St. John’s Wort and Drug Interactions
By Aaron H. Burstein, PharmD
One of the most popular herbal therapies in the United States, St. John’s wort is thought by many consumers to be a safe, natural alternative to traditional antidepressant therapy. However, recent reports describe a number of drug interactions, both pharmacokinetic and pharmacodynamic, with St. John’s wort.1-13 (See Table 1 for a summary of available literature regarding St. John’s wort drug interactions.) The Food and Drug Administration recently issued a health advisory warning against the use of St. John’s wort in patients taking protease inhibitors and non-nucleoside reverse transcriptase inhibitors. Included in this advisory was a warning that other cytochrome p450-metabolized medications may be affected.14
| Table 1-Summary of St. John's wort drug interactions | ||||||
| Object medication | Effect of St. John's wort (Hypericum perforatum) on object medication | |||||
| Clinical studies with markers of CYP activity | ||||||
| 6-ß-hydroxycortisol urinary clearance2 | Increased clearance from 257.7 mg/d to 363.2 mg/d | |||||
| Urine 6-ß-hydroxycortisol:cortisol1 | Increased ratio by 114% | |||||
| Urine dextromethorphan:3-methoxymorphinan6 | Trend toward decreased ratio | |||||
| CYP2D6 marker | ||||||
| Urinary dextromethorphan:dextrorphan1,6,13 | No effect | |||||
| CYP1A2 marker | ||||||
| Urine paraxanthine:caffeine3 | No effect | |||||
| Case reports | ||||||
| Theophylline7 | Decreased theophylline concentrations | |||||
| Cyclosporin8,9 | Decreased cyclosporin concentrations | |||||
| Oral contraceptives9 | Breakthrough bleeding | |||||
| Warfarin4 | Decreased INR | |||||
| Clinical Studies | ||||||
| Digoxin5 | Decreased digoxin AUC by 25%, Cmax by 26%, Cmin by 33% | |||||
| Phenprocoumon10 | Decreased phenprocoumon AUC by approximately 17% | |||||
| Indinavir11 | Decreased indinavir AUC by 57%, Cmin by 81% | |||||
| Amitriptyline12 | Decreased amitriptyline AUC by 21.7%, decreased nortriptyline AUC by 40.6% | |||||
| Alprazolam13 | No effect | |||||
Administration of St. John’s wort may result in induction of cytochrome p450 (CYP) isozymes 3A4,1,2 1A2,3 and 2C94 and induction of intestinal p-glycoprotein.5 The implications would be increased clearance, decreased systemic exposure, and decreased concentrations of medications that are substrates for these pathways, possibly resulting in therapeutic failure.
Initial research using surrogate markers of CYP3A4 activity (the urine 6-ß-hydroxycortisol:cortisol ratio, urine 6-ß-hydroxycortisol clearance, urine dextromethorphan:3-methoxymorphinan ratio) provided conflicting results. St. John’s wort (standardized to 0.3% hypericin) administration for 14 days increased the urine 6-ß-hydroxycortisol:cortisol ratio1 and increased the clearance of urine 6-ß-hydroxycortisol:cortisol.2 These findings suggest potent induction of CYP3A4. In contrast, a study using urine dextromethorphan:3-methoxymorphinan ratios noted only a trend to induction following eight days of St. John’s wort that failed to achieve statistical significance.6 One proposed explanation for the conflicting results is the different treatment durations.
Case reports describe the interaction of St. John’s wort with theophylline,7 cyclosporin,8,9 oral contraceptives,9 and warfarin.4 In all reports, the common finding is loss of therapeutic effect and/or the need to increase doses to maintain the desired therapeutic effect when St. John’s wort is administered concurrently.
Controlled clinical studies have been conducted to evaluate the effect of St. John’s wort, or hypericum extract, on the pharmacokinetics of digoxin,5 phenprocoumon10 (an anticoagulant not available in the United States), indinavir,11 amitriptyline,12 and alprazolam.13 In all but one study, St. John’s wort or hypericum extract administration was associated with decreased concentrations or area under the curve (AUC) of the object medication.5,10-12 St. John’s wort showed no effect on alprazolam pharmacokinetics.13 The lack of a significant interaction with alprazolam may be related to the small sample size studied and the short treatment duration (four days) relative to the other studies (10-14 days).
A recent in vitro investigation demonstrates the complexities in evaluating drug interactions with herbal therapies. The investigators compared the effects of a methanolic solution of St. John’s wort, made from commercially available capsules, and pure hypericin on CYP3A4 activity using 6-ß-hydroxytestosterone production. In this model, the methanolic solution exhibited potent inhibition of CYP3A4 activity, in direct contrast to clinical and research findings of induction. However, the hypericin constituent did not inhibit CYP3A4 activity.15 This study questions the reliability of extrapolating data and results from in vitro studies of herbal therapies in which a product may contain multiple active constituents or may exert different effects following acute and chronic therapy. Human microsomal models for evaluating drug metabolism inhibition are unable to detect induction. It may be postulated that components in St. John’s wort inhibit CYP3A4; however, these effects are overwhelmed by potent CYP3A4 induction from other potential constituents such as hypericin or hyperforin.
In addition to the pharmacokinetic drug interactions described above, a number of case reports suggest that coadministration of St. John’s wort with serotonin reuptake inhibitors (SRIs) may result in symptoms consistent with central and peripheral serotonin excess. In five elderly patients (ages 64-84 years) receiving stable doses of SRIs (four sertraline, one nefazodone), the addition of St. John’s wort was associated with dizziness, nausea, vomiting, headache, anxiety, confusion, and/or irritability.16 In two cases (involving sertraline), the serotonin receptor antagonist cyproheptadine was administered with symptom resolution within four to seven days. In a separate report, a 50-year-old woman discontinued paroxetine and initiated St. John’s wort 600 mg/d.17 Eleven days later, the patient took 20 mg of paroxetine to facilitate sleep. The following morning, the patient was lethargic and complained of nausea, weakness, and fatigue. These symptoms subsequently resolved without intervention.
Early in vitro experiments with hypericin found some monoamine oxidase inhibitor (MAOI) activity, but this has not been borne out clinically or in later studies. The very weak MAOI activity only occurs at very high concentrations.18 St. John’s wort cannot be considered to have any significant MAOI activity.
Health care practitioners should be attentive to the potential for herbal therapies, including St. John’s wort, to interact with conventional medications. A knowledge of the drug metabolism/clearance pathways affected by St. John’s wort allows prediction of other conventional medications likely to produce interactions. Little is known regarding the time course of induction following addition or cessation of St. John’s wort. Clinicians should anticipate the need to adjust doses of conventional medications following initiation or discontinuation of St. John’s wort.
Dr. Burstein is a Pharmacokineticist in the Clinical Center, Pharmacy Department of the National Institutes of Health. The views presented in this article are those of the author and do not necessarily represent the policy of the National Institutes of Health (NIH), the NIH Clinical Center, or the Food and Drug Administration.
References:
1. Roby CA, et al. St. John’s wort: Effect on CYP3A4 activity. Clin Pharmacol Ther 2000;67:451-457.
2. Kerb R, et al. Urinary 6ß-hydroxycortisol excretion rate is affected by treatment with hypericum extract [abstract]. Eur J Clin Pharmacol 1997;52(suppl):A186.
3. Gewertz N, et al. Determination of the differential effects of St. John’s wort on the CYP1A2 and NAT2 metabolic pathways. Poster presented at: The 39th Annual Meeting of the New Clinical Drug Evaluation Unit; June 1999; Boca Raton, FL.
4. Yue QY, et al. Safety of St. John’s wort. Lancet 2000;355:576-577.
5. Johne A, et al. Pharmacokinetic interaction of digoxin with an herbal extract from St. John’s wort (Hypericum perforatum). Clin Pharmacol Ther 1999;66:338-345.
6. Ereshefsky B, et al. Determination of SJW differential metabolism at CYP2D6 and CYP3A4, using dextromethorphan probe methodology. Poster presented at: The 39th Annual Meeting of the New Clinical Drug Evaluation Unit; June 1999; Boca Raton, FL.
7. Nebel A, et al. Potential metabolic interaction between St. John’s wort and theophylline. Ann Pharmacother 1999;33:502.
8. Ruschitzka F, et al. Acute heart transplant rejection due to St. John’s wort. Lancet 2000;355:548-549.
9. Ernst E. Second thoughts about safety of St. John’s wort. Lancet 1999;354:2014-2016.
10. Maurer A, et al. Interaction of St. John’s wort extract with phenprocoumon. Eur J Clin Pharmacol 1999;55:A22.
11. Piscitelli SC, et al. Marked reduction in indinavir exposure by St. John’s wort. Lancet 2000; 355:547.
12. Roots I, et al. Interaction of a herbal extract from St. John’s wort with amitriptyline and its metabolites. Clin Pharmacol Ther 2000;67:159.
13. Markowitz JS, et al. Effect of St. John’s wort (Hypericum perforatum) on cytochrome P-450 2D6 and 3A4 activity in healthy volunteers. Life Sci 2000;66:PL133-139.
14. Food and Drug Administration. FDA Public Health Advisory. Risk of drug interactions with St. John’s wort and indinavir and other drugs. Available at: http://www.fda.gov/cder/drug/ advisory/stjwort.htm. Accessed May 9, 2000.
15. Carson SW, et al. Inhibitory effect of methanolic solutions of St. John’s wort (Hypericum perforatum) on cytochrome p450 3A4 activity in human liver microsomes. Clin Pharmacol Ther 2000;67:99.
16. Lantz MS, et al. St. John’s wort and antidepressant drug interactions in the elderly. J Geriatr Psychiatry Neurol 1999;12:7-10.
17. Gordon JB. SSRIs and St. John’s wort: Possible toxicity? Am Fam Physician 1998;57:950-953.
18. Nathan PJ. The experimental and clinical pharmacology of St. John’s wort (Hypericum perforatum L.). Mol Psychiatry 1999;4:333-338.
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