St. John’s Wort


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Jun J. Mao, MD, MSCE

Jun J. Mao, MD, MSCE

Jyothirmai Gubili, MS

Jyothirmai Gubili, MS

The ASCO Post’s Integrative Oncology series is intended to facilitate the availability of evidence-based information on integrative and complementary therapies commonly used by patients with cancer. In this installment, Jun J. Mao, MD, MSCE, and Jyothirmai Gubili, MS, explore the role of St. John’s wort in treating some conditions and discuss what physicians should know if any of their patients with cancer ask about use of the botanical.

Overview

A perennial herb prevalent in Europe, West Asia, and North Africa, St. John’s wort is associated with a long medicinal history as a remedy to treat wounds, headaches, kidney problems, nerve disorders, and melancholia. The herb has been extensively studied, with its active constituents hyperforin and hypericin being the focus of most research. Data from clinical trials support its effectiveness in alleviating mild to moderate depression. A few studies also indicate its benefits in controlling vasomotor symptoms in peri- and postmenopausal women.

Marketed in supplemental form, the flowering tops of the herb are used to prepare capsules, tablets, liquid extracts, tinctures, and teas, as well as skin lotions for topical use to facilitate wound healing. Although primarily taken for depression, St. John’s wort is also used to address menopausal symptoms, attention-deficit hyperactivity disorder, and obsessive-compulsive disorder. However, its interactions with prescription medications, including certain chemotherapy agents, are the most documented in the literature.

The Science

In vitro and in vivo studies indicate that St. John’s wort has neuroprotective properties1 and the ability to relieve neuropathic pain.2 In addition, clinical studies suggest that St. John’s wort may be as effective as selective serotonin-reuptake inhibitors (SSRIs) such as fluoxetine3 and citalopram4 for the treatment of mild to moderate depression as well as being comparable to paroxetine5 against moderate to severe depression. Furthermore, it has been reported to be safe in the long term6 and to be a cost-effective alternative to generic antidepressants,7 with sustained reductions in depression following continued use in patients with acute moderate depression.8 However, data are inconsistent when all types of depression are analyzed,9,10 and a randomized trial failed to find any effect in patients with minor depression.11

St. John’s wort may also be useful for managing premenstrual syndrome12 and vasomotor symptoms in peri- and postmenopausal women.13

OF NOTE

St. John’s wort is widely popular as an antidepressant. However, physicians should be aware of the adverse effects associated with its use and, more importantly, its potential to interact with myriad prescription drugs that include chemotherapeutics and antidepressants, often resulting in their reduced efficacy.

Investigations into the mechanism of action revealed that St. John’s wort inhibits serotonin, norepinephrine, and dopamine reuptake by neurons in vitro.14,15 One of the active compounds, hyperforin was shown to activate transient receptor potential C6 channels and possibly influence monoamine uptake16 and to stimulate the development and function of oligodendrocytes.17 In another study, hypericin suppressed voltage-dependent calcium channel and mitogen-activated protein kinase activity resulting in glutamate release.18

Studies have also been conducted to determine how St. John’s wort induces or modulates different enzymes, altering the pharmacokinetics of corresponding drug substrates. Hyperforin was shown to induce CYP3A4 via activation of the pregnane X receptor19; a St. John’s wort extract modulated UDP-glucuronosyltransferase20 and P-glycoprotein (P-gp) activity via protein kinase C (PKC).21

Adverse Reactions

Photosensitivity or photodermatitis and acute neuropathy have been reported with St. John’s wort.22

Acute transplant rejection: Two patients with prior heart transplantation experienced transplant rejection directly linked to the use of St. John’s wort.23 A subsequent report of 45 kidney or liver transplant recipients also described rejection linked to ingestion of St. John’s wort.24

Cardiovascular collapse: Hypotension without anaphylactic symptoms occurred shortly after induction of general anesthesia, which was potentially linked to long-term use of St. John’s wort.25

Mania was reported in three patients with underlying bipolar disorder, which resolved in two patients following discontinuation of St. John’s wort, whereas the third experienced persistent agitation for several months.22

Serotonin syndrome: Hypertension, diaphoresis, agitation, dizziness, and weakness with acute onset have been reported following 10 days of St. John’s wort intake.26

Erythroderma developed 4 days after initiation of St. John’s wort and resolved after 5 weeks of concomitant treatment with oral steroids.27

Sexual dysfunction: Decreased sexual libido was reported and normalized following discontinuation of St. John’s wort.28

Withdrawal syndrome: Nausea, anorexia, dry retching, dizziness, dry mouth, thirst, cold chills, and extreme fatigue were observed in a patient following intake of St. John’s wort for 32 days.29

Prolonged facial dystonia: A 58-year-old woman suffered prolonged facial dystonia following the use of bupropion along with St. John’s wort.30

Herb-Drug Interactions

St. John’s wort induces cytochrome P450 isoenzyme 3A4 and 2C9, thereby affecting the metabolism of certain medications and reducing serum concentrations and efficacy. Drugs metabolized by these enzymes include the following agents:

  • Human papillomavirus (HIV) protease inhibitors such as indinavir [Crixivan]31; and HIV non-nucleoside reverse transcriptase inhibitors such as nevirapine32
  • Cyclosporine,23 tacrolimus,33 irinotecan,34 imatinib,35 docetaxel,36 and methotrexate37
  • Diltiazem/nifedipine,22 warfarin,38 and clopidogrel39
  • Triptans22; SSRIs including citalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline26; tricyclic antidepressants22; zolpidem40; alprazolam41; dextromethorphan41; antipsychotics such as clozapine42
  • Oral contraceptives43
  • Statins including simvastatin,44 atorvastatin,45 and rosuvastatin46
  • Oxycodone47
  • Gliclazide48
  • P-gp substrate drugs including digoxin,49 talinolol,50 and fexofenadine.51 St. John’s wort may also cause serious adverse effects in conjunction with pegylated interferon alpha.52
  • Uridine 5-diphospho-glucuronosyltransferase substrates: St. John’s wort was also shown to modulate uridine 5-diphospho-glucuronosyltransferase enzymes in vitro and may therefore increase the side effects of drugs such as acetaminophen.20

Summary

Due to its potential interactions with many prescription drugs and conventional anticancer treatments, St. John’s wort should not be recommended for patients who are undergoing active treatment or taking other types of prescription drugs. If patients strongly desire to take St. John’s wort, careful monitoring is needed to ensure its safe use.

DISCLOSURE: Dr. Mao and Ms. Gubili reported no conflicts of interest.

REFERENCES

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2. Galeotti N, Vivoli E, Bilia AR, et al: St. John’s wort reduces neuropathic pain through a hypericin-mediated inhibition of the protein kinase Cgamma and epsilon activity. Biochem Pharmacol 79:1327-1336, 2010.

3. Fava M, Alpert J, Nierenberg AA, et al. A double-blind, randomized trial of St John’s wort, fluoxetine, and placebo in major depressive disorder. J Clin Psychopharmacol 25:441-447, 2005.

4. Singer A, Schmidt M, Hauke W, et al: Duration of response after treatment of mild to moderate depression with Hypericum extract STW 3-VI, citalopram and placebo: A reanalysis of data from a controlled clinical trial. Phytomedicine 18:739-742, 2011.

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10. Linde K, Berner MM, Kriston L: St John’s wort for major depression. Cochrane Database Syst Rev (4):CD000448, 2008.

11. Rapaport MH, Nierenberg AA, Howland R, et al: The treatment of minor depression with St. John’s wort or citalopram: Failure to show benefit over placebo. J Psychiatr Res 45:931-941, 2011.

12. Canning S, Waterman M, Orsi N, et al: The efficacy of Hypericum perforatum (St John’s wort) for the treatment of premenstrual syndrome: A randomized, double-blind, placebo-controlled trial. CNS Drugs 24:207-225, 2010.

13. Abdali K, Khajehei M, Tabatabaee HR: Effect of St John’s wort on severity, frequency, and duration of hot flashes in premenopausal, perimenopausal and postmenopausal women: A randomized, double-blind, placebo-controlled study. Menopause 17:326-331, 2010.

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17. Wang Y, Zhang Y, He J, et al: Hyperforin promotes mitochondrial function and development of oligodendrocytes. J Neurochem 119:555-568, 2011.

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25. Irefin S, Sprung J: A possible cause of cardiovascular collapse during anesthesia: Long-term use of St. John’s wort. J Clin Anesth 12:498-499, 2000.

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29. Dean AJ, Moses GM, Vernon JM: Suspected withdrawal syndrome after cessation of St. John’s wort. Ann Pharmacother 37:150, 2003.

30. Milton JC, Abdulla A: Prolonged oro-facial dystonia in a 58 year old female following therapy with bupropion and St John’s wort. Br J Clin Pharmacol 64:717-718, 2007.

31. Piscitelli SC, Burstein AH, Chaitt D, et al: Indinavir concentrations and St John’s wort. Lancet 355:547-548, 2000.

32. de Maat MM, Hoetelmans RM, Math t RA, et al: Drug interaction between St John’s wort and nevirapine. AIDS 15:420-421, 2001.

33. Mai I, Störmer E, Bauer S, et al: Impact of St John’s wort treatment on the pharmacokinetics of tacrolimus and mycophenolic acid in renal transplant patients. Nephrol Dial Transplant 18:819-822, 2003.

34. Mathijssen RH, Verweij J, de Bruijn P, et al: Effects of St. John’s wort on irinotecan metabolism. J Natl Cancer Inst 94:1247-1249, 2002.

35. Frye RF, Fitzgerald SM, Lagattuta TF, et al: Effect of St John’s wort on imatinib mesylate pharmacokinetics. Clin Pharmacol Ther 76:323-329, 2004.

36. Komoroski BJ, Parise RA, Egorin MJ, et al: Effect of the St. John’s wort constituent hyperforin on docetaxel metabolism by human hepatocyte cultures. Clin Cancer Res 11(19 Pt 1):6972-6979, 2005.

37. Yang SY, Juang SH, Tsai SY, et al: St. John’s wort significantly increased the systemic exposure and toxicity of methotrexate in rats. Toxicol Appl Pharmacol 263:39-43, 2012.

38. Jiang X, Williams KM, Liauw WS, et al: Effect of St John’s wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol 57:592-599, 2004.

39. Lau WC, Welch TD, Shields T, et al: The effect of St John’s wort on the pharmacodynamic response of clopidogrel in hyporesponsive volunteers and patients: Increased platelet inhibition by enhancement of CYP3A4 metabolic activity. J Cardiovasc Pharmacol 57:86-93, 2011.

40. Hojo Y, Echizenya M, Ohkubo T, et al: Drug interaction between St John’s wort and zolpidem in healthy subjects. J Clin Pharm Ther 36:711-715, 2011.

41. Markowitz JS, Donovan JL, DeVane CL, et al: Effect of St John’s wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. JAMA 290:1500-1504, 2003.

42. Van Strater AC, Bogers JP: Interaction of St John’s wort (Hypericum perforatum) with clozapine. Int Clin Psychopharmacol 27:121-124, 2012.

43. Vlachojannis J, Cameron M, Chrubasik S: Drug interactions with St. John’s wort products. Pharmacol Res 63:254-258, 2011.

44. Eggertsen R, Andreasson A, Andrén L: Effects of treatment with a commercially available St John’s wort product (Movina) on cholesterol levels in patients with hypercholesterolemia treated with simvastatin. Scand J Prim Health Care 25:154-159, 2007.

45. Andrén L, Andreasson A, Eggertsen R: Interaction between a commercially available St. John’s wort product (Movina) and atorvastatin in patients with hypercholesterolemia. Eur J Clin Pharmacol 63:913-916, 2007.

46. Gordon RY, Becker DJ, Rader DJ: Reduced efficacy of rosuvastatin by St. John’s wort. Am J Med 122(2):e1-e2, 2009.

47. Nieminen TH, Hagelberg NM, Saari TI, et al: St John’s wort greatly reduces the concentrations of oral oxycodone. Eur J Pain 14:854-859, 2010.

48. Xu H, Williams KM, Liauw WS, et al: Effects of St John’s wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide. Br J Pharmacol 153:1579-1586, 2008.

49. Gurley BJ, Swain A, Williams DK, et al: Gauging the clinical significance of P-glycoprotein-mediated herb-drug interactions: Comparative effects of St. John’s wort, Echinacea, clarithromycin, and rifampin on digoxin pharmacokinetics. Mol Nutr Food Res 52:772-779, 2008.

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

51. Xie R, Tan LH, Polasek EC, et al: CYP3A and P-glycoprotein activity induction with St. John’s wort in healthy volunteers from 6 ethnic populations. J Clin Pharmacol 45:352-356, 2005.

52. Piccolo P, Gentile S, Alegiani F, et al: Severe drug induced acute hepatitis associated with use of St John’s wort (Hypericum perforatum) during treatment with pegylated interferon alpha. BMJ Case Rep 2009; 2009.


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