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DRUG RECORD

 

ST. JOHN’S WORT

(HYPERICUM PERFORATUM)

OVERVIEW
St. John’s Wort

 

Introduction

St. John’s wort is a popular herbal medication and extract derived from the plant Hypericum perforatum which is purported to be beneficial in depression and anxiety.  St. John’s wort has not been implicated convincingly in cases of clinically apparent, acute liver injury, although it may increase the hepatotoxicity of other agents by herb-drug interactions that alter drug metabolism.

 

Background

St. John’s wort is an extract prepared from the flowers and leaves of a flowering plant native to Europe commonly known as St. John’s wort, Tipton’s weed or chase-devil (Hypericum perforatum).  St. John’s wort is a yellow flowering perennial herb indigenous to Europe that has been introduced elsewhere.  Its name refers to the Saint’s day on which it is typically harvested – June 24th.  The genus name Hypericum means “above the picture” in reference to its use to ward off evil by hanging the plant over a religious picture or icon.  St. John’s wort is an invasive weed in many countries where it has been introduced, where it can be toxic to livestock.  St. John’s wort has been used widely as an herbal treatment for depression.  It is available as an over-the-counter herbal in the United States, but in other countries is actively prescribed for mild-to-moderate depression.  Extracts of St. John’s wort contain many polyphenols, including flavonoids (rutin, hyperoside, isoquercetin, quercitrin, quercetin and others), phenolic acids, naphthodianthrones (hypericin, pseudohypericin, protohypericin and others), and phloroglucinols (hyperforin, adhyperforin).  The active principle responsible for the antidepressant effects of St. John’s wort is not known, the most likely candidates being hypericin, pseudohypericin and hyperforin.  In controlled trials, St. John’s wort has shown evidence of an antidepressant effect in patients with mild to moderate depression.  Side effects can occur with St. John’s wort including gastrointestinal upset, dizziness, confusion, fatigue, anxiety and photosensitivity.  Importantly, St. John’s wort has effects on the cytochrome P450 system (induction of CYP 3A4 and 2C9) as well as the major drug transport protein – P-glycoprotein.  As a result, St. John’s wort has major drug interactions, particularly with birth control pills, transplant rejection agents, antiretroviral agents, digoxin, platelet inhibitors, anticoagulants and psychotropic agents.  Caution should be taken and specific interactions sought when using St. John’s wort with other medications.

 

Hepatotoxicity

Despite wide spread use, there have been no convincing case reports linking use of St. John’s wort and hepatotoxicity.  In controlled trials, St. John’s wort has not been linked to serum enzyme elevations or to clinically apparent liver injury.  Because of its many herb-drug interactions and effects on the P450 system and drug transport and excretion, St. John’s wort may increase or decrease the likelihood of drug induced liver injury from other medications.

 

Other Names:   Goatweed, Hypericum

 

Drug Class:  Herbal and Dietary Supplements

 

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PRODUCT INFORMATION
St. John’s Wort

 

REPRESENTATIVE TRADE NAMES
St. John’s Wort – Generic

 

DRUG CLASS
Herbal and Dietary Supplements

 

SUMMARY INFORMATION

Fact Sheet at National Center for Complementary and Integrative Health, NIH

 

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CHEMICAL FORMULA AND STRUCTURE
St. John’s Wort
DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
St. John’s Wort 68917-49-7 Herbal mixture Not applicable

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ANNOTATED BIBLIOGRAPHY
St. John’s Wort

 

References updated: 03 January 2014

 

  1. Zimmerman HJ. Unconventional drugs. Miscellaneous drugs and diagnostic chemicals. In, Zimmerman, HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott,1999: pp. 731-4.  (Expert review of hepatotoxicity published in 1999; St. John’s wort is not discussed).

  2. Seeff L, Stickel F, Navarro VJ. Hepatotoxicity of herbals and dietary supplements. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 631-58.  (Review of hepatotoxicity of herbal and dietary supplements [HDS]; St. John’s wort is listed as nonhepatotoxic).

  3. St. John’s Wort. In, PDR for Herbal Medicines. 4th ed. Montvale, New Jersey: Thomson Healthcare Healthcare Inc. 2007: pp. 797-820.  (Compilation of short monographs on herbal medications and dietary supplements).

  4. De Smet PAGM. Herbal remedies. N Engl J Med 2002; 347: 2046-56. PubMed Citation  (Review of status and difficulties of herbal medications, including lack of standardization, federal regulation, contamination, safety, hepatotoxicity and herb-drug interactions; specific discussion of 4 herbs with therapeutic promise: ginkgo, hawthorn, saw palmetto and St. John’s wort).

  5. Stedman C. Herbal hepatotoxicity. Semin Liver Dis 2002; 22: 195-206. PubMed Citation  (Review and description of patterns of liver injury, including discussion of potential risk factors, and herb-drug interactions; St. John’s wort is not discussed).

  6. Schiano TD. Hepatotoxicity and complementary and alternative medicines. Clin Liver Dis 2003; 7: 453-73. PubMed Citation  (Comprehensive review of herbal associated hepatotoxicity; St. John’s wort is not listed as causing hepatotoxicity).

  7. Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug-induced liver injury in the United States. Liver Transpl 2004; 10: 1018-23. PubMed Citation  (Among ~50,000 liver transplants reported to UNOS between 1990 and 2002, 270 [0.5%] were done for drug induced acute liver failure, including 7 [5%] for herbal medications, none attributed to St. John’s wort).

  8. García-Cortés M, Borraz Y, Lucena MI, Peláez G, Salmerón J, Diago M, Martínez-Sierra MC, et al. [Liver injury induced by “natural remedies”: an analysis of cases submitted to the Spanish Liver Toxicity Registry]. Rev Esp Enferm Dig 2008; 100: 688-95. Spanish. PubMed Citation  (Among 521 cases of drug induced liver injury submitted to Spanish registry, 13 [2%] were due to herbals but none attributed to St. John’s wort).

  9. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation  (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, 9% of cases were attributed to herbal medications; St. John’s wort is not listed).

  10. Etogo-Asse F, Boemer F, Sempoux C, Geubel A. Acute hepatitis with prolonged cholestasis and disappearance of interlobular bile ducts following tibolone and Hypericum perforatum(St. John's wort). Case of drug interaction? Acta Gastroenterol Belg 2008; 71: 36-8. PubMed Citation  (57 year old woman developed jaundice 2 years after starting tibolone for menopausal symptoms and 10 weeks after starting St. John’s wort [bilirubin 6.3 rising to 37 mg/dL, ALT 424 U/L, Alk P 162 U/L, ANA 1:320], with prolonged jaundice and persistent Alk P elevations, biopsy showing paucity of bile ducts; authors suggest that St. John’s wort may have potentiated the hepatotoxicity of tibolone).

  11. Wang N, Li P, Wang Y, Peng W, Wu Z, Tan S, Liang S, et al. Hepatoprotective effect of Hypericum japonicum extract and its fractions. J Ethnopharmacol 2008; 116: 1-6. PubMed Citation  (Extracts of St. John’s wort provided partial protection against carbon tetrachloride injury in a rat model; fractionation of the extract suggested some of the effect was attributable to flavonoids).

  12. Knüppel L, Linde K. Adverse effects of St. John's Wort: a systematic review. J Clin Psychiatry 2004; 65: 1470-9. PubMed Citation  (Systematic review of side effects of St. John’s wort, including 35 controlled trials found side effects were similar to those reported for placebo recipients and no serious adverse events were attributed to the herbal; case reports of adverse events included serotonin syndrome [18, with SSRIs], decrease in cyclosporine or tacrolimus levels after transplantation [16], increased INR on anticoagulants [13], phototoxic [9] and allergic reactions [8]; among 722 reports to drug monitoring agencies, 24 [3%] were listed as hepatobiliary but no details were provided).

  13. Gaster B, Holroyd J. St John's wort for depression: a systematic review. Arch Intern Med 2000; 160: 152-6. PubMed Citation  (Systematic review of the literature concluded that St. John’s wort is more effective than placebo in treatment of mild-to-moderate depression and has a low rate of side effects, occurring in only 2.4% of 3250 patients in open label studies and at rates only mildly higher than with placebo [and in lower rates that with conventional antidepressants] in controlled trials; no mention of ALT elevations or hepatotoxicity).

  14. Ernst E. Risks of herbal medicinal products. Pharmacoepidemiol Drug Saf 2004; 13: 767-71. PubMed Citation  (Review of the adverse effects of over-the-counter herbal medications, focusing on the hepatotoxicity of kava, drug interactions with St. John’s wort, and contamination of traditional Chinese medications with heavy metals [arsensic, lead, mercury, thallium] and conventional western medications).

  15. Jacobson JM, Feinman L, Liebes L, Ostrow N, Koslowski V, Tobia A, Cabana BE, et al. Pharmacokinetics, safety, and antiviral effects of hypericin, a derivative of St. John's wort plant, in patients with chronic hepatitis C virus infection. Antimicrob Agents Chemother 2001; 45: 517-24. PubMed Citation  (19 patients with chronic hepatitis C were treated with purified hypericin orally for 8 weeks; there were no changes in HCV RNA or ALT levels, but skin photosensitivity reactions were common).

  16. Domínguez Jiménez JL, Pleguezuelo Navarro M, Guiote Malpartida S, Fraga Rivas E, Montero Alvarez JL, Poyato González A. [Hepatotoxicity associated with Hypericum(St. John's wort)]. Gastroenterol Hepatol 2007; 30: 54-5. Spanish. PubMed Citation  (23 year old woman found to have chronic elevations in serum enzymes [ALT 48 to 265 U/L, GGT 28, Alk P 173 U/L] while taking St. John’s wort; results on stopping herbal were not provided).

  17. Navarro VJ. Herbal and dietary supplement hepatotoxicity. Semin Liver Dis 2009; 29: 373-82. PubMed Citation  (Overview of the regulatory environment, clinical patterns, and future directions in research with HDS; St. John's wort is not discussed).

  18. Jacobsson I, Jönsson AK, Gerdén B, Hägg S. Spontaneously reported adverse reactions in association with complementary and alternative medicine substances in Sweden. Pharmacoepidemiol Drug Saf 2009; 18: 1039-47. PubMed Citation  (Review of 778 spontaneous reports of adverse reactions to herbals to Swedish Registry mentions 44 reactions to St. John's wort, but none were categorized as hepatic).

  19. Choi YH, Chin YW, Kim YG. Herb-drug interactions: focus on metabolic enzymes and transporters. Arch Pharm Res 2011; 34: 1843-63. PubMed Citation  (Review of herb-drug interactions and their mechanistic basis; while in vitro studies suggest that St. John's wort might inhibit various P450 enzymes, in vivo studies show that it induces CYP 3A4, 1A and 2C9 as well as P-glycoprotein, leading to a lowering of serum levels of many drugs such as amitriptyline, cyclosporine, digoxin, fexofenadine, indinavir, methadone, midazolam, simvastatin, tacrolimus, theophylline and warfarin).

  20. Chen XW, Sneed KB, Pan SY, Cao C, Kanwar JR, Chew H, Zhou SF. Herb-drug interactions and mechanistic and clinical considerations. Curr Drug Metab 2012; 13: 640-51. PubMed Citation  (Review of literature on herb-drug interactions mentions that St. John's wort can lower concentrations of cyclosporine, tacrolimus, midazolam, digoxin, amitriptyline, indinavir, warfarin and theophylline).

  21. Teschke R, Wolff A, Frenzel C, Schulze J, Eickhoff A. Herbal hepatotoxicity: a
    tabular compilation of reported cases. Liver Int 2012; 32: 1543-56. PubMed Citation  (A systematic compilation of all publications on the hepatotoxicity of specific herbals identified 185 publications on 60 different herbs, herbal drugs and supplements: St. John's wort is not discussed).

  22. Bunchorntavakul C, Reddy KR. Review article: herbal and dietary supplement
    hepatotoxicity. Aliment Pharmacol Ther 2013; 37: 3-17. PubMed Citation  (Systematic review of literature on HDS associated liver injury mentions that St. John's wort is a potent inducer of CYP 3A4 and can cause clinically significant herb-drug interactions with warfarin, aspirin, cyclosporine, methotrexate, HIV protease inhibitors, and can potentiate the intrinsic hepatotoxicity of other agents such as acetaminophen). 

  23. Posadzki P, Watson L, Ernst E. Herb-drug interactions: an overview of systematic reviews. Br J Clin Pharmacol 2013; 75: 603-18. PubMed Citation  (Review of systematic reviews of herb-drug interactions, mentions that St. John's wort can cause induction of CYP 3A and affect levels of several drugs; no mention of adverse hepatic effects).

  24. Posadzki P, Watson LK, Ernst E. Adverse effects of herbal medicines: an overview of systematic reviews. Clin Med 2013; 13: 7-12. PubMed Citation  (Systematic review of systematic reviews of adverse effects of herbals mentions that Hypericum perforatum has been associated only with minor adverse events).

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OTHER REFERENCE LINKS
St. John’s Wort

 

  1. PubMed logoRecent References on St. John’s Wort

  2. Clinical Trials logoTrials on St. John’s Wort

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