Two weeks of St John's wort doubled the clearance of alprazolam and halved its half-life in healthy volunteers
After 14 days of St John's wort 300 mg three times a day, alprazolam exposure fell twofold and its half-life shortened from 12.4 to 6.0 hours. The authors: this may mean "diminished clinical effectiveness" for all CYP3A4 substrates.
Suggestive but preliminary. Not settled. how we score evidence
Caveat on this rating: Twelve healthy young volunteers, fixed treatment order, one St John's wort product; extracts vary in the hyperforin content thought to drive induction, so other products may induce less or more.
St John's wort is taken for mood without a prescription, which means the prescriber of the other drugs often does not know. This trial measured what it does to a common benzodiazepine.
Significant findings
Markowitz and colleagues (JAMA, 2003) ran an open-label crossover study in 12 healthy volunteers aged 22 to 38. Probe drugs, alprazolam for CYP3A4 and dextromethorphan for CYP2D6, were given before and after 14 days of St John's wort, "one 300-mg tablet 3 times per day."
"A 2-fold decrease in the area under the curve for alprazolam plasma concentration vs time (P<.001) and a 2-fold increase in alprazolam clearance (P<.001) were observed following St John's wort administration. Alprazolam elimination half-life was shortened from a mean (SD) of 12.4 (3.9) hours to 6.0 (2.4) hours (P<.001)." The dextromethorphan ratio did not change significantly (P = .26), so CYP2D6 was not induced.
The conclusion: "A 14-day course of St John's wort administration significantly induced the activity of CYP 3A4 as measured by changes in alprazolam pharmacokinetics. This suggests that long-term administration of St John's wort may result in diminished clinical effectiveness or increased dosage requirements for all CYP 3A4 substrates, which represent at least 50% of all marketed medications."
Worth asking
The direction matters. Grapefruit blocks CYP3A4 and raises drug levels; St John's wort induces it and lowers them. The zolpidem label in this wave lists St John's wort as reducing the sleeping pill's effect, and the same enzyme clears many antipsychotics, some antidepressants, oral contraceptives and HIV and transplant drugs. The other risk with St John's wort is the opposite one, serotonin syndrome when it is combined with an SSRI; every SSRI label read for this wave lists it. If you take it, tell the prescriber and the pharmacist, because it will not be on their list unless you put it there.
Source
Effect of St John's wort on drug metabolism by induction of cytochrome P450 3A4 enzyme — Markowitz JS, Donovan JL, DeVane CL, Taylor RM, Ruan Y, Wang JS, Chavin KD (2003)
Top-tier peer-reviewed journal
Read the source: https://doi.org/10.1001/jama.290.11.1500
DOI: 10.1001/jama.290.11.1500
How this was scored
- Study design
- Case series or case report
- Funding
- Independently funded
- Published in
- Top-tier peer-reviewed journal
- Sample size
- 12
- Preregistered
- not recorded
- Conflicts disclosed
- not recorded
- Independent of proponent
- not recorded
- Retracted
- No
Read the full scoring rubric, including what it can't tell you.
Published September 21, 2026.
Questions
How strong is the evidence behind this?
veisund rates this source "early signal". Suggestive but preliminary. Not settled. It scores 47 out of 100 on our published rubric. One caveat travels with that badge: Twelve healthy young volunteers, fixed treatment order, one St John's wort product; extracts vary in the hyperforin content thought to drive induction, so other products may induce less or more. The score is calculated from recorded facts about the source — study design, funding, publication venue, sample size, preregistration — not typed in by an editor.
What is the source for this?
Effect of St John's wort on drug metabolism by induction of cytochrome P450 3A4 enzyme — Markowitz JS, Donovan JL, DeVane CL, Taylor RM, Ruan Y, Wang JS, Chavin KD (2003). Published in: Top-tier peer-reviewed journal. DOI: 10.1001/jama.290.11.1500. The full source is linked on this page so you can read it yourself.
Who paid for this research, and does that matter?
Study design: Case series or case report. Funding: Independently funded. Independence from the proponent is not recorded. Industry sponsorship is one of the most reliably measured biases in medicine, which is why funding carries real weight in the score rather than sitting in a footnote.
Is this medical advice?
This is information to bring to your prescriber, not medical advice and not a reason to change anything on your own. Nothing here is an instruction to stop or reduce a medication. If you are in crisis, call or text 988.
This is information to bring to your prescriber, not medical advice and not a reason to change anything on your own. Nothing here is an instruction to stop or reduce a medication. If you are in crisis, call or text 988.