St. John’s Wort

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Hypericum perforatum L.

[Fam. Clusiaceae]

Overview

St. John’s wort (SJW) has been used for various ailments since the ancient Greeks; the Greek physician Hippocrates (ca.400 B.C.E.) was one of the first to document its therapeutic use. Since the time of the Swiss physician Paracelsus (ca. 1540 C.E.) it was used to treat mental disorders (Blumenthal et al., 2000; Hobbs, 1988/89). SJW rose from virtual obscurity in the U.S. to become the fifth best-selling dietary supplement in mainstream retail stores in 2000 (Blumenthal, 2001) following major media coverage of clinical research documenting its relative safety and efficacy for treating mild to moderate depression. In 1998 and 1999 it had risen to second place in mainstream sales (Brevoort, 1998), but fell to fifth place due, in part, to some adverse publicity regarding reports of its interactions with several classes of prescription drugs (Blumenthal, 2001). The National Institutes of Health’s (NIH) National Center for Complementary and Alternative Medicine (NCCAM) recently sponsored a three-year, multi-center trial comparing the effects of a standardized extract of SJW and the selective serotonin reuptake inhibitor (SSRI) sertraline (Hypericum Depression Trial Study Group, 2002). Since 1979, there have been more than 35 controlled clinical studies of SJW extracts for the treatment of mild to moderate depression (Blumenthal et al., 2000). Two meta-analyses have documented the relative safety and suggested probable efficacy of this phytomedicine (Linde and Mulrow, 2001; Linde et al., 1996). SJW is prescribed frequently by healthcare providers in Germany, where approximately 130 million daily doses containing hypericum were prescribed in 1999 (Schulz, 2001). SJW preparations have also been used in traditional European herbal medicine for topical antimicrobial and skin healing purposes (Reichling et al., 2001).

Description

St. John’s wort (Hypericum perforatum L., Fam. Clusiaceae) preparations consist of dried above-ground parts (flowers and stems), gathered during the flowering season. Preparations include aqueous extracts (teas), standardized extracts, alcoholic tinctures, dry extracts in capsules or tablets, and oil infusions (topical) (Blumenthal et al., 2000). Standardization is typically to 0.3% hypericin, or 2–4.5% hyperforin (Bruneton, 1999). In vitro research suggests that hyperforin may be the main antidepressive constituent (Muller et al., 1998). However, flavonoids and other fractions have also shown antidepressant activity, suggesting “additive or synergistic actions of different single compounds may be responsible for the antidepressant efficacy of SJW” (Butterweck et al., 2002b). The German Drug Codex formerly required that SJW preparations be standardized to hypericins content; this is no longer a required chemical marker (Bühler, 1995). The U.S. National Formulary requires not less than 0.04% total hypericins, calculated as hypericin (usp, 2002).

Primary Uses

Internal

Depression

Mild to moderate (Harrer et al., 1994; Harrer and Sommer, 1994; Laakmann et al., 1998a; Lenoir et al., 1999; Linde et al., 1996; Linde and Mulrow, 2001; Philipp et al., 1999; Wheatley, 1997; WHO, 2002; Woelk, 2000)

External

Healing wounds (acute and contused injuries) according to the German Commission E (Blumenthal et al., 1998)

First-degree burns (Blumenthal et al., 1998)

Relieving myalgia (muscle pain) (Blumenthal et al., 1998)

Other Potential Uses

(Based mainly on pilot studies)

Seasonal Affective Disorder (SAD) (Kasper, 1997; Martinez et al., 1994)

Obsessive-Compulsive Disorder (OCD) (Taylor and Kobak, 2000)

Premenstrual syndrome (Stevinson and Ernst, 2000)

Menopause (Grube et al., 1999)

Fatigue (according to a pilot study) (Stevinson et al., 1998)

Pediatric nocturnal incontinence (clinical experience) (Weiss and Fintelmann, 2000)

Dosage

Internal

Crude Preparations

Fluid extract: 1:1 (g/ml), 2 ml, twice daily.

Dry extract: 5–7:1, 300 mg, 3 times daily (Blumenthal et al., 2000).

Standardized Preparations

Extract: Standardized to 0.3% hypericin, 900 mg daily in 3 doses of 300 mg each; or products standardized to 2–4.5% hyperforin, 900 mg/day in 3 doses (Bruneton, 1999).

External

Oily macerate (Oleum hyperici): Fresh-flowering tops in olive oil or wheatgerm oil are macerated for several weeks, stirred often, strained through a cloth and the pulp pressed. To be applied directly to affected areas (Blumenthal et al., 2000).

Duration of Administration

For depression, the onset of response to SJW is similar to that for conventional antidepressants, requiring 2–4 weeks, or as long as 6 weeks. To prevent relapse, antidepressant should be continued at full therapeutic doses for at least 6 months after remission (AHCPR, 1999).

Chemistry

SJW contains 6.5–15% catechin-type tannins and condensed-type proanthocyanidins (catechin, epicatechin, leucocyanidin); 2–5% flavonoids, mostly 0.5–2% hyperoside, 0.3–1.6% rutin, 0.3% quercitrin, 0.3% isoquercitrin, quercetin, and kaempferol; bioflavonoids (about 0.26% biapigenin), phloroglucinol derivatives (up to 4% hyperforin); phenolic acids (caffeic, chlorogenic, ferulic); 0.05–1.0% volatile oils, mainly higher n-alkanes, 0.05–0.15% naphthodianthrones (hypericin and pseudohypericin); sterols (sitosterol); vitamins C and A, up to 10 ppm xanthones; and choline (Bruneton, 1999; ESCOP, 1996; Leung and Foster, 1996; Newall et al., 1996; Upton, 1997; Wichtl and Bisset, 1994).

Pharmacological Actions

Standardized Preparations

Human

The primary action of SJW is antidepressant (Phillipp et al., 1999; Lenoir et al., 1999; Leakmann et al., 1998a, 1998b; Wheatley, 1997; Linde et al., 1996). Some references refer to relaxant effects in relation to the Commission E approval for anxiety and nervous unrest, but this may only be in the context of the overall antidepressant activity (Schulz et al., 2000) or in small studies on sleep continuity (Schulz et al., 1995) or resting EEG (Johnson et al., 1994). Other actions include improved mental performance possibly resulting from improvement of depressed states (Lehrl et al., 1993). SJW does not appear to change alertness or have sedative effects; there may be some additional central nervous system effects, again related to improvement of depression including improvement of concentration, memory, and receptivity (Schulz et al., 2000; Schulz et al., 1994; Johnson et al., 1994; Lehrl, 1993).

Animal

Many animal studies have been published on SJW demonstrating a variety of actions, including the following, suggesting antidepressant activity: SJW potentiates dopaminergic behavioral responses (alcoholic extracts), and serotoninergic effects (carbon dioxide extracts) (Bhattacharya, 1998); reduces alcohol intake in rats (Rezvani et al., 1999); SJW extract and hypericin given daily for 8 weeks significantly increased 5-HT (serotonin) levels in rat hypothalamus (Butterweck et al., 2002a); and flavonoids from SJW showed antidepressant activity in rats in the forced swimming test (Butterweck et al., 2000).

In vitro

There has been confusion about the potential monoamine oxidase (MAO) inhibiting effect of SJW. Earlier research suggested that SJW possibly inhibits MAO, using 80% pure hypericin (Suzuki et al., 1984). However, a more recent study suggests that 95% pure hypericin does not inhibit MAO, but a crude ethanolic extract (Herb Pharm, Williams, OR) does, at 2 mcg/ml (Cott, 1995). MAOI activity has not been reported in vivo in animals or in humans (Cott, 1997). SJW unspecifically inhibits biogenic amine and amino acid neurotransmitter uptake (serotonin, dopamine, noradrenaline, GABA, L-glutamate) (Chatterjee et al., 1998; Butterweck et al., 1997); inhibits serotonin reuptake (Perovic and Müller, 1995; Müller and Rossol, 1994; Holzl, 1989); is antiretroviral (using purified hypericin) (Lavie et al., 1990; Meruelo et al., 1988); modulates interleukin-1x (hypericin) (Panossian et al., 1996) and interleukin-6 (SJW) (Thiele et al., 1994); is antiviral (influenza and herpes simplex type 1) (Serkedjieva et al., 1990), and is antimicrobial (primarily hyperforin) toward methicillin-resistant Staphylococcus aureus but not against gram-negative bacteria or Candida albicans (Reichling et al., 2001). Isolated hypericin from SJW extracts showed highest phototoxicity in vitro, but this was controlled by the flavonoid fraction, particularly quercitrin (Wilhelm et al., 2001).

Mechanism of Action

Components of a hydro-ethanolic SJW extract bound with high affinity at GABAA, GABAB_, adenosine, benzodiazepine, inositol, triphosphate, and MAO-A and MAO-B receptors (Cott, 1997).

May inhibit uptake of several neurotransmitters (Müller and Rossol, 1994; Perovic and Müller, 1995; Holzl, 1989; Chatterjee et al., 1998; Raffa, 1998; Butterweck et al., 1997).

May inhibit uptake of neuropeptides and neurosteroids (Perovic and Müller, 1995; Holzl et al., 1989; Chatterjee et al., 1998; Raffa, 1998; Butterweck et al., 1997).

SJW may inhibit 5-hydroxytryptamine (5HT, serotonin) receptor expression resulting in inhibition of 5HT reuptake (Müller and Rossol, 1994).

One indirect study based on changes in hormone levels suggests that antidepressant effects might be mediated mainly through changes in serotonin and dopamine neurotransmission but not noradrenaline (in humans) (Franklin and Cowen, 2001).

May act on information substances (shared components of immune and nervous systems) such as leukotriene B4 and interleukin-1a inhibiting release of arachidonic acid, leukotriene B4, production of IL–1a, and activating NO synthesis (Panossian et al., 1996; Thiele et al., 1994).

Hyperforin, but not hypericin, in SJW induces CYP3A4 expression in human hepatocytes and activates the steroid X receptor, possibly suggesting a mechanism for drug interactions (Moore et al., 2000; Wentworth et al., 2000).

Hyperforin from SJW leads to elevation of Na⁺, thus explaining its apparent effect on serotonin uptake inhibition into platelets and synaptosomes and the non-selective profile on many neurotransmitter transport systems which are driven by Na⁺ gradient membranes (Müller et al., 2001).

Contraindications

The Commission E stated “none known” in 1984 and in the 1990 monograph revision (Blumenthal et al., 1998). Recent drug interaction reports suggest professional guidance when certain conventional pharmaceuticals may be simultaneously administered (see Drug Interactions).

Pregnancy and Lactation: No known restrictions. Animal reproductive studies did not produce mutagenicity at relatively high doses (Upton et al., 1997). Due to lack of available data, the WHO monograph recommends that SJW not be administered during pregnancy or nursing without advice of a healthcare provider (WHO, 2002).

Adverse Effects

In general, SJW produces few adverse side effects. Between October 1991 and December 1999, over 8 million patients are estimated to have been treated with Germany’s leading SJW preparation (Jarsin^® or Jarsin^®300); during this period only 95 reports of side effects were received by the German Adverse Drug Reaction Recording System. These included “allergic” skin reactions (27 reports), increased Quick Values (prothrombin time) (16), gastrointestinal complaints (9), breakthrough bleeding (birth control pill) (8), plasma cyclosporin reductions (7), and others (Schulz, 2001). Photosensitization, depicted by erythema (redness of the skin) with exposure to sunlight or other ultra-violet radiation is possible, although this is relatively rare and is sometimes reported in fair-skinned individuals taking excessive dosages (1,800 mg/day) (Brockmuller, 1997; Blumenthal et al., 1998). A recent review of SJW adverse reactions suggests that this precaution should not constitute a general contraindication, since the incidence of photosensitization is so rare and because sunlight can promote recovery from depression (Schulz, 2001).

Drug Interactions

Potential drug interactions with SJW have become the primary area of concern with this popular phytomedicine. However, one source suggests that some of these concerns may not be borne out by clinical experience. In a review of drug interactions reportedly associate with SJW, the author calculates one interaction per 300,000 treatments with the leading German SJW product (Jarsin^®, Schulz, 2001).

SJW should not be taken in combination with any pharmaceutical antidepressants (Gordon, 1998; Prost et al., 2000), unless under professional guidance. SJW is believed to interact with oral contraceptives and anticoagulants (e.g., warfarin) (TGA, 2000; Di Carlo et al., 2001; Lantz et al., 1999; McGuffin et al., 1997). Preliminary findings suggest that SJW does not interact with the effects of alcohol; however, patients with depression should avoid alcohol (Schmidt, 1993). An uncontrolled study on 13 subjects taking SJW at normal doses (900 mg of the standardized extract/day), resulted in significant increases in urinary 6–beta–hydroxycortisol/cortisol ratio, suggesting that SJW is an inducer of CYP3A4, since cortisol is metabolized primarily by CYP3A4 (Roby et al., 2000). A recent study (Moore, 2000) revealed that constituents of SJW extract, especially hyperforin, are a potent ligand (K(i) = 27 nM) for the pregnane X receptor, an orphan nuclear receptor that regulates expression of the cytochrome P450 (CYP) 3A4 monooxygenase. Treatment of primary human hepatocytes with SJW extracts, or hyperforin, results in a marked induction of CYP3A4 expression. CYP3A4 is involved in the oxidative metabolism of more than 50% of all drugs, and can cause a decrease in the therapeutic activity and concentration of such drugs, including contraceptives (Moore, 2000) and possibly theophylline (Baede-van Dijk et al., 2000). SJW also may increase clearance from the bloodstream of the protease inhibitor indinavir, and the anti-rejection drug cyclosporine (Piscitelli et al., 2000; Ruschitzka et al., 2000), and may also interfere with the absorption of digoxin (Tatro, 2000). A recent study found that SJW induces intestinal P-glycoprotein/MDR1 (in rats and humans), and induces intestinal and hepatic CYP3A4 (in humans), thereby decreasing plasma levels of cyclosporine, indinavir, and digoxin (Dürr et al., 2000). However, a review of SJW drug interactions questions the clinical relevance of interactions that are postulated solely on the basis of pharmacokinetic measurements, with digoxin, theophylline, and amitriptyline needing to be examined critically, since reduced plasma levels are not the same as reduced active levels at the receptors. The author states that to-date there are no reported cases suggestive of a clinically significant weakening in effect of the three drugs cited (Schulz, 2001). One 14-day study on 10 patients, using the anti-seizure drug carbamazepine (Tegretol^®), found that 300 mg St. John’s wort extract, three times daily, did not increase the clearance of the drug (Burstein et al., 2000). Sudden discontinuation of SJW after prolonged use may lead to higher plasma levels of these drugs if used simultaneously, with the risk of adverse effects (Baede-van Dijk et al., 2000).

American Herbal Products Association (AHPA) Safety Rating

Class 2d: Based on earlier in vitro research and the Commission E monograph, AHPA cautioned that SJW may potentiate pharmaceutical MAO-inhibitors (McGuffin et al., 1997), although there are no animal or human data to support this.

Regulatory Status

Australia: Complementary medicine available without prescription from pharmacies, health food shops, supermarkets, and complementary medicine practitioners (TGA, 2000). Required label warning: “St. John’s wort affects the way some prescription medicines work. Consult your doctor.” (Trickey, 2000).

Canada: Nonprescription drug for internal or external use classified as either “Schedule OTC Herbs and Natural Products” or “Schedule Homeopathic Products,” in either case requiring premarketing authorization and assignment of Drug Identification Number (DIN) by the Therapeutic Products Programme (TPP) (Health Canada, 2001a). In January 2001, added to “Drugs of Current Interest (DOCI) List” maintained by the Canadian Adverse Drug Reaction Monitoring Program (Health Canada, 2001b). Potential drug-interaction warning statement required.

European Union: Whole or cut, dried, flowering tops harvested during flowering time, containing no less than 0.08% total hypericins, official in the European Pharmacopoeia (Ph.Eur., 2001).

France: Dried flowering top or aerial part official in French Pharmacopoeia approved only for external use but not prior to sun exposure (Bruneton, 1999; ESCOP, 1996).

Germany: Approved by Commission E as a nonprescription drug for internal and external use (Blumenthal et al., 1998). Whole or cut aerial parts, collected just before or during the flowering period, official for internal or external use in the German Drug Codex supplement to the German Pharmacopoeia (DAC, 1998). Whole, fresh, flowering plant for preparation of mother tincture is official in German Commission D monographs and corresponding German Homeopathic Pharmacopoeia (BAnz, 1985; GHP, 1993).

Sweden: Classified as Natural Remedy, requiring premarket authorization. As of January 2001, nine SJW-containing products are listed in the Medical Products Agency (MPA) “Authorised Natural Remedies,” and a monograph is published with the approved indication: “Traditionally used in case of slight mood lowering and for minor nervous tension” (MPA, 1999; 2001a; Tunón, 1999). St. John’s wort homeopathic preparations are also registered drugs (MPA, 2001b).

Switzerland: Official in Swiss Pharmacopoeia (Upton et al., 1997; Wichtl, 1997). Herbal medicine with positive classification (List D) by the Interkantonale Konstrollstelle für Heilmittel (IKS) and corresponding sales Category D with sale limited to pharmacies and drugstores, without prescription (Morant and Ruppanner, 2001; Ruppanner and Schaefer, 2000). Numerous SJW phytomedicines and homeopathic preparations are listed in the Swiss Codex 2000/01 (Ruppanner and Schaefer, 2000).

U.K.: Licensed product for internal use; General Sale List (GSL), Table B (external use only), Schedule 1 (requires full product license) (GSL, 1994). A recent article reviewed the benefits and risks of SJW and their regulatory implications in the U.K. (McIntyre, 2000).

U.S.: Dietary supplement (USC, 1994). Dried, flowering tops gathered shortly before or during flowering, containing no less than 0.04% total hypericins, official in U.S. National Formulary, 19th edition (USP, 2002).

Clinical Review

Twenty-three studies are outlined in the following table, “Clinical Studies on St. John’s Wort”, including a total of 2,745 participants. All but three of these studies (Lenoir et al., 1999; Shelton et al., 2001; Hypericum Depression Trial Study Group, 2002) demonstrate positive effects of SJW on depression. Five randomized, double-blind, placebo-controlled (R, DB, PC) studies have been performed on 626 participants, concluding that SJW significantly benefits patients with depression without significant side effects (Philipp et al., 1999; Laakmann et al., 1998a, 1998b; Harrer and Sommer 1994; Hübner et al., 1994; Hänsgen et al., 1994). Five R, DB multicenter (MC) trials, with 1,191 participants, found equal effectiveness to tricyclic antidepressant drugs (amitriptyline, imipramine, malprotiline) with greater tolerability for SJW (Wheatley, 1997; Vorbach et al., 1994; Harrer et al., 1994), and that SJW was safer for the heart than tricyclic antidepressants (Czekalla et al., 1997).

Three small pilot studies on a total of 60 patients show promising findings for the conditions of fatigue and SAD (Stevinson et al., 1998; Kasper, 1997; Matinez et al., 1994), and one small open-label (OL) study on 12 patients indicated the potential benefits of SJW for OCD (Taylor and Kobak, 2000). One small pilot study of SJW for the treatment of PMS suggests that SJW might improve the severity and duration of premenstrual symptoms, warranting a larger R, DB trial (Stevinson and Ernst, 2000). A drug-monitoring study on menopausal symptoms suggests that SJW is useful for treatment of associated symptoms, and increasing the sense of sexuality in middle-age women (Grube et al., 1999).

In a review of 17 studies on SJW and 9 studies on fluoxetine (Prozac^®), researchers showed that SJW was as effective as fluoxetine in the treatment of subthreshold and mild depression (Volz, 2000). Researchers concluded that SJW is effective in subthreshold depression exhibiting very few or no side effects, easy availability, and may be a viable approach to avoiding the risk that mild depression becomes a full-blown disorder.

A review and meta-analysis of 23 clinical studies on SJW showed that the extract was more effective than placebo in treating mild to moderate depression (Linde et al., 1996). Based on the evidence available at the time, the same review concluded that further studies were needed to establish whether SJW is as effective as conventional antidepressant drugs (Linde et al., 1996). A follow-up meta-analysis by the Cochrane Center of 27 trials with 2,291 patients concluded that SJW was significantly superior to placebo (Linde and Mulrow, 2001). The review concluded that the short term use of SJW might be valuable in less severe forms of depression as an alternative to watchful waiting or the commonly used approach to low doses of tricyclic antidepressants and that SJW has less short term adverse side effects than tricyclics. A recent trial comparing SJW with the conventional antidepressant imipramine is the first to compare the two agents at the normal daily dose of imipramine (150 mg) (Woelk, 2000). Previous trials used only 75 mg imipramine in order to reduce adverse side effects and maintain patient compliance. This study is the largest comparison trial to date and concluded that the SJW extract used in the study (Remotiv^® marketed by Bayer in Germany) is equivalent to imipramine in efficacy, and is more well-tolerated by patients. A newer, larger trial (n=240) comparing SJW (Ze 117) directly with fluoxetine concluded that SJW was of equivalent efficacy as fluoxetine, particularly in depressive patients suffering from anxiety, and was better tolerated for safety than the SSRI (Friede et al., 2001). A total of 11 studies have compared SJW preparations with conventional antidepressants (7 tricyclic; 4 SSRI) concluding that SJW is effective for mild to moderate depression with a low side effect profile (Kasper, 2001).

A recently published systematic review of R, C, DB trials selected, and assessed for methodological quality, eight well-controlled studies (Gaster and Holroyd, 2000). The results suggest that SJW is more effective than placebo in the treatment of mild to moderate depression. The absolute increased response rate with the use of SJW ranged from 23% to 55% higher than with placebo, but ranged from 6% to 18% lower compared with tricyclic antidepressants. The treatment with SJW and the commonly used SSRI fluoxetine (Prozac^®), was compared in patients with mild to moderate depression. The results showed that SJW and fluoxetine are equipotent with respect to all main parameters used to investigate antidepressants in this population. Although SJW may be superior in improving the responder rate, the main difference between the two treatments is safety. SJW was superior to fluoxetine in overall incidence of side effects, number of patients with side effects, and the type of side effect reported (Schrader, 2000). A previous review of 15 controlled clinical trials (12 PC) reported that the only substantial documentation for the use of SJW in mild to moderate depression is for the products Jarsin^® 300 (Lichtwer Pharma) and Psychotonin-M^® (Steigerwald) (Volz, 1997). The review concluded that SJW should not be taken for more than 6 weeks, since most trials showing efficacy have been conducted over a shorter period of time. A recent study by Shelton et al. (2001) received considerable media attention due to its negative findings on patients with severe depression. The study was noted for its lack of an active control (no SSRI or other active drug was used to measure the response rate of severely depressed patients vs. SJW and placebo) (Cott et al., 2001).

Results were recently published for the first study funded by the NIH’s NCCAM. This long awaited and much publicized R, DB, PC, MC, 3-arm study (340 participants) found that neither sertraline (Zoloft^®) nor SJW were effective compared to placebo for moderately severe major depressive disorder. Critics emphasize that the initial design included patients with major depression of only mild to moderate severity (HAMD score > 15) but was later changed to include patients with moderate to severe depression (HAMD score > 20). Widespread publicity on this trial focused on the failure of SJW without equally noting the failure of sertraline which was given a slight edge over SJW because of sertraline’s better performance on a secondary measure (a Clinical Global Impression scale that included partial responders).  (Outcomes on secondary measurements are not considered appropriate measures for ascribing success or failure.)  The authors of this study acknowledged that 35% of clinical trials on known antidepressant drugs failed. More than 50% of trials with investigational antidepressant drugs fail (Robinson and Rickels, 2000).

Branded Products*

Hyperiforce^®: Bioforce AG / CH-9325 Roggwil TG / Switzerland / Tel: +41 71 454 61 61 / Fax: +41 71 454 61 62 / www.bioforce.com / Email: info@bioforce.ch. 275 mg/tablet of a 1:9.0 ethanol/water extract of fresh tips of shoots. One tablet 3 times/day after meals provides 1 mg hypericin/day.

Jarsin^® 300: Lichtwer Pharma AG / Wallenroder Strasse 8-14 / 13435 Berlin / Germany / Tel: +49-30-40-3700 / Fax: +49-30-40-3704-49 / www.lichtwer.de. 300 mg St. John’s wort extract/capsule in coated tablets standardized to 0.3% total hypericins.

Kira^®: Lichtwer Pharma AG, c/o ABKIT, INC. / 207 East 94th Street / New York, NY 10128 / U.S.A. / Tel: 800-226-6227 / Fax: 212-860-8323 / www.abkit.com / Email: info@abkit.com. 300 mg dried methanolic extract produced from leaves, stems, and flowers standardized to 300 mcg total hypericin.

LI 160: Lichtwer Pharma AG. 300 mg St. John’s wort extract/capsule in coated tablets standardized to 0.3% total hypericins.

Remotiv^®: Bayer Vital GmbH & Co. KG / Consumer Care / Welser Strasse 5 – 7 / 51149 Köln / Germany / Tel: + 49-01-30-82-6301 / www.bayer-ag.de. Each 250 mg film-coated tablet of St. John’s wort extracted in 50% alcohol, standardized to 2% hypericins.

STEI 300: Steiner Arzneimittel / Postfach 450520 / 12175 Berlin / Germany / Tel: +49-03-07-1094-0 / Fax: +49-03-07-1250-12 / www.steinerarznei-berlin.de. Each 350 mg capsule contains 0.2%–0.3% hypericin, and 2%–3% hyperforin.

WS 5570: Dr. Willmar Schwabe Pharmaceuticals / International Division / Willmar Schwabe Str. 4 / D-76227, Karlsruhe / Germany / Tel: +49-721-4005 ext. 294 / Email: melville-eaves@schwabe.de / www.schwabepharma.com. An 80% v/v hydroalcoholic extract of St. John’s wort, drug to extract ratio 3–7.1.

WS 5572: Dr. Willmar Schwabe Pharmaceuticals. St. John’s wort extract standardized to 5% hyperforin.

WS 5573: Dr. Wilmar Schwabe Phramaceuticals. Each 300 mg capsule contains dry SJW extract standardized to 0.5% hyperforin.

Ze 117: Zeller AG / Seeblickstrasse 4 / CH-8590 Romanshorn 1 / Switzerland / www.zellerag.ch. St. John’s wort extracted in 50% alcohol, standardized to 2% hypericins in a 250 mg tablet, drug to extract ratio 4–7:1.

*American equivalents are found in the Product Table beginning on page 398.

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