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Hypericum perforatum L.

Nomenclature

SCN: St. John’s wort
Part: flowering top, herb

Classifications

Safety: 2d
Interaction: C*

Quick Reference Summary

Contraindications

St. John’s wort should not be used during phototherapy (laser or ultraviolet) (Beattie et al. 2005).

Other Precautions

Avoidance of excessive exposure to sunlight during St. John’s wort use is warranted in fair-skinned persons (Martindale and Reynolds 1996; Weiss and Meuss 2001; Wichtl 2004).

Drug and Supplement Interactions

St. John’s wort has been shown to induce certain drug-metabolizing enzymes in the CYP450 enzyme system and the drug transporter protein P-glycoprotein (P-gp). Such induction may decrease the blood levels of certain orally administered drugs through increased metabolism or efflux, resulting in decreased therapeutic activity of these drugs. In human studies, significant induction of the enzyme CYP3A4 (Bauer et al. 2003; Dresser et al. 2003; Gurley et al. 2002, 2005; Wang et al. 2001) and some evidence of induction of the enzyme CYP2C19 have been shown (Wang et al. 2004a, 2004b), leading to reduced plasma levels of drugs metabolized by these enzymes or transported by P-gp. See CYP450 in Appendix 3 for more information.

The compound hyperforin is believed to be primarily responsible for the effects of St. John’s wort on CYP450 enzymes and P-gp (Gerhard 2005; Mueller et al. 2004). *Low-hyperforin and hyperforin-free extracts are commercially available and are believed to be less likely to interact with drugs than extracts with standard amounts of hyperforin (Madabushi et al. 2006).

Human studies and case series have demonstrated that St. John’s wort may decrease plasma levels of the following drugs (Borrelli and Izzo 2009):
Immunosuppressants: Cyclosporine (Bauer et al. 2003; Mai et al. 2004), tacrolimus (Hebert et al. 2004; Mai et al. 2003)
Anticoagulants: Warfarin (Jiang et al. 2004, 2006), phenprocoumon (Maurer et al. 1999)
Antiarrhythmics: Digoxin (Durr et al. 2000; Johne et al. 1999; Mueller et al. 2004), verapamil (Tannergren et al. 2004)
Calcium channel blockers: Nifedipine (Smith et al. 2001), verapamil (Tannergren et al. 2004)
Anti-anginals: Ivabradine (Portoles et al. 2006)
Hormonal contraceptives: Ethinylestradiol, norethindrone (Hall et al. 2003; Murphy et al. 2005; Pfrunder et al. 2003)
Anxiolytics: Quazepam (Kawaguchi et al. 2004), midazolam (Dresser et al. 2003; Gurley et al. 2002, 2005; Mueller et al. 2006; Xie et al. 2005), alprazolam (Markowitz et al. 2000, 2003)
Antidepressants (tricyclic): Amitriptyline (Johne et al. 2002)
Antivirals: Indinavir (Piscitelli et al. 2000), nevirapine (de Maat et al. 2001; L’homme et al. 2006)
Statins: Simvastatin (Sugimoto et al. 2001), atorvastatin (Andrén et al. 2007)
Anticancer drugs (chemotherapy and other) Irinotecan (Mathijssen et al. 2002), imatinib (Frye et al. 2004; Smith 2004)
Beta-adrenergic blockers: Talinolol (Schwarz et al. 2007)
Hypoglycemics: Gliclazide (Xu et al. 2008)
Antiulcer agents: Omeprazole (Wang et al. 2004a)
Antifungals: Voriconazole (Rengelshausen et al. 2005) (increase of plasma levels with single St. John’s wort dose, decrease after continued use)
Anticonvulsants: Mephenytoin (Wang et al. 2004b)
Skeletal muscle relaxants: Chlorzoxazone (Gurley et al. 2002, 2005)
Antifungals: Voriconazole (Rengelshausen et al. 2005)
Antihistamines: Fexofenadine (studies have indicated mixed results, with some reporting that plasma levels are increased while others indicating that plasma levels are decreased) (Dresser et al. 2003; Hamman et al. 2001; Wang et al. 2002)

St. John’s wort may decrease plasma levels of other drugs metabolized by the isoenzyme CYP3A4. See CYP450 in Appendix 3 for more information.

Human studies have shown a lack of interaction between St. John’s wort and some drugs including prednisone (Bell et al. 2007), mycophenolic acid (Mai et al. 2003), pravastatin (Sugimoto et al. 2001), tolbutamide (Wang et al. 2001), dextromethorphan (Markowitz et al. 2000, 2003; Wang et al. 2001; Wenk et al. 2004), carbamazepine (Burstein et al. 2000), and theophylline (Morimoto et al. 2004).

Due to the photosensitizing potential of St. John’s wort, concomitant use with photosensitizing drugs is not advised (Fiume 2001).

Notice

Photosensitizing (Brockmoller et al. 1997; Cotterill 2001; Schempp et al. 2001, 2003); see Appendix 2.

Adverse Events and Side Effects

A systematic review of clinical trials indicated that St. John’s wort has been well tolerated in trials, with no serious adverse effects reported. Patient dropout rates and adverse effects reports were similar to those of placebo (Knuppel and Linde 2004).

Evidence from clinical trials suggests that concerns regarding phototoxicity of St. John’s wort are not a problem in the general population, but caution regarding excessive exposure to sunlight during St. John’s wort use is warranted in fair-skinned persons. St. John’s wort should not be used in persons undergoing phototherapy (laser or ultraviolet) or those taking photosensitizing drugs (Schempp et al. 2001; Schulz 2001; Woelk et al. 1994). Hypericin is the compound primarily responsible for phototoxic effects (Gulick et al. 1999; Jacobson et al. 2001). Cases of phototoxicity have been reported after oral and topical uses of St. John’s wort products. Severe cases have been reported in persons undergoing laser or UV therapy and in persons taking the compound hypericin (Bove 1998; Cotterill 2001; Golsch et al. 1997; Gulick et al. 1999; Jacobson et al. 2001; Lane-Brown 2000).

Cases of adverse events that have been reported in two or more persons are hypomania and psychosis (Fahmi et al. 2002; Guzelcan et al. 2001; Khawaja et al. 1999; Laird and Webb 2001; Lal and Iskandar 2000; Moses and Mallinger 2000; Nierenberg et al. 1999; O’Breasail and Argouarch 1998; Shimizu et al. 2004; Shuster 1999) (note that in many of these reports, patients had a history of psychiatric illness or concomitant diagnoses of psychiatric disorders), hypertension (Patel et al. 2002; Zullino and Borgeat 2003), and sexual dysfunction (Assalian 2000; Bhopal 2001). The relationship between these events and St. John’s wort use is not known.

Pharmacological Considerations

St. John’s wort has been shown to induce the drug-metabolizing isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp), leading to lower plasma levels of drugs metabolized by CYP3A4 or transported by P-gp (Borrelli and Izzo 2009). The effect on CYP3A4 lasts for approximately 7 days after St. John’s wort use (Imai et al. 2008).

Pregnancy and Lactation

Studies on the effect of prenatal consumption of St. John’s wort on pregnancy in mice and rats were generally associated with normal gestation and offspring development (Borges et al. 2005; Cada et al. 2001; Ferguson et al. 1999; Rayburn et al. 2000, 2001a, 2001b). A limited number of human case reports indicated healthy pregnancies and infants when St. John’s wort was used prenatally (Gregoretti et al. 2004).

In studies of nursing mothers, the compound hyperforin was detected in low concentrations in mother’s milk while the compound hypericin was not detected in milk (Klier et al. 2002, 2006).

Food Use


Review Details

    Multiple studies have demonstrated that St. John’s wort significantly induces the drug-metabolizing enzyme CYP3A4 (Bauer et al. 2002; Dresser et al. 2003; Durr et al. 2000; Frye et al. 2004; Gurley et al. 2002; Kawaguchi et al. 2004; Markowitz et al. 2003; Roby et al. 2000; Wang et al. 2001; Xie et al. 2005). Clearance of probe drugs such as midazolam, cyclosporine, and imatinib increased by 40 to 90% (Dresser et al. 2003; Frye et al. 2004; Gurley et al. 2002; Wang et al. 2001). Most studies were conducted with a dose of 300 mg St. John’s wort three times daily for 2 weeks.

    In healthy men orally administered 5 mg of midazolam before or during 900 mg daily of St. John’s wort, clearance of midazolam increased significantly during St. John’s wort and returned to normal 7 days after cessation of St. John’s wort (Imai et al. 2008).

    The effects of St. John’s wort ingestion on CYP2C19 were shown to vary from no significant effect (Burstein et al. 2000) to significant induction (Rengelshausen et al. 2005; Wang et al. 2004a, 2004b). Among the studies that showed induction, two indicated that all 2C19 genotypes (including wild and mutant) produced similar results (Wang et al. 2004a, 2004b), while a third study indicated that individuals with wild-type CYP2C19 were more affected than others (Rengelshausen et al. 2005).

    In two studies, St. John’s wort ingestion significantly induced the activity of CYP2E1 (Gurley et al. 2002, 2005).

    Trials gave conflicting results on the effect of St. John’s wort on CYP1A2 and CYP2D6 activity. Results indicated no effect (Gerhard 2005; Gurley et al. 2008; Markowitz et al. 2000; Wang et al. 2004b) and significant induction (Gurley et al. 2002).

    In one study, St. John’s wort demonstrated nonsignificant induction of CYP2C9 (Gerhard 2005).

    In healthy volunteers orally administered St. John’s wort capsules at the manufacturer’s recommended dose (amount not specified) daily for two weeks, no effects on platelet function or other hematological parameters were observed, including prothrombin time, partial thromboplastin time, thrombin time, bleeding time, the collagen/epinephrine assay, or the collagen/adenosine diphosphate assay. Aspirin (325 mg daily) was used as a positive control and markedly inhibited platelet function (Beckert et al. 2007).

    Animal Pharmacological Studies

    Animal pharmacological studies were identified but omitted due to the availability of human data.

    In Vitro Pharmacological Studies

    In vitro pharmacological studies were identified but omitted due to the availability of human data.

  • IV. Pregnancy and Lactation

    A number of studies on the effect of prenatal consumption of St. John’s wort on pregnancy and offspring development in mice and rats were associated with normal gestation and offspring development (Borges et al. 2005; Cada et al. 2001; Ferguson et al. 1999; Rayburn et al. 2000, 2001a, 2001b). Morphological abnormalities were noted in rat embryos excised and exposed to high concentrations of hypericin (71.0 or 142.0 ng/ml) (Chan et al. 2001). One study noted hepatic and renal lesions in lactating rats that had ingested 100 or 1000 mg/kg/day St. John’s wort (Gregoretti et al. 2004).

    Two cases of healthy human pregnancy and baby were reported in mothers taking St. John’s wort (Grush et al. 1998).

    In nursing mothers taking 900 mg St. John’s wort daily, levels of hypericin and hyperforin in mothers’ milk and in mother and infant plasma were as follows: in mother’s milk, hypericin was below quantification limits, hyperforin ranged from 0.58 to 18.20 ng/ml; in mother’s plasma, hypericin was 10.71 ng/ml; hyperforin was 22.8–151 ng/ml; and in infant plasma, hypericin was below quantification limit and hyperforin was from below detection limits to 0.1 ng/ml (Klier et al. 2002, 2006). In a prospective study of breast-feeding mothers, no significant difference between the St. John’s wort and control groups were reported (Lee et al. 2003).

  • V. Toxicity Studies

    Acute Toxicity

    The LD50 of orally administered St. John’s wort extract (up to 5% in olive oil) could not be determined at doses up to 20 ml/kg (Fiume 2001).

    The LD50 of intraperitoneally administered extract fractions of St. John’s wort administered to mice is 780 mg/kg for the polyphenol fraction, 4300 mg/kg for the lipophile fraction, and 2800 mg/kg for the water-soluble fraction (Fiume 2001; Yevstifeyeva and Sibiryak 1996).

    Short-Term Toxicity

    Sheep fed St. John’s wort flowers at doses of 4 to 16 g/kg for 14 days exhibited some signs of toxicity including restlessness, photophobia, tachycardia, and erythema of the exposed parts of the tail and legs (Fiume 2001; Kako et al. 1993).

    Chronic Toxicity

    In rats fed St. John’s wort as 5% of their daily diet, significant weight loss was reported as compared to control. No other toxicities were reported (Garrett et al. 1982).

    Genotoxicity

    St. John’s wort (Hypericum perforatum) contains hypericin and hypericin-like substances as well as flavonoids, of which particularly quercetin has generated a widespread controversial discussion with respect to mutagenic action.

    No mutagenic activity of a hydroethanolic extract of St. John’s wort was observed in in vivo and in vitro studies, including the fur spot test in mice, the chromosome aberration test with bone marrow cells of the Chinese hamster, the hypoxanthine guanidine phosphoribosyltransferase test, the cell transformation test using Syrian hamster embryo cells, and the unscheduled DNA synthesis test (Okpanyi et al. 1990).

    In the Ames test for mutagenicity with Salmonella typhimurium strains TA98 and TA100 with or without metabolic activation from S9, a tincture of St. John’s wort increased the number of revertants in TA98 with and without metabolic activation and in TA100 with metabolic activation (Goggelmann and Schimmer 1986).

    Ethanol, chloroform, and ethyl acetate extracts of St. John’s wort were assayed at concentrations of 10 or 40 μl in the Ames test for mutagenicity with Salmonella typhimurium strains TA98 and TA100 with or without metabolic activation by S9. The ethanol and ethyl acetate extracts had mutagenic activity with and without metabolic activation. Testing of fractions of the extracts indicated that mutagenicity of the full extract was found exclusively in quercetin and that hypericin was not mutagenic (Poginsky et al. 1988). The compound quercetin is recognized to have mutagenic activity in vitro but is regarded as safe in humans (Harwood et al. 2007).

  • Literature Cited

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    Kawaguchi, A., M. Ohmori, S. Tsuruoka, et al. 2004. Drug interaction between St. John’s wort and quazepam. Br. J. Clin. Pharmacol. 58(4):403-410.

    Khawaja, I.S., R.F. Marotta, and S. Lippmann. 1999. Herbal medicines as a factor in delirium. Psychiatr. Serv. 50(7):969-970.

    Klier, C.M., M.R. Schafer, B. Schmid-Siegel, G. Lenz, and M. Mannel. 2002. St. John’s wort (Hypericum perforatum)—Is it safe during breastfeeding? Pharmacopsychiatry 35(1):29-30.

    Klier, C.M., B. Schmid-Siegel, M.R. Schafer, et al. 2006. St. John’s wort (Hypericum perforatum) and breastfeeding: Plasma and breast milk concentrations of hyperforin for 5 mothers and 2 infants. J. Clin. Psychiatr. 67(2):305-309.

    Knuppel, L., and K. Linde. 2004. Adverse effects of St. John’s wort: A systematic review. J. Clin. Psychiatr. 65(11):1470-1479.

    L’homme, R.F., T. Dijkema, A.J. van der Ven, and D.M. Burger. 2006. Brief report: Enzyme inducers reduce elimination half-life after a single dose of nevirapine in healthy women. J. Acquir. Immune Defic. Syndr. 43:193-196.

    Laird, R.D., and M. Webb. 2001. Psychotic episode during use of St. John’s wort. J. Herbal Pharmacother. 1(2):81-87.

    Lal, S., and H. Iskandar. 2000. St. John’s wort and schizophrenia. Can. Med. Assoc. J. 163(3):262-263.

    Lane-Brown, M.M. 2000. Photosensitivity associated with herbal preparations of St. John’s wort (Hypericum perforatum). Med. J. Austr. 172(6):302.

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

    Lee, A., R. Minhas, N. Matsuda, M. Lam, and S. Ito. 2003. The safety of St. John’s wort (Hypericum perforatum) during breastfeeding. J. Clin. Psychiatr. 64(8):966-968.

    Madabushi, R., B. Frank, B. Drewelow, H. Derendorf, and V. Butterweck. 2006. Hyperforin in St. John’s wort drug interactions. Eur. J. Clin. Pharmacol. 62(3):225-233.

    Mai, I., S. Bauer, E.S. Perloff, et al. 2004. Hyperforin content determines the magnitude of the St. John’s wort-cyclosporine drug interaction. Clin. Pharmacol. Ther. 76(4):330-340.

    Mai, I., K. Budde, E. Starmer, et al. 2003. Impact of St. John’s wort treatment on the pharmacokinetics of tacrolimus and mycophenolic acid in renal transplant patients. Nephrol. Dial. Transplant. 18(4):819-822.

    Mai, I., H. Kruger, K. Budde, et al. 2000. Hazardous pharmacokinetic interaction of Saint John’s wort (Hypericum perforatum) with the immunosuppressant cyclosporin. Int. J. Clin. Pharmacol. Ther. 38(10):500-502.

    Mandelbaum, A., F. Pertzborn, M. Martin-Facklam, and M. Wiesel. 2000. Unexplained decrease of cyclosporin trough levels in a compliant renal transplant patient. Nephrol. Dial. Transplant. 15(9):1473-1474.

    Markowitz, J.S., C.L. DeVane, D.W. Boulton, et al. 2000. Effect of St. John’s wort (Hypericum perforatum) on cytochrome P-450 2D6 and 3A4 activity in healthy volunteers. Life Sci. 66(9):PL133-139.

    Markowitz, J.S., J.L. Donovan, C.L. DeVane, et al. 2003. Effect of St. John’s wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. J. Am. Med. Assoc. 290(11):1500-1504.

    Martindale, W., and J.E.F. Reynolds. 1996. The extra pharmacopoeia. 31st ed. London: Pharmaceutical Press.

    Mathijssen, R.H., J. Verweij, P. de Bruijn, W.J. Loos, and A. Sparreboom. 2002. Effects of St. John’s wort on irinotecan metabolism. J. Natl. Cancer Inst. 94(16):1247-1249.

    Maurer, A., A. Johne, and S. Bauer. 1999. Interaction of St. John’s wort extract with phenprocoumon [abstract]. Eur. J. Clin. Pharmacol. 55:A22.

    Morimoto, T., T. Kotegawa, K. Tsutsumi, et al. 2004. Effect of St. John’s wort on the pharmacokinetics of theophylline in healthy volunteers. J. Clin. Pharmacol. 44(1):95-101.

    Moschella, C., and B.L. Jaber. 2001. Interaction between cyclosporine and Hypericum perforatum (St. John’s wort) after organ transplantation. Am. J. Kidney Dis. 38(5):1105-1107.

    Moses, E.L., and A.G. Mallinger. 2000. St. John’s wort: Three cases of possible mania induction. J. Clin. Psychopharmacol. 20(1):115-117.

    Mueller, S.C., J. Majcher-Peszynska, B. Uehleke, et al. 2006. The extent of induction of CYP3A by St. John’s wort varies among products and is linked to hyperforin dose. Eur. J. Clin. Pharmacol. 62(1):29-36.

    Mueller, S.C., B. Uehleke, H. Woehling, et al. 2004. Effect of St. John’s wort dose and preparations on the pharmacokinetics of digoxin. Clin. Pharmacol. Ther. 75(6):546-557.

    Murphy, P.A., S.E. Kern, F.Z. Stanczyk, and C.L. Westhoff. 2005. Interaction of St. John’s wort with oral contraceptives: Effects on the pharmacokinetics of norethindrone and ethinyl estradiol, ovarian activity and breakthrough bleeding. Contraception 71(6):402-408.

    Nebel, A., B.J. Schneider, R.K. Baker, and D.J. Kroll. 1999. Potential metabolic interaction between St. John’s wort and theophylline. Ann. Pharmacother. 33(4):502.

    Nierenberg, A.A., T. Burt, J. Matthews, and A.P. Weiss. 1999. Mania associated with St. John’s wort. Biol. Psychiatr. 46(12):1707-1708.

    O’Breasail, A.M., and S. Argouarch. 1998. Hypomania and St. John’s wort. Can. J. Psychiatr. 43(7):746-747.

    Okpanyi, S.N., H. Lidzba, B.C. Scholl, and H.G. Miltenburger. 1990. [Genotoxicity of a standardized Hypericum extract.] Arzneimittelforschung 40(8):851-855.

    Parker, V., A.H. Wong, H.S. Boon, and M.V. Seeman. 2001. Adverse reactions to St. John’s wort. Can. J. Psychiatr. 46(1):77-79.

    Patel, S., R. Robinson, and M. Burk. 2002. Hypertensive crisis associated with St. John’s wort. Am. J. Med. 112(6):507-508.

    Pfrunder, A., M. Schiesser, S. Gerber, et al. 2003. Interaction of St. John’s wort with low-dose oral contraceptive therapy: A randomized controlled trial. Br. J. Clin. Pharmacol. 56(6):683-690.

    Piscitelli, S.C., A.H. Burstein, D. Chaitt, R.M. Alfaro, and J. Falloon. 2000. Indinavir concentrations and St. John’s wort [erratum in Lancet 2001 Apr. 14; 357(9263):1210]. Lancet 355(9203):547-548.

    Poginsky, B., J. Westendorf, N. Prosenc, M. Kuppe, and H. Marquardt. 1988. St. John’s wort (Hypericum perforatum L.) genotoxicity induced by quercetin content. Dtsch. Apoth. Ztg. 128:13464-13466.

    Portoles, A., A. Terleira, A. Calvo, I. Martinez, and G. Resplandy. 2006. Effects of Hypericum perforatum on ivabradine pharmacokinetics in healthy volunteers: An open-label, pharmacokinetic interaction clinical trial. J. Clin. Pharmacol. 46(10):1188-1194.

    Rayburn, W.F., H.D. Christensen, and C.L. Gonzalez. 2000. Effect of antenatal exposure to Saint John’s wort (Hypericum) on neurobehavior of developing mice. Am. J. Obstet. Gynecol. 183(5):1225-1231.

    Rayburn, W.F., C.L. Gonzalez, H.D. Christensen, T.L. Harkins, and T.C. Kupiec. 2001a. Impact of Hypericum (St.-John’s-wort) given prenatally on cognition of mice offspring. Neurotoxicol. Teratol. 23(6):629-637.

    Rayburn, W.F., C.L. Gonzalez, H.D. Christensen, and J.D. Stewart. 2001b. Effect of prenatally administered Hypericum (St. John’s wort) on growth and physical maturation of mouse offspring. Am. J. Obstet. Gynecol. 184(2):191-195.

    Rengelshausen, J., M. Banfield, K. Riedel, et al. 2005. Opposite effects of short-term and long-term St. John’s wort intake on voriconazole pharmacokinetics. Clin. Pharmacol. Ther. 78(1):25-33.

    Roby, C.A., G.D. Anderson, E. Kantor, D.A. Dryer, and A.H. Burstein. 2000. St. John’s wort: Effect on CYP3A4 activity. Clin. Pharmacol. Ther. 67(5):451-457.

    Ruschitzka, F., P.J. Meier, M. Turina, T.F. Luscher, and G. Noll. 2000. Acute heart transplant rejection due to Saint John’s wort [see comment]. Lancet 355(9203):548-549.

    Schempp, C.M., K. Muller, B. Winghofer, J. Schulte-Monting, and J.C. Simon. 2001. Single-dose and steady-state administration of Hypericum perforatum extract (St. John’s wort) does not influence skin sensitivity to UV radiation, visible light, and solar-simulated radiation. Arch. Dermatol. 137(4):512-513.

    Schempp, C.M., B. Winghofer, K. Muller, et al. 2003. Effect of oral administration of Hypericum perforatum extract (St. John’s wort) on skin erythema and pigmentation induced by UVB, UVA, visible light and solar simulated radiation. Phytother. Res. 17(2):141-146.

    Schulz, V. 2001. Incidence and clinical relevance of the interactions and side effects of Hypericum preparations. Phytomedicine 8(2):152-160.

  • I. Drug and Supplement Interactions

    Clinical Trials of Drug or Supplement Interactions

    Immunosuppressants

    In kidney transplant patients orally administered 600 mg of St. John’s wort daily for 2 weeks in addition to their standard dose of cyclosporine, an increase in the clearance of cyclosporine was observed. The maximum plasma concentration of cyclosporine was reduced by an average of 42% (Bauer et al. 2003). Similar effects were observed in healthy volunteers administered 2.5 mg/kg cyclosporine after daily administration of 900 mg St. John’s wort for 14 days (Dresser et al. 2003).

    In kidney transplant patients orally administered 900 mg daily of a low-hyperforin (0.6 mg hyperforin daily) or regular (42 mg hyperforin daily) St. John’s wort preparation in addition to the standard dose of cyclosporine, no clinically relevant changes in cyclosporine levels were observed during the low-hyperforin treatment period. During treatment with the regular St. John’s wort extract, a 45% reduction in plasma levels (AUC0-12) of cyclosporine was observed (Mai et al. 2004). Cyclosporine is metabolized by CYP3A4 (Dresser et al. 2003).

    In healthy volunteers orally administered 0.1 mg/kg of tacrolimus before or during 18 days of St. John’s wort administration at a dose of 900 mg daily, a significant decrease in blood levels of tacrolimus was observed after St. John’s wort dosing. Induction of CYP3A4 and P-gp were proposed as the mechanism for this interaction (Hebert et al. 2004).

    In kidney transplant patients orally administered 600 mg St. John’s wort daily for 2 weeks in addition to the regular regimen of tacrolimus and mycophenolic acid, a significant decrease in plasma levels of tacrolimus was observed. No changes in mycophenolic acid levels were observed (Mai et al. 2003).

    No changes in plasma levels of prednisone were observed in healthy volunteers orally administered 900 mg St. John’s wort daily for 4 weeks before or after single doses of prednisone (Bell et al. 2007).

    Anticoagulants

    A significant decrease in plasma levels of (S)-warfarin was observed in healthy volunteers orally administered 900 mg daily St. John’s wort for 18 days. No change in the efficacy of (S)-warfarin was observed (Jiang et al. 2004, 2006). Both (S)-warfarin and (R)-warfarin were affected (Jiang et al. 2004).

    In healthy volunteers orally administered 12 mg phenprocoumon before or after administration of 900 mg St. John’s wort daily for 11 days, a significant reduction in plasma levels of phenprocoumon was observed after St. John’s wort dosing (Maurer et al. 1999).

    Antiarrhythmics

    Clinical trials of standard St. John’s wort and digoxin showed a significant decrease in plasma levels of digoxin both after a single dose (Durr et al. 2000) and after continued dosing of St. John’s wort (Durr et al. 2000; Johne et al. 1999; Mueller et al. 2004). Digoxin is a P-gp substrate (Durr et al. 2000). In trials with low-hyperforin (3.5 mg hyperforin daily) St. John’s wort products, the St. John’s wort did not affect digoxin blood levels (Gerhard 2005; Mueller et al. 2004).

    Calcium channel blockers

    In healthy volunteers orally administered 10 mg nifedipine before or after 18 days of 900 mg St. John’s wort daily, a significant decrease in the nifedipine plasma concentration was observed after St. John’s wort dosing (Smith et al. 2001).

    Concomitant use of 900 mg St. John’s wort and 120 mg/l (R)- and (S)-verapamil (administered, via a tube, directly to the small intestine) caused a 77% decrease in the maximum plasma concentration of the (R)- and (S)-verapamil. Verapamil is primarily metabolized by CYP3A4 (Tannergren et al. 2004).

    Anti-anginals

    In healthy volunteers orally administered a single oral dose of ivabradine before or after 900 mg St. John’s wort daily, a significant decrease in plasma levels of ivabradine was observed after St. John’s wort dosing. Ivabradine is metabolized by CYP3A4 (Portoles et al. 2006).

    Hormonal contraceptives

    In healthy women using a hormonal contraceptive (ethinyl estradiol and norethindrone) and orally administered 900 mg St. John’s wort daily for three menstrual cycles, a decrease in serum levels of ethinyl estradiol and norethindrone were observed. Testing with the CYP3A4 substrate midazolam on the last day of St. John’s wort treatment confirmed activity of St. John’s wort. Serum concentrations of follicle-stimulating hormone, luteinizing hormone, and progesterone were not significantly affected by St. John’s wort dosing. Breakthrough bleeding occurred in 2 of 12 women in the control phase compared with 7 of 12 women in the St. John’s wort phase. The oral clearance of midazolam after St. John’s wort dosing was greater in women who had breakthrough bleeding than in those who did not (Hall et al. 2003). In another study with the same St. John’s wort dosing regimen, a 15% decrease in exposure to ethinyl estradiol and norethindrone was observed along with an increase in intracyclic bleeding and evidence of follicle growth (Murphy et al. 2005). Participants in a third trial reported increased intracyclic bleeding as compared with contraceptive alone, but had no significant change in follicle maturation or serum estradiol and progesterone concentrations (Pfrunder et al. 2003).

    In healthy volunteers who had taken a low-dose oral contraceptive (0.02 mg ethinylestradiol and 0.15 mg desogestrel) for at least 3 months, oral administration of 500 mg of a low-hyperforin (less than 1 mg hyperforin) St. John’s wort extract daily for 14 days produced no significant effects on serum levels of the hormones or their metabolites (Will-Shahab et al. 2009).

    Anxiolytics

    In healthy volunteers orally administered a single dose of quazepam before or after oral administration of 900 mg St. John’s wort daily for 14 days, a significant reduction in plasma levels of quazepam was observed after St. John’s wort dosing. In subjective testing of volunteers, no significant effects of St. John’s wort on quazepam activity were observed. Quazepam is metabolized by CYP3A4 (Kawaguchi et al. 2004).

    A number of human studies have shown that St. John’s wort decreases plasma levels of alprazolam (Markowitz et al. 2000, 2003) and midazolam (Dresser et al. 2003; Gurley et al. 2002, 2005; Wang et al. 2001; Xie et al. 2005) in healthy volunteers. These effects are not observed with low hyperforin-containing extracts (Arold et al. 2005) or after a short duration (3 days or less) of treatment (Markowitz et al. 2000).

    Antidepressants (tricyclic)

    Reduced serum levels of amitriptyline and its metabolite, nortriptyline, were observed in depressed patients taking amitriptyline along with 900 mg St. John’s wort daily for 12 to 14 days (Johne et al. 2002).

    Antivirals

    A significant reduction in serum levels of indinavir was observed after oral administration of 800 mg indinavir to healthy volunteers who had been taking 900 mg St. John’s wort daily for 2 weeks, as compared to indinavir administered prior to St. John’s wort. Indinavir is metabolized by CYP3A4 (Piscitelli et al. 2000).

    In HIV patients being treated with nevirapine, self-treatment with varying doses of St. John’s wort led to a reduction in plasma levels of nevirapine. Nevirapine induces CYP3A4 (de Maat et al. 2002). In healthy volunteers orally administered 2 g of St. John’s wort as an infusion daily for 14 days, before or after administration of single doses of nevirapine, a significant reduction in the half-life of nevirapine was observed after St. John’s wort dosing (L’homme et al. 2006).

    Statins

    In healthy volunteers orally administered 900 mg St. John’s wort daily for 14 days prior to oral administration of 10 mg simvastatin and 20 mg pravastatin, lowered plasma concentrations of simvastatin and its active metabolite were observed. Pravastatin concentrations were not significantly altered. Simvastatin is metabolized by CYP3A4 (Sugimoto et al. 2001).

    In patients with hypercholesterolemia treated with a stable dose of atorvastatin (10–40 mg/day) for at least 3 months, administration of 600 mg of St. John’s wort daily for 4 weeks resulted in an increased serum level of LDL cholesterol and total cholesterol. No significant changes were observed in HDL cholesterol or in triglycerides (Andrén et al. 2007). Atorvastatin is metabolized by CYP3A4 and is also a substrate for P-glycoprotein.

    Anticancer drugs

    In cancer patients undergoing treatment with irinotecan (350 mg/m2, intravenously), oral administration of 900 mg daily of St. John’s wort decreased plasma concentrations of the irinotecan active metabolite by 42%. Irinotecan is metabolized by CYP3A4 (Mathijssen et al. 2002).

    In healthy volunteers orally administered 400 mg imatinib before and after oral administration of 900 mg St. John’s wort daily for 14 days, a significant reduction in plasma levels of imatinib was observed after St. John’s wort treatment. Imatinib is metabolized by CYP3A4 (Frye et al. 2004). Similar effects were observed in a second study with imatinib (Smith 2004).

    Beta-adrenergic blockers

    In healthy volunteers orally administered 900 mg St. John’s wort daily for 12 days before or after single doses of talinolol, a significant reduction in plasma levels of talinolol was observed (Schwarz et al. 2007).

    Hypoglycemics

    In healthy volunteers orally administered 80 mg glicazide with or without 900 mg St. John’s wort daily for 15 days, a reduction in plasma levels of glicazide was observed in the St. John’s wort group (Xu et al. 2008).

    Antiulcer drugs

    In healthy volunteers orally administered 900 mg St. John’s wort daily for 14 days, before or after single doses of omeprazole, a significant reduction in plasma levels of omeprazole was observed (Wang et al. 2004a).

    Skeletal muscle relaxants

    In healthy volunteers orally administered 900 mg St. John’s wort daily for 28 days before or after single doses of 500 mg chlorzoxazone, a reduction in plasma levels of chlorzoxazone was observed (Gurley et al. 2002, 2005).

    Anticonvulsants

    In healthy volunteers orally administered 900 mg St. John’s wort daily for 14 days, before or after single doses of mephenytoin, a significant increase in excretion of a mephenytoin metabolite was observed after St. John’s wort dosing. The effect was observed in volunteers with the CYP2C19 wild genotype, but not in those who are CYP2C19 poor metabolizers (Wang et al. 2004b).

    In healthy volunteers orally administered carbamazepine before or after 900 mg St. John’s wort daily for 11 days, no changes in plasma levels of carbamazepine were observed. Plasma levels of hypericin and pseudohypericin from St. John’s wort were also monitored, and a slight decrease in pseudohypericin levels was observed (Johne et al. 2004).

    No significant changes in plasma levels of carbamazepine were observed in healthy volunteers orally administered 900 mg St. John’s wort with 400 mg carbamazepine daily for 14 days (Burstein et al. 2000).

    Antifungals

    In healthy volunteers orally administered 900 mg St. John’s wort daily for 15 days, voriconazole was administered before and on days 1 and 15 of St. John’s wort consumption. Administration of voriconazole on day 1 resulted in an elevation of voriconazole plasma levels, although the elevation was considered clinically irrelevant. Plasma levels of voriconazole were significantly decreased when administered on day 15 of St. John’s wort consumption (Rengelshausen et al. 2005).

    Antihistamines

    Findings on the use of St. John’s wort and fexofenadine, a P-gp substrate, are mixed. In healthy volunteers orally administered single doses of 60 mg fexofenadine before and after a single dose of 900 mg St. John’s wort or the same dose repeated for 14 days, the single dose of St. John’s wort was found to significantly increase plasma concentrations of fexofenadine. After repeated dosing with St. John’s wort, no significant changes in fexofenadine disposition were observed as compared to the non-St. John’s wort portion of the experiment (Wang et al. 2002). An increase in oral clearance, with no changes in elimination half-life, was observed in healthy volunteers orally administered a single dose of 60 mg fexofenadine after oral administration of 900 mg St. John’s wort daily for 10 days (Xie et al. 2005). A significant increase in oral clearance of fexofenadine was observed in healthy volunteers orally administered 180 mg fexofenadine after oral administration of 900 mg of St. John’s wort daily for 14 days (Dresser et al. 2003).

    Bronchodilators

    No significant changes in plasma levels of theophylline were observed in healthy volunteers orally administered 900 mg daily St. John’s wort for 15 days before and after dosing with 400 mg theophylline (Morimoto et al. 2004).

    Other

    Administration of St. John’s wort was associated with significantly reduced methadone plasma levels in patients being treated in a methadone clinic (Eich-Hochli et al. 2003).

    Also see Human pharmacological studies for this entry.

    Case Reports of Suspected Drug or Supplement Interactions

    Immunosuppressants

    Cyclosporine and tacrolimus are substrates of the drug-metabolizing isoenzyme CYP3A4. Multiple case reports have demonstrated that St. John’s wort decreases blood levels of cyclosporine (Ahmed et al. 2001; Alscher and Klotz 2003; Barone et al. 2000; Beer and Ostermann 2001; Breidenbach et al. 2000a, 2000b; Karliova et al. 2000; Mai et al. 2000; Mandelbaum et al. 2000; Moschella and Jaber 2001; Ruschitzka et al. 2000; Turton-Weeks et al. 2001). St. John’s wort consumption for as little as 3 days was correlated with decreased cyclosporine blood levels (Mandelbaum et al. 2000).

    One case report noted a decrease in the blood level of tacrolimus in a patient taking St. John’s wort (Bolley et al. 2002).

    Anticoagulants

    One publication reported seven cases of decreased INR (a standardized scale used to report the results of blood coagulation tests; decreased INR indicates accelerated blood clotting) in patients taking warfarin and St. John’s wort. Several of the cases reported a return to normal INR levels after cessation of St. John’s wort; results of other cases were not reported (Yue et al. 2000).

    Hormonal contraceptives

    Several cases of intermenstrual bleeding and one case of unwanted pregnancy have been reported in women taking oral contraceptives and St. John’s wort (Schwarz et al. 2003; Yue et al. 2000).

    Antivirals

    In patients taking St. John’s wort and nevirapine, mild to moderate increases in oral clearance of nevirapine were recorded (de Maat et al. 2001, 2002).

    Antidepressants (SSRI)

    Several cases of suspected serotonin syndrome (Barbenel et al. 2000; Demott 1998; Gordon 1998; Lantz et al. 1999; Waksman et al. 2000) and one report of hypomania (Spinella and Eaton 2002) were reported in patients taking both St. John’s wort and SSRIs (selective serotonin reuptake inhibitors).

    Antipsychotics and anxiolytics

    One case of possible serotonin syndrome was reported in a patient taking St. John’s wort and buspirone (Dannawi 2002).

    Bronchodilators

    One case of lowered theophylline level was reported in a patient taking St. John’s wort, theophylline, and numerous other drugs. Theophylline level returned to normal after St. John’s wort was stopped (Nebel et al. 1999).

    Animal Trials of Drug or Supplement Interactions

    Animal trials of drug or supplement interactions were identified but omitted due to the availability of human data.

  • II. Adverse Events

    Adverse Events Reported in Clinical Trials

    A systematic review of adverse events reported in clinical trials of St. John’s wort indicated that data from 35 double-blind randomized trials showed that dropout and adverse event rates in patients receiving St. John’s wort extracts were similar to placebo, lower than with older antidepressants, and somewhat lower than with SSRI antidepressants. Dropout rates due to adverse events ranged from 0 to 5.7% in 17 observational studies that included 35,562 patients. No serious adverse events were reported in any of the studies (Knuppel and Linde 2004).

    Case Reports of Adverse Events

    A 35-year-old woman who had been taking 500 mg St. John’s wort daily for 4 weeks developed subacute polyneuropathy after exposure to sunlight. Symptoms were restricted to areas of skin that were exposed to sunlight and abated after St. John’s wort was discontinued (Bove 1998).

    A 45-year-old woman developed a severe phototoxic reaction to laser treatment after taking St. John’s wort (dose, duration, and product not specified). No adverse effects occurred during the same treatment prior to using or after discontinuation of St. John’s wort (Cotterill 2001).

    A 61-year-old woman developed recurring elevated itching erythematous lesions in light-exposed areas after taking six tablets daily of St. John’s wort for 3 years. Routine patch testing did not reveal any relevant reactions and photo patch testing was negative. Using a systemic oral photoprovocation test with St. John’s wort, a decrease of the MED-UVB (<0.039 J/cm2) was observed and was reversible after discontinuation of St. John’s wort (Golsch et al. 1997).

    A 52-year-old woman with a history of cutaneous lupus developed a severe phototoxic reaction after using St. John’s wort oil topically and orally three times daily for 2 weeks (Lane-Brown 2000).

    A 63-year-old man with a history of psoriasis had a severe phototoxic reaction within 30 minutes of UVB phototherapy. The man had been taking six capsules of St. John’s wort daily for an unspecified amount of time (Lane-Brown 2000).

    A 45-year-old woman who had been using a topical St. John’s wort cream for 3 weeks developed a phototoxic reaction after spending a day at the beach (Lane-Brown 2000).

    Data from the 2002 U.S. National Health Interview Survey indicated a correlation between St. John’s wort use and development of cataracts (Booth and McGwin 2009).

    Cases of hypomania (Fahmi et al. 2002; Guzelcan et al. 2001; Nierenberg et al. 1999; O’Breasail and Argouarch 1998; Shuster 1999), mania (Moses and Mallinger 2000), psychosis (Laird and Webb 2001; Lal and Iskandar 2000; Shimizu et al. 2004), and delirium (Khawaja et al. 1999) have been associated with the use of St. John’s wort. In many of these reports, patients were noted to have psychiatric histories or concomitant diagnoses of psychiatric disorders.

    St. John’s wort has been associated with hypertension in patients with no previous history of hypertension (Patel et al. 2002; Zullino and Borgeat 2003).

    Sexual dysfunction was reported in a patient who had experienced similar dysfunction while on sertraline (Assalian 2000). Diminished libido was reported in a patient with a history of depression and anxiety (Bhopal 2001).

    Other adverse events associated with the use of St. John’s wort include the following: erythematous eruption (Holme and Roberts 2000), hair loss (Parker et al. 2001), cardiovascular collapse during anesthesia (Irefin and Sprung 2000), serotonin syndrome (Parker et al. 2001), bone marrow necrosis (Demiroglu et al. 2005), reduced TSH levels (Ferko and Levine 2001), and nausea and related physical or mental symptoms (Brown 2000; Dean et al. 2003).

  • III. Pharmacology and Pharmacokinetics

    Human Pharmacological Studies

    In trials of commercial St. John’s wort extracts, humans ingesting up to 3600 mg of St. John’s wort extract (11.25 mg of total hypericin) did not experience phototoxicity (Brockmoller et al. 1997). In patients taking the compound hypericin, doses as low as 0.05 mg/kg were associated with phototoxic reactions (Gulick et al. 1999; Jacobson et al. 2001).

    St. John’s wort ingestion has been associated with changes in P-gp expression. Studies have shown that single doses of St. John’s wort inhibit P-gp expression (Hamman et al. 2001; Wang et al. 2002) but that doses taken over multiple days induce P-gp expression (Durr et al. 2000; Hennessy et al. 2002; Johne et al. 1999; Mueller et al. 2004; Schwarz et al. 2002; Wang et al. 2002; Xie et al. 2005). Conversely, one study showed that multiple doses had no effect on P-gp expression (Hamman et al. 2001). A hyperforin-free St. John’s wort extract was shown to have a nonsignificant effect on P-gp expression as compared to an extract containing hyperforin (Mueller et al. 2004).

    Schwarz, U., H. Hanso, G. Dresser, et al. 2002. St. John’s wort reduces oral bioavailability of talinolol in healthy volunteers. Clin. Pharmacol. Ther. 71(2):33.

    Schwarz, U.I., B. Buschel, and W. Kirch. 2003. Unwanted pregnancy on self-medication with St. John’s wort despite hormonal contraception. Br. J. Clin. Pharmacol. 55(1):112-113.

    Schwarz, U.I., H. Hanso, R. Oertel, et al. 2007. Induction of intestinal P-glycoprotein by St. John’s wort reduces the oral bioavailability of talinolol. Clin. Pharmacol. Ther. 81(5):669-678.

    Shimizu, K., M. Nakamura, K. Isse, and P.J. Nathan. 2004. First-episode psychosis after taking an extract of Hypericum perforatum (St. John’s wort). Human Psychopharmacol. 19(4):275-276.

    Shuster, J. 1999. Hypomanic episode with St. John’s wort. Hosp. Pharm. 34(Jun.):693-694.

    Smith, M., K. Lin, and Y. Zheng. 2001. An open trial of nifedipine-herb interactions: Nifedipine with St. John’s wort, ginseng or Ginko biloba. Clin. Pharmacol. Ther. 69(2):abstr. PIII-89.

    Smith, P. 2004. The influence of St. John’s wort on the pharmacokinetics and protein binding of imatinib mesylate. Pharmacotherapy 24(11):1508-1514.

    Spinella, M., and L.A. Eaton. 2002. Hypomania induced by herbal and pharmaceutical psychotropic medicines following mild traumatic brain injury. Brain Injury 16(4):359-367.

    Sugimoto, K., M. Ohmori, S. Tsuruoka, et al. 2001. Different effects of St. John’s wort on the pharmacokinetics of simvastatin and pravastatin. Clin. Pharmacol. Ther. 70(6):518-524.

    Tannergren, C., H. Engman, L. Knutson, et al. 2004. St. John’s wort decreases the bioavailability of R- and S-verapamil through induction of the first-pass metabolism. Clin. Pharmacol. Ther. 75(4):298-309.

    Turton-Weeks, S.M., G.W. Barone, B.J. Gurley, et al. 2001. St. John’s wort: A hidden risk for transplant patients. Prog. Transplant. 11(2):116-120.

    Waksman, J., K. Heard, and H. Joliff. 2000. Serotonin syndrome associated with the use of St. John’s wort (Hypericum perforatum) and paroxetine [abstract]. J. Toxicol. Clin. Toxicol. 38:521.

    Wang, L.S., G. Zhou, B. Zhu, et al. 2004a. St. John’s wort induces both cytochrome P450 3A4-catalyzed sulfoxidation and 2C19-dependent hydroxylation of omeprazole. Clin. Pharmacol. Ther. 75(3):191-197.

    Wang, L.S., B. Zhu, A.M. El-Aty, et al. 2004b. The influence of St. John’s wort on CYP2C19 activity with respect to genotype. J. Clin. Pharmacol. 44(6):577-581.

    Wang, Z., J.C. Gorski, M.A. Hamman, et al. 2001. The effects of St. John’s wort (Hypericum perforatum) on human cytochrome P450 activity. Clin. Pharmacol. Ther. 70(4):317-326.

    Wang, Z., M.A. Hamman, S.M. Huang, L.J. Lesko, and S.D. Hall. 2002. Effect of St. John’s wort on the pharmacokinetics of fexofenadine. Clin. Pharmacol. Ther. 71(6):414-420.

    Weiss, R.F., and A.R. Meuss. 2001. Weiss’s herbal medicine. Classic ed. New York: Thieme.

    Wenk, M., L. Todesco, and S. Krahenbuhl. 2004. Effect of St. John’s wort on the activities of CYP1A2, CYP3A4, CYP2D6, N-acetyltransferase 2, and xanthine oxidase in healthy males and females. Br. J. Clin. Pharmacol. 57(4):495-499.

    Wichtl, M. 2004. Herbal drugs and phytopharmaceuticals: A handbook for practice on a scientific basis. 3rd ed. Boca Raton, FL: CRC Press.

    Will-Shahab, L., S. Bauer, U. Kunter, I. Roots, and A. Brattstrom. 2009. St. John’s wort extract (Ze 117) does not alter the pharmacokinetics of a low-dose oral contraceptive. Eur. J. Clin. Pharmacol. 65(3):287-294.

    Woelk, H., G. Burkard, and J. Gruenwald. 1994. Benefits and risks of the Hypericum extract LI 160: Drug monitoring study with 3250 patients. J. Geriatr. Psychiatr. Neurol. 7(Suppl. 1):S34-S38.

    Xie, R., L.H. Tan, E.C. Polasek, et al. 2005. CYP3A and P-glycoprotein activity induction with St. John’s wort in healthy volunteers from 6 ethnic populations. J. Clin. Pharmacol. 45(3):352-356.

    Xu, H., K.M. Williams, W.S. Liauw, et al. 2008. Effects of St. John’s wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide. Br. J. Pharmacol. 153(7):1579-1586.

    Yevstifeyeva, T.A., and S.V. Sibiryak. 1996. Immunotropic properties of biologically active products obtained from St. John’s wort. Eksp. Klin. Farmakol. 59:54.

    Yue, Q.Y., C. Bergquist, and B. Gerden. 2000. Safety of St. John’s wort (Hypericum perforatum). Lancet 355(9203):576-577.

    Zullino, D., and F. Borgeat. 2003. Hypertension induced by St. John’s wort—A case report. Pharmacopsychiatry 36(1):32.

    Most Recent Revision

    June 18, 2014