone exposure: rifampin 600 mg daily for 5 days lowered the AUC of a single 30 mg dose by 54 percent. If a CYP2C8 inducer is started or stopped during treatment, changes in diabetes treatment may be needed based on clinical response without exceeding 45 mg daily. Topiramate lowered pioglitazone exposure by 15 percent with larger falls in the active metabolites. Gemfibrozil, a strong CYP2C8 inhibitor, raises exposure about 3-fold and caps the dose at 15 mg.

How this applies: Exact pioglitazone (RxCUI 33738) tablets; the CYP2C8 inducer warning is written for rifampin and does not address St John's wort.

St John's wort is not named in the label; rifampin data cannot establish the size or presence of an interaction with St John's wort.