Is it Safe to Take St. John's Wort with Xanax (Alprazolam)?
No, combining St. John's wort with Xanax (alprazolam) is not recommended due to significant pharmacokinetic interactions that reduce alprazolam's effectiveness, potentially leading to breakthrough anxiety, withdrawal symptoms, or treatment failure.
Mechanism of Interaction
St. John's wort is a potent inducer of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein, which accelerates the metabolism and elimination of alprazolam, thereby reducing its plasma concentrations and therapeutic effectiveness 1, 2, 3. This induction effect persists for several months after discontinuing St. John's wort due to the herb's long-lasting enzymatic effects 1.
Clinical Evidence
Multiple clinical trials and systematic reviews have documented that St. John's wort significantly reduces plasma concentrations of alprazolam through CYP3A4 induction 2, 3, 4. Alprazolam is a benzodiazepine that is primarily metabolized by CYP3A4, making it particularly vulnerable to this interaction 3, 5.
The Public Health Service guidelines specifically list alprazolam (along with midazolam and triazolam) as contraindicated with certain medications that interact with St. John's wort due to the potential for serious adverse events including prolonged sedation or respiratory depression when drug levels become unpredictable 6.
Clinical Consequences
The primary concern is loss of therapeutic effect rather than direct toxicity:
- Breakthrough anxiety symptoms as alprazolam levels drop below therapeutic range 2
- Potential benzodiazepine withdrawal symptoms if alprazolam levels decrease rapidly in patients on chronic therapy 3
- Unpredictable dosing requirements making it difficult to maintain stable therapeutic levels 5
Critical Timing Considerations
If a patient must transition between these medications:
- Discontinue St. John's wort at least 2 weeks before starting alprazolam to allow enzyme activity to normalize 7
- Monitor for 24-48 hours after discontinuing St. John's wort, as symptoms can emerge during this transition period 7
- The enzymatic induction effects can persist for several months, requiring extended monitoring 1
Alternative Management Strategies
For patients requiring treatment for both anxiety and depression:
- Choose cognitive behavioral therapy or second-generation antidepressants (SSRIs) as first-line treatment for depression instead of St. John's wort 6, 7
- Avoid St. John's wort entirely in patients on benzodiazepines due to the high potential for clinically significant interactions 2, 3
- If St. John's wort is preferred for depression, consider non-benzodiazepine anxiolytics that are not CYP3A4 substrates 3
Additional Safety Concerns
St. John's wort poses multiple additional risks:
- Not FDA-regulated: No standardization of content or potency in U.S. preparations, meaning patients cannot reliably obtain preparations with consistent effects 6, 7, 8
- Multiple drug interactions: Also reduces effectiveness of oral contraceptives, immunosuppressants, warfarin, cardiovascular medications, HIV medications, and cancer drugs 1, 7, 3
- Contraindicated with SSRIs and MAOIs: Risk of serotonin syndrome if combined with other antidepressants 7, 2
Common Pitfall to Avoid
Do not assume that because St. John's wort is "natural" it is safe to combine with prescription medications. The herb has one of the highest potentials for clinically significant drug interactions among all herbal medicines 2, 4. Always obtain a complete herbal supplement history from patients taking alprazolam or other benzodiazepines 1.