St. John's Wort -- Benefits, Dosage and Side Effects

Quality-controlled, standardized extract in each Pure Matters St John's Wort capsule.

Description

Medicinal Parts

The medicinal parts include the fresh buds and flowers separated from the inflorescences, the aerial parts collected during the flowering season and dried, and the entire fresh flowering plant.

Flower and Fruit

The golden yellow flowers are in sparsely blossomed terminal cymes. The 5 sepals are ovate-lanceolate to lanceolate and very pointed. The sepals are also smooth, serrate at the tip, and marked by many light and dark glands. The 5 petals and numerous stamens are fused into 3 bundles. The ovary has a broad or narrow oval shape. The fruit is a 3-valvular capsule, which is triangular and oval. The seeds are cylindrical and shortly pointed at both ends. The seeds are 1 to 3 mm long, either black or dark brown, and covered in small warts.

Leaves, Stem, and Root

The perennial plant is 30 to 60 cm and contains a long-living branched root and rhizome, which tapers toward each end. The reddish stem is erect, has 2 raised edges, and can reach 100 cm in height. The oval-shaped, translucent, punctate leaves are attached directly at the base and often covered in black glands.

Characteristics

The flowers release an odorless red juice when squeezed, which tastes weakly bitter and irritating.

Habitat

The plant is indigenous to all of Europe, western Asia and northern Africa. It has been introduced to eastern Asia, Australia and New Zealand, and it is cultivated in Poland and Siberia.

Production

St. John's Wort consists of the dried above-ground parts of Hypericum perforatum gathered during flowering season. The herb is cut at the start of the flowering season and dried quickly in bunches in order to preserve the oil and secreted contents.

Not to be Confused With

The plant may be mistaken for other Hypericum species, such as Hypericum barbatum, Hypericum hirsutum, Hypericum maculatum, Hypericum montanum, and Hypericum tetrapterum.

Other Names

Amber, Hardhay, Goatweed, Klamath Weed, Saint John's Word, St. Johnswort, Tipton Weed

Quality-controlled, standardized extract in each Pure Matters St John's Wort capsule.

Actions & Pharmacology

Compounds

Anthracene derivatives (0.1-0.15%): favoring naphthodianthrones, especially hypericin, pseudohypericin

Flavonoids (2-4%): in particular, hyperoside, quercitrin, rutin, isoquercitrin, and also biflavonolids, including amentoflavone

Xanthones (0.15-0.72%): 1,3,6,7-tetrahydroxy-xanthone

Acylphloroglucinols: hyperforin with small quantities of adhhyperforin

Volatile oil: chief components are aliphatic hydrocarbons, including, among others, 2-methyloctane, undecane; also dodecanol, mono- and sesquiterpenes, including, among others, alpha-pinene, caryophyllene; also 2-methyl-3-but-3-en-2-ol

Oligomers

Procyanidines and other catechin tannins (6.5-15%)

Caffeic acid derivatives: including chlorogenic acid

Effects

St. John's Wort extracts were more effective than placebo in the treatment of mild to moderate depression in multiple controlled clinical trials. St. John's Wort demonstrated similar efficacy to amitriptyline, imipramine, maprotiline, and fluoxetine as well as to diazepam and desipramine when combined with valerian. Antimicrobial and antifungal effects have been studied in vitro. St. John's Wort was effective against cancer in vitro. The herb has shown anti-inflammatory, antioxidant, and cardiac effects as well.

Serotonin reuptake inhibition and monoamine oxidase inhibition have been reported. The antidepressant effect of St. John's Wort may also be mediated via reduction of corticotropin releasing hormone (CRH) secretion through suppression of interleukin-6 release. Anti-inflammatory activity may be related to inhibited release of arachidonic acid from membrane phospholipids, inhibition of nuclear factor-kappa B and protein kinase C. The cardiac effect may be due to inhibition of cellular phosphodiesterase, with positive inotropic effects at low concentrations and negative inotropic effects at high concentrations. A 2006 systematic review of prospective clinical trials found reasonable evidence to suggest that high-dose hyperforin extracts induce CYP3A (Whitten, 2006). St. John's Wort may induce cytochrome P450 3A4 and other isoenzymes in humans through the induction of the pregnane X receptor, which regulates CYP3A4 transcription. St. John's Wort also may induce CYP1A2, 2E1, and 2D6. St. John's Wort has demonstrated ability to induce P-glycoprotein. Antimicrobial action of St. John's Wort may be due to hyperforin, a phloroglucin derivative.

Antianxiety Effects

The anxiolytic effect of St. John's Wort may be due to benzodiazepine receptor activation. The antidepressant mechanism of action may be due to effects on many neurotransmitters including serotonin, norepinephrine, dopamine, L-glutamate, and GABA. Hypericum perforatum extract increased rearing in open field tests with rats and latency time was significantly enhanced in the light-dark model of anxiety. Individual components of this extract did not demonstrate the same effect. Administration of the benzodiazepine antagonist flumazenil, with Hypericum perforatum, completely negated the anxiolytic activity. Investigators concluded that benzodiazepine receptor activation is the basis for the use of St. John's Wort in the treatment of anxiety (Zanoli et al, 1998).

Antidepressant Effects

The mechanism of the antidepressant effect of St. John's Wort has not been fully determined. It is likely a result of synergistic and/or additive effects of several different constituents of St. John's Wort. In vitro, hyperforin inhibited the uptake of norepinephrine, dopamine, L-glutamate, and GABA (Wonnemann et al, 2000). Hyperforin inhibited dopamine receptors D1 and D5 and selectively inhibited the norepinephrine transporter in vitro. Hypericin inhibited dopamine receptors D3 and D4 and the flavonoid rutin inhibited D2. The bioflavonoid amentoflavone was the only substance studied that demonstrated significant inhibition at serotonin receptors, specifically 5-HT(1D) and 5-HT(2C). Amentoflavone also inhibited the benzodiazepine receptor and opioid receptor subtype h-delta (Butterweck et al, 2002). Rutin was necessary for the antidepressant activity of a methanolic St. John's Wort extract in rats, but was not effective alone. Rutin may increase the bioavailability of other essential constituents in St. John's Wort through effects on transport through biological membranes, P-glycoprotein, or the cytochrome P450 system (Noldner & Schotz, 2002).

An elevated level of corticotropin releasing hormone (CRH) has been implicated in the pathogenesis of depression. When human blood cells from patients with depression and healthy subjects were stimulated with phytohemagglutinin or lipopolysaccharides and treated with hypericum extract, interleukin-6 (IL-6), and, to a lesser extent, interleukin 1 beta (IL-1b) and tumor necrosis factor alpha (TNF-alpha) were suppressed. IL-6 production was suppressed in all blood samples (from patients with depression and healthy subjects) treated with hypericum extract. IL-1b production was suppressed in the blood of 2 of 4 patients with depression while no change was observed in healthy subjects (n=5). TNF-alpha release was suppressed in all but one blood sample (from a healthy patient) treated with hypericum extract. If hypericum extract reduces IL-6 production in vivo, the antidepressant effects of St. John's Wort may be mediated via reduction of CRH secretion, as IL-6 induces the release of CRH (Thiele et al, 1994).

It has been demonstrated in rats that the antidepressant activity of St. John's Wort depends on its hyperforin content, possibly due to its effects on serotonergic transmission. Other central nervous system activity is mediated by other components of St. John's Wort. Hyperforin is not involved in the dopaminergic activity of alcoholic extracts (Bhattacharya et al, 1998). Dopamine-mediated CNS activity of Hypericum perforatum extract LI160 was again demonstrated in mouse bioassays with the help of dopamine receptor antagonists (Butterweck et al, 1997).

Anti-inflammatory Effects

Amentoflavone, found in St. John's Wort, has anti-inflammatory and anti-ulcerogenic properties (Berghofer & Holzl, 1989). A St. John's Wort extract suppressed leukocyte infiltration in mice treated with carageenan and prostaglandin E1 (Shipochliev et al, 1981). Hypericin dose-dependently inhibited the release of arachidonic acid from membrane phospholipids in calcium ionophore-stimulated human granulocytes. The calcium ionophore was not the only inducer. Inhibitory activities were noted in concentrations of hypericum under 0.4 micromoles. This inhibition resulted in the suppression of leukotriene B and interleukin production but did not affect prostaglandin E2. The end result is an immunosuppressive effect (Panossian et al, 1996). Anti-inflammatory effects of hypericin may be partly due to nuclear factor-kappa B (NF-kB) inhibition. Hypericum may inhibit protein kinase C (PKC), suggesting an inhibitory effect on PKC-regulated transcription factors. Hypericin was not confirmed as an antioxidant since it did not affect hydrogen peroxide-induced NF-kB activation (Bork et al, 1999).

Antimicrobial Effects

Hyperforin, an extract isolated from St. John's Wort, has demonstrated significant antimicrobial activity against strains of Staphylococcus aureus. A butanol fraction of St. John's Wort inhibited the growth of Helicobacter pylori. Antibacterial effects of St. John's Wort may be related to the simultaneous effects of radiation from the sun (Reichling et al, 2001). In vitro antibacterial activity of hyperforin against methicillin-resistant Staphylococcus aureus (MRSA) has been documented at a minimum inhibitory concentration of 1 mcg/mL. Standard therapeutic dosing of 300 mg 3 times daily resulted in a steady-state plasma concentration of 100 ng/mL, lower than that necessary for therapeutic antibacterial activity (Reichling et al, 2001; Voss & Verweij, 1999).

Antineoplastic Effects

In vitro studies demonstrated cytoxicity against human colon carcinoma. Hypericin was studied for antitumor effects in A431 human cancer cells. Hypericin inhibited leukemia cells and gastrointestinal tumor cells. Hypericin also inhibited autophosphorylation of the epidermal growth factor (EGF) receptor as well as the tyrosine phosphorylation of peptides catalyzed by the EGF receptor. The T cell, PTK, P56, was also dose-dependently inhibited by hypericin. The study concluded hypericin has direct inhibitory effects on tumor cells (Kil et al, 1996).

Antioxidant Effects

Dilutions of Hypericum extract, standardized to either hypericin or hyperforin, demonstrated significant antioxidant effects in both cell-free and human vascular tissue (Hunt et al, 2001). Cytochrome P450 Induction Effects

St. John's Wort significantly induced cytochrome P450 1A2, 3A4, 2E1, and 2D6 in a randomized, open-label trial of 12 healthy subjects (Durr et al, 2000).

Neuroendocrine Effects

Oral administration of 600 mg of a St. John's Wort extract containing hyperforin (WS 5570) stimulated cortisol secretion 30 to 90 minutes following intake. No cortisol stimulation was observed following oral intake of 300 mg WS 5570. The results of this study suggested that hyperforin (not hypericin) is the active component in St. John's Wort extracts which influence certain neurotransmitters in the central nervous system (Schule et al, 2001). Norepinephrine Reuptake Inhibition Effects: Alteration of biogenic amine synthesis was proposed as a possible mechanism of action. Hypericum extract (0.01% to 0.1%) demonstrated 50% synaptosomal norepinephrine reuptake inhibition and some beta-adrenergic and muscarinic receptor inhibition at higher concentrations (Mueller & Schaefer, 1996).

P-Glycoprotein Induction Effects

A single dose of St. John's Wort (900 mg) significantly inhibited p-glycoprotein while long term use of St. John's Wort nonsignificantly induced p-glycoprotein in an open-label study of 12 healthy subjects. Fexofenadine (60 mg) was studied as a marker p-glycoprotein substrate. Fexofenadine Cmax increased 45% and oral clearance decreased 20% (both p<0.05 compared to pretreatment) (Wang et al, 2002).

St. John's Wort significantly increased P-glycoprotein expression and associated drug efflux in a randomized, single-blinded, placebo-controlled trial of 22 healthy subjects (13 female, 9 male). Subjects received St. John's Wort (Good n' Natural, standardized to 0.15% hypericin) 600 mg (n=15) or placebo (n=7) three times daily for 16 days. P-glycoprotein expression in peripheral blood mononuclear cells increased 4.2-fold with St. John's Wort after 16 days (29.5 ± 14.3 median fluorescence intensity (MFI, a measure of P-glycoprotein expression) versus 7 ± 1.9 MFI, p<0.05, 95% confidence interval (CI): 13.5, 31.6) (Hennessy et al, 2002). In 8 healthy male volunteers, St. John's Wort significantly induced intestinal P-glycoprotein/MDR1 and hepatic cytochrome P450 3A4. Subjects were nonsmokers, ages 23 to 35 years, and abstained from caffeine, alcohol, citrus fruits, and medications for 5 days prior to and during the study (Durr et al, 2000).

Wound-Healing Effects

In a comparative study in rats, oral St. John's Wort was more effective for wound healing than a topical tincture of calendula (marigold). Primary endpoints of the study were rates of wound contraction, epithelization time, and wound breaking strength; incision, excision, and dead space wounds were investigated. Both treatments demonstrated greater wound healing compared with placebo (Rao et al, 1991).

Quality-controlled, standardized extract in each Pure Matters St John's Wort capsule.

Clinical Trials

Anxiety

Three cases have been reported of patients with generalized anxiety disorder experiencing relief of symptoms with St. John's Wort at doses of 900 mg twice daily. Two patients had taken kava previously without effectiveness. The 900-mg dose improved sleep, ability to relax, and ability to cope with daily stress, and reduced worry within 4 weeks in a 45-year-old female with chronic anxiety for 8 years. At 12 months of therapy with St. John's Wort, the patient continued to report effectiveness without side effects or relapse. St. John's Wort 900 mg twice daily reduced anxiety symptoms on the Symptoms Checklist 90 from 74 to 25 by week 9 in a 43-year-old female. Prior to treatment, she had persistent tension, worry, irritability, muscle tightness, bruxism, and insomnia. After 9 weeks of treatment, she slept better and had increased ability to cope (Davidson & Connor, 2001).

Cognitive Function

Hypericum extract containing 5% hyperforin increased quantitative pharmaco electroencephalogram (qEEG) power performances to a greater extent than the 0.5% extract but overall differences only reached statistical significance compared to placebo. In a double-blinded, placebo-controlled, parallel group comparison, the effect of hyperforin content on the pharmacological effects of St. John's Wort was measured via the qEEG. Fifty-five volunteers received 900 mg hypericum extract containing 0.5% or 5% hyperforin as a single dose for 1 week. qEEG data represented the mean power values of the absolute electrical power of 17 electrodes during 10-minute intervals of “eyes open” and “eyes shut” conditions. Increases in power were recorded in delta, theta, and alpha-1 frequencies with the most significant effect occurring in the theta frequency band during “eyes closed” conditions. The most significant power increases occurred 6 hours after extract administration. Alpha-2 frequency power values for the extracts were not appreciably different from placebo. Both extracts were well tolerated and no relevant adverse effects were reported (Schellenberg et al, 1998).

St. John's Wort extract demonstrated a trend toward greater cognitive ability in a placebo-controlled, double-blinded, multicenter 4-week trial of 50 patients with neurotic depression. St. John's Wort not only prevented a further reduction in cognitive ability but also improved it. It was also noted that this patient group, which included treatment-resistant cases, were selected from general practice, not from neurological practice, where a higher response rate is usually seen due to better patient selection (Lehrl et al, 1993).

Depression

The evidence from quality clinical trials to date is inconsistent and confusing as to whether St. John's Wort extracts are better than placebo or standard antidepressants in alleviating depression in adults, the authors of a 2005 Cochrane Database review of current publications conclude. Several specific extracts of the herb may help with mild to moderate depression, they found; the studies overall seem to show that they are more effective than placebo and similarly effective as prescription antidepressants for depression that is mild to moderate in severity. But benefits for treating major depression are likely minimal. Trials were included in the analysis if they were randomized, double-blind, included people with depression and outcomes such as symptoms, and compared the herb to a placebo or standard antidepressant. A total of 37 trials were identified. The 12 trials that compared the extract to placebo in people with major depression found the herb to be more effective than placebo, but the bigger and more precise trials indicated only a small benefit [rate ratio 1.15]. But trials that included not only people with major depression but those with mild and moderate symptoms as well indicated notable benefits for St. John's Wort. While side effects from the herb are uncommon and usually mild, there is a substantial risk of unwanted and risky interactions with a number of other medicines, so consultation with a physician before starting to take the herb is crucial. Also, effectiveness and safety indicated in this review hinge on the use of certain marketed preparations, which may vary notably from those sold in most venues (Linde, 2005).

The authors of a 2006 review of evidence from the above Cochrane database review and other (primarily) English-language literature—25 systematic reviews, 10 meta-analyses, one qualitative research study—for St. John's wort in treating depression conclude that intensive and regular publications of this kind have been published over the past decade. Overall, most report positive findings for the extract when compared with placebo for mild to moderate depression. Recently, however, the focus of studies has shifted from questions of effectiveness to potential interactions and safety of St. John's Wort. The authors of a 2004 review of adverse effects (from case reports) conclude that the most relevant risks involve interactions with other medicines, such as with cyclosporine in people with organ transplants. St. John's Wort increases metabolism and consequently reduced plasma concentrations of drugs that are metabolized by the cytochrome P450 enzyme system. Of all the research published on St. John's Wort for depression, only one was identified that focused on the patient's motivation in considering the herb over standard medications. The authors note that this area of examination warrants more attention (Pilkington, 2006).

A systematic large-scale observational study of St. John's Wort extract a year earlier found the herb extracts to be well tolerated and apparently effective in routine treatment of mild to moderate depression. The review was based on 16 observational (nonrandomized) and phase IV studies in primary care settings that included a minimum of 100 patients with primarily depressive illnesses and treated with a St. John's Wort extract. Altogether, 34,804 patient experiences with the extract were included in the pooled analysis. The daily extract dosage used varied from 360 to 1200 mg, and most studies were 4 to 6 weeks long. No serious side effects or interactions were reported; the most common side effect reported was gastrointestinal upset, and the second most common was increased sensitivity to light and skin reactions (Linde & Knuppel, 2005).

The same author of an earlier systematic review, in 2002, found thtat St. John's Wort was significantly more effective than placebo (17 trials; n = 1168) and similarly effective as tricyclic antidepressants and benzodiazepines, with fewer adverse effects, in 8 trials including 1,132 patients with mild-to-moderate depression. St. John's Wort preparations were tested at doses ranging from 350 milligrams (mg) to 1800 mg daily. Limitations of the trials reviewed included heterogeneity of the patient population and St. John's Wort extracts and doses used, low doses of comparison antidepressants, and short observation periods of 4 to 6 weeks (Linde & Mulrow, 2002).

A meta-analysis concluded that St. John's Wort was more effective than placebo and similarly effective as tricyclic antidepressants in moderate depression. Two German trials comparing St. John's Wort and placebo and 4 trials (3 German) comparing St. John's Wort to amitriptyline, maprotiline, and imipramine were included. The usual St. John's Wort dose used was 300 mg 3 times daily (total daily dose ranged from 200 mg to 900 mg). To be included in the analysis, the studies had to be blinded and controlled with placebo or standard antidepressants; patients (n=651 combined) had to have depressive disorders diagnosed using ICD-10, DSM-IIIR, or DSM-IV criteria; patients had to have similar sociodemographic backgrounds; and the clinical outcome had to be measured using the Hamilton Depression Scale (HAMD). Baseline HAMD scores ranged from 15 to 24. When compared with placebo, St. John's Wort demonstrated a significantly higher response rate (73.2% versus 37.9%) and had a lower dropout rate (12.2% versus 19.5%). St. John's Wort demonstrated a similar response rate when compared to tricyclic antidepressants (64% versus 66.4%) and a lower dropout rate due to side effects or inadequate efficacy (12.6% versus 16.2%) (Kim et al, 1999). The studies included in this meta-analysis are also included in the systematic review by Linde & Mulrow, 2000; however, this meta-analysis reflects a less heterogenous patient population due to more stringent inclusion criteria.

St. John's Wort significantly reduced symptoms of depression in a randomized, double-blinded, placebo-controlled trial of 375 patients with mild-to-moderate depression. Patients had a single-blind, placebo run-in phase for 3 to 7 days. Responders to the placebo phase, defined as 25% or greater reduction in the Hamilton depression scale, were excluded from continuing the trial. Remaining patients were randomized to receive St. John's Wort extract WS 5570 300 mg 3 times daily for 6 weeks. WS 5570 is a hydroalcoholic extract standardized to contain 3% to 6% hyperforin and 0.12% to 0.28% hypericin. Previous studies have generally used extracts standardized to 0.3% hypericin and/or 3% hyperforin. The mean Hamilton depression scale (HAMD) score for all patients decreased from baseline 21.9 ± 1.7 by a mean of 9.9 ± 6.8 with WS 5570 and 8.1 ± 7.1 with placebo (p=0.03 versus placebo). In patients with a baseline HAMD score of at least 22, the HAMD decreased by 10.5 ± 7.0 with WS 5570 and 8.5 ± 7.7 with placebo (p = 0.04). In patients with baseline HAMD score <22, no significant difference was noted between WS 5570 and placebo. In the intention-to-treat analysis, 52.7% of patients were responders (defined as a decrease of at least 50% in HAMD score from baseline) to WS 5570 versus 42.3% with placebo (p less than 0.05 versus placebo). Patients withdrawing from the trial included 18 (9.7%) WS 5570 patients and 25 (13.2%) placebo patients. Adverse events were reported by 30.6% of WS 5570 patients compared with 37% of placebo patients. Two patients taking WS 5570 were withdrawn and hospitalized due to worsening symptoms (Lecrubier et al, 2002).

St. John's Wort in 3 different daily doses reduced the symptoms of mild-to-moderate depression in a randomized, double-blinded, multicenter, parallel-group study (Lenoir et al, 1999).

Depressive symptoms continued to be controlled with open-label St. John's Wort therapy given for an additional 6 months following a 7-week double-blinded trial comparing St. John's Wort with sertraline in 18 patients with mild-to-moderate depression (Brenner et al, 2002).

Other trials have shown similar results in the treatment of mild-to-moderate depression (Schrader et al, 1998; Laakmann et al, 1998; Harrer, 1999, 1994; Vorbach, 1997, 1994; Steger, 1985; Behnke et al, 2002; Philipp et al, 1999) No significant difference was demonstrated between St. John's Wort and imipramine in the treatment of depression in a randomized, double-blind, parallel-group, multicenter trial of 324 patients. Patients received Hypericum extract (ZE 117, standardized to 0.2% hypericin) 250 mg or imipramine 75 mg twice daily for 6 weeks.

No significant differences were found between groups using the Hamilton Depression Scale, Clinical Global Impression scale, and the patient's global impression scale. Adverse effects were reported by 39% (62/157) of patients taking St. John's Wort and 63% (105/167) of patients taking imipramine (Woelk, 2000).

Depression, Major

A multicenter, randomized, double-blind phase III study was conducted to test and compare the efficacy and safety of Hypericum extract WS 5570 to paroxetine in patients suffering from moderate or severe depression according to DSM-IV criteria. One hundred thirty patients were included. The results showed that WS 5570 and paroxetine were similar in preventing relapse in a continuation treatment after recovery from an episode of moderate to severe depression (Anghelescu et al, 2006).

The objective of a double-blind, randomized, placebo-controlled trial was to study the antidepressant efficacy and safety of Hypericum perforatum extract WS 5570 at doses of 600 mg/day (once daily) and 1200 mg/day (600 mg twice daily). Patients (n=332) with an episode of mild or moderate major depressive episode were randomized to take either WS 5570 600 mg/day, WS 5570 1200 mg/day, or placebo over a period of six weeks. The primary outcome measure was the change in total score on the Hamilton Rating Scale for Depression (HAM-D, 17 item version). Significantly more patients in the WS 5570 groups showed treatment response and remission. St. John's wort was consistently more effective than placebo in patients with either less severe or more severe baseline impairment. Patients in the WS 5570 1200 mg/day group experienced higher remission than in the group receiving WS 5570 600 mg/day. Incidence of adverse events was low in all groups (Kasper et al, 2006).

In a postmarketing surveillance study, single-dose-administration of highly dosed St. John's wort was studied in 4,337 patients with depressive symptoms over a 12-week period. States of mental and physical health were documented using the SF-12-sumscore as a measure for quality of life. Physicians and patients rated efficacy and tolerability. Results showed that SF-12-sumscore improved significantly. About 80% of the physicians and patients judged the efficacy and safety of the drug as “good” or “very good”. Tolerability was assessed as “good” or “very good” in more than 95% (Rudolf & Zeller, 2004).

The antidepressant efficacy of Hypericum perforatum was investigated in an 8-week, double-blind, placebo-controlled study and compared to the antidepressant, fluoxetine. Seventy-two outpatients were randomly assigned to receive Hypericum perforatum 900 mg/day, fluoxetine 20 mg/day, or placebo. Efficacy measures included the HAM-D21 scale, the Montgomery-Asberg Rating Scale, and the Clinical Global Impression. Safety was assessed with the UKU Side Effect Rating Scale. In the intention-to-treat analysis, no differences between the mean scores of the three treatment groups were found. In the analysis of observed cases, patients receiving Hypericum had the lowest remission rates (12%, p=0.016) compared to fluoxetine (34.6%) and placebo (45%). In conclusion, Hypericum perforatum was less efficacious than both fluoxetine and placebo (Moreno et al; 2006). A previous well-designed trial by Bjerkenstedt et al revealed different results. One-hundred sixty outpatients received the same doses as above over four weeks. Treatment with hypericum was still not more effective in short-term treatment in mild to moderate depression than placebo, but remission rates were higher with 24% compared to fluoxetine (28%) and placebo (7%). In this trial, hypericum was furthermore significantly better tolerated than fluoxetine (Bjerkenstedt et al, 2005).

In contrast, St. John's wort was assessed to be more effective than fluoxetine in a study by Fava et al. In a double-blind, placebo-controlled study, patients with major depressive disorders were randomized to 12 weeks of double-treatment with LI 160 St. John's wort extract (900 mg/day), fluoxetine (20 mg/day), or placebo. Remission rates of 38% for hypericum, 30% for fluoxetine and 21 % for placebo were found (Fava et al, 2005).

A 2005 randomized and double-blind trial concluded that a specific extract of St. John's wort—WS 5570—is at least as effective as paroxetine, a selective serotonin reuptake inhibitor (SSRI), and also is better tolerated than this drug, when taken over the course of six weeks in people with moderate or severe depression. In all, 251 adults with acute major depression at 21 psychiatric primary care practices in Germany were randomized to St. John's wort [900 mg three times daily) or paroxetine (20 mg once daily). Those who did not respond sufficiently to the initial dose after two weeks got benefit from an increased dose. By the end of six weeks, 71% of those randomized to take St. John's Wort compared to 60% of those rancomized to take paroxetine had a 50% or greater reduction in depression symptoms (Szegedi, 2005).

A comparison with sertraline found favorable effects of a hypericum extract (STW3) found. A once-daily dose of 612 mg of hypericum was not inferior to sertraline in 241 patients with moderate depressive disorders in a long-term treatment (Gastpar et al, 2005).

Safety and efficacy of hypericum extract STW-VI in comparison to the SSRI citalopram was assessed using a double-blind, randomized, multicenter, placebo-controlled study design. Outpatients (n=388) suffering from moderate depression received hypericum extract (900mg/day), citalopram (20 mg/daily), or placebo. The statistical significant therapeutic equivalence of hypericum extract STW3-VI to citalopram (p<0.0001) and the superiority of this hypericum extract over placebo (p<0.0001) was demonstrated. At the end of the treatment, 54.2% (hypericum extract), 55.9% (citalopram), and 39.2% (placebo) of the patients were assessed as therapy responders. In most cases, the investigators judged the tolerability of hypericum extract, citalopram, and placebo as “good” or “very good.” Thus, hypericum extract STW3-VI is a good alternative to chemically defined antidepressants in the treatment of outpatients with moderate depression (Gastpar et al, 2006). These findings support the results of a previous study carried out by Uebelhack et al (Uebelhack et al, 2004).

By contrast, St. John's Wort was no more effective than placebo or sertraline for major depression in a randomized, double-blinded, placebo-controlled, multicenter trial. After a one-week, single-blind, placebo run-in phase including 428 patients, nonresponding patients (n=340) were randomized to receive either hypericum extract (LI 160, Lichtwer Pharma, Berlin, Germany) 900 mg daily divided into 3 doses (n=113), sertraline 50 mg daily (with two placebo doses; n=109), or placebo 3 times daily for 8 weeks (n=116). After weeks 3 or 4, daily hypericum doses could be increased to 1200 mg and sertraline doses to 75 mg. The average hypericum and sertraline doses received between week 3 and 8 were 1299 mg and 75 mg, respectively. During the continuation phase, the hypericum and sertraline doses could be increased to 1800 mg and 150 mg daily (Hypericum Depression Trial Study Group, 2002).

St. John's Wort was not more effective than placebo for the treatment of major depression in a randomized, double-blinded, placebo-controlled trial of 200 patients (Shelton et al, 2001).

Depression, Pediatric

A notable improvement in symptoms of depression and psychovegetative disorders in children was noted during a 6-week treatment with St. John's Wort extract (LI 160 Lichtwer Pharma). Seventy-four children ages 1 to 12 years (median age 9) with symptoms of depression, psychovegetative disturbance, anxiety, and/or restlessness were administered St. John's Wort extract at doses ranging from 300 mg daily to 900 mg daily, at the discretion of their physician, for an intended 4-week study period that was extended to 6 weeks. Efficacy and tolerance of treatment were evaluated based on the terms “worsened,” “unchanged,” “good,” and “excellent,” as assessed by both physicians and parents. In addition to the four general symptoms assessed, 8 specific symptoms, including listlessness, exhaustion, irritability, sleep disturbance, nervousness, concentration disturbance, dejection, and lack of drive were evaluated. Physicians rated overall efficacy either good or excellent in 72% of children by week 2, 97% after 4 weeks of treatment, and 100% after 6 weeks. Parents' ratings were similar at 65% improvement after 2 weeks, 93% after 4 weeks, and 98% after 6 weeks. Treatment was well tolerated and no adverse effects were reported. One case of worsening of nervousness presented when symptoms changed from “not present” at baseline to “mild” at 2 weeks. This was self-limiting (Hubner & Kirste, 2001).

Dermatitis

A significant improvement in symptoms of subacute atopic dermatitis was noted in patients following a 4-week treatment with a cream containing Hypericum extract standardized to 1.5% hyperforin (verum). Twenty-one patients with mild-to-moderate atopic dermatitis randomly applied verum or placebo twice daily to the left or right side of the body, respectively. Eighteen patients completed the double-blind trial. Intensity of eczematous lesions was compared and evaluated at days 7, 14, and 28. At each clinic visit, the hypericum cream was significantly superior to placebo (p<0.05), with a lack of anti-Staphylococcal aureus activity (p=0.064). Tolerance of the hypericum cream as well as placebo was good or excellent (Schempp et al, 2003).

Fatigue

Hypericum significantly reduced fatigue, anxiety, and depression in an open, uncontrolled study. Patients (n=20) with self-reported complaints of fatigue, tiredness, and exhaustion of at least 2 weeks duration (but no self-reported depression) received Hypericum (135 to 225 mg dried extract) 3 times daily for 6 weeks. The study concluded with a reduction of fatigue, depression, and anxiety. Without a control group, it was difficult to determine which results were from Hypericum or from a placebo effect. Further controlled studies were recommended (Stevinson et al, 1998).

Menopausal Symptoms

The efficacy of a fixed combination of black cohosh (Cimicifuga racemosa) and St. John's wort (Hypericum perforatum) extracts in women with climacteric complaints with a pronounced psychological component was investigated in a double-blind, randomized, placebo study involving 301 women. The treatment was superior to placebo (P<0.001) in alleviating climacteric complaints (Uebelhack et al, 2006).

Marked improvement of subjective and physical symptoms of menopause was observed in pre- and postmenopausal women following a 12-week treatment with Kira®, a St. John's Wort extract standardized to a total hypericin content of 300 mcg/tablet. One hundred and six women, 43 to 65 years old, were supplemented with 1 tablet St. John's Wort extract orally 3 times daily for a total of 12 weeks. Patients were excluded from the study if they were using hormone replacement therapy with estrogens or estrogen-progestogen combinations. The Menopause Rating Scale (MRS) (including changes in libido, dryness of the vagina, and urinary complaints) ranked symptoms from “not present” to “very marked.” The average total MRS score fell from marked intensity of symptoms to slight intensity after 12 weeks of St. John's Wort treatment (p<0.001) (Grube et al, 1999).

Otalgia, Pediatric

A reduction in ear pain in children was noted following the use of naturopathic herbal extract eardrops (NHED) containing St. John's Wort extract. One hundred and seventy-one children ages 5 to 18 years with otalgia related to acute otitis media (AOM) were randomly divided into 4 groups and treated with NHED (containing allium sativum (0.05%), verbascum thapsus (25%), calendula flores (28%), hypericum perforatum (30%), lavender (5%), and vitamin E (2%) in olive oil) 5 drops 3 times daily, alone; topical anesthetic (amethocaine and phenazone in glycerin) 5 drops 3 times daily, alone; NHED with oral amoxicillin 80 mg/kg/day; or topical anesthetic with oral amoxicillin 80 mg/kg/day. All treatments were for 3 days. The study was double-blinded and randomized. A 93.4% reduction in ear pain in the NHED group compared to an 80.9% reduction in the anesthetic group was observed. Visual analog scale was used to assess pain. Treatment was considered successful when the subjects or parents reported a reduction in ear pain after 48 hours. On both days 2 and 3, the NHED group reported less pain than the anesthetic group. Both groups who received drops alone reported significantly greater pain relief on both days 2 and 3 than the patients who were given eardrops plus oral antibiotics. No adverse effects were documented in any of the groups. The results of the NHED group cannot be directly correlated to the activity of St. John's Wort since the drops contained multiple herbal extracts. Another consideration the authors had taken into account was that AOM is usually a self-limiting condition that abates within 2 to 3 days on its own, suggesting that time alone may account for much of the reduction in pain (Sarrell et al, 2003).

A 3-day course of herbal ear drops that contained extract of Hypericum perforatum was as effective as a topical anesthetic in reducing ear pain in children. One hundred and three children 6 to 18 years completed this randomized trial. Sixty-one children received the combination herbal ear drops (Otikon Otic Solution), which contained Allium sativum, Verbascum thapsus, Calendula flores, and Hypericum perforatum in olive oil. Forty-two children received anesthetic eardrops containing amethocaine and phenazone in glycerin. The dose for both groups was 5 drops of Otikon or anesthetic applied to the affected ear canal three times daily. A significant reduction in ear pain for both groups (p<0.007) was observed. There was not a significant difference between the 2 groups although there was less pain 30 minutes following instillation with Otikon (p=0.007). No adverse effects were reported (Sarrell et al, 2001).

Premenstrual Syndrome

St. John's Wort significantly reduced symptoms of premenstrual syndrome in an observational study of 19 women. Subjects were given one 300 mg tablet of St. John's Wort daily, standardized to 900 mcg hypericin. Daily symptom ratings recorded by the subjects were significantly reduced (p<0.01) from a baseline of 128.42 to 70.11 after one menstrual cycle. Significant improvements were also demonstrated by scores on the Hospital Anxiety and Depression scale (p<0.01) and the modified Social Adjustment Scale (p<0.05). Improvements were greatest after one cycle of treatment (Stevinson & Ernst, 2000).

Sleep Quality

Hypericum extract increased slow-wave sleep but had no effect on REM sleep in a double-blinded, placebo-controlled, randomized, crossover study of 12 healthy female volunteers (mean age 59.8 years). Subjects received Hypericum extract LI 160 (Jarsin®) 300 mg 3 times daily for 4 weeks. Sleep onset and total sleep time did not change following supplementation. There was a slight drop in the total sleep amount and a corresponding increase in waking period occurred. Slow-wave sleep (sleep stages 3 and 4) increased from 1.5% to 6.0%. This increase in slow-wave sleep has been postulated by several investigators to be a significant contributor to the antidepressant effect of St. John's Wort (Schulz & Jobert, 1994).

Somatoform Disorders

A prospective, randomized, double-blind and placebo-controlled trial concluded that 600 mg of St. John's Wort extract LI 160 daily is both effective and safe in treating acute mild to moderately severe somatoform disorders. Statistically significant medium to large-sized superiority of St. John's wort treatment over placebo was shown (p<.0001) for each of the six primary efficacy measures as well as for the combined test in the intention-to-treat populations (n=173). All were adults being treated as outpatients. The findings confirm the results of a 2002 study in the journal Phamacology (by Volz HP, et al) In the current study, St. John's Wort was as safe and well-tolerated as the placebo (Muller, 2004).

Weight Loss

In a randomized, double-blinded, placebo-controlled trial, subjects taking a combination supplement containing St. John's Wort lost a statistically significant amount of body weight (1.4 kg; p<0.05) and body fat (2.9% change; p>0.05). Twenty-three subjects were assigned to 1 of 3 groups. Group A, the treatment group, received Citrus aurantium extract 975 mg, caffeine 528 mg, and St. John's Wort 900 mg daily. Group B received a placebo while group C served as the control and received nothing. All subjects participated in a circuit training exercise program 3 times a week for 45 minutes. Subjects also received instructions to follow the 1,800 kilocalorie/day American Heart Association Step One diet. The treatment group experienced an insignificant decrease in both plasma cholesterol and triglycerides. Neither the placebo nor control group lost a significant amount of body weight or body fat (Colker et al, 1999).

Quality-controlled, standardized extract in each Pure Matters St John's Wort capsule.

Indications & Usage

Approved by Commission E:

Anxiety
Depressive moods
Inflammation of the skin
Blunt injuries
Wounds and burns

Internally, the drug is used for psychovegetative disturbances, depressive moods, anxiety and nervous unrest. Externally, the oily Hypericum preparations are used for treatment and post-therapy of acute and contused injuries and for first-degree burns.

Unproven uses

The herb has been used for worm infestation, bronchitis and asthma, gallbladder disease, gastritis (also diarrhea), nocturnal enuresis, gout, and rheumatism. Oily Hypericum preparations are used internally for dyspeptic complaints, and externally for the treatment of myalgia.

Chinese Medicine

In a gargle solution, the herb is used externally for tonsillitis. The herb is also administered externally as a lotion for dermatoses.

Homeopathic Uses

The herb has been used for treatment of peripheral and central nervous system injuries, depressive moods, asthma and cerebral-vascular calcification.

Quality-controlled, standardized extract in each Pure Matters St John's Wort capsule.

Contraindications

Contraindications to use include a history of photosensitivity or a hypersensitivity to St. John's Wort.

Quality-controlled, standardized extract in each Pure Matters St John's Wort capsule.

Precautions & Adverse Reactions

The potential risk for adverse interactions with other medicines (antidepressants, anticoagulants, cyclosporine, others) has emerged as an important risk and precaution in the use of St. Johns Wort (Schulz 2006; Pilkington 2006, Whitten 2006, Linde 2005).

The tannin content of the drug can lead to digestive complaints, such as feeling of fullness or constipation. Photosensitization has been demonstrated in a controlled clinical trial using metered doses of hypericin and subsequent exposure to UVA/UVB radiation (Roots, 1996). Patients with a previous history of photosensitization to various chemicals should be cautious of direct sun exposure (Wheatley, 1998). Also, concomitant use of St. John's Wort and drugs metabolized by cytochrome P450 3A4, 1A2, or 2E1 may result in decreased drug concentrations and subsequent loss of drug effectiveness (Gurley et al, 2002).

Cardiac Effects

Swelling (edema) was reported by 21 of 113 patients taking St. John's Wort versus 9 of 116 patients taking placebo (p=0.02) for major depression in a randomized, double-blinded, placebo-controlled, multicenter trial (Hypericum Depression Trial Study Group, 2002). A case of hypertensive crisis possibly related to the consumption of wine and aged cheese with St. John's Wort therapy has been reported (Patel et al, 2002). The significance of any monoamine oxidase inhibition by St. John's Wort is controversial, though constituents of St. John's Wort have demonstrated mild monoamine oxidase inhibitory effects (Thiede & Walper, 1994; Demisch et al, 1989; Suzuki et al, 1984). Although St. John's Wort was initially characterized as a monoamine oxidase inhibitor (MAOI), it is believed that insufficient MAO inhibition occurs to explain the clinical activity of St. John's Wort as an antidepressant (DeSmet & Nolen, 1996; Bladt & Wagner, 1994). It remains possible that the mild MAOI property of St. John's Wort may lead to hypertensive crisis when combined with tyramine-containing foods (Demisch et al, 1989). Advise patients to use caution if they consume tyramine-containing foods while taking St. John's Wort and to immediately report any unusual symptoms to their healthcare provider.

Central Nervous System Effects

Restlessness (0.3%) and fatigue (0.4%) occurred in 3,250 patients in one study of depressed patients (Woelk, 1994). In another study, fatigue/tiredness was reported in 5% of subjects, and restlessness in 6% (Vorbach, 1997). Symptoms are difficult to evaluate since the herb is being used to treat depression, which may have similar symptoms. Headache was noted in 7% of studies reviewed (Wheatley, 1998).

Dermatologic Effects

Multiple studies have reported photosensitivity (Jacobson, 2001; Brockmoller et al, 1997; Roots et al, 1996) while other studies demonstrated a lack of photosensitivity with St. John's Wort (Schempp et al, 2001; Schempp et al, 2000; Kerb et al, 1996). Hypericin is an active, photodynamic pigment and is considered the phototoxic constituent of St. John's Wort (Siegers, 1993). No significant phototoxic effects occurred from ingestion of a hypericum extract in both a single-dose and multiple-dose study (Schempp et al, 2001).

Genitourinary Effects

Frequent urination was reported by 30 of 113 patients taking St. John's Wort versus 13 of 116 patients taking placebo (p=0.003) for major depression in a randomized, double-blinded, placebo-controlled, multicenter trial (Hypericum Depression Trial Study Group, 2002). Anorgasmia was reported by 28 of 113 patients taking St. John's Wort versus 16 of 116 patients taking placebo (p=0.04) for major depression in a randomized, double-blinded, placebo-controlled, multicenter trial (Hypericum Depression Trial Study Group, 2002).

Neurological Effects

Headache was noted in 7% of studies reviewed (Wheatley, 1998). Nerve hypersensitivity reactions were reported in 6% (4/70) of patients treated with high dose hypericum by one practitioner. These reactions only occurred in patients who ingested liquid hypericum preparations with sediment. The practitioner linked this adverse effect to substances contained in the sediment. This reaction involved hypersensitivity of the hands and feet to cold, heat, and touch, to the point of being painful (Baillie, 1998).

Coordination, concentration, and attentiveness (necessary for the safe operation of motor vehicles) were not impaired in 32 depressed patients receiving 900 mg hypericum extract daily (1080 micrograms hypericin content) for 4 weeks in a double-blinded, placebo-controlled study (Schmidt, 1991). A case was reported of acute neuropathy following concomitant use of St. John's Wort and sun exposure. A 35-year-old woman took 500 milligrams/day of St. John's Wort for 4 weeks. She developed stinging pain on her face and hands, areas exposed to sun. During an examination, she had painful reactions to light brushing, air gusts at room temperature, and exposure to cold (5 to 10 degrees Celsius). Three weeks after discontinuing St. John's Wort, her symptoms improved and completely disappeared in 2 months (Bove, 1998).

Psychiatric Effects

Numerous cases of mania, hypomania, anxiety, and schizophrenia relapse have been reported (van Gurp et al, 2002; Brown, 2000; Lal & Iskandar, 2000; Anon, 1999; O'Bresail & Argouarch, 1998).

Thyroid Hormone Effects

St. John's Wort was weakly associated with increased thyroid stimulating hormone (TSH) levels in two cases in a retrospective case control study involving 37 patients with elevated TSH levels and 37 control patients matched for gender and age (Ferko & Levine, 2001). The design and conclusions of the study by Ferko and Levine were criticized in a commentary article (Hauben, 2002).

Pregnancy

St. John's Wort is contraindicated during pregnancy. High concentrations of St. John's Wort in vitro were mutagenic to sperm cells and adversely effected oocytes. The data suggest that St. John's Wort given at high concentrations damages reproductive cells (Ondrizek, 1999).

Quality-controlled, standardized extract in each Pure Matters St John's Wort capsule.

Drug Interactions

Contraindicated

Irinotecan

Concurrent use may result in reduced irinotecan effectiveness and treatment failure. Clinical Management: Avoid concomitant use of St. John's Wort with irinotecan. The effect of St. John's Wort on metabolizing enzymes of irinotecan may last several weeks after St. John's Wort is discontinued. If a patient is to receive a course of therapy with irinotecan and is found to be taking St. John's Wort, discontinue St. John's Wort and if possible, delay the course of irinotecan for at least 2 weeks. An appropriate dose increase has not been determined in the case that the irinotecan course cannot be delayed.

Non-Nucleoside Reverse Transcriptase Inhibitors

Concurrent use may result in decreased non-nucleoside reverse transcriptase inhibitor concentrations and an increased risk of antiretroviral resistance and treatment failure. Clinical Management: Patients receiving therapy with non-nucleoside reverse transcriptase inhibitors should be advised to avoid the use of St. John's Wort. Coadministration of non-nucleoside reverse transcriptase inhibitors with St. John's Wort is expected to decrease non-nucleoside reverse transcriptase inhibitor concentrations leading to suboptimal serum concentrations of non-nucleoside reverse transcriptase inhibitors and an increased risk of antiretroviral resistance and treatment failure.

Protease Inhibitors

Concurrent use may result in decreased protease inhibitor concentrations and an increased risk of antiretroviral resistance and treatment failure. Clinical Management: Avoid concomitant use of St. John's Wort and protease inhibitors.

Rasagiline

Concurrent use may result in an increased risk of serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes) and/or an increased risk of hypertensive crisis. Clinical Management: The concurrent administration of rasagiline and St John's Wort is contraindicated. Allow at least a 14-day washout period after stopping rasagiline before starting St John's Wort. Given the terminal half-life of St John's Wort of 41.7 hours, wait at least 5 half-lives (9 days) after stopping St John's Wort before initiating rasagiline.

Selegiline

Concurrent use may result in an increased risk of serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes) and/or an increased risk of hypertensive crisis. Clinical Management: The concurrent administration of selegiline and St John's Wort is contraindicated. Allow at least a 14-day washout period after stopping selegiline before starting St John's Wort. Given the terminal half-life of St John's Wort of 41.7 hours, wait at least 5 half-lives (9 days) after stopping St John's Wort before initiating selegiline.

Major Risk

Amiodarone

Concurrent use may result in reduced amiodarone levels. Clinical Management: Concurrent use of amiodarone and St. John's Wort is not recommended. Given the extended half-life of amiodarone, potential for drug interaction may exist even after discontinuation of amiodarone.

Amsacrine

Concurrent use may result in reduced effectiveness of amsacrine. Clinical Management: Avoid concomitant use of St. John's Wort and amsacrine.

Anesthetics

Concurrent may result in an increased risk of cardiovascular collapse and/or delayed emergence from anesthesia. Clinical Management: Discontinue St. John's Wort at least 5 days before surgery using anesthetics.

Anticoagulants

Concurrent use may result in decreased warfarin plasma concentrations leading to reduced anticoagulant effectiveness. Clinical Management: Concomitant use of anticoagulants with St. John's Wort is not recommended. If patients elect to remain on St. John's Wort, symptoms of decreased anticoagulant efficacy and prothrombin times should be closely monitored. Upward dose titration of the anticoagulant should be undertaken only if the patient takes a consistent daily dose of St. John's Wort with a reputable product containing a consistent amount of active ingredients of St. John's Wort. Patients should be advised that if they discontinue use of St. John's Wort, they may have an increased risk of bleeding complications. Patients should not discontinue St. John's Wort without notifying their health care provider.

Cyclophosphamide

Concurrent use may result in reduced cyclophosphamide effectiveness. Clinical Management: Avoid concomitant use of St. John's Wort and cyclophosphamide.

Cyclosporine

Concurrent use may result in decreased cyclosporine levels, acute transplant rejection, and graft loss. Clinical Management: Extreme caution is advised when cyclosporine to patients who are taking St. John's Wort as concomitant use has resulted in significantly decreased cyclosporine levels, organ transplant rejection, and graft loss. If concurrent use is warranted, monitor cyclosporine blood levels and adjust cyclosporine dose as necessary (Prod Info NEORAL® soft gelatin oral capsules, oral solution, 2006; Prod Info SANDIMMUNE® oral capsules, oral solution, IV injection, 2006).

Darunavir

Concurrent use may result in decreased darunavir plasma concentrations and potential loss of darunavir efficacy. Clinical Management: Coadministration of darunavir/ritonavir and St. John's Wort (Hypericum perforatum) may result in significantly decreased darunavir plasma concentrations due to induction of CYP3A-mediated darunavir metabolism by St. John's Wort. As this may lead to loss of darunavir efficacy, darunavir/ritonavir and St. John's Wort should not be used concurrently.

Digoxin

Concurrent use may result in reduced digoxin efficacy. Clinical Management: Avoid concomitant use of St. John's Wort and digoxin. If patients elect to combine products despite this advice, digoxin levels should be monitored closely, noting that by day 10, trough digoxin concentrations may be decreased by 33% with further reductions possible. Upward dosage titration of digoxin should be undertaken only if the patient engages in consistent daily intake of St. John's Wort with a reputable product containing a constant amount of active ingredients of St. John's Wort. Under these circumstances, patients should be advised that if they discontinue use of St. John's Wort, that digoxin blood levels may escalate to toxic levels. Patients should not discontinue St. John's Wort without notifying their physician.

Erlotinib

Concurrent use may result in increased erlotinib clearance and reduced serum concentrations. Clinical Management: Avoid concomitant use of erlotinib and St. John's Wort. If concomitant erlotinib and St. John's Wort is not avoidable, doses of erlotinib greater than 150 mg may be required.

Etoposide

Concurrent may result in reduced effectiveness of etoposide. Clinical Management: Avoid concomitant use of St. John's Wort with etoposide.

Imatinib

Concurrent use may result in increased imatinib clearance. Clinical Management: Coadministration of imatinib and St. John's Wort, a CYP3A4 inducer, may result in a significant reduction in exposure to imatinib. Caution is advised when these two agents are coadministered. Consider using alternatives to St. John's Wort with less enzyme induction potential. However, if imatinib is used concurrently with St. John's Wort, consider an increase in imatinib dose by at least 50% to maintain therapeutic efficacy and monitor clinical response closely.

Lapatinib

Concurrent use may result in decreased lapatinib exposure or plasma concentrations. Clinical Management: Coadministration of lapatinib with St. John's Wort, a CYP3A4-inducer, may result in significantly decreased lapatinib AUC and should be avoided. However, if concurrent use is warranted, then consider titrating the dose of lapatinib gradually from 1250 mg/day up to 4500 mg/day, depending on tolerability. Once St. John's Wort is discontinued, reduce the increased lapatinib dose to the indicated dose (Prod Info TYKERB® oral tablets, 2007).

Linezolid

Concurrent use may result in CNS toxicity or serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes). Clinical Management: Concurrent use of linezolid and St John's Wort may result in serotonin syndrome. Monitor for serotonin syndrome effects including confusion, delirium, restlessness, tremors, blushing, diaphoresis, and hyperpyrexia. Consider a waiting period of 14 days between administration of these drugs.

Monoamine Oxidase Inhibitors

Concurrent use may result in an increased risk of serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes) and/or an increased risk of hypertensive crisis. Clinical Management: Avoid concomitant use of St. John's Wort and monoamine oxidase inhibitors (MAOIs). Allow at least a 14-day washout period after stopping the MAOI before starting St. John's Wort. Given the terminal half-life of St. John's Wort of 41.7 hours, if an MAOI is to replace St. John's Wort, wait at least 5 half-lives (9 days) after stopping St. John's Wort.

Paclitaxel

Concurrent use may result in reduced paclitaxel effectiveness. Clinical Management: Avoid concomitant use of St. John's Wort and paclitaxel.

Phenytoin

Concurrent use may result in reduced phenytoin effectiveness. Clinical Management: Avoid concomitant use of St. John's Wort and phenytoin. If patients elect to continue St. John's Wort while taking phenytoin, they must take a consistent dose of St. John's Wort with a reputable product containing a constant about of active ingredients of St. John's Wort. Phenytoin levels should be monitored and stabilized, and symptoms of reduced effectiveness (e.g. increased seizure activity) should be carefully monitored. If patients discontinue St. John's Wort, dosage of phenytoin may need to be decreased, and symptoms of phenytoin toxicity (e.g. nystagmus, ataxia, dysarthria, hyperreflexia, CNS depression, mental status changes, and hallucinations) should be monitored.

Selective Serotonin Reuptake Inhibitors

Concurrent use may result in an increased risk of serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes). Clinical Management: Patients should be advised to wait two weeks after stopping St. John's Wort before restarting selective serotonin reuptake inhibitor therapy. If a patient plans to replace selective serotonin reuptake inhibitor (SSRI) therapy with St. John's Wort, the half-life of the specific SSRI should be taken into consideration, waiting at least 5 half-lives for the SSRI to be metabolized out of the body.

Sirolimus

Concurrent use may result in subtherapeutic sirolimus levels resulting in possible transplant rejection. Clinical Management: Patients should be advised not to take St. John's Wort concurrently with sirolimus. If patients are found to be taking St. John's Wort and sirolimus, discontinue St. John's Wort and monitor sirolimus blood levels as sirolimus dosage may need to be reduced.

Sunitinib

Concurrent use may result in decreased sunitinib plasma concentrations. Clinical Management: The concomitant administration of sunitinib and St. John's Wort may result in an unpredictable decrease in sunitinib concentrations and is not recommended.

Tacrolimus

Concurrent use may result in subtherapeutic tacrolimus levels resulting in possible transplant rejection. Clinical Management: Advise patients not to take St. John's Wort concurrently with tacrolimus. If patients are found to be taking St. John's Wort and tacrolimus, discontinue St. John's Wort and monitor tacrolimus blood levels as tacrolimus dosage may need to be reduced.

Tamoxifen

Concurrent use may result in reduced tamoxifen effectiveness. Clinical Management: Avoid concomitant use of St. John's Wort and tamoxifen.

Trazodone

Concurrent use may result in an increased risk of serotonin syndrome (hypertension, hyerthermia, myoclonus, mental status changes). Clinical Management: Avoid concomitant use of St. John's Wort and trazodone. Given the half-life of trazodone of up to 15 hours, St. John's Wort should be avoided for at least 5 half-lives (3 days) following trazodone discontinuation.

Moderate Risk

Aminoleuvulinic acid

Concurrent use may result in increased risk of phototoxic reaction. Clinical Management: Avoid concomitant use of St. John's Wort and aminolevulinic acid.

Amitryptyline

Concurrent use may result in decreased effectiveness of amitriptyline and possible increased risk of serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes). Clinical Management: Avoid concomitant use of St. John's Wort with amitriptyline.

Antidiabetic agents

Concurrent use may result in hypoglycemia. Clinical Management: Caution is advised if patients take St. John's Wort with antidiabetic agents. Monitor closely for signs and symptoms of hypoglycemia.

Atorvastatin

Concurrent use of may result in reduced effectiveness of atorvastatin. Clinical Management: Advise patients taking atorvastatin not to start therapy with St. John's Wort without consulting their health care provider. Patients taking St. John's Wort with atorvastatin may require a higher dose of atorvastatin to retain effectiveness. If a patient has been taking atorvastatin and St. John's Wort, advise the patient not to stop St. John's Wort without consulting their health care provider, as atorvastatin levels may increase, leading to adverse effects.

Benzodiazepines

Concurrent use may result in reduced benzodiazepine effectiveness. Clinical Management: If patients take St. John's Wort with a benzodiazepine, monitor for alterations in the therapeutic and adverse effects of the benzodiazepine. If a patient is found to be taking St. John's Wort at the time of surgery during which midazolam or any other benzodiazepine is to be used for sedation, monitor the patient closely for signs of reduced benzodiazepine effectiveness and adjust the benzodiazepine dose if necessary.

Beta-Adrenergic Blockers

Concurrent use may result in decreased effectiveness of beta-adrenergic blockers. Clinical Management: Concomitant use of St. John's Wort and beta-adrenergic blockers is not recommended. If patients elect to take St. John's Wort and a beta-adrenergic blocker, increased dosage of the beta-adrenergic blocker may be necessary to achieve therapeutic goals. Patients should not discontinue St. John's Wort without consulting their physician as downward dose adjustment of the beta-adrenergic blocker may be required.

Buspirone

Concurrent use may result in an increased risk of serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes) or hypomania. Clinical Management: Caution patients taking buspirone to discuss the use of nonprescription medicines, herbs, and dietary supplements with their doctor or pharmacist. If a patient presents with hypomanic or serotonergic symptoms when taking buspirone, inquire about the use of nonprescription medicines, herbs, and dietary supplements. It is recommended to avoid St. John's Wort in patients taking buspirone, especially in combination with other psychotropic medicines.

Calcium Channel Blockers

Concurrent use may result in reduced bioavailability of calcium channel blockers. Clinical Management: Caution is advised if St. John's wort and calcium channel blockers are taken together. Monitor for continued effectiveness of the calcium channel blocker.

Carbamazepine

Concurrent use may result in altered carbamazepine blood concentrations. Clinical Management: Caution is advised if St. John's Wort and carbamazepine are taken concomitantly. Patients must take a consistent dose of St. John's Wort with a reputable product containing a consistent amount of active ingredients of St. John's Wort. Carbamazepine concentrations should be monitored if patients report the loss of seizure control or new side effects while taking St. John's Wort concomitantly. When patients discontinue St. John's Wort, carbamazepine levels and symptoms of carbamazepine toxicity (e.g. drowsiness, ataxia, slurred speech, nystagmus, dystonic reactions, hallucinations and vomiting) should be monitored.

Cerivastatin

Concurrent use may result in reduced effectiveness of cerivastatin. Clinical Management: Cerivastatin is no longer available in the United States; however, there may be a few patients who remain taking cerivastatin. Advise patients taking cerivastatin not to start therapy with St. John's Wort without consulting their health care provider. Patients taking St. John's Wort with cerivastatin may require a higher dose of cerivastatin to retain effectiveness. If a patient has been taking cerivastatin and St. John's Wort, advise the patient not to stop St. John's Wort without consulting their health care provider, as cerivastatin levels may increase, leading to adverse effects.

Clozapine

Concurrent use may result in reduced clozapine efficacy. Clinical Management: Avoid concomitant use of clozapine with St. John's Wort. If patients elect to remain on St. John's Wort, they should maintain consistent dosing. Clozapine dosage may need to be increased. Patients should not discontinue St. John's Wort without first consulting their clinician as downward adjustments in clozapine dose may be necessary as well as monitoring for increased side effects of clozapine (e.g. decreased white blood cell count, increased salivation, orthostatic hypotension, tachycardia, sedation, seizures).

Contraceptives, Combination

Concurrent use may result in decrease in plasma concentrations of estrogens and in contraceptive effectiveness. Clinical Management: Avoid concomitant use of St. John's Wort and hormonal contraceptives. Advise patient to use an alternate nonhormonal contraceptive method of birth control. Monitor patient closely for signs of breakthrough bleeding and/or pregnancy.

Estrogens

Concurrent use may result in decrease in plasma concentrations of estrogens and in estrogen effectiveness. Clinical Management: Caution is advised if St. John's Wort is taken with estrogen. Monitor the patient for a decreased response to estrogen replacement therapy (i.e. increase in vasomotor symptoms).

Fenfluramine

Concurrent use may result in an increased risk of serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes). Clinical Management: Avoid concomitant use. Given the half-life of fenfluramine of 20 hours (Prod Info Pondimin®, 1997), St. John's Wort should be avoided for at least 5 half-lives (4 to 5 days) following fenfluramine discontinuation. Given the terminal half-life of St. John's Wort of 41.7 hours (Wheatley, 1998), St. John's Wort should be avoided for at least 5 half-lives (9 days) before starting fenfluramine.

Fluvastatin

Concurrent use may result in reduced effectiveness of fluvastatin. Clinical Management: St. John's Wort may not affect the metabolism of fluvastatin. However, patients taking St. John's Wort with fluvastatin should be monitored for continued lipid-lowering effectiveness. If a patient has been taking fluvastatin and St. John's Wort, advise the patient not to stop St. John's Wort without consulting their health care provider, as fluvastatin levels may increase, leading to adverse effects.

Ginkgo

Concurrent use may result in changes in mental status. Clinical Management: If a patient presents with hypomanic symptoms, inquire about the use of nonprescription medicines, herbs, and dietary supplements.

Loperamide

Concurrent use may result in delirium with symptoms of confusion, agitation, and disorientation. Clinical Management: Caution is advised if St. John's Wort and loperamide are taken together. Monitor the patient closely for signs of altered mental status.

Lovastatin

Concurrent use may result in reduced effectiveness of lovastatin. Clinical Management: Advise patients taking lovastatin not to start therapy with St. John's Wort without consulting their health care provider. Patients taking St. John's Wort with lovastatin may require a higher dose of lovastatin to retain effectiveness. If a patient has been taking lovastatin and St. John's Wort, advise the patient not to stop St. John's Wort without consulting their health care provider, as lovastatin levels may increase, leading to adverse effects.

Methadone

Concurrent use may result in reduced methadone levels and increased risk of withdrawal symptoms. Clinical Management: Advise patients taking methadone to avoid concomitant St. John's Wort use. In patients presenting with symptoms of methadone withdrawal or requesting increased methadone doses, inquire about the use of St. John's Wort. If St. John's Wort and methadone are used concomitantly, advise the patient to take a consistent daily dose of St. John's Wort with a reputable product containing a standardized amount of active ingredients of St. John's Wort.

Nefazodone

Concurrent use may result in an increased risk of serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes). Clinical Management: Avoid concomitant use. Given the half-life of nefazodone and its active metabolites of up to 33 hours, St. John's Wort should be avoided for at least 5 half-lives (6 to 7 days) following nefazodone discontinuation. A two-week washout period is suggested after discontinuing St. John's Wort before starting an SSRI, and may be applied to nefazodone as well.

Nortriptyline

Concurrent use may result in decreased effectiveness of nortriptyline and possible increased risk of serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes). Clinical Management: Avoid concomitant use of St. John's Wort with nortriptyline.

Olanzapine

Concurrent use may result in reduced olanzapine efficacy. Clinical Management: Avoid concomitant use of olanzapine with St. John's Wort. If patients elect to remain on St. John's Wort, they should maintain consistent dosing. Olanzapine dosage may need to be increased. Patients should not discontinue St. John's Wort without first consulting their clinician, as downward adjustments in olanzapine dose may be necessary as well as monitoring for increased side effects of olanzapine (e.g. somnolence, nausea, constipation, dry mouth, asthenia).

Omeprazole

Concurrent use may result in decreased serum concentration of omeprazole. Clinical Management: Advise patients taking omeprazole to not start therapy with St. John's wort without consulting their health care provider. Patients taking omeprazole with St. John's wort may require a higher dose of omeprazole to retain effectiveness.

Opioid Analgesics

Concurrent use may result in increased sedation. Clinical Management: Caution is advised if St. John's Wort is taken with opioid analgesics. Monitor the patient closely for signs of excessive central nervous system sedation.

Pravastatin

Concurrent use may result in reduced effectiveness of pravastatin. Clinical Management: St. John's Wort did not affect the metabolism of pravastatin in one study. However, patients taking St. John's Wort with pravastatin should be monitored for continued lipid-lowering effectiveness. If a patient has been taking pravastatin and St. John's Wort, advise the patient not to stop St. John's Wort without consulting their health care provider, as pravastatin levels may increase, leading to adverse effects.

Reserpine

Concurrent use may result in reduced reserpine effectiveness. Clinical Management: Caution is advised if reserpine and St. John's wort are used concomitantly. Monitor for continued effectiveness of reserpine.

Rosuvastatin

Concurrent use may result in reduced effectiveness of rosuvastatin. Clinical Management: St. John's Wort may not affect the metabolism of rosuvastatin. However, patients taking St. John's Wort with rosuvastatin should be monitored for continued lipid-lowering effectiveness. If a patient has been taking rosuvastatin and St. John's Wort, advise the patient not to stop St. John's Wort without consulting their health care provider, as rosuvastatin levels may increase, leading to adverse effects.

Serotonin Agonists

Concurrent use may result in additive serotonergic effects and risk of cerebral vasoconstriction disorders. Clinical Management: It is recommended to avoid concomitant use of St. John's Wort and serotonin receptor agonists. If both agents are necessary, monitor closely for symptoms of serotonin syndrome and cerebral vasoconstriction.

Simvastatin

Concurrent use may result in reduced effectiveness of simvastatin. Clinical Management: Advise patients taking simvastatin not to start therapy with St. John's Wort without consulting their health care provider. Patients taking St. John's Wort with simvastatin may require a higher dose of simvastatin to retain effectiveness. If a patient has been taking simvastatin and St. John's Wort, advise the patient not to stop St. John's Wort without consulting their health care provider, as simvastatin levels may increase, leading to adverse effects.

Sorafenib

Concurrent use of may result in decreased sorafenib concentrations. Clinical Management: Coadministration of St. John's wort and sorafenib may result in decreased sorafenib concentrations due to induction of cytochrome P450-mediated sorafenib metabolism by St. John's wort. Use caution if St. John's wort and sorafenib are administered concurrently. Monitor patients for clinical response to sorafenib.

Theophylline

Concurrent use may result in reduced theophylline efficacy. Clinical Management: Concomitant use of theophylline with St. John's Wort is not recommended. If patients elect to remain on St. John's Wort, symptoms of decreased theophylline efficacy and theophylline levels should be closely monitored. A stable dose of St. John's Wort is recommended and patients should be advised not to abruptly discontinue St. John's Wort without consulting with their physician. Patients who experience decreased theophylline levels without apparent reason should be questioned about taking St. John's Wort. Theophylline doses may need to be increased to maintain a therapeutic level.

Tramadol

Concurrent may result in decreased tramadol exposure. Clinical Management: Monitor patients for tramadol efficacy.

Trycyclic Antidepressants

Venlafaxine

Concurrent use may result in an increased risk of serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes). Clinical Management: Avoid concomitant use. Given the half-life of venlafaxine of up to 11 hours, St. John's Wort should be avoided for at least 5 half-lives (one to two days) following venlafaxine discontinuation. A two-week washout period is suggested after discontinuing St. John's Wort before starting a SSRI, and may be applied to venlafaxine as well.

Verapamil

Concurrent use may result in reduced bioavailability of verapamil. Clinical Management: Caution is advised if St. John's wort and verapamil or similar calcium channel blockers are taken together. Monitor for continued effectiveness of the calcium channel blocker.

Minor Risk

Barbiturates

Concurrent use may result in decreased central nervous system depressive effect of barbiturates. Clinical Management: If patients take St. John's Wort with a barbiturate, monitor for alterations in the therapeutic and adverse effects of the barbiturate.

Chlorzoxazone

Concurrent use may result in reduced chlorzoxazone effectiveness. Clinical Management: Monitor patients for continued effectiveness of chlorzoxazone.

Potential Interactions

Acitretin

Concurrent use of St. John's Wort and acitretin may result in unplanned pregnancy and birth defects. Clinical Management: Avoid concomitant use of St. John's Wort and acitretin in female patients. Advise female patients starting acitretin therapy not to self-medicate with St. John's Wort.

Debrisoquin

Concurrent use of St. John's Wort and debrisoquin may result in reduced debrisoquin effectiveness. Clinical Management: Monitor patients taking St. John's Wort with debrisoquin for continued effectiveness of debrisoquin.

Fexofenadine

Investigators concluded that the modest changes in fexofenadine disposition with long term St. John's Wort use would not likely result in a clinically significant drug interaction. Long term administration of St. John's Wort (300 milligrams three times daily for 14 days) did not significantly alter bioavailability of fexofenadine, a selective P-glycoprotein substrate, compared to pretreatment (Wang et al, 2002).

Iron

The tannin content of St. John's Wort may complex with concomitantly administered iron, resulting in nonabsorbable insoluble complexes and may result in adverse sequelae on blood components. Clinical Management: It is unknown to what extent the amount of tannin in St. John's Wort may affect iron absorption clinically. Until more is known, patients who need iron supplementation should be advised to separate administration times of these two compounds by one to two hours.

Drug-Food Interactions

Minor Risk

Caffeine

Concurrent use of St. John's Wort and caffeine may result in increased caffeine metabolism. St. John's Wort significantly increased metabolism of caffeine, studied as a marker substance for metabolism through cytochrome P450 1A2, after 4 weeks in a randomized, open-label study of 12 healthy subjects (Gurley et al, 2002). In contrast, St. John's Wort did not affect pharmacokinetic parameters of caffeine after 2 weeks in an open-label study of 12 healthy volunteers (Wang et al, 2001).

Tyramine foods

Concurrent use may result in increased risk of hypertensive crisis. Clinical Management: The significance of the single case report of hypertensive crisis associated with consumption of St. John's Wort with tyramine containing foods (wine, aged cheese, others) is unknown. Advise patients to use caution if they consume tyramine containing foods while taking St. John's Wort, and to immediately report any unusual symptoms to their health care provider.

Quality-controlled, standardized extract in each Pure Matters St John's Wort capsule.

Dosage

Mode of Administration

Comminuted drug, herb powder, liquid and solid preparations for internal use; liquid and semi-solid preparations for external use; preparations made with fatty oils for external and internal use.

How Supplied

Capsules - (standardized at 0.3% hypericin) 125mg, 150mg, 250mg, 300mg, 350mg, 370mg, 375mg, 400mg, 424mg, 434mg, 450mg, 500mg, 510mg
Capsules, Extended Release - (standardized at 0.3% hypericin) 450mg, 900mg, 1000mg
Dried Herb
Extract - 1:1
Injection - 1%
Liquid - 300 mg/5ml, 250 mg/ml
Liquid Dilutions - 3x, 6x, 30x, 12c, 30c
Pellets - 3x, 6x, 12x, 12c, 30c
Tablets - (standardized at 0.3% hypericin) 100mg, 150mg, 300mg, 450mg
Tincture - 1:10
Transdermal - 900 mg/24 hr

Preparation

To prepare an infusion, use 2 teaspoonfuls of drug in 150 mL boiling water and steep for 10 minutes.

Daily Dosage

In general, a range of 200 to 1,000 mcg/day of hypericin is recommended for treatment of depression (Anon, 1996). Total hypericin concentrations of Hypericum extracts may vary widely; therefore caution should be taken in determining dosage (Fachinfo Helarium Hypericum, 1996; Fachinfo Remotiv, 1996; Hansgen, 1993; Schmidt & Sommer, 1993; Vorbach, 1994; Woelk, 1994).

For depressive moods, it is recommended the herb be administered for the duration of 4 to 6 weeks; if no improvement is apparent, a different therapy should be initiated.

Depression:

Capsules/tablets - 300 mg of the standardized extract should be administered 3 times daily (Clausson & Muller, 1997; Fachinfo Helarium Hypericum, 1996).

Dried herb - 2 to 4 g taken 3 times daily (Fachinfo Helarium Hypericum, 1996; Fachinfo Remotiv, 1996; Hansgen, 1993; Schmidt & Sommer, 1993; Vorbach, 1994; Woelk, 1994).

Tea - St. John's Wort as a tea is the traditional method of administration, with a single dose of 2 to 3 g dried herb placed in boiling water. If dried herb of 2 g is used, and the dried herb to extract ratio is 6, a usual dose of the extract would be 300 mg (Schultz, 1997).

Liquid extract 1:1 in 25% ethanol - 2 to 4 mL taken 3 times daily (Fachinfo Helarium Hypericum, 1996; Fachinfo Remotiv, 1996; Haensgen, 1993; Schmidt & Sommer, 1993; Vorbach, 1994; Woelk, 1994).

Tincture: (1:10) in 45% ethanol - 2 to 4 mL, 3 times a day (Fachinfo Helarium Hypericum, 1996; Fachinfo Remotiv, 1996; Hansgen, 1993; Schmidt & Sommer, 1993; Vorbach, 1994; Woelk, 1994).

Wounds, bruising, and swelling:

The herb is applied topically and locally for treatment. The activity of the topical preparations is based on the hyperforin content, which is highly variable depending on the method of oil preparation. The preparation may be stable for a few weeks up to 6 months. (Maisenbacher & Kovar, 1992)

Homeopathic Dosage

The daily dosage for homeopathic indications is 5 drops, 1 tablet or 10 globules every 30 to 60 minutes for acute therapy, and 1 to 3 times daily for chronic use. Parenterally, 1 to 2 mL subcutaneously administered 3 times daily for acute therapy and once daily for chronic therapy. The ointment is applied 1 to 2 times daily for acute and chronic use (HAB1).

Storage

Store at room temperature, away from heat, moisture and direct light. Hyperici oleum has a limited shelf life. One study showed that a sample containing 62 mg of hyperforin (the active ingredient in the oil) contained no hypericin in 14 days. If sunlight is not used to prepare the oil, then the breakdown is slower, but still less than 30 days. Various oil preparation methods have been described, including one with eutanol G, which showed stability for 6 months. Researchers evaluated 6 commercial samples of oil of Hypericum containing 2.2 to 20.8 milligrams/deciliter. All hyperforin was gone by the end of five weeks (Maisenbacher, 1992).

Quality-controlled, standardized extract in each Pure Matters St John's Wort capsule.

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Nervenheilkunde 12:320-322. 1993.Siepman M, Krause S, Joraschky P, et al: The effects of St. John's wort extract on heart rate variability, cognitive function and quantitative EEG: a comparison with amitriptyline and placebo in healthy men. Br J Clin Pharmacol 54(3):277-282. 2002.Singer A, Wonnemann M, Muller WE. Hyperforin, a major antidepressant constituent of St. John's wort, inhibits serotonin uptake by elevating free intracellular Na+. J Pharmacol Exp Ther 290(3):1361-1368. 1999.Singhal AB, Caviness VS, Begleiter AF, et al: Cerebral vasoconstriction and stroke after use of serotonergic drugs. Neurology 58(1):130-133. 2002.Smith M, Lin KM, Zheng YP. An open trial of nifedipine-herb interactions: nifedipine with St. John's Wort, ginseng, or Ginkgo biloba (abstract). Clin Pharmacol Ther 69(2):P86. 2001.Sommer H, Harrer G: Placebo-controlled double-blind study examining the effectiveness of an Hypericum preparation in 105 mildly depressed patients. J Geriatr Psychiatry Neurol 7 (suppl 1):S9-S11. 1994.Southwell IA, Campbell MH: Hypericin content variation in Hypericum perforatum in Australia. Phytochemistry 30(2):475-478. 1991.Spinella M, Eaton LA. Hypomania induced by herbal and pharmaceutical psychotropic medicines following mild traumatic brain injury. i 16(4):359-367. 2002.Staffeldt B, Kerb R, Brockmoller J, et al: Pharmacokinetics of hypericin and pseudohypericin after oral intake of the hypericum perforatum extract LI 160 in healthy volunteers. J Geriat Psych Neurol 7(1):47-53. 1994.Steger W. Depressive Verstimmungen. Randomisierte Doppelblindstudie zum Wirksamskeitvergleich einer pflanzlichen Wirkstoffkombination und eines synthetischen Antidepressivums. Z Allg Med 61:914-918. 1985.Sternbach H. Danger of MAOI therapy after fluoxetine withdrawal (letter). Lancet 2:850-851. 1988.Sternbach H. The serotonin syndrome. i 148:705-713. 1991.Stevinson C, Dixon M, Ernst E. Hypericum for fatigue - a pilot study. Phytomedicine 5(6):443-447. 1998.Stevinson C, Ernst E. A pilot study of Hypericum perforatum for the treatment of premenstrual syndrome. Br J Obstet Gynaecol 107(7):870-876. 2000.Stock S, Holzl J. Pharmacokinetic test of (14 C)-labeled hypericin and pseudohypericin from Hypericum perforatum and serum kinetics of hypericin in man. Planta Med 57 (suppl 2): A61-A62. 1991.Sugimoto K, Ohmori M, Tsuruoka S, et al: Different effects of St. John's Wort on the pharmacokinetics of simvastatin and pravastatin. Clin Pharmacol Ther 70(6):518-524. 2001.Suzuki O, Katsumata Y, Oya M, et al: Inhibition of monoamine oxidase by hypericin. Planta Med 50(3): 272-274. 1984.Szegedi A, Kohnen R, Dienel A, et al. Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St John's wort): randomized controlled double blind non-inferiority trial versus paroxetine. BMJ; 330(7490): 503. 2005.Thiede HM, Walper A. Inhibition of MAO and COMT by hypericum and hypericum extracts. J Geriatr Psychiatry Neurol 7 (suppl 1):S54-S56. 1994.Thiele B, Brink I, Ploch M. Modulation of cytokine expression by hypericum extract. J Geriatr Psychiatry Neurol 7(suppl 1):S60-S62. 1994.Uebelhack R, Blohmer JU, Graubaum HJ, et al. Black cohosh and St. John's wort for climacteric complaints: a randomized trial. Obstet Gynecol; 107(2 Pt)1): 247-255. 2006.Uebelhack R, Gruenwald J, Graubaum HJ, Busch R. Efficacy and tolerability of Hypericum extract STW 3-VI in patients with moderate depression: a double-blind, randomized, placebo-controlled clinical trial. Adv Ther; 21(4): 265-275. 2004.Uehleke B, Mueller SC, Uehleke B, et al: Interaction of St. John's Wort with digoxin, the relation to dosage and formulation (abstract). Phytomedicine 7(SII):20. 2000.Upton R (ed): St. John's Wort, Hypericum perforatum: quality control, analytical and therapeutic monograph. Am Herbal Pharmacopoeia, Santa Cruz, CA. 1-32. 1997.van Gurp G, Meterissian GB, Haiek LN, et al: St John's wort or sertraline? Can Fam Physician 48:905-912. 2002.Vasilchenko EA. Analgesic action of flavonoids of Rhododendron luteum Sweet, Hypericum perforatum L., Lespedeza bicolor Turcz. and L. hedysaroides (Pall.) Kitag. Rastit Resur 1986; 22:12-21. 1986.Verotta L, Appendino G, Belloro E, et al: Furohyperforin, a prenylated phloroglucinol from St. John's wort (Hypericum perforatum). J Nat Prod 62:770-772. 1999.Vitiello B. Hypericum perforatum extracts as potential antidepressants. J Pharm Pharmacol 51(5):513-517. 1999.Volz HP. Controlled clinical trials of hypericum extracts in depressed patients - an overview. Pharmacopsychiatry 30 (suppl):72-76. 1997.Vorbach EU, Arnold KH, Hubner WD. Efficacy and tolerability of St. John's Wort extract hypericum extract LI 160 in patients with severe depressive incidents according to ICD-10. Pharmacopsychiatry 30 (suppl 1):S81-S85. 1997.Vorbach EU, Huebner WD, Arnoldt KH. Effectiveness and tolerance of the hypericum extract LI 160 in comparison with imipramine: randomized double- blind double-blind study to 135 outpatients. J Geriatr Psychiatry Neurol 7(suppl 1): S19-S23. 1994.Voss A, Verweij P. Antibacterial activity of hyperforin from St. John's wort. Lancet 354:777. 1999.Wagner H, Bladt S. Pharmaceutical quality of hypericum extracts. J Geriatr Psychiatry Neurol 7 (suppl 1):S65-S68. 1994.Waksman JC, Heard K, Jolliff H, et al: Serotonin syndrome associated with the use of St. John's Wort (Hypericum perforatum) and paroxetine (abstract). Clin Toxicol 38(5):521. 2000.Wang Z, Gorski JC, Hamman MA, et al: The effects of St. John's Wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther 70(4):317-326. 2001.Wang Z, Hamman MA, Huang SM, et al: Effect of St. John's wort of the pharmacokinetics of fexofenadine. Clin Pharmacol Ther 71(6): 414-420. 2002.Warnecke G. Beeinflussung klimakterischer Depressionen. Therapieergebnisse mit Hypericin (Johanniskraut-Extract). Z Allg Med 62:1111-1113. 1986.Wentworth JM, Agostini M, Love J, et al: St. John's Wort, a herbal antidepressant, activates the steroid X receptor. J Endocrinol 166(3):R11-R16. 2000.Werth W. Psychotonin(R) versus Imipramin in der Chirurgie. Der Kassenarzt 15(64):64-68. 1989.Wheatley D. Hypericum extract: potential in the treatment of depression. CNS Drugs 9(6):431-440. 1998.Wheatley D. Hypericum in seasonal affective disorder (SAD). Curr Med Res Opin 15(1):33-37. 1999.Wheatley D. LI 160, an extract of St. John's Wort, versus amitriptyline in mildly to moderately depressed outpatients - a controlled 6-week clinical trial. Pharmacopsychiatry 30(suppl II):S77-S80. 1997.Whitten DL, Myers SP, Hawrelak JA, et al. The effect of St. John's wort extract on CYP3A: a systematic review of prospective clinical trials. Br J Clin Pharmacol; 62: 5: 1365-2125. 2006.Winterhoff H, Hambrugge M, Vahlensieck U. Pharmacological screening of Hypericum perforatum L. in animals. Nervenheilkunde 12:341-345. 1993.Woelk H, Burkard G, Gruenwald J. Benefits and risks of the Hypericum extract LI 160: drug monitoring with 3250 patients. J Geriatr Psychiatry Neurol 7(suppl 1):534-538. 1994.Woelk H. Comparison of St. John's Wort and imipramine for treating depression: randomised controlled trial. BMJ 321:536-539. 2000.Wonnemann M, Singer A, Muller WE. Inhibition of synaptosomal uptake of H-L-glutamate and H- GABA by hyperforin, a major constituent of St. John's Wort: the role of amiloride sensitive sodium conductive pathways. Neuropsychopharmacology 23(2):188-197. 2000.Wood S, Huffman J, Weber N, et al: Antiviral activity of naturally occurring anthraquinones and anthraquinone derivatives. Planta Med 56:651-652. 1990.Yu DK. The contribution of P-glycoprotein to pharmacokinetic drug-drug interactions. J Clin Pharmacol 39:1203-1211. 1999.Yue QY, Bergquist C, Gerden B. Safety of St. John's Wort (Hypericum perforatum) (letter). Lancet 355(9203):576-577. 2000.Zanoli P, Truzzi C, Cannazza G, et al: Evidence that hypericum perforatum extracts exert anxiolytic effects in rats. Fitoterapia 69(5):30. 1998.Zhang W, Lawa R, Hintona D, et al: Growth inhibition and apoptosis in human neuroblasoma SK-N-SH cells induced by hypericin, a potent inhibitor of protein kinase C. Cancer Lett 96:31-35. 1995.

Quality-controlled, standardized extract in each Pure Matters St John's Wort capsule.

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Pure Matters

St. John's Wort

This Ingredient Helps With:

Description

Medicinal Parts

Flower and Fruit

Leaves, Stem, and Root

Characteristics

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Production

Not to be Confused With

Other Names

Actions & Pharmacology

Compounds

Effects

Antianxiety Effects

Antidepressant Effects

Anti-inflammatory Effects

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P-Glycoprotein Induction Effects

Wound-Healing Effects

Clinical Trials

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Depression

Depression, Major

Depression, Pediatric

Dermatitis

Fatigue

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Otalgia, Pediatric

Premenstrual Syndrome

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Weight Loss

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Approved by Commission E:

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