St. John's Wort
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Anorexia Nervosa
Multiple Sclerosis
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Antiretroviral Agents
Monoamine Oxidase Inhibitors (MAOIs)
Oral Contraceptives
Protease Inhibitors
Reserpine-containing Medications
Selective Serotonin Reuptake Inhibitors (SSRIs)
Theophylline-containing Medications
Tricyclic Antidepressants (TCAs)
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Look Up > Herbs > St. John's Wort > Interactions
Interactions with St. John's Wort

Two cases of heart transplant rejection in patients who took St. John's wort while being treated with cyclosporin have been reported (Ruschitzka et al. 2000). One patient had been maintained uneventfully on a regimen of cyclosporin (125 mg bid), azathioprine, and corticosteroids for 11 months. The other patient had also been stable on an immunosuppressive regimen that included cyclosporin (125 mg bid). Although cyclosporin levels had been within the therapeutic range for both patients, ingestion of St. John's wort (300 mg tid) for three weeks diminished blood concentrations of cyclosporin to subtherapeutic levels and prompted episodes of rejection in each of these patients. Cyclosporin concentrations returned to therapeutic range with discontinuation of St. John's wort in both of these cases.

Additional reports of 30 interactions between cyclosporin A and St. John's wort in kidney transplant recipients were recently described (Breidenbach et al. 2000). After beginning St. John's wort therapy, cyclosporin blood levels fell by an average of 47%; cyclosporin dosages were increased 46% to account for this drop. Upon discontinuation of St. John's wort, cyclosporin blood levels increased by an average of 187%. While the mechanism for this interaction is not entirely clear, St. John's wort may either decrease cyclosporin absorption, induce cytochrome P-450 in the liver and/or small intestine, or induce P-glycoprotein (a drug transporter) in the small intestine. Because cyclosporin has a narrow therapeutic range, the researchers caution against concomitant use of St. John's wort.


The interaction between the hypericum extract of St. John's wort (900 mg/day) and digoxin (0.25 mg/day) was investigated in a single-blind, placebo-controlled parallel study in 25 healthy volunteers (Johne et al. 1999). The combination resulted in decreased plasma concentrations of digoxin over the 10-day period. This interaction was thought to involve induction of transport proteins, specifically P-glycoprotein.


There is a report in the literature of a possible interaction between loperamide and St. John's wort (Khawaja et al. 1999). A 39-year-old woman was admitted to the hospital in a state of delirium. She had been taking St. John's wort and valerian for 6 months, and she had recently ingested loperamide for diarrhea. Because the patient's clinical condition resembled a MAOI reaction, this interaction was thought to occur as a result of a MAOI-induced mechanism, possibly associated with an interaction either between the herbal agents or the herbal agents and loperamide.

Monoamine Oxidase Inhibitors (MAOIs)

Research regarding interactions between St. John's wort and MAOIs remains incomplete and controversial. A recent report suggested that St. John's wort and phenelzine, a MAOI, should not be used concomitantly (Miller 1998).

Oral Contraceptives

Eight women between the ages of 23 and 31 who had used St. John's wort while taking oral contraceptives reported breakthrough bleeding or changes in menstrual bleeding (Yue et al. 2000). There have been additional reports cited in the literature of breakthrough bleeding in women taking oral contraceptives with St. John's wort (Ernst 1999). Because oral contraceptives are metabolized via the cytochrome P450 pathway, enzyme induction is thought to be the mechanism behind this interaction.

Protease Inhibitors

The Food and Drug Administration (FDA) has issued a public health advisory concerning an interaction between indinavir and St. John's wort that resulted in significantly decreased plasma concentrations of this protease inhibitor (FDA 2000). This advisory warning was based on results of an NIH-conducted open-label study of eight healthy volunteers receiving indinavir (800 mg) and later indinavir with St. John's wort (300 mg tid standardized to 0.3% hypericin) for 14 days (Piscitelli et al. 2000). Plasma concentrations of indinavir dropped significantly from levels obtained prior to the introduction of St. John's wort. This interaction may be secondary to induction of the cytochrome P450 metabolic pathway.

The FDA recommends against concomitant administration of St. John's wort with antiretroviral medications that are protease inhibitors or nonnucleoside reverse transcriptase inhibitors because this interaction could lead to subtherapeutic plasma concentrations of these medications with the potential for lack of efficacy and/or resistance (FDA 2000).


St. John's wort antagonized the effect of the sympatholytic agent reserpine in animal studies (Okpanyi and Weischer 1987).

Selective Serotonin Reuptake Inhibitors (SSRIs)

In five cases, elderly patients receiving St. John's wort and prescription antidepressants (SSRIs) developed symptoms of serotonergic syndrome, including headache, dizziness, nausea, agitation, and anxiety (Lantz et al. 1999). A washout period of two weeks has been recommended when switching between SSRIs and St. John's wort because the combination of St. John's wort (600 mg) and paroxetine (20 mg) reportedly resulted in symptoms of incoherence and lethargy in a patient (Gordon 1998). Concomitant use of SSRIs with St. John's wort is not recommended. If these agents are used concomitantly, patients should be monitored very closely. Patients must be carefully weaned from one before starting on the other.


Use of St. John's wort supplement (300 mg bid standardized to 0.3% hypericin) decreased a patient's theophylline concentration, requiring an increase in dosage to 800 mg bid (Nebel et al. 1999). Discontinuation of St. John's wort caused the theophylline concentration to more than double in this individual case. St. John's wort may enhance hepatic enzyme (CYP1A2) activity, leading to increased theophylline clearance.

Tricyclic Antidepressants (TCAs)

Unpublished data suggest that St. John's wort may lower plasma concentrations of amitriptyline (De Smet and Touw 2000). This lends support to the possibility that the mechanism of drug interactions with St. John's wort involves induction of hepatic enzymes that are part of the cytochrome P450 system.


There have been seven case reports filed with the Medical Products Agency (MPA) in Sweden involving reduced effectiveness of warfarin when taken concomitantly with St. John's wort as evidenced by clinically significant decreases in INR values (Yue et al. 2000). Adjustments in warfarin doses or discontinuation of St. John's wort resulted in a return of INR values to desired levels. This interaction may be due to induction of hepatic enzymes, specifically cytochrome P450 2C9. In addition, there was a literature report of lower serum concentrations of warfarin in a 75-year-old woman who also took St. John's wort (Ernst 1999).


Breidenbach T, Kliem V, Burg M, Radermacher J, Hoffman MW, Klempnauer J. Profound drop of cyclosporin A whole blood trough levels caused by St. John's wort (Hypericum perforatum) [letter]. Transplantation. 2000;69(10):2229-2230.

De Smet P, Touw D. Safety of St. John's wort (Hypericum perforatum) [letter]. Lancet. 2000;355:575-576.

Ernst E. Second thoughts about safety of St John's wort. Lancet. 1999;354:2014-2015.

Food and Drug Administration. Risk of Drug Interactions with St John's Wort and Indinavir and Other Drugs. Rockville, Md: National Press Office; February 10, 2000. Public Health Advisory.

Gordon JB. SSRIs and St. John's Wort: possible toxicity? [letter] Am Fam Physician. 1998;57(5):950,953.

Johne A, Brockmoller J, Bauer S, Maurer A, Langheinrich M, Roots I. Pharmacokinetic interaction of digoxin with an herbal extract from St John's wort (Hypericum perforatum). Clin Pharmacol Ther. 1999;66(4):338-345.

Khawaja IS, Marotta RF, Lippmann S. Herbal medicines as a factor in delirium. Psychiatr Serv. 1999;50:969-970.

Lantz MS, Buchalter E, Giambanco V. St. John's wort and antidepressant drug interactions in the elderly. J Geriatr Psychiatry Neurol. 1999;12(1):7-10.

Miller LG. Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med. 1998;158(20):2200-2211.

Nebel A, Schneider BJ, Baker RK, et al. Potential metabolic interaction between St. John's wort and theophylline [letter]. Ann Pharmacother. 1999;33:502.

Okpanyi SN, Weischer ML. Experimental animal studies of the psychotropic activity of the Hypericum extract. Arzneim-Forsch. 1987;37:10-13.

Piscitelli S, Burstein A, Chaitt D, Alfaro R, Falloon J. Indinavir concentrations and St John's wort [letter]. Lancet. 2000;355:547-548.

Ruschitzka F, Meier P, Turina M, Luscher T, Noll G. Acute heart transplant rejection due to Saint John's wort [letter]. Lancet. 2000;355:548-549.

Yue Q, Bergquist C, Gerden B. Safety of St. John's wort (Hypericum perforatum) [letter]. Lancet. 2000;355:576-577.

Copyright © 2000 Integrative Medicine Communications

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