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St. John's Wort

April 24, 2008

20 Min Read
St. John's Wort

Editor's note: This article was adapted from the American Botanical Council's new continuing education module and reference book, The ABC Clinical Guide to Herbs (ABC, 2003).

In the fifth century B.C.E., the Greek physician Hippocrates was one of the first to document therapeutic uses for St. John's wort (Hypericum perforatum). By the dawn of the 21st century, it had risen from virtual obscurity in the United States to the fifth best-selling dietary supplement in mainstream retail stores.1 Major media coverage of clinical research documenting its relative safety and efficacy for treating mild to moderate depression stimulated consumer acceptance and retail sales.

Since 1979, there have been more than 35 controlled clinical studies of SJW extracts for treating mild to moderate depression.2 Several meta-analyses document the relative safety and probable efficacy of this phytomedicine.3,4 SJW is prescribed frequently by health care providers in Germany, where approximately 130 million SJW preparations were prescribed in 1999.5

The herb is used internally for mild to moderate depression,3,4,6,7,8,9,10,11,12,13 and externally for healing wounds (acute and contused injuries)14 as well as for treating first-degree burns and muscle pain.14 Its other potential uses include treating seasonal affective disorder,15,16 obsessive-compulsive disorder,17 menopause,18 fatigue,19 pediatric nocturnal incontinence20 and premenstrual syndrome.21 SJW has no known contraindications, according to the German Commission E, and is safe for use during pregnancy and lactation.14

SJW is primarily an antidepressant.4,8,9,11,22 Some references cite its relaxant effects in relation to the Commission E's approval of the herb for anxiety and nervous unrest, but this may only be in the context of its overall antidepressant activity23 in small studies on sleep continuity24 or resting EEG.25 SJW may improve mental performance, possibly as a result of relieving depression.26 SJW does not appear to change alertness or cause sedation. There may be some additional central nervous system effects, again related to improving depression, including improved concentration, memory and receptivity.23,24,25,26

Dose And Administration
For depression, the onset of response to SJW is similar to that for conventional antidepressants, usually requiring two to four weeks and sometimes up to six weeks. To prevent relapse, patients should continue at full therapeutic doses for at least six months after remission.27 For internal administration, crude preparations can be dosed as follows:

  • Fluid extract: 1:1 (g/mL) herb-to-fluid ratio, 2 mL, twice daily.

  • Dry extract: 5-7:1, 300 mg, three times daily.2

    For standardized preparations:

  • Liquid or dry extract: Standardized to 0.3 percent hypericin, 900 mg daily in three divided doses; standardized to 2 percent to 4.5 percent hyperforin, 900 mg daily in three divided doses.28

    For external applications, an oily solution is made with the fresh-flowering tops plus olive oil or wheat germ oil. The herb is macerated and soaked in the oil for several weeks, stirred often, strained through a cloth and the pulp pressed. The fluid can be applied directly to affected areas.2

Adverse Effects
In general, SJW produces few adverse side effects. Between October 1991 and December 1999, more than 8 million patients are estimated to have been treated with Germany's leading SJW preparation, with only 95 reports of side effects. These included "allergic" skin reactions (27 reports); lengthened prothrombin (blood clotting) time (16); gastrointestinal complaints (9); breakthrough bleeding while on birth control pills (8); and reductions in the blood level of immunosuppressant (cyclosporine) medications (7).5 Photosensitization, evidenced by skin reddening with exposure to sunlight or other ultraviolet radiation, is possible, but relatively rare. It is sometimes reported in fair-skinned individuals taking excessive dosages (1,800 mg daily).14,29 A recent review of SJW adverse reactions suggests this precaution should not constitute a general contraindication because photosensitization is so rare and because sunlight can promote recovery from depression.5

Drug Interactions
Potential drug interactions with SJW have become the primary area of concern with this popular phytomedicine. However, in a review of drug interactions reportedly associated with SJW, calculations show one interaction per 300,000 treatments with the leading German SJW product.5

Although the herb is safe, there are some precautions. SJW should not be combined with any pharmaceutical antidepressants without professional guidance.30,31 SJW also may interact with oral contraceptives and anticoagulants, such as warfarin.32,33,34,35 Preliminary findings suggest SJW does not interact with the effects of alcohol; however, patients with depression should avoid alcohol.36

ABC Offers Safety Labeling Program
In response to consumer and professional demand for evidence-based information about the products it uses and recommends, the American Botanical Council initiated the Safety Labeling Program for manufacturers. As an objective third party, ABC evaluates current scientific literature about selected herbs to write Safety Information Sheets. Each SIS presents a rational interpretation of the literature and provides accurate, useful information on drug interactions, contraindications and adverse effects. A panel of expert reviewers ensures that each SIS is accurate and comprehensive. Participating manufacturers include the SIS with product packaging. Each SIS will be updated as needed and forwarded to manufacturers so they may amend their product labels and company literature. For more information on this program, contact Wayne Silverman, Ph.D., at [email protected] or 512.926.4900, ext. 120.

Several studies suggest SJW is metabolized by CYP3A4, a liver enzyme involved in metabolizing more than 50 percent of all drugs.37,38 Using SJW can decrease the therapeutic activity and concentration of such drugs, including contraceptives38 and the asthma medication theophylline.39 SJW may increase clearance of the anti-HIV drug indinavir and the immunosuppressant drug cyclosporine40,41 from the bloodstream and may also interfere with the absorption of the cardiac medication digoxin.42 However, a review of SJW drug interactions suggests digoxin, theophylline and amitriptyline should be examined critically because reduced plasma levels are not the same as reduced activity levels at the receptors. None of the reported cases to date suggest a clinically significant weakened effect of the three drugs cited.5 In one 14-day study involving 10 patients using the anti-seizure drug carbamazepine (Tegretol®), researchers found that 300 mg SJW extract, three times daily, did not increase the clearance of the drug.43 Patients should be cautioned that suddenly discontinuing SJW after prolonged simultaneous use may lead to higher plasma levels of these drugs and increase the risk of adverse effects.39

Clinical Review
The complete monograph in The ABC Clinical Guide to Herbs covers a range of conditions including mild to moderate depression, severe depression, fatigue and seasonal affective disorder, menopausal symptoms and others. This adaptation is limited to the evidence regarding the effects of SJW on mild to moderate depression, the only form of depression for which SJW is indicated.

All 12 studies outlined in the table summarizing clinical studies (1,936 total participants) demonstrate positive effects when SJW is used to treat mild to moderate depression. In several randomized, double-blind, placebo-controlled studies (626 participants), researchers concluded SJW significantly benefits patients with this type of depression without significant side effects.7,8,10,22,44,45 In five randomized, double-blind, multicenter trials (1,191 participants), researchers found SJW to be as effective as tricyclic antidepressant drugs (amitriptyline, imipramine, maprotiline), but SJW was more tolerable7,11,46 and safer for the heart.47

In a review of 17 studies on SJW and nine studies on fluoxetine (Prozac®), researchers showed that SJW was as effective as fluoxetine for treating mild depression.48 Reviews and meta-analyses of at least 50 clinical studies on SJW show the standardized extract was more effective than placebo for treating mild to moderate depression. Patients had fewer short-term adverse side effects than those taking tricyclic antidepressants.3,4 In the largest randomized, double-blind, placebo-controlled clinical trial to date involving SJW and placebo, researchers found a significant antidepressant effect for SJW in a patient population with mild to moderate depression.49

In at least 11 studies comparing SJW preparations with conventional tricyclic and selective serotonin reuptake inhibitor antidepressants, researchers have concluded SJW is effective for mild to moderate depression with minimal side effects.50

Recently, in a large trial comparing SJW with the conventional antidepressant imipramine, researchers concluded SJW is as effective as imipramine and is better tolerated by patients.13 In a newer, larger trial (240 participants) comparing SJW directly with fluoxetine, researchers concluded SJW was as effective and safer than fluoxetine, particularly in patients suffering depression and anxiety.51

The National Institutes of Health has recently launched a four-year multicenter study, funded by the National Institute of Mental Health, the National Center for Complementary and Alternative Medicine and the Office of Dietary Supplements, to determine the safety and effectiveness of SJW for patients with minor depression. The 12-week randomized, double-blind trial will compare SJW, the SSRI Celexa™ and a placebo in 300 patients with minor depression.

Depression affects millions of Americans each year. Your customers looking for alternatives to prescription antidepressants should work with a health care provider to ensure adequate care, especially in cases of severe depression. In those cases, SJW is not indicated or recommended. SJW is a promising treatment for cases of mild to moderate depression.


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6. Harrer G, et al. Effectiveness and tolerance of the Hypericum extract LI 160 compared to maprotiline: a multicenter double-blind study. J Geriatr Psychiatry Neurol 1994;7 (suppl.1):S24-8.

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10. Philipp M, et al. Hypericum extract versus imipramine or placebo in patients with moderate depression: randomized multicenter study of treatment for eight weeks. BMJ 1999;319:1534-8.

11. Wheatley D. LI 160, an extract of St. John's wort, versus amitriptyline in mildly to moderately depressed outpatients—a controlled six-week clinical trial. Pharmacopsychiatry 1997; 30(suppl.):77-80.

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23. Schulz V, et al. Rational phytotherapy: a physicians' guide to herbal medicine. 4th ed. New York: Springer; 2000;57-77.

24. Schulz H, Jobert M. Effects of Hypericum extract on the sleep EEG in older volunteers. J Geriatr Psychiatry Neurol 1994;7(suppl.1):S39-43.

25. Johnson D, et al. Effects of Hypericum extract LI 160 compared with maprotiline on resting EEG and evoked potentials in 24 volunteers. J Geriatr Psychiatry Neurol 1994;7(suppl.1):S44-6.

26. Lehrl S, et al. Results from measurements of the cognitive capacity in patients during treatment with Hypericum extract. Nervenheikunde 1993; 12:268-366.

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30. Gordon JB. SSRIs and St. John's wort possible toxicology. Am Fam Physician 1998; 57(5):950, 953.

31. Prost N, et al. St. John's wort-venlafaxine interaction. Presse Med 2000; 29(23):1285-6.

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34. Lantz M, et al. St. John's wort and antidepressant drug interactions in the elderly. J Geriatr Psychiatry Neurol 1999;12:7-10.

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37. Roby CA, et al. St. John's wort: effect on CYP3A4 activity. Clin Pharm Ther 2000;67(5):451-7.

38. Moore LB, et al. St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci USA 2000 Jun 20;97(13):7500-2.

39. Baede-van Dijk P, et al. Drug interactions of Hypericum perforatum (St. John's wort) are potentially hazardous. Ned Tijdschr Geneeskd 2000 Apr 22;144(17):811-2.

40. Piscitelli S, et al. Indinavir concentrations and St John's wort. Lancet 2000;355:547-8.

41. Ruschitzka F, et al. Acute heart transplant rejection due to St. John's wort. Lancet 2000;355:548-9.

42. Tatro DS. Drug interactions with St. John's wort. Druglink 2000 May;34-8.

43. Burstein A, et al. Lack of effect of St. John's wort on carbamazepine pharmacokinetics in healthy volunteers. Clin Pharm Ther 2000 Dec;68(6):605-12.

44. Hübner W, et al. Hypericum treatment of mild depressions with somatic symptoms. J Geriatr Psychiatry Neurol 1994;7(suppl.1):S12-4.

45. Hänsgen K, et al. Multicenter double-blind study examining the antidepressant effectiveness of the Hypericum extract LI 160. J Geriatr Psychiatry Neurol 1994;7(suppl.1):S15-8.

46. Vorbach E, et al. Effectiveness and tolerance of the Hypericum extract LI 160 in comparison with imipramine: randomized double-blind study with 135 outpatients. J Geriatr Psychiatry Neurol 1994; 7(suppl.1):S19-23.

47. Czekalla J, et al. The effect of Hypericum extract on cardiac conduction as seen in the electrocardiogram compared to that of imipramine. Pharmacopsychiatry 1997;30:86-8.

48. Volz HP, Laux P. Potential treatment for subthreshold and mild depression: a comparison of St. John's wort extracts and fluoxetine. Compr Psychiatry 2000;41(2 Suppl.1):133-7.

49. Brown DJ. St. John's wort effectively treats mild to moderate depression in large French trial. HerbalGram 2003;57:26-8.

50. Kasper S. Hypericum perforatum-review of clinical studies. Pharmacopsychiatry 2001;34 (Suppl.1):S51-5.

51. Friede M, et al. Differential therapy of mild to moderate depressive episodes (ICD-10 F 32.1) with St. John's wort. Pharmacopsychiatry 2001;34(Suppl.1):S38-41.

52. Brenner R, et al. Comparison of an extract of Hypericum (LI 160) and sertraline in the treatment of depression: a double-blind, randomized pilot study. Clinical Therapeutics 2000;22(4).

53. Schrader E, et al. Hypericum treatment of mild-moderate depression in a placebo-controlled study. A prospective, double-blind, randomized, placebo-controlled, multicentre study. Hum Psychopharmacol 1998;13:163-9.

Natural Foods Merchandiser volume XXIV/number 10/p. 44, 48

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