Clinical Overview

St. John’s Wort St. John’s wort Hypericum perforatum L. [Fam. Clusiaceae]

OVERVIEW Internal In the fifth century B.C.E., the Greek physician Hippocrates was Crude Preparations LUID EXTRACT one of the first to document therapeutic uses of St. John’s wort F : 1:1 (g/ml), 2 ml, twice daily. Clinical Overview (SJW). It rose from virtual obscurity in the U.S. to become the Standardized Preparations fifth best-selling dietary supplement in mainstream retail stores in DRY EXTRACT: 5–7:1, 300 mg, 3 times daily. the U.S. after major media coverage of clinical research docu- EXTRACT: Standardized to 0.3% hypericin, 900 mg daily in 3 menting its relative safety and efficacy for treating mild to mod- divided doses; standardized to 2–4.5% hyperforin, 900 mg daily erate depression. The National Institutes of Health’s National in 3 divided doses. Center for Complementary and Alternative Medicine recently External funded a three-year, multi-center trial comparing the effects of a OILY MACERATE (OLEUM HYPERICI): Fresh-flowering tops in olive standardized extract of SJW and the selective serotonin reuptake ® oil or wheatgerm oil are macerated for several weeks, stirred inhibitor (SSRI), sertraline (Zoloft ). Since 1979, there have been often, strained through a cloth and the pulp pressed. To be more than 35 controlled clinical studies of SJW extracts for the applied directly to affected areas. treatment of mild to moderate depression. Several meta-analyses have documented the relative safety and probable efficacy of this CONTRAINDICATIONS phytomedicine. SJW is prescribed frequently by healthcare None known, according to the Commission E (1984, 1990 revi- providers in Germany, where approximately 130 million prepara- sion) tions containing SJW were prescribed in 1999. PREGNANCY AND LACTATION: No known restrictions.

PRIMARY USES St. John’s wort ADVERSE EFFECTS Internal In general, SJW produces few adverse side effects. Between • Depression, mild to moderate October 1991 and December 1999, over 8 million patients are External estimated to have been treated with Germany’s leading SJW • Healing wounds (acute and contused injuries) preparation with only 95 reports of side effects. These included • First-degree burns “allergic” skin reactions (27), increased Quick Values (prothrom- • Myalgia (muscle pain) bin time) (16), gastrointestinal complaints (9), breakthrough bleeding (birth control pill) (8), plasma cyclosporin reductions OTHER POTENTIAL USES (7), and others. Photosensitization, depicted by erythema (red- • Seasonal Affective Disorder ness of the skin) with exposure to sunlight or other ultraviolet radiation, is possible, but relatively rare and is sometimes report- • Obsessive-Compulsive Disorder ed in fair-skinned individuals taking excessive dosages (1,800 • Menopause mg/day). A recent review of SJW adverse reactions suggests this • Fatigue precaution should not constitute a general contraindication, since • Pediatric nocturnal incontinence photosensitization is so rare and because sunlight can promote recovery from depression. •PMS DRUG INTERACTIONS PHARMACOLOGICAL ACTIONS Potential drug interactions with SJW have become the primary Antidepressant, relaxant, improves mental performance, does not area of concern with this popular phytomedicine. However, some change alertness or have sedative effect; may have relaxing effect of these concerns may not be supported by clinical experience. In and improve concentration, memory, and receptivity. a review of drug interactions reportedly associated with SJW, cal- DOSAGE AND ADMINISTRATION culations show one interaction per 300,000 treatments with the leading German SJW product. For depression, the onset of response to SJW is similar to that for conventional antidepressants, requiring 2–4 weeks, or as long as SJW should not be taken in combination with any pharmaceuti- 6 weeks. To prevent relapse, antidepressant should be continued cal antidepressants, without professional guidance. SJW is at full therapeutic doses for at least 6 months after remission. believed to interact witsh oral contraceptives and anticoagulants (e.g., warfarin). Preliminary findings suggest that SJW does not

The ABC Clinical Guide to Herbs 303 Clinical Overview

interact with the effects of alcohol; however, patients with depres- etine in the treatment of subthreshold and mild depression. sion should avoid alcohol. An uncontrolled study on 13 subjects Researchers concluded that SJW may be a viable approach to taking SJW at normal doses (900 mg standardized extract/day), avoiding the risk that mild depression becomes a full-blown dis- resulted in significant increases in urinary 6–beta–hydroxycorti- order. sol/cortisol ratio, suggesting that SJW is an inducer of CYP3A4, A review and meta-analysis of 23 clinical studies on SJW showed since cortisol is metabolized primarily by CYP3A4. A recent that the standardized extract was more effective than placebo in study revealed that constituents of SJW extract, especially hyper- treating mild to moderate depression. A follow-up meta-analysis forin, are potent ligands (K(i) = 27 nM) for the pregnane X recep- (27 trials; 2,291 patients) concluded that SJW was significantly tor, an orphan nuclear receptor that regulates expression of the superior to placebo and that short term use of SJW might be cytochrome P450 (CYP) 3A4 monooxygenase. Treatment of pri- valuable in less severe forms of depression as an alternative to mary human hepatocytes with SJW extracts, or hyperforin, watchful waiting or low doses of tricyclic antidepressants with results in a marked induction of CYP3A4 expression. CYP3A4 is fewer short term adverse side effects. A recent trial comparing involved in the oxidative metabolism of more than 50% of all SJW with the conventional antidepressant imipramine is the drugs, and can cause a decrease in the therapeutic activity and largest comparison trial to date and the first to compare the two concentration of such drugs, including contraceptives and theo- agents at the normal daily dose of imipramine (150 mg). phylline. SJW also may increase clearance from the bloodstream (Previous trials used 75 mg imipramine to reduce adverse side of the protease inhibitor indinavir, and the anti-rejection drug effects and maintain patient compliance.) This study concluded cyclosporine and may also interfere with the absorption of digox- that SJW is equivalent to imipramine in efficacy, and is better- in. A recent study found that SJW induces intestinal P-glycopro- tolerated by patients. A newer, larger trial (n=240) comparing tein/MDRI (in rats and humans), and induces intestinal and SJW directly with fluoxetine concluded that SJW was equivalent hepatic CYP3A4 (in humans), thereby decreasing plasma levels of to fluoxetine in efficacy, particularly in depressive patients suffer- cyclosporine, indinavir, and digoxin. However, a review of SJW ing from anxiety, and was better tolerated for safety. A total of 11 drug interactions questions the clinical relevance of interactions studies have compared SJW preparations with conventional anti- based solely on pharmacokinetic measurements, with digoxin, depressants (7 tricyclic; 4 SSRI) concluding that SJW is effective theophylline, and amitryptaline needing to be examined critical- for mild to moderate depression with a low side effect profile. ly, since reduced plasma levels are not the same as reduced active A recently published systematic review of 8 well-controlled R, levels at the receptors. To-date there are no reported cases sug- DB, controlled (C), trials suggested that SJW is more effective gesting clinically significant weakening in effect of the three drugs than placebo in the treatment of mild to moderate depression. cited. One 14-day study on 10 patients, using the anti-seizure The absolute increased response rate with SJW ranged from 23% drug carbamazepine (Tegretol®), found that 300 mg SJW extract, to 55% higher than with placebo, but ranged from 6% to 18% three times daily, did not increase the clearance of the drug. lower compared with tricyclic antidepressants. Treatment with Sudden discontinuation of SJW after prolonged use may lead to SJW and fluoxetine, was compared in patients with mild to mod- higher plasma levels of these drugs if used simultaneously, with erate depression. Results showed that SJW and fluoxetine are the risk of adverse effects. equipotent with respect to all main parameters used to investigate CLINICAL REVIEW antidepressants in this population. Although SJW may be superi- Of 24 studies outlined in the table of clinical studies on SJW or in improving the responder rate, the main difference between (2,765 total participants), all but two studies demonstrate posi- the two treatments is safety. SJW was superior to fluoxetine in tive effects of SJW on depression. Five randomized, double-blind, overall incidence of side effects, number of patients with side placebo-controlled (R, DB, PC) studies (626 participants) con- effects, and the type of side effect reported. A previous review of cluded that SJW significantly benefits patients with depression 15 controlled clinical trials (12 PC) reported that the only sub- without significant side effects. Five R, DB, multicenter (MC) stantial documentation for the use of SJW in mild to moderate depression is for the products Jarsin® 300 (Lichtwer Pharma) and trials (1,191 participants) found equal effectiveness to tricyclic ® antidepressant drugs (amitriptyline, imipramine, malprotiline) Psychotonin-M (Steigerwald). The review concluded that SJW with greater tolerability, and that SJW was safer for the heart. should not be taken for more than 6 weeks, since most trials showing efficacy have been conducted over a shorter period of Three small pilot studies (60 total patients) show promising find- time. A recent study received considerable media attention due to ings for fatigue and seasonal affective disorder (SAD), and one its negative findings on patients with severe depression; however, small open-label study (12 patients) indicated potential benefits the study lacked an active control (no active drug was used to for obsessive-compulsive disorder. One small pilot study of SJW measure the response rate of severely depressed patients vs. SJW for the treatment of premenstrual syndrome suggests that SJW and placebo). The first study funded by the NIH’s NCCAM (R, might reduce the severity and duration of premenstrual symp- DB, PC, MC, 340 participants) found that neither sertraline nor toms, warranting a larger R, DB trial. A drug-monitoring study SJW were effective compared to placebo for moderately severe on menopausal symptoms suggests that SJW is useful for treat- major depressive disorder. Critics emphasize that the initial ment of associated symptoms and increasing the sense of sexuali- design was changed from less severely depressed patients to ty in middle-age women. patients with moderately severe major depression. In a review of 17 studies on SJW and 9 studies on fluoxetine (Prozac®), researchers showed that SJW was as effective as fluox-

304 The ABC Clinical Guide to Herbs Patient Information Sheet hlrnadpt.Consult your healthcare provider with any questions. children and pets. the reach of and keeping itout of storing itasadvised on the label, ed, medication bytaking itasdirect- supplement asyou would any typeof Treatamong different herbs when taken your at the sametime. herbal Interactions may occur between medications and herbs or even taking. allherbs and medications you are inform your healthcare provider of please As with allmedications and dietarysupplements, treatment. of product throughout the period usethe same brand of For best results, purchase itfrom areliable source. When using adietarysupplement, Comments [Fam. Hypericum perforatum John’s wort St. D doses. 900mgdailyin3divided icin or2–4.5%hyperforin; P No known contraindications. C F D turnal incontinence;PMS. compulsive disorder; menopause;fatigue;pediatricnoc- related seasons,especiallywinter);obsessive- tocertain Seasonal Affective Disorder (SAD:mentaldepression O (myalgia). Wound healing; first-degree burns;musclepain External Depression (mildtomoderate). Internal U occurring chemicalsfoundintheplant. (3-5%),twonaturally hypericin (0.3%),orhyperforin typically standardized tocontainaconsistent level of form,orstandardizedin itscrude preparation. SJWis teas, alcoholictinctures, andtabletsusingeithertheplant speak ofthehealthbenefitsSJW. Preparations include Hippocrates (ca.460-377B.C.E.),wasoneofthefirstto to moderatedepression. The Greek physician, showing thatSJWissafeandeffective fortreating mild came afterthenationalmediareported clinicalresearch in mainstream retail stores intheU.S.Its risetofame supplement U.S., tobecomethefifthbest-sellingdietary St. John’s rose obscurityinthe from virtual (SJW) wort O E UDEXTRACT LUID ENNYAND REGNANCY XTRACT YEXTRACT RY ONTRAINDICATIONS SES VERVIEW OSAGE THER Clusiaceae ( P STANDARDIZED OTENTIAL : 5–7:1,300mg,3timesdaily. ] : 1:1( L ACTATION g/ml ), 2ml,twicedaily. U :standardized to 0.3% hyper- ): SES No known restrictions. : Illustration ©2002PeggyIllustration Duke counter orprescription medications. professional before usingSJWwithanyotherover-the- are advisedtoconsultwithaproperly qualifiedhealthcare and possiblyothers,consumersandpatients these drugs, hol. Because SJWhasbeenshown topotentiallyactwith (Tegretol increase likecarbamazepine theconcentrationofdrugs digoxin. Abruptly stoppingSJWafterprolonged usemay pressant cyclosporine, drug andthecardiac medication indinavir,phylline, theanti-HIVdrug theimmunosup- theo- theasthmadrug likewarfarin, anticoagulant drugs guidance. SJWmayinteractwithoralcontraceptives, maceutical antidepressants unlessunderprofessional SJW shouldnotbetakenincombinationwithanyphar- D (1,800 mg/day),butthisreaction isrelatively rare. fair-skinned individuals,mayoccurwithexcessive dosages to sunlightorotherultravioletradiation)especiallyin Photosensitization (redness oftheskin causedby exposure A DVERSE RUG ® I ). Patients withdepression shouldavoid alco- NTERACTIONS their website at www.herbalgram.org. GuideClinical toHerbs To order provider who gave you sheet. this mation about herb this please consult the healthcare For more detailedinfor- herbs. on the medicinaluseof pendent member-based educational organization focusing ABC aninde- is the American BotanicalCouncil (ABC). excerpted from The information contained on this sheet hasbeen E FFECTS The ABC ClinicalGuideto Herbs The ABC Clinical Guide ABCClinical The toHerbs rbcm ebro B,visit ABC, or become amember of The ABC The © 2002by

305

St. John’s wort John’s St. wort John’s St. Patient Information Sheet Information Patient St. John’s Wort Hypericum perforatum L. [Fam. Clusiaceae]

OVERVIEW DESCRIPTION t. John’s wort (SJW) has been used for various ailments St. John’s wort (Hypericum perforatum L., Fam. Clusiaceae) since the ancient Greeks; the Greek physician Hippocrates preparations consist of the dried above-ground parts (flowers and S(ca.400 B.C.E.) was one of the first to document its ther- stems), gathered during the flowering season. Preparations apeutic use. Since the time of the Swiss physician Paracelsns (ca. include aqueous extracts (teas), standardized extracts, alcoholic 1540 C.E.) it was used to treat mental disorders (Blumenthal et tinctures, dry extracts in capsules or tablets, and oil infusions al., 2000; Hobbs, 1988/89). SJW rose from virtual obscurity in (topical) (Blumenthal et al., 2000). Standardization is typically the United States to become the fifth best-selling dietary sup- to 0.3% hypericin, or at 2–4.5% hyperforin (Bruneton, 1999). plement in mainstream retail stores in the U.S. in 2000 Recent research suggests that the compound hyperforin may be (Blumenthal, 2001) following major media coverage of clinical the main antidepressive constituent (Müller et al., 1998). The research documenting its relative safety and efficacy for treating German Drug Codex formerly required that SJW preparations be mild to moderate depression. In 1998 and 1999 it had risen to standardized to hypericins content; however, this in no longer second place in mainstream sales (Brevoort, 1998), but fell to required as a chemical marker (Bühler, 1995). The United States fifth place due, in part, to some adverse publicity regarding National Formulary requires not less than 0.04% of total hyper- reports of its interactions with several classes of prescription icins, calculated as hypericin (USP, 1999).

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 • Seasonal Affective Disorder (Martinez et al., 1994) • Obsessive-Compulsive Disorder (Taylor and Kobak, 2000) Photo © 2002 stevenfoster.com • Pre-menstrual syndrome (Stevinson and Ernst, 2000) • Menopause (Grube et al., 1999) drugs (Blumenthal, 2001). The National Institutes of Health’s National Center for Complementary and Alternative Medicine • Fatigue (according to a pilot study) (Stevinson et al., 1998) recently funded a three-year, multi-center trial comparing the • Pediatric nocturnal incontinence (Weiss and Fintelmann, effects of a standardized extract of SJW and the selective sero- 2000) tonin reuptake inhibitor (SSRI) sertraline (Hypericum Depression Trial Study Group, 2002). Since 1979, there have DOSAGE been more than 35 controlled clinical studies of SJW extracts Internal for the treatment of mild to moderate depression (Blumenthal Crude Preparations et al., 2000). Two meta-analyses have documented the relative FLUID EXTRACT: 1:1 (g/ml), 2 ml, twice daily. safety and suggested probable efficacy of this phytomedicine DRY EXTRACT: 5–7:1, 300 mg, 3 times daily (Blumenthal et al., (Linde and Mulrow, 2001; Linde et al., 1996). SJW is pre- 2000). scribed frequently by healthcare providers in Germany, where approximately 130 million daily doses containing hypericum Standardized Preparations were prescribed in 1999 (Schulz, 2001). SJW preparations have EXTRACT: Standardized to 0.3% hypericin, 900 mg daily in 3 also been used in traditional European herbal medicine for top- doses of 300 mg each; or products standardized to 2–4.5% ical antimicrobial and skin healing purposes (Reichling et al., hyperforin, 900 mg/day in 3 doses (Bruneton, 1999). 2001). External OILY MACERATE (OLEUM HYPERICI): Fresh-flowering tops in olive 306 © 2002 American Botanical Council. Excerpted from The ABC Clinical Guide to Herbs St. John’s wort Monograph St. John’s wort et 307 ., Candida , thus + et al , 1994). 2000). , but this was con- , but this et al. ., 1997). ., 2001). et al., 1990), and is antimi- 1990), ., 1989; Chatterjee , and activating NO , and activating α et al et al in vitro et al et al., adenosine, benzodiazepine, inosi- adenosine, benzodiazepine, 300); during this period only 95 The ABC Clinical Guide to Herbs The ABC Clinical Guide to Herbs : Animal restrictions. known No , ® , 1994); is antiviral (influenza and (influenza is antiviral , 1994); ., 1996; Thiele ., 1996; B ., 1998). Recent drug interaction ., 1998). Recent et al 1994). ., 2001). Isolated hypericin from SJW hypericin from Isolated ., 2001). et al. 2000; Wentworth 2000; Wentworth CTION , et al ., 1997). Due to lack of available data, the to lack of available ., 1997). Due A or Jarsin , GABA et al ACTATION ., 1998; Raffa, 1998; Butterweck., 1998; Raffa, 1998; A et al ® L et al., 1994; Perovic and Müller, 1995; Holzl, 1989; 1995; Holzl, Müller, and 1994; Perovic et al , FFECTS ., 2001). but not against gram-negative bacteria or gram-negative but not against E et al gradient membranes (Müller (Reichling (Reichling + ., 1998; Raffa, 1998; Butterweck synthesis (Panossian synthesis (Panossian tol, triphosphate, and MAO-A and MAO-B receptors MAO-B and MAO-A tol, triphosphate, and (Cott, 1997). and Rossol Chatterjee X the steroid in human hepatocytes and activates expression a mechanism for drug possibly suggesting interac- receptor, tions (Moore platelets and uptake into explaining its effect on serotonin on many profile but also the non-selective synaptozomes by all driven transportneurotransmitter which are systems Na 1997). 1995; Holzl and Müller, (Perovic al tor expression resulting in inhibition of 5HT reuptake resulting tor expression (Müller and Rossol but and dopamine neurotransmission changes in serotonin and Cowen, (in humans) (Franklin not noradrenaline 2001). immune and nervous systems) such as leukotriene B4 and of arachidonic acid, interleukin-1a inhibiting release of IL–1 leukotriene B4, production ECHANISM OF ONTRAINDICATIONS DVERSE • (Müller neurotransmitters of several inhibit uptake May • induces CYP3A4 but not hypericin, in SJW Hyperforin, •Na of SJW leads to an elevation from Hyperforin • and neurosteroids of neuropeptides inhibit uptake May • recep- serotonin) inhibit 5-hydroxzytryptamine(5HT, May • through effects may be mediated mainly Antidepressant • components of act on information substances (shared May • at GABA Bind REGNANCY AND leukin-6 (SJW)leukin-6 (Thiele type 1) (Serkedjieva simplex herpes methicillin-resistant (primarily hyperforin)crobial toward aureus Staph. albicans highest phototoxicity extracts showed particularly fraction, the flavonoid quercitrin by trolled (Wilhelm A few side effects. Between general, SJW produces adverse In 8 million patients are 1999, over 1991 and December October leading SJW with Germany’s been treated estimated to have (Jarsin preparation C in 1984 and in 1990 known” The Commission E stated “none (Blumenthal revision M guidance when certain suggest professional reports conventional (see Drug pharmaceuticals may be simultaneously administered Interactions). P WHO monograph recommends that SJW not be administered WHO monograph recommends or nursing without advice of a healthcare during pregnancy (WHO, 2002). provider reproductive studies did not produce mutagenicity at relatively studies did not produce reproductive high doses (Upton ., ., in et al et al., 1999; et al ., 1994; ., 1993); © 2002 American Botanical Council. Excerpted from et al et al et al., ., 2000). , 1997); inhibits ., 1994; Johnson been reported been reported et al , 1996) and inter- ., 1988); modulates et al not et al. et al et al. ., 1994); may have a relax- ., 1994); may have et al ., 1994; Johnson ., 1994; Johnson ., 1999; Lenoir 2000; Schulz CTIONS et al ., 1996; Upton, 1997; Wichtl and Wichtl 1997; ., 1996; Upton, A et al 1998; Butterweck et al., et al ., 1990; Meruelo ., 1990; Meruelo DMINISTRATION A et al., et al ., 1994; Johnson ., 1994; Johnson , 2000). ., 1998a, 1998b; Wheatley, 1997; Linde Wheatley, ., 1998a, 1998b; et al ., 1984). However, a more recent study suggests recent a more ., 1984). However, ., 2000; Schulz et al. et al et al et al , 1994); improves mental performance (Lehrl , 1994); improves in animals or in humans (Cott, 1997). SJW unspecifically URATION OF HEMISTRY HARMACOLOGICAL vivo inhibits biogenic amine and amino acid neurotransmitter GABA, L-gluta- dopamine, noradrenaline, uptake (serotonin, mate) (Chatterjee and 1995; Müller and Müller, (Perovic reuptake serotonin (using purified 1989); is antiretroviral 1994; Holzl, Rossol, hypericin) (Lavie interleukin-1x (hypericin) (Panossian interleukin-1x (hypericin) (Panossian that 95% pure hypericin does not inhibit MAO, but a crude but hypericin does not inhibit MAO, that 95% pure OR) does, at 2 Williams, Pharm, ethanolic extract (Herb activity has mcg/ml (Cott, 1995). MAOI There has been confusion about the potential monoamine oxi- There suggested Earlier research inhibiting effect of SJW. dase (MAO) hypericin using 80% pure that SJW possibly inhibits MAO, (Suzuki In vitro vitro In Laakmann Animal (alcoholic dopaminergic behavioral responses Potentiates extracts) dioxide effects (carbon extracts), and serotoninergic alcohol intake (Rezvani (Bhattacharya, 1998); reduces 1999); stimulatory effects on the central nerv- and antidepressant sleep time; analgesic activity which ous system; prolonged nearly acetic acid by induced by abdominal stretching reduced intestinal motility 50% and spasmolytic activity which reduced (Jakovljevic Antidepressant (Philipp (Philipp Antidepressant P Standardized Preparations Human (Schulz 1996); relaxant C catechin-type tannins and condensed- SJW contains 6.5–15% (catechin, epicatechin, leucocyanidin); type proanthocyanidins 0.3–1.6% rutin, 0.5–2% hyperoside, mostly 2–5% flavonoids, and kaempferol; quercetin, 0.3% isoquercitrin, 0.3% quercitrin, deriva- biapigenin), phloroglucinol (about 0.26% bioflavonoids (up to 4% hyperforin);tives chlorogenic, phenolic acids (caffeic, ferulic); n-alkanes, oils, mainly higher 0.05–1.0% volatile and pseudohyper- (hypericin 0.05–0.15% naphthodianthrones to 10 ppm xan- vitamins C and A, up (sitosterol); icin); sterols 1996; Leung and 1999; ESCOP, thones; and choline (Bruneton, 1996; Newall Foster, 1994). Bisset, D that for to SJW is similar to onset of response the depression, For as long as or 2–4 weeks, requiring antidepressants, conventional should be continued antidepressant relapse, prevent To 6 weeks. doses for at least 6 months after remission at full therapeutic (AHCPR, 1999). oil or wheatgerm oil are macerated for several weeks, stirred weeks, several for macerated oil are wheatgerm oil or be To pressed. the pulp and a cloth through strained often, (Blumenthal areas to affected applied directly ing effect and improve concentration, memory, and receptivity concentration, memory, ing effect and improve (Schulz Lehrl 1993). et al. does not change alertness or have sedative effect (Schulz does not change alertness sedative or have 2000; Schulz reports of side effects were received by the German Adverse Drug seizure drug carbamazepine (Tegretol®), found that 300 mg St. Reaction Recording System. These included “allergic” skin reac- John’s wort extract, three times daily, did not increase the clear- tions (27 reports), increased Quick Values (prothrombin time) ance of the drug (Burstein et al., 2000). Sudden discontinuation (16), gastrointestinal complaints (9), breakthrough bleeding of SJW after prolonged use may lead to higher plasma levels of (birth control pill) (8), plasma cyclosporin reductions (7), and these drugs if used simultaneously, with the risk of adverse effects others (Schulz, 2001). Photosensitization, depicted by erythema (Baede-van Dijk et al., 2000). (redness of the skin) with exposure to sunlight or other ultravio- let radiation is possible, although this is relatively rare and is AMERICAN HERBAL PRODUCTS ASSOCIATION sometimes reported in fair-skinned individuals taking excessive (AHPA) SAFETY RATING dosages (1,800 mg/day) (Brockmuller, 1997; Blumenthal et al., CLASS 2D: Based on earlier in vitro research and the Commission 1998). A recent review of SJW adverse reactions suggests that this E monograph, AHPA cautioned that SJW may potentiate phar- precaution should not constitute a general contraindication, since maceutical MAO-inhibitors (McGuffin et al., 1997), although the incidence of photosensitization is so rare and because sunlight there are no animal or human data to support this. can promote recovery from depression (Schulz, 2001). REGULATORY STATUS RUG NTERACTIONS D I AUSTRALIA: Complementary medicine available without prescrip- Potential drug interactions with SJW have become the primary tion from pharmacies, health food shops, supermarkets, and area of concern with this popular phytomedicine. However, one complementary medicine practitioners (TGA, 2000). Required source suggests that some of these concerns may not be borne out label warning: “St. John’s wort affects the way some prescription by clinical experience. In a review of drug interactions reportedly medicines work. Consult your doctor.” (Trickey, 2000). associate with SJW, the author calculates one interaction per CANADA: Non-prescription drug for internal or external use clas- 300,000 treatments with the leading German SJW product sified as either “Schedule OTC Herbs and Natural Products” or (Jarsin®). “Schedule Homeopathic Products,” in either case requiring pre- SJW should not be taken in combination with any pharmaceuti- marketing authorization and assignment of Drug Identification cal antidepressants (Gordon, 1998; Prost et al., 2000), unless Number (DIN) by the Therapeutic Products Programme (TPP) under professional guidance. SJW is believed to interact with oral (Health Canada, 2001a). In January 2001, added to “Drugs of contraceptives and anticoagulants (e.g., warfarin) (TGA, 2000; Current Interest (DOCI) List” maintained by the Canadian Di Carlo et al., 2001; Lantz et al., 1999; McGuffin et al., 1997). Adverse Drug Reaction Monitoring Program (Health Canada, Preliminary findings suggest that SJW does not interact with the 2001b). Potential drug-interaction warning statement required. effects of alcohol; however, patients with depression should avoid EUROPEAN UNION: Whole or cut, dried, flowering tops harvested alcohol (Schmidt, 1993). An uncontrolled study on 13 subjects during flowering time, containing no less than 0.08% total taking SJW at normal doses (900 mg of the standardized hypericins, official in the European Pharmacopoeia (Ph.Eur., extract/day), resulted in significant increases in urinary 2001). 6–beta–hydroxycortisol/cortisol ratio, suggesting that SJW is an inducer of CYP3A4, since cortisol is metabolized primarily by FRANCE: Dried flowering top or aerial part official in French CYP3A4 (Roby et al., 2000). A recent study (Moore, 2000) Pharmacopoeia approved only for external use but not prior to revealed that constituents of SJW extract, especially hyperforin, sun exposure (Bruneton, 1999; ESCOP, 1996). are a potent ligand (K(i) = 27 nM) for the pregnane X receptor, GERMANY: Approved by Commission E as a nonprescription drug an orphan nuclear receptor that regulates expression of the for internal and external use (Blumenthal et al., 1998). Whole or cytochrome P450 (CYP) 3A4 monooxygenase. Treatment of pri- cut aerial parts, collected just before or during the flowering peri- mary human hepatocytes with SJW extracts, or hyperforin, od, official for internal or external use in the German Drug Codex results in a marked induction of CYP3A4 expression. CYP3A4 is supplement to the German Pharmacopoeia (DAC, 1998). Whole, involved in the oxidative metabolism of more than 50% of all fresh, flowering plant for preparation of mother tincture is offi- drugs, and can cause a decrease in the therapeutic activity and cial in German Commission D monographs and corresponding concentration of such drugs, including contraceptives (Moore, German Homeopathic Pharmacopoeia (BAnz, 1985; GHP, 1993). 2000) and theophylline (Baede-van Dijk et al., 2000). SJW also ITALY: No information available. may increase clearance from the bloodstream of the protease SWEDEN: Classified as Natural Remedy, requiring premarket inhibitor indinavir, and the anti-rejection drug cyclosporine authorization. As of January 2001, nine SJW-containing prod- (Piscitelli et al., 2000; Ruschitzka et al., 2000), and may also ucts are listed in the Medical Products Agency (MPA) interfere with the absorption of digoxin (Tatro, 2000). A recent “Authorised Natural Remedies,” and a monograph is published study found that SJW induces intestinal P-glycoprotein/MDRI with the approved indication: “Traditionally used in case of slight (in rats and humans), and induces intestinal and hepatic CYP3A4 mood lowering and for minor nervous tension” (MPA, 1999; (in humans), thereby decreasing plasma levels of cyclosporine, 2001a; Tunón, 1999). St. John’s wort homeopathic preparations indinavir, and digoxin (Dürr et al., 2000). However, a review of are also registered drugs (MPA, 2001b). SJW drug interactions questions the clinical relevance of interac- tions that are postulated solely on the basis of pharmacokinetic SWITZERLAND: Official in Swiss Pharmacopoeia (Upton et al., measurements, with digoxin, theophylline, and amitryptaline 1997; Wichtl, 1997). Herbal medicine with positive classification needing to be examined critically, since reduced plasma level are (List D) by the Interkantonale Konstrollstelle für Heilmittel (IKS) not the same as reduced active levels at the receptors. The author and corresponding sales Category D with sale limited to pharma- states that to-date there are no reported cases suggestive of a clin- cies and drugstores, without prescription (Morant and ically significant weakening in effect of the three drugs cited Ruppanner, 2001; Ruppanner and Schaefer, 2000). Numerous (Schulz, 2001). One 14-day study on 10 patients, using the anti- SJW phytomedicines and homeopathic preparations are listed in

308 © 2002 American Botanical Council. Excerpted from The ABC Clinical Guide to Herbs St. John’s wort Monograph St. John’s wort ), ® 309 et al. 300 (Lichtwer ® 20). Widespread 20). ≥ ., 2001). (Steigerwald) (Volz, 1997). The 1997). (Volz, (Steigerwald) The ABC Clinical Guide to Herbs The ABC Clinical Guide to Herbs ® et al marketed by Bayer in Germany) is equiv- in Germany) Bayer by marketed ® 15) but was later changed to patients with mod- ≥ ., 2001). A total of 11 studies have compared SJW compared 11 studies have ., 2001). A total of et al publicity on this trial focused on the failure of SJW without publicity on this trial focused on the failure of sertraline a slight which was given equally noting the failure better performance on a sec- SJW because of sertraline’s edge over scale that included ondary Impression (a Clinical Global measure on secondary (Outcomes partial are responders). measurements ascribing success or fail- for measures appropriate not considered that 35% of clini- The authors of this study acknowledged ure.) than 50% drugs failed. More anti-depressant cal trials on known drugs fail (Robinson antidepressant of trials with investigational and Rickels, 2000). imipramine is the first to compare the two agents at the normal agents the two compare the first to is imipramine tri- Previous 2000). (Woelk, (150 mg) dose of imipramine daily side adverse to reduce in order 75 mg imipramine als used only study is the largest This maintain patient compliance. effects and SJW extract used that the trial to date and concluded comparison (Remotiv in the study (2001) received considerable media attention due to its negative (2001) received noted The study was depression. findings on patients with severe drug (no SSRI or other active was control for its lack of an active patients depressed rate of severely the response used to measure vs. SJW and placebo) (Cott the published for the first study funded by recently were Results R, DB, This long awaited and much publicized NCCAM. NIH’s PC, MC, 3 arm study (340 participants) found that neither ser- to placebo for moder- compared effective traline nor SJW were that the emphasize Critics disorder. major depressive ately severe patients depressed initial design included only less severely (HAMD score score (HAMD major depression erately severe review concluded that SJW should not be taken for more than 6 concluded that SJW should not be taken for more review been conducted efficacy have since most trials showing weeks, Shelton study by a shorter period of time. A recent over Pharma) and Psychotonin-M Pharma) was compared in patients with mild to moderate depression. The in patients with mild to moderate depression. was compared equipotent with are that SJW and fluoxetine showed results antidepressants to investigate to all main parameters used respect be superior in improving in this population. Although SJW may the two treat- between rate, the main difference the responder inci- in overall SJW was superior to fluoxetine ments is safety. with side effects, and the dence of side effects, number of patients of review 2000). A previous (Schrader, type of side effect reported that reported clinical trials (12 placebo-controlled) 15 controlled the use of SJW in mild to the only substantial documentation for Jarsin is for the products moderate depression alent to imipramine in efficacy, and is more well-tolerated by well-tolerated is more and in efficacy, alent to imipramine 117) SJW (Ze trial (n=240) comparing larger newer, patients. A of equivalent concluded that SJW was with fluoxetine directly patients suffering particularly in depressive efficacy as fluoxetine, the SSRI and was better tolerated for safety than anxiety, from (Friede preparations with conventional antidepressants (7 tricyclic; 4 (7 tricyclic; antidepressants with conventional preparations for mild to moderate that SJW is effective SSRI) concluding 2001). (Kasper, side effect profile with a low depression of R, C, DB trials select- published systematic review A recently well-controlled eight methodological quality, ed, and assessed for that SJW suggest results The 2000). and Holroyd, studies (Gaster mod- of mild to than placebo in the treatment effective is more rate with the response The absolute increased erate depression. than with placebo, 23% to 55% higher use of SJW ranged from anti- with tricyclic compared 6% to 18% lower but ranged from used with SJW and the commonly The treatment depressants. (Prozac inhibitor (SSRI) fluoxetine reuptake serotonin selective , ., et et al., et al (GSL), ., 1994; © 2002 American Botanical Council. Excerpted from et al ., 1996). A fol- ., 1999; Shelton et al et al ., 1994; Harrer ., 1994; Harrer General Sale List Sale General U.S. National Formulary U.S. National ., 1999; Laakmann et al ., 1996). Based on the evi- ., 1996). Based et al 1998; Kasper, 1997; Matinez 1997; Matinez 1998; Kasper, et al et al., (Ruppanner and Schaefer, 2000). and Schaefer, (Ruppanner ., 1997). et al EVIEW R ., 1994). Five R, DB multicenter trials, with 1,191 ., 1999). et al ), researchers showed that SJW was as effective as fluox- as that SJW was as effective showed ), researchers et al ® 2001) demonstrate positive effects of SJW on depression. positive 2001) demonstrate Swiss Codex 2000/01 Codex Swiss LINICAL ., 1994), and one small open-label study on 12 patients indi- ., 1994), and one small open-label study low-up meta-analysis by the Cochrane Center of 27 trials with meta-analysis by low-up 2,291 patients concluded that SJW was significantly superior to concluded that The review 2001). placebo (Linde and Mulrow, forms the short in less severe term use of SJW might be valuable to watchful waiting or the com- as an alternative of depression and antidepressants doses of tricyclic to low monly used approach A that SJW has less short side effects than tricyclics. term adverse antidepressant trial comparing SJW with the conventional recent Table B (external use only), Schedule 1 (requires full product full 1 (requires only), Schedule B (external use Table and the benefits article reviewed 1994). A recent license) (GSL, and their regulatoryrisks of SJW in the U.K. implications 2000). (McIntyre, U.S.: tops flowering Dietary 1994). Dried, supplement (USC, less containing no or during flowering, shortly before gathered official in than 0.04% total hypericins, 1999). 19th edition (USP, U.K.: use; internal for product Licensed dence available at the time, the same review concluded that fur- at the time, the same review dence available needed to establish whether SJW is as effective ther studies were drugs (Linde antidepressant as conventional etine in the treatment of subthreshold and mild depression (Volz, and mild depression of subthreshold etine in the treatment in subthresh- that SJW is effective concluded 2000). Researchers exhibiting veryold depression few or no side effects, easy avail- the risk that to avoiding approach and may be a viable ability, disorder. becomes a full-blown mild depression and meta-analysis of 23 clinical studies on SJW showed A review mild than placebo in treating effective that the extract was more (Linde to moderate depression In a review of 17 studies on SJW and 9 studies on fluoxetine of 17 studies on a review In (Prozac 1998a, 1998b; Harrer and Sommer 1994; Hübner and Sommer 1998a, 1998b; Harrer Hänsgen antide- heart1994), and that SJW was safer for the than tricyclic (Czekalla pressants promis- small pilot studies on a total of 60 patients show Three and seasonal affective ing findings for the conditions of fatigue (SAD) (Stevinson disorder al dis- obsessive-compulsive cated the potential benefits of SJW for small pilot study of SJW 2000). One Kobak, and (Taylor order suggests that SJW syndrome of premenstrual for the treatment symp- and duration of premenstrual the severity might improve and Ernst, (Stevinson toms, warranting a larger R, DB trial 2000). A drug-monitoring study on menopausal symptoms sug- of associated symptoms, gests that SJW is useful for treatment women the sense of sexuality in middle-age and increasing (Grube participants, found equal effectiveness to tricyclic antidepressant participants, to tricyclic found equal effectiveness tol- drugs with greater (amitriptyline, imipramine, malprotiline) Vorbach 1997; erability (Wheatley, C table, “Clinical in the following outlined studies are Twenty-four including a total of 2,765 partici- Wort”, John’s on St. Studies of these studies (Lenoir pants. All but three the et al., PC) (R, DB, double-blind, placebo-controlled randomized, Five been performedstudies have on 626 participants, concluding without with depression that SJW significantly benefits patients significant side effects (Philipp BRANDED PRODUCTS* taining Hypericum extracts in behavioral models. Pharmacopsychiatry 1998;31 (suppl. 1):22–9. Hyperiforce™: Bioforce AG / 437 Rt. 295 / Chatham, NY Bladt S, Wagner H. Inhibition of MAO by fractions and constituents of Hypericum 12037 / U.S. / Tel.: (800) 641-7555 x100 / Fax: (518) 392-8794 extract. J Geriatr Psychiat Neurol 1994; 7(1):557-9. / Email: [email protected] / www.bioforceUSA.com. 275 Blumenthal M. Herb sales down 15% in mainstream market. HerbalGram mg/tablet of a 1:9.0 ethanol/water extract of fresh tips of shoots. 2001;51:69. Blumenthal M, Busse WR, Goldberg A, Gruenwald J, Hall T, Riggins CW, Rister One tablet 3 times/day after meals provides 1 mg hypericin/day. RS (eds.). Klein S, Rister RS (trans.). The Complete German Commission E Jarsin® 300: Lichtwer Pharma / Wallenroder Strasse 8-14 / 13435 Monographs—Therapeutic Guide to Herbal Medicines. Austin, TX: American Berlin / Germany / Tel.: +49-30-40-3700 / Fax: +49-30-40- Botanical Council; Boston: Integrative Medicine Communication; 1998. Blumenthal M, Goldberg A, Brinckmann J, eds. Herbal Medicine: Expanded 3704-49 / www.lichtwer.de. 300 mg St. John’s wort extract/cap- Commission E Monographs. Austin TX: American Botanical Council; Newton MA; sule in coated tablets standardized to 0.3% total hypericins. Integrative Medicine Communications; 2000. Kira®: Lichtwer Pharma, c/o ABKIT, Inc., New York, New York. Brenner R, Azbel V, Madhusoodanan S, Pawlowska, M. Comparison of an Extract of 300 mg dried methanolic extract produced from leaves, stems, Hypericum (LI 160) and Sertraline in the Treatment of Depression: A Double- Blind, Randomized Pilot Study. Clinical Therapeutics 2000; 22(4). and flowers standardized to 300 mcg total hypericin. Brevoort P. The booming U.S. botanical market: an overview. HerbalGram LI 160: Lichtwer Pharma, Berlin: 300 mg St. John’s wort 1998;44:33–40. extract/capsule in coated tablets standardized to 0.3% total Brinker F. Herb Contraindications and Drug Interactions, 3d ed. Sandy, OR: Eclectic Medicinal Publications; 2001:178–84. hypericins. Brockmuller J, Reum T, Bauer S, et al. Roots I: Hypericin and pseudohypericin: phar- Neuroplant® (WS 5572; a.k.a. Perika®): Dr. Wilmar Schwabe macokinetics and effects on photosensitivity in humans. Pharmacopsychiatry 1997; GmbH & Co / International Division / Willmar Schwabe Str. 4 30 (suppl. 2):94–101. Bruneton, J. Pharmacognosy, Phytochemistry, Medicinal Plants, 2nd ed. Paris, France: / D-76227 Karlsruhe / Germany / www.schwabepharma.com / Lavoisier Publishing; 1999. Each 300 mg capsule contains dry SJW extract standardized to Bühler. Communication from BfarM (German Federal Institute for Drugs and Medical 5.0% hyperforin. Devices) to German Non-prescription Drug Association (BAH), Sept. 11, 1999. Perika®: Dr. Wilmar Schwabe GmbH & Co., U.S. distributor: Bundesanzeiger (BAnz). Monographien der Kommission D. Cologne, Germany: BAnz. 10.10.1985;Nr.190a. Nature’s Way Products, Inc. / 10 Mountain Spring Parkway / Burstein A, Horton R, Dunn T et al. Lack of effect of St. John’s wort on carba- Springville, Utah 84663 / U.S. / Tel.: (801) 489-1500 / mazepine pharmacokinetics in healthy volunteers. Clin Pharm & Ther 2000 www.naturesway.com. Each 300 mg capsule contains dry SJW Dec;68(6):605–12. extract standardized to 5.0% hyperforin. Butterweck V, Wall A, Lieflander-Wulf U, et al. Effects of the total extract and frac- tions of Hypericum perforatum in animal assays for antidepressant activity. ® Remotiv (Ze117): Bayer Vital GmbH & Co. / Consumer Care Pharmacopsychiatry 1997;30(2):117–24. / Welser Strasse 5 – 7 / 51149 Köln / Germany / Tel.: + 49-01- Chatterjee, S, Noldner M, Koch E, Erdelmeier C. Antidepressant activity of 30-82-6301 / www.bayer-ag.de. Each 250 mg film-coated tablet Hypericum perforatum and hyperforin: the neglected possibility. of St. John’s wort extracted in 50% alcohol, standardized to 2% Pharmacopsychiatry 1998;31 (suppl. 1):7–15. Cott J. In vitro receptor binding and enzyme inhibition by Hypericum perforatum hypericins. extract. Pharmacopsychiatry 1997; 30 (suppl. 2):108–12. STEI 300: Steiner Arzneimittel / Postfach 450520 / 12175 Berlin Cott J. Medicinal plants and dietary supplements: sources for innovative treatments / Germany / Tel.: +49-03-07-1094-0 / Fax: +49-03-07-1250-12 or adjuncts: an introduction. Psychopharm Bulletin 1995; 31(1):131–7. Cott J, Fugh-Berman A. Is St. John’s wort (Hypericum perforatum) an effective anti- / www.steinerarznei-berlin.de Each 350 mg capsule contains depressant? J Nerv Ment Dis 1998;186(8):500–1. 0.2%–0.3% hypericin, and 2%–3% hyperforin. Cott J, Rosenthal N, Blumenthal M. St. John’s wort and major depression. JAMA WS 5570: Dr. Wilmar Schwabe GmbH & Co, Karlsruhe, 2001;286(1):42. Czekalla J, Gastpar M, Hübner W et al. The effect of hypericum extract on cardiac Germany. An 80% v/v hydroalcoholic extract of St. John’s wort, conduction as seen in the electrocardiogram compared to that of imipramine. drug to extract ratio 3–7.1. Pharmacopsychiatry 1997; 30:86–8. WS 5572: see Neuroplant® and Perika®. DAC. See: Deutscher Arzneimittel-Codex. De Smet P, Nolen W. St. John’s wort as an antidepressant. BMJ 1996; WS 5573: Dr. Wilmar Schwabe GmbH & Co, Karlsruhe, 313(7052):241–2. Germany. Each 300 mg capsule contains dry SJW extract stan- Deutscher Arzneimittel-Codex (DAC 1998 Ergänzungsbuch zum Arzneibuch, Band dardized to 0.5% hyperforin. II). Stuttgart, Germany: Deutscher Apotheker Verlag. 1998;J–010;1–5. Di Carlo G, Borrelli F, Ernst E, Izzo AA. St. John’s wort: Prozac from the plant king- Ze 117: Zeller Medical / Seeblickstrasse 4 / CH-8590 dom. Trends Pharm Sci 2001;22(6):292–6. Romanshorn 1 / Switzerland / www.zellerag.ch. St. John’s wort Dürr D, Steiger B, Gerd A, Kullak-Ublick G et al. St. John’s Wort induces intestinal extracted in 50% alcohol, standardized to 2% hypericins in a 250 P-glycoprotein/MDRI and intestinal and hepatic CYP3A4. Clin Pharm & Ther mg tablet, drug to extract ratio 4–7:1. 2000 Dec;68(6):598–604. ESCOP. See: European Scientific Cooperative on Phytotherapy. *American equivalents are found in the Product Table on page European Pharmacopoeia (Ph.Eur. 3rd ed. 1997 Supple. 2001). Strasbourg, France: XXX. Council of Europe. 2001;972–3. European Scientific Cooperative on Phytotherapy (ESCOP). Hyperici Herba — St. John’s Wort. In: ESCOP Monographs on the Medicinal Uses of Plant Drugs. Exeter, U.K.: ESCOP. March 1996. REFERENCES Felter HW, Lloyd JU. 1983. King’s American Dispensatory, 18th ed., 3rd rev. Portland, Agency for Health Care Policy and Research. Treatment of Depression–Newer OR: Eclectic Medical Publications; [reprint of 1898 original], 1083–9. Pharmacotherapties. Summary, Evidence report/Technology Assessment: Number Franklin M, Cowen PJ. Researching the antidepressant actions of Hypericum perfora- 7, March 1999. tum (St. John’s wort) in animals and man. Pharmacopsychiatry 2001;34 AHCPR. See: Agency for Health Care Policy and Research. Suppl.1:S29–37. Baede-van Dijk P, van Galen E, Lekkerkerker J. Drug interactions of Hypericum per- Friede M, Henneicke von Zepelin H-H, Freudenstein. Differential therapy of mild to foratum (St. John’s wort) are potentially hazardous. Ned Tijdschr Geneeskd 2000 Apr moderate depressive episodes (ICD–10 F 32.1) with St. John’s wort. 22;144(17):811-2. Pharmacopsychiatry 2001;34 Suppl. 1:S38–41. BAnz. See: Bundesanzeiger. Fugh-Berman A and Cott J. Dietary supplements and natural products as psy- Bhattacharya S, Chakrabarti A, Chatterjee S. Activity profiles of two hyperforin-con- chotherapeutic agents. Psychosom Med 1999 Sept/Oct;61(5):712–28.

310 © 2002 American Botanical Council. Excerpted from The ABC Clinical Guide to Herbs St. John’s wort Monograph . 2000 2000 311 (as of 1998; 1995; J Clin Alcohol Uppsala, Presse Med Presse J Pharmacol 2001. Basel, extract (St. John’s wort) John’s extract (St. Pharmacopsychiatry 2000;6(2):115–24. Proc Sci USA Acad Natl Int Clin Psychopharmacol Int 1998;62(16):PL265–70. Arzneimittelforschung American Herbal Product Association’s Product Herbal American 2001;34 Suppl.1:S116–8. Immunosuppressive effects of hyper- Immunosuppressive Life Sci Life 2001;34 Suppl. 1:S98–102. 2001;34 Suppl. Hyperforin represents the neurotransmit- represents Hyperforin et al. 2001 Apr;137(4):512–3. . St. John’s wort: effect on CYP3A4 activity. John’s . St. ): the implications with regard to the regula- with regard ): the implications St. John’s wort induces hepatic drug metabo- John’s St. Herbal Medicines: A Guide for Health-Care A Guide Medicines: Herbal . 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Products Medical Sweden: Uppsala, (updated 2001–02-–26). Sweden: Medical Products Agency. 1999. Agency. Products Medical Sweden: and diones hypericin polycyclic doses: aromatic at effective ty and little toxicity pseudohypericin Robinson DS, Rickels K. Concerns about clinical drug [editorial]. trials Robinson CA, Anderson GD, Kantor E Roby H, Schaefer U (eds.). Ruppanner M, Turina P, Meier F, Ruschitzka JC. Single-dose J, Simon B, Shulte-Monting Winghofer K, CM, Muller Schempp, Rezvani A, Overstreet D, Yang Y, Y, Yang D, A, Overstreet Rezvani Reichling J, Weseler A, Saller R. A current review of the antimicrobial activity of of the antimicrobial review R. A current A, Saller Weseler J, Reichling Schilcher H. Schmidt U, Harrer G, Kuhn U, G, Kuhn Schmidt U, Harrer a random- wort 117) and fluoxetine: extract (Ze John’s of St Schrader E. Equivalence Prost N, Tichadou F, Rodor F, F, Rodor F, Tichadou N, Prost and uptake-site activity of hypericin component of St. of receptor Raffa R. Screen Perovic S, Müller W. Pharmacological profile of Hypericum extract; effect on sero- of Hypericum profile Pharmacological W. S, Müller Perovic Newall C, Anderson L, Phillipson J. L, Phillipson C, Anderson Newall constituents of St. P450 enzymes by of human cytochrome R. Inhibition Obach V, E, Manvelian A, Gabrielian Panossian See: Ph.Eur. or placebo imipramine extract versus K. Hypericum R, O’Hiller M, Kohnen Philipp A, Chaitt D, S, Burstein Piscitelli Müller W, Singer A, Wonneman M., Wonneman A, Singer W, Müller McGuffin M, Hobbs C, Upton R, Goldberg A. R, Goldberg Upton C, M, Hobbs McGuffin drug events, and safety of interactions, of the benefits, adverse A review M. McIntyre Agency (MPA). Products Medical H (eds.). J, Ruppanner Morant Agency. Products Medical See: MPA. a novel activity by M. Hyperforin–Antidepressant Wonnemann A, Singer W, Müller of serotonin extract on the expression of Hypericum R. Effects Rossol W, Müller McCaleb R, Leigh E, Morien K. 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EEG and evoked resting on with maprotiline LI 160 compared extract Hypericum potentials in 24 volunteers. (1):189–192;(2):125, 1994. Publications; 1:S51–5. 2001;34 Suppl. Pharmacopsychiatry of hyperforin for the clinical efficacy. the relevance depression: 1998a; 31(suppl. 1):54–9. severities. of different disorders extracts on depressive cy of Hypericum Phytomedicine actions in the elderly. actions in the elderly. Sci Drugs Cosmetics and 33. 96. January Programme. Therapeutic Products Canada Health Ontario: Ottawa, 2001b. perforatum depressant effectiveness of the Hypericum extract LI 160. of the Hypericum effectiveness depressant 1994;7(suppl. 1):S15–8. wort extract Lottyp-57 and fluoxetine. John’s Phytomedicine 2001a. Programme. Therapeutic Products Canada Health Ontario: extract LI 160 compared to maprotiline: a multicenter double-blind study. a multicenter double-blind study. to maprotiline: extract LI 160 compared Geriatr Psychiatry Neurol Psychiatry Geriatr treatment with Hypericum extract. with Hypericum treatment different concentrations of a standardized fresh plant extract obtained from the plant extract obtained from fresh concentrations of a standardized different shoot tips of Software. Update 1, 2001. Oxford; Cochrane Library, clinical trials. overviewwort and meta-analysis of randomized for depression—an BMJ disorders sonal affective 57(5):950, 953. origin. symptoms of psychological 1991. Translation of the German “ of the German Translation 1991. 1994. London, U.K.: Her Majesty’s Stationery Office (HMSO). 1994. (HMSO). Office Stationery Majesty’s U.K.: Her 1994. London, 1993. Verlag. Apotheker Deutscher Germany: Stuttgart, Ausgabe.” Med ( Drugs) Veterinary Than Other (Products Hübner W, Lande S, Podzuweit H. Hypericum treatment of mild depressions with of mild depressions treatment H. Hypericum Lande S, Podzuweit W, Hübner Lj. A, Gvozdenovic N, Sabo M, Mimica-Dukic, Popovic V, Jakovljevic Hypericum Depression Trial Study Group. Effect of Effect Group. Study Trial Depression Hypericum of A. Effects E, Frauendorf H, Sauerwein-Giese Woelk D, Ksciuk H, Johnson Karnick C. Kasper S. extract. (SAD) with Hypericum disorder of seasonal affective Treatment Kasper S. wort in mild to moderate John’s Kieser M. St. T, Laakmann, G, Schüle C, Baghai A, Kieser M. Clinical significance of hyperforinLaakmann, G, Deniel for the effica- Lantz M, Buchalter E, Giambanco V. St. John’s wort and antidepressant drug wort inter- and antidepressant John’s St. V. E, Giambanco Lantz M, Buchalter Lavie G, Mazur Y, Lavie D, Y, Lavie G, Mazur Lehrl S, S. 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312 © 2002 American Botanical Council. Excerpted from The ABC Clinical Guide to Herbs St. John’s wort Monograph – cohort, CH – uncontrolled, – meta-analysis, – parallel group, U MA PG 313 – single-center, SC – longitudinal cohort, – placebo-controlled, – Diagnostic and Statistical Manual of Mental – Diagnostic and Statistical Manual LC PC DSM – single-blind, – clinical global severity impression scale, impression – clinical global severity SB – patient-blind, CGI-S The ABC Clinical Guide to Herbs PB – surveillance, S – prospective, SJW was more effective than placebo and as effective as and as effective than placebo effective SJW was more of depression imipramine in the treatment 100 mg/day HAMD, by as measured HAMA, Clinical Global and scales.Impression also demon- quality of life Improved scale.strated in Zung self-rating depression safe Proven than imipramine. effects with less adverse tine for both overall depressive symptoms and the main symptoms and the depressive both overall tine for disorders.symptoms of depressive SJW is particularly anxiety from patients suffering depressive in effective better safety SJW revealed for symptoms.Tolerability fluoxetine. (p<0.001) than for 157 subjects on SJW had HAMD scores drop from drop 157 subjects on SJW had HAMD scores end, mean or 22.4 at baseline to 12.00 at 12 weeks of 22.1 to 167 imipramine patients’ scores compared between to 12.75 (no statistical difference dropping groups). mean of 2.22 of 7 for at end were CGI scores (no statistical imipramine group and 2.42 for SJW group groups). between difference self-assessment, In mean imipramine (no SJW and 2.60 for 2.44 for were scores scores groups).Tolerability between statistical difference SJW (1.65) than drug (2.35); better for were (no statis- groups). between tical difference concluded Researchers mild equal to imipramine for that SJW is therapeutically is and tolerated better.This to moderate depression largest trial on SJW comparing it to imipramine at stan- dose (150 mg/day). dard Severity of symptoms,Severity HAMD and the by as measured reduced scale was significantly Clinical Gobal Impression (p<0.01).The groups in both treatment in difference clinical response, each in HAMD for based on reduction group, significant. was not statistically SJW extract was as sertraline in treating to be at least as effective found mild to moderate depression. The number of patients with a remission of depression of patients with a remission The number higher with SJW than placebo (p=0.2), was significantly rates 14.3% with SJW vs. low had but they 4.9% for analysis.placebo in the full intention-to-treat SJW was tolerated,well being effect adverse with the only headaches (41% vs. 25%).The the for random analyses HAMD, HAMA, CGI-S, significant and CGI-I showed or time-by-treat- treatment but not for time for effects ment interaction.The study concluded that SJW was (no active major depression in treating not effective used). control Initial treatment phase = 8 weeks.Initial treatment Patients responding addition- for treatments respective given were positively al 18 weeks. 2 primary On the nei- outcome measures ther sertraline differ- significantly nor SJW performed placebo, from ently based on HAMD or CGI scale. Full in 31.9% placebo group, occurred response 24.8% ser- (p=0.26),traline group (p=0.21). and 23.9% SJW group Sertralineplacebo on a secondary was better than measure: partial scale that included a CGI improvement (p=0.02).Authorsresponders concluded that the study does not support of SJW in moderately the efficacy depression, major severe assay the low acknowledging sensitivity of this trial, the fact that 35% of trials on and in failure. result antidepressants known P – International Classification of Disease, – von Zerssen depression severity scale, severity Zerssen depression – von - retrospective, ) ICD RS D-S L. – odds ratio, – odds OR STEI 300 vs. imipramine Ze 117 in efficacy (p=0.09) to fluoxe- SJW extract is equivalent Remotiv® (Ze 117) vs. imipramine LI 160 or ser- traline SJW standard- ized extract (LI 160) or placebo LI-160 SJW extract stan- to dardized between 0.12% and 0.28% hyper- icin; sertraline (Zoloft®) – clinical global improvement impression scale, impression – clinical global improvement – double-blind, DB – open label, CGI-I OL – Hamilton Depression Scale,– Hamilton Depression SJW , 350 mg, 3x/day vs. dos- daily ing of 50 mg, 25 mg, then 25 mg (100 mg total/day) imipramine Ze 117 vs. flu- 20 mg/day oxetine extract, 2x/day; 75 mg imipramine, 2x/day day of stan- day SJW dardized extract or 50 of mg per day sertraline for 1 week, fol- 900 by lowed of mg per day SJW or 75 mg of per day sertraline 900 mg/day to increased 1200 mg/day or placebo SJW/day or SJW/day 50–100mg sertraline/day or placebo; divided into 3 doses/day © 2002 American Botanical Council. Excerpted from – retrospective cross-sectional, – retrospective HAMD - cross-sectional, Hypericum perforatum RCS CS – observational, OB 2 months 1050 mg/day 6 weeks 500 mg/day 6 weeks 250 mg SJW 7 weeks mg per 600 SJW for 4 SJW for (n=98) weeks or placebo 8 (n=102) for weeks 8–18 weeks 900–1500mg – crossover, – clinical global impression scale,– clinical global impression – open, O CO CGI – reference-controlled, – Hamilton Anxiety Scale, – Hamilton 20 20. RC R, DB, MC, PG, PC, Cm n=262 R, DB, MC n=240 (HAMD 16–24) scores R, DB, PG, MC (40 centers) n=324 HAMD scale >18. Mean HAMD 22.4 (SJW); 22.1 (imipramine) (ages >18 years) R, DB, PC, MC n=200 patients with baseline HAMD ≥ R, DB, PC, MC n=340 adults with baseline total HAMD score ≥ R, DB, C n=30 HAMA – comparison, – case-control, Cm – vehicle-controlled. CC – randomized, VC R Moderate depression Mild to moderate depression moderate depression without suicidal ideation (ICD-10) Severe depression Major depression Mild to moderate depression; comparison of SJW and selective serotonin reuptake inhibitors (SSRIs) – epidemiological, ., , ., ., E – controlled, et al et al. et al et al – multi-center, of patients, n – number – unpublished, – pilot study, – confidence interval, CI UP KEY: C Disorders, PS MC 1999 Philipp 2001 Woelk, 2000 Mild to Shelton 2001 Friede Author/Year Subject Author/Year Hypericum Design Depression Study Trial Group, Duration 2002 Dosage Preparation Results/Conclusion Depression Brenner 2000 Clinical Studies on St. on Studies Clinical wort ( John’s Clinical Studies on St. John’s wort (Hypericum perforatum L. ) (cont.)

Depression (cont.) Author/Year Subject Design Duration Dosage Preparation Results/Conclusion Lenoir et al., Mild to R, DB, PG, 6 weeks 1 tablet Hyperiforce™ At the end of the treatment period, a reduction of 1999 moderate Cm, MC 3x/day (1 mg tablets con- about 50% in Hamilton Depression scores was depression n =260 (over total hyper- taining observed in all groups. No significant differences (ICD-10) 20 years old) icin/day or 33 approximately between dosages. SJW was determined to be effective mg total 60 mg SJW in all 3 doses and is well tolerated. hypericin/day extract or 17 mg total (4–5:1) of hypericin/day) shoot tips standardized to 0.33 mg total hypericin content/tablet (controls standardized to 0.11 mg or 0.055 mg total hypericin/ tablet)

Laakmann et Mild to R, DB, PC, 7 weeks 900 mg/day WS 5573 Study demonstrated relationship between hyperforin al., 1998a moderate MC, PG (300 mg, (0.5% hyper- dose and antidepressant efficacy. 5% hyperforin SJW depression n=145 (mean 3x/day) forin) or WS product enhanced patients’ quality of life by producing age, 51 years 5572 (5% appreciable relief from symptoms compared to 0.5% placebo; 48.7 hyperforin) or (p=0.017) and placebo (p=0.004). No statistical differ- years placebo ence between 0.5% and placebo. Study suggests hyper- WW5573 forin is a therapeutically active constituent with antide- group; 47.3 pressant activity. years SJW group)

Wheatley, Mild to R, DB, PG, MC 6 weeks 900 mg/day LI 160 vs. Comparable efficacy to amitriptyline with clear tolera- 1997 moderate n=156 SJW extract amitriptyline bility advantage. No statistically significant difference in depression (HAMD score (300 mg, response rate was shown between SJW and amitripty- (DSM-IV), between 3x/day) or line (p=0.064). In the CGI item "side-effects of drugs," 17–24, mean amitriptyline greater tolerability for SJW was apparent (p<0.001 at score (3x25 mg in a week 2, p<0.05 at weeks 4 and 6). SJW=20.6 fixed dose amitriptylline= manner) 20.8) (ages 20–65 years)

Schrader et Mild to R, P,DB, PC, 6 weeks One, 250 mg Ze 117 Of SJW patients, 56% were deemed responsive to treat- al., 1998 moderate MC tablets SJW SJW extract ment compared to 15% on placebo.There were few depression n=159 extract 2x standardized adverse effects: 5 placebo, 6 SJW (mostly minor gas- daily (1 mg to 0.5 mg trointestinal upsets in SJW group). Researchers noted hypericin hypericin/ that the good tolerability profile contributed to the high daily) tablet compliance of the SJW group.

Vorbach et al., Typical R, DB, Cm, 6 weeks 900 mg/day LI 160 vs. SJW showed equal effectiveness to and better tolerabili- 1994 depression MC SJW extract imipramine ty than imipramine. Improved HAMD total score by with single n=130 (Mean (300 mg, 56% on SJW and 45% on imipramine. episode, HAMD score 3x/day) vs. SJW caused less frequent and less severe side effects recurrent 20.2 SJW imipramine than imipramine. episode, neu- group, 19.4 (3x25mg rotic depres- imipramine daily) sion, and group) (ages adjustment 18–75 years) disorder with depressed mood (DSM-III-R).

Harrer et al., Depression R, DB, Cm, 4 weeks 900 mg/day LI 160 vs. Showed roughly equal efficacy to maprotiline. No signifi- 1994 (ICD-10) MC SJW extract maprotiline cant difference between groups on HAMD, D-S, and n=102 (300 mg, CGI scores (HAMD score >16). 25% in SJW group and (HAMD score 3x/day), 35% in maprotiline group reported adverse drug effects. >16) (ages maprotiline, 25–65 years) (25 mg 3x/day)

KEY: C – controlled, CC – case-control, CGI – clinical global impression scale, CGI-I – clinical global improvement impression scale, CGI-S – clinical global severity impression scale, CH – cohort, CI – confidence interval, Cm – comparison, CO – crossover, CS - cross-sectional, DB – double-blind, D-S – von Zerssen depression severity scale, DSM – Diagnostic and Statistical Manual of Mental Disorders, E – epidemiological, HAMA – Hamilton Anxiety Scale, HAMD – Hamilton Depression Scale, ICD – International Classification of Disease, LC – longitudinal cohort, MA – meta-analysis, MC – multi-center, n – number of patients, O – open, OB – observational, OL – open label, OR – odds ratio, P – prospective, PB – patient-blind, PC – placebo-controlled, PG – parallel group, PS – pilot study, R – randomized, RC – reference-controlled, RCS – retrospective cross-sectional, RS - retrospective, S – surveillance, SB – single-blind, SC – single-center, U – uncontrolled, UP – unpublished, VC – vehicle-controlled.

314 © 2002 American Botanical Council. Excerpted from The ABC Clinical Guide to Herbs St. John’s wort Monograph – cohort, CH – uncontrolled, – meta-analysis, – parallel group, U MA PG 315 – single-center, SC – longitudinal cohort, – placebo-controlled, – Diagnostic and Statistical Manual of Mental – Diagnostic and Statistical Manual LC PC DSM – single-blind, – clinical global severity impression scale, impression – clinical global severity SB – patient-blind, CGI-S The ABC Clinical Guide to Herbs PB – surveillance, S – prospective, Significant improvement in symptoms over time with in symptoms over Significant improvement SJW and bright light (p=0.001). drug reac- No adverse tions reported. melanin index) in either the single or multiple doses melanin index) in either the single or multiple administered, with the exception of a slight, (p=0.50) pigmentation.The authors influence on UV-B-induced concluded that this study did not indicate phototoxic potential in the oral administration of higher than thera- depression. peutic doses (2–4 times) of SJW for Significantly reduced depression scores when given with when given scores depression reduced Significantly by well or without bright light therapy.Tolerated patients. (p<0.05) and reduced significantly more after 6 weeks more significantly (p<0.05) and reduced (p<0.01) . of mean scores (p<0.05) reduced Significantly and anxiety. depression was observed stimulation (p>0.05) in SJW No prolactin or placebo.A significant (p<0.05) small but statistically after 300 mg hormone occurred in growth increase SJW, 600 mg SJW.After cortisol was clearly stimulation after applica- 30 to 90 minutes observed (p<0.05) from tion. Significantly (p<0.05) reduced depressive symptoms depressive reduced (p<0.05) Significantly further (p<0.01) 4 weeks after even and after 2 weeks to placebo.compared were side effects No notable reported. in SJW group score in HAMD Significant reduction to placebo (p<0.01).compared Final score=7.17. to place- asleep compared in falling Significant reduction bo (p<0.01). tolerability with good Benefited patients and high compliance (p<0.05). 4, By week 5% statistical placebo and SJW in HAMD between level difference groups. reported. effects No adverse Significantly improved all 4 psychometric tests vs. improved Significantly place- bo, reported: with no serious side effects Hamilton scale (p<0.001),depression scale of von depression Zerssen (p<0.001), inventory, complaint Clinical Global Scale.Impression P – International Classification of Disease, (cont.) – von Zerssen depression severity scale, severity Zerssen depression – von - retrospective, ) ICD RS D-S L. – odds ratio, – odds OR LI 160 with bright light (3000 lux) vs. LI 160 with dim light (<300 lux) LI 160 observed (erythema No significant changes were and LI 160 vs. light therapy Kira® fatigue after 2 weeks perceived lowered Significantly WS 5570 SJW extract or placebo LI 160 vs. placebo LI 160 vs. placebo LI 160 vs. placebo – clinical global improvement impression scale, impression – clinical global improvement – double-blind, DB – open label, CGI-I OL – Hamilton Depression Scale,– Hamilton Depression (300 mg, 3x/day) Single dose: 6 or 12 coated tablets, 3x (contain- daily ing 5400 or 10,800 mcg of total hyper- icins). Steady-state trial: initial dose of 6 tablets (1800 mcg of hyper- icins) followed 3 x 1 by tablets (2700 mcg) per day 7 days for (300 mg 3x/day) hypericin (300 mcg 3x/day) WS 5570, 600 mg WS 5570, or placebo (300 mg, 3x/day) (300 mg, 3x/day) (300 mg, 3x/day) © 2002 American Botanical Council. Excerpted from – retrospective cross-sectional, – retrospective HAMD - cross-sectional, Hypericum perforatum RCS CS – observational, OB 4 weeks mg/day 900 Single-dose or Steady-state 7 days 1 month mg/day 900 6 weeks mcg/day 900 5 hours 300 mg 1 month 900 mg/day 4 weeks 900 mg/day 6 weeks 900 mg/day – crossover, – clinical global impression scale,– clinical global impression – open, O CO CGI – reference-controlled, – Hamilton Anxiety Scale, – Hamilton RC R, SB n=20 (ages 29-63 years) O n= 20 (ages 18–65 years) R, P n=72 R, PC, CO n=12 males healthy 20 between and 35 years old n=20 (mean age, 44.4 years) R, DB, PC, MC n=89 (HAMD <20) score (ages 20–64 years) R, DB, PC n=39 (Mean HAMD score 12.55 SJW group, 12.37 placebo (ages group) 20–64 years) R, DB, PC, MC n=72 (HAMD >16) score (ages 18–70 years) HAMA – comparison, – case-control, Cm – vehicle-controlled. CC – randomized, (cont.) VC R Seasonal affec- disorder tive (SAD) (DSM-III-R) HAMD scale>16 tive disorder tive (SAD) (DSM-IV) Phototoxicity of SJW in of treatment depression (UV-B, UV-A, visible light, solar-simulat- ed radiation) Effect of SJW Effect on cortisol, hor- growth mone, and prolactin Fatigue O, U, pilot Mild depres- sion and somatic symp- toms (ICD- 09). Mild to mod- erate depres- sion (ICD-9) Major depres- sion and tem- porary depressive neurosis (DSM-III-R) ., – epidemiological, ., E et , – controlled, et et et al et al et al – multi-center, of patients, n – number – unpublished, – pilot study, – confidence interval, ., 1994 ., 2001 ., 1998 CI UP KEY: C Disorders, PS MC Martinez al Kasper, 1997 Seasonal affec- Schempp al Hänsgen Other Subject Author/Year Shüle Design Duration Dosage Preparation Results/Conclusion 2001 Stevinson Stevinson al Fatigue and Seasonal Affective Disorder Disorder Affective and Seasonal Fatigue Subject Author/Year Design Duration Dosage Preparation Results/Conclusion 1994 Hübner Author/Year Subject Author/Year and Harrer Design Sommer, 1994 Duration Dosage Preparation Results/Conclusion Depression Depression 1994 Clinical Studies on St. on Studies Clinical wort ( John’s Clinical Studies on St. John’s wort (Hypericum perforatum L. ) (cont.)

Other (cont.) Author/Year Subject Design Duration Dosage Preparation Results/Conclusion Burnstein et SJW effects U 21 days 100 mg 2x St. John’s wort The study concluded that SJW did not increase clear- al., 2000 on steady n=8 daily for 3 (0.3% stan- ance of carbamazepine. state carba- days, then 200 dardized ma-zepine and mg, 2x daily tablet) or car- carbama- for 3 days, bama-zepine zepine-10,11- then 400 mg (brand not epoxide phar- once daily for stated) maco-kinetics 14 days; then 300 mg SJW with carba- maze-pine, 3x daily for 14 days

Taylor and Obsessive- O 12 weeks 450 mg SJW 450 mg SJW Significant change from baseline, with mean change in Kobak, 2000 compulsive n=12 patients extract, 2x/day extract stan- Yale-Brown Obsessive-Compulsive Scale of 7.4 points disorder with 12 dardized to (p=0.01).At end of trial, 5 patients were rated much or (OCD) months diag- 0.3% hypericin very much improved on clinician CGI, 6 were minimally nosis of OCD (brand not improved, and 1 had no change. Side effects included (DSM-IV) stated) diarrhea (3 subjects) and restless sleep (2 subjects). Improvements noted in first week. Results warrant placebo-controlled study of SJW for obsessive-compul- sive disorder.

Grube et al., Menopausal O 12 weeks One, 300 mg Kira® Self-assessment by Menopause Rating Scale for assessing 1999 symptoms Drug moni- tablet, 3x/day sexuality and CGI. Psychological, psychosomatic, and tori-ng study vasomotor symptoms recorded at baseline, 5, 8, and 12 n=106 weeks. Significant improvement in psychological and psy- Women chosomatic symptoms. Menopausal symptoms reduced 43–65 years or disappeared in majority (76.4% by patient assess- old ment; 79.2% by physician assessment).About 80% of with symp- women considered sexuality was improved with SJW toms charac- teristic of pre- and post- menopause

Czekalla et al., Electro-car- R, DB, Cm, 6 weeks 1800 mg/day Jarsin® 300 SJW did not delay conduction through the atria or 1997 diogram MC or vs. imipramine depolarization and repolarisation in the ventricles. effects in n=209 150 mg/ day Imipramine increased heart rate and can cause patho- patients with imipramine logical repolarisation. High-dose SJW extract (i.e., 2x depression normal daily dose) produced fewer cardiac conduction defects than tricyclic antidepressants for treating elderly patients or patients with a pre-existing conductive dys- function, and should be considered safer than tricyclic antidepressants, especially in patients with pre-existing conduction disorders.

KEY: C – controlled, CC – case-control, CGI – clinical global impression scale, CGI-I – clinical global improvement impression scale, CGI-S – clinical global severity impression scale, CH – cohort, CI – confidence interval, Cm – comparison, CO – crossover, CS - cross-sectional, DB – double-blind, D-S – von Zerssen depression severity scale, DSM – Diagnostic and Statistical Manual of Mental Disorders, E – epidemiological, HAMA – Hamilton Anxiety Scale, HAMD – Hamilton Depression Scale, ICD – International Classification of Disease, LC – longitudinal cohort, MA – meta-analysis, MC – multi-center, n – number of patients, O – open, OB – observational, OL – open label, OR – odds ratio, P – prospective, PB – patient-blind, PC – placebo-controlled, PG – parallel group, PS – pilot study, R – randomized, RC – reference-controlled, RCS – retrospective cross-sectional, RS - retrospective, S – surveillance, SB – single-blind, SC – single-center, U – uncontrolled, UP – unpublished, VC – vehicle-controlled.

316 © 2002 American Botanical Council. Excerpted from The ABC Clinical Guide to Herbs