The use of dietary supplements by patients with cancer has increased significantly over the past 2 decades despite insufficient evidence of safety and effectiveness. Finding reliable sources of information about dietary supplements can be daunting. Patients typically rely on family, friends, and the Internet, often receiving misleading information.
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. We chose St. John’s wort for this issue because of its popularity among cancer patients.
Compiled by Barrie R. Cassileth, PhD, and Jyothi Gubili, MS, Memorial Sloan Kettering Cancer Center. The free About Herbs website is managed by K. Simon Yeung, PharmD, MBA, LAc, Memorial Sloan Kettering Cancer Center.
St. John's Wort
Scientific name: Hypericum perforatum
Common names: Saint John’s wort, hypericum, goatweed, God’s wonder plant, witches herb
Overview
A perennial herb indigenous to Europe, West Asia, and North Africa, St. John’s wort has a centuries-long history as a remedy to treat wounds, headaches, kidney problems, nerve disorders, and melancholia. Brought to the United States by the colonists, it grows in many areas of the country.
Today, St. John’s wort is used to alleviate anxiety and depression, as well as for sleep disorders. It is available in health food stores and online in the form of capsules, tablets, liquid extracts, tinctures, and teas. It is also a common ingredient in skin lotions.
St. John’s wort is among the more extensively researched herbs. Data from clinical trials strongly support its effectiveness in treating mild to moderate depression. A few studies indicate benefit in controlling vasomotor symptoms in peri- and postmenopausal women.
Interactions between St. John’s wort and prescription drugs, including chemotherapeutic agents, are well documented in the literature.
The Science
Among several bioactive compounds discovered, hyperforin and hypericin are thought to be responsible for the beneficial effects of St. John’s wort. In vitro and in vivo experiments with the herb have shown neuroprotective effects1 and the ability to relieve neuropathic pain in a rat model.2
Current evidence indicates that St. John’s wort may be as effective as selective serotonin-reuptake inhibitors in treating mild to moderate depression.3 It is seen as a cost-effective alternative to generic antidepressants.4 Studies have shown that the effects of St. John’s wort are comparable to those of paroxetine5 and other selective serotonin-reuptake inhibitors6 in controlling moderate to severe depression. It is well tolerated, with sustained reductions in depression following continued use in those with acute moderate depression.7 However, analyses of all types of depression yielded inconsistent data,8,9 and a randomized trial found St. John’s wort ineffective in treating minor depression.10
A few studies support its efficacy in controlling premenstrual syndrome11 and vasomotor symptoms in peri- and postmenopausal women.12
Adverse Effects
Case reports: Mania was reported in three patients with underlying bipolar disorder, which resolved in two patients following discontinuation; the third experienced persistent agitation for several months.13
Serotonin syndrome: Hypertension, diaphoresis, agitation, dizziness, and weakness with acute onset were reported following 10 days of St. John’s wort intake. The syndrome resolved following discontinuation of St. John’s wort.14
Skin disease: Erythroderma developed 4 days after initiation of St. John’s wort; resolved after 5 weeks of concomitant treatment with oral steroids.15
Sexual dysfunction: Decreased sexual libido was reported with St. John’s wort; the condition normalized following discontinuation of the herb.16
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.17
Prolonged facial dystonia: A 58-year-old Caucasian woman suffered prolonged facial dystonia following use of bupropion along with St. John’s wort.18
Cardiovascular issues: Long-term use of St. John’s wort was identified as a potential contributor to cardiovascular collapse during anesthesia in a patient.19
Photosensitivity: Photosensitivity reactions occurred in individuals who used topical and/or oral St. John’s wort preparations prior to sun exposure or undergoing phototherapy.20
Herb-Drug Interactions
Cytochrome P450 3A4 substrates: St. John’s wort induces cytochrome P450 isoenzyme 3A4, thereby affecting metabolism of certain medications and reducing serum concentrations.21 Examples of drugs metabolized by 3A4 include:
Irinotecan: Due to changes in hepatic metabolism caused by St. John’s wort, levels of SN-38, a metabolite of the chemotherapy agent irinotecan, may be lowered by as much as 40% for up to 3 weeks following discontinuation of St. John’s wort.22
Warfarin: St. John’s wort may increase or decrease warfarin activity when the two agents are administered concomitantly. International normalized ratio (INR) should be monitored routinely.23
Tricyclic antidepressants: An increased serotonergic effect and possible serotonin syndrome is seen when St. John’s wort is combined with nefazodone, amitriptyline, or imipramine. Possible reduction in efficacy of antidepressants may be due to metabolism changes induced by St. John’s wort.13
Alprazolam: St. John’s wort may reduce blood levels of alprazolam, resulting in decreased efficacy.24
Dextromethorphan: St. John’s wort may reduce blood levels of dextromethorphan, resulting in decreased efficacy.24
P-glycoprotein substrates: St. John’s wort induces intestinal P-glycoprotein, resulting in decreased absorption and lowered plasma concentrations of certain drugs including digoxin.25
UGT (Uridine 5’-diphospho-glucuronosyltransferase) substrates: St. John’s wort modulates UGT enzymes in vitro, and can increase the side effects of drugs metabolized by them.26 ■
Disclosure: Ms. Gubili reported no potential conflicts of interest.
References
1. Griffith TN, Varela-Nallar L, Dinamarca MC, et al: Neurobiological effects of hyperforin and its potential in Alzheimer’s disease therapy. Curr Med Chem 17:391-406, 2010.
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. Linde K, Knuppel L: Large-scale observational studies of hypericum extracts in patients with depressive disorders—a systematic review. Phytomedicine 12:148-157, 2005.
4. Solomon D, Adams J, Graves N: Economic evaluation of St. John’s wort (Hypericum perforatum) for the treatment of mild to moderate depression. J Affect Disord 148:228-234, 2013.
5. Szegedi A, Kohnen R, Dienel A, et al: Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St John’s wort): Randomised controlled double blind non-inferiority trial versus paroxetine. BMJ 330:503, 2005.
6. Rahimi R, Nikfar S, Abdollahi M: Efficacy and tolerability of Hypericum perforatum in major depressive disorder in comparison with selective serotonin reuptake inhibitors: A meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 33:118-127, 2009.
7. Kasper S, Volz HP, Moller HJ, et al: Continuation and long-term maintenance treatment with Hypericum extract WS((R)) 5570 after recovery from an acute episode of moderate depression: A double-blind, randomized, placebo controlled long-term trial. Eur Neuropsychopharmacol 18:803-813, 2008.
8. Linde K, Mulrow CD, Berner M, et al: St John’s wort for depression. Cochrane Database Syst Rev (2):CD000448, 2005.
9. Linde K, Berner MM, Kriston L: St John’s wort for major depression. Cochrane Database Syst Rev (4):CD000448, 2008.
10. 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.
11. 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.
12. 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.
13. Barnes J, Anderson LA, Phillipson JD: St John’s wort (Hypericum perforatum L.): A review of its chemistry, pharmacology and clinical properties. J Pharm Pharmacol 53:583-600, 2001.
14. Parker V, Wong AH, Boon HS, et al: Adverse reactions to St John’s Wort. Can J Psychiatry 46:77-79, 2001.
15. Holme SA, Roberts DL: Erythroderma associated with St John’s wort. Br J Dermatol 143:1127-1128, 2000.
16. Bhopal JS: St John’s wort-induced sexual dysfunction. Can J Psychiatry 46:456-457, 2001.
17. Dean AJ, Moses GM, Vernon JM: Suspected withdrawal syndrome after cessation of St. John’s wort. Ann Pharmacother 37:150, 2003.
18. 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.
19. 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.
20. Lane-Brown MM: Photosensitivity associated with herbal preparations of St John’s wort (Hypericum perforatum). Med J Aust 172:302, 2000.
21. Imai H, Kotegawa T, Tsutsumi K, et al: The recovery time-course of CYP3A after induction by St John’s wort administration. Br J Clin Pharmacol 65:701-707, 2008.
22. 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.
23. 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.
24. 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.
25. 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.
26. Mohamed ME, Frye RF: Effects of herbal supplements on drug glucuronidation. Review of clinical, animal, and in vitro studies. Planta Med 77:311-321, 2011.
Integrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan Kettering Cancer Center, New York.
The Integrative Medicine Service at Memorial Sloan Kettering Cancer Center developed and maintains a free website—About Herbs (www.mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 269 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings.
In addition, the About Herbs app, Memorial Sloan Kettering Cancer Center’s very first mobile application, can be downloaded at http://itunes.apple.com/us/app/about-herbs/id554267162?mt=8. The app is compatible with iPad, iPhone, and iPod Touch devices.
