About Herbs

Bottom Line: St. John's wort can help relieve depression; however, there is little or no proof that it can treat other symptoms. This herb can affect the activity of many drugs, including those used in chemotherapy (see below).

St. John's wort acts as an antidepressant in many animal and human studies. Numerous laboratory and animal studies have been performed to reveal the active components of St. John's wort. Some studies point to a compound called hypericin as the main component, while others point to a compound known as hyperforin. Both compounds might interact with chemicals and counteract processes in the brain that are associated with depression and anxiety.

To treat depression
Several studies in humans support the use of this herb for depression.

To treat anxiety
Although many studies support its use in depression, none have studied it to treat anxiety. No clinical evidence supports this use.

To treat chronic fatigue
Some research supports this use, but more is needed.

To treat insomnia
There is not enough evidence to support this use.

To reduce the symptoms of premenstrual syndrome (PMS)
A small study showed an improvement in PMS symptoms, but more research is needed to confirm this.

To treat seasonal affective disorder (SAD)
So far, a few studies show that St. John's wort is not effective for this use.

Topically, for wound healing
In laboratory studies, wort acts as an antibiotic and antiviral agent, but there is no proof from clinical trials that it can help wounds heal.

To treat HIV
A small study showed high toxicity and no benefit.

To attention-deficit/hyperactivity disorder (ADHD)
A small study showed that St. John's wort is not effective for this use.

Depression:
In a recent trial, 251 patients with acute major depression were given hypericum extract or paroxetine, an SSRI, daily for six weeks. Researchers found that both the treatment groups showed significant decrease in depression scores. St John's Wort appears to be as effective as paroxitene in the management of severe depression. However, care should be taken while taking St John's Wort as it can interact with other drugs.

A clinical trial carried out at multiple hospitals compared 900-1200 mg per day of St. John's wort to placebo in 167 patients with major depression. There were no significant differences in depression, anxiety, or functioning between the two groups, indicating that patients with severe depression should not use St. John's wort alone as a treatment.

In a clinical trial with 28 patients who had mild to moderate depression, 900 mg/day of St. John's wort was just as effective as 75 mg/day of sertraline (Zoloft®, a common antidepressant) in treating depression when given for seven weeks.

In a larger study of 240 patients with mild to moderate depression, 500 mg/day of St. John's wort was just as effective as 20 mg/day of fluoxetine (Prozac® or SarafemTM) in treating depression when given for six weeks.

To study the ability of St. John's wort to prevent depression relapse, 426 patients with recurrent, moderate depression were given a St. John's wort extract (3˟300 mg/day) or placebo for 6 months. Patients taking St. John's wart showed a significant decrease in depression scores. Also, there was no difference in adverse events reported between the 2 groups.

Premenstrual syndrome (PMS):
The effect of St. John's wort on premenstrual syndrome (PMS) was studied in a trial of 25 women. The treatment dose was 300 mg three times a day. After 2 months, a 51% improvement in symptoms was seen. Larger studies are recommended to establish if St. John's wort is truly effective in relieving symptoms of PMS.

This product may cause your skin to be more sensitive to sunlight, leading to sunburn, rash, or redness of the skin.

This product is regulated by the FDA as a dietary supplement. Unlike approved drugs, supplements are not required to be manufactured under specific standardized conditions. This product may not contain the labeled amount or may be contaminated. In addition, it may not have been tested for safety or effectiveness.

You are pregnant or nursing

You are undergoing treatment with UV light (Since St. John's wort makes the skin more sensitive to light).

You have bipolar disorder (This herb caused mania in a few patients with bipolar disorder. Take with caution).

You are taking warfarin (Patients should have their bleeding time monitored routinely. St. John's wort may interfere with the action of warfarin).

You are taking digoxin (St. John's wort might lessen its effect).

You are taking triptans such as sumatriptan, naratriptan, rizatriptan, or zolmitriptan (St. John's wort might have additive effects).

You are taking selective serotonin reuptake inhibitors (SSRIs) such as citalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline (St. John's wort might have additive effects).

You are taking tricyclic antidepressants such as nefazodone, amitriptyline, or imipramine.

You are taking birth control pills (St. John's wort can increase the risk of pregnancy).

You regularly consume alcohol (St. John's wort may result in increased sedation. Take with caution).

You plan to undergo general anesthesia for surgery (St. John's wort should be discontinued two weeks before surgery).

You are undergoing chemotherapy with drugs such as cyclophosphamide, paclitaxel, docetaxel, irinotecan, or etoposide (St. John's wort has been shown to reduce the effectiveness of chemotherapy).

You are taking tamoxifen (St. John's wort may lessen its effect).

You are taking sympathomimetics (St. John's wort may increase the effect).

You are taking HIV protease inhibitors such as indinavir, nelfinavir, ritonavir, saquinavir (St. John's wort has been known to lessen their effects).

You are taking any of the following drugs: theophylline, efavirenz, nevirapine, cyclosporin, tacrolimus, diltiazem, nifedipine, alprazolam, dextromethorphan, simvastatin, atorvastatin, gliclazide (St. John's wort can lessen their effects).

Headache

Gastrointestinal upset: nausea, abdominal discomfort, constipation

Dizziness, confusion, sedation · Sleep disturbances

Fatigue

Dry mouth

Skin sensitivity to sunlight

Contact your doctor if you experience: pain or tingling in the extremities, wounds that will not heal, or yellowing of the eyes or skin.

There is one case report of serotonin syndrome, consisting of high blood pressure, profuse perspiration, agitation, dizziness, and weakness.

There is one case report of sexual dysfunction.

Do not use St. John's wort if you are undergoing chemotherapy.

St. John's wort interferes with the action of many different drugs. Check with your doctor or pharmacist to make sure that other medications you are taking do not interact with St. John's wort.

Saint John's wort, hypericum, goatweed, God's wonder plant, witches herb

Derived from the flowering parts of the plant, St. John's wort generally is used for depression, seasonal affective disorder, and anxiety. Products currently are standardized based on hypericin content, although the hyperforin and bioflavonoid contents are also believed responsible for activity. Some studies comparing St. John's wort to standard antidepressants suggest it may be as effective as imipramine or selective serotonin reuptake inhibitors (SSRIs) to treat mild to moderate depression ^{(1) (2) (3)}. Results from another clinical trial indicate that the effectiveness of St. John's Wort is comparable to paroxetine, an SSRI, in the treatment of moderate to severe depression and is well tolerated ⁽⁴⁾ In addition, reductions in depression were sustained with continued use of St. John's wort in those with acute moderate depression ^{(5) (6)}. However, meta-analyses show that while data is inconsistent when all types of depression are analyzed ^{(7) (8)}. Studies also show possible efficacy in the management of anxiety and premenstrual syndrome ⁽⁹⁾, although additional research is necessary. St. John's wort was ineffective for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents ⁽¹⁰⁾and individuals with stomatodynia⁽¹¹⁾. St. John's wort can interact with many medications due to induction of cytochrome p450 (CYP) 3A4, CYP2C9 ⁽¹²⁾and other mechanisms ⁽¹³⁾. Significant interactions include decreased efficacy of, cyclosporin, tacrolimus, irinotecan, and other chemotherapeutic agents. Serotonin syndrome may occur when combined with sympathomimetics, antidepressants, or triptans ⁽¹⁴⁾. Frequently reported adverse events include nausea, headache, constipation, dizziness, confusion, fatigue, and dry mouth. St. John's wort should be used under medical supervision

Depression

Fatigue

Insomnia

Pain

Pediatric nocturnal incontinence

Premenstrual syndrome

Seasonal affective disorder (SAD)

Wound healing

The overall mechanism of action for St. John's wort is unknown. The hypericin component was thought to be responsible for antidepressant activity, but conflicting reports exist. It was initially shown to inhibit monoamine oxidase although this effect has not been demonstrated with use of the whole botanical. Hypericin demonstrates modest receptor affinity for muscarinic cholinergic and sigma receptors. In vitro studies with whole plant exact of St. John's wort reports weak inhibition of catechol-O-methyl-transferase (COMT) and limited reuptake of norepinephrine. Hyperforin, a phloroglucinol, has been shown to inhibit the reuptake of serotonin, dopamine, norepinephrine, GABA, and L-glutamine in vitro. In addition, hyperforin activates transient receptor potential (TRP) C6 channels, inducing neurite outgrowth and possible influencing monoamine uptake ⁽¹⁶⁾. Hyperforin is also responsible for CYP 3A4 induction through activation of the pregnane X receptor ⁽¹⁷⁾. Analgesic and CNS activity may be due to the bioflavonoid content.⁽¹⁵⁾

Hypericin: Oral administration peak concentration at approximately 2 hours, elimination half-life approximately 25 hours. Steady state concentrations with three times daily dosing occurred by day 4. Terminal half-life is 42 hours.

Hyperforin: Oral administration peak concentration occurred at approximately 3.5 hours. Elimination half-life is approximately 9 hours. Steady state concentration with 300 mg St. John's wort (standardized to 14.8 mg hyperforin) equal to 100 ng/ml.

Pseudohypericin: Oral administration peak concentration at approximately 30 minutes. Terminal half-life is approximately 23 hours. ⁽¹³⁾

May cause photosensitivity.

St. John's wort should be discontinued one week before surgery or chemotherapy.

Pregnant or nursing women should not consume St. John's wort.

Common: Headache, nausea, abdominal discomfort, constipation, dizziness, confusion, fatigue, dry mouth, sleep disturbances, and sedation.
Infrequent: Photosensitivity or photodermatitis, elevated liver function tests, acute neuropathy, increased prothrombin time (PT) ^{(13) (15)}.
Case reports: Mania in 3 patients with underlying bipolar disorder. Resolved promptly in 2 patients following discontinuation while the third experienced persistent agitation for several months ⁽¹³⁾.
Serotonin syndrome: Hypertension, diaphoresis, agitation, dizziness, and weakness with acute onset following 10 days of St. John's wort. Syndrome resolved following supportive care and discontinuation of St. John's wort ⁽¹⁴⁾.
Erythroderma affecting both light-exposed and non light-exposed areas of skin. Developed 4 days after initiation of St. John's wort and resolved after 5 weeks with concomitant oral steroids ⁽¹⁸⁾.
Sexual dysfunction: Decreased sexual libido that returned following discontinuation of St. John's wort ⁽¹⁹⁾.
Withdrawal syndrome: Nausea, anorexia, dry retching, dizziness, dry mouth, thirst, cold chills, and extreme fatigue in patient within 24 hours of stopping treatment of St. John's wort after 32 days of treatment ⁽²⁰⁾.

Cytochrome P450 3A4: St. John's wort has been shown to induce cytochrome isoenzyme 3A4, therefore affecting metabolism of certain medications and reducing serum concentrations. CYP 3A4 levels return to normal 1 week after discontinuing St. John's wort 21. Drugs metabolized by 3A4 include:

• Theophylline: Blood levels of theophylline may be significantly reduced, resulting in decreased efficacy.
• HIV protease inhibitors: Blood levels of indinavir, nelfinavir, ritonavir, and saquinavir can be significantly reduced, resulting in increased HIV viral load and development of viral resistance.
• HIV non-nucleoside reverse transcriptase inhibitors: Blood levels of efavirenz and nevirapine can be significantly reduced, resulting in increased HIV viral load.
• Cyclosporin / Tacrolimus: Blood levels of cyclosporin or tacrolimus can be significantly reduced, resulting in decreased efficacy.
• Diltiazem / Nifedipine: Blood levels of diltiazem or nifedipine can be reduced, resulting in decreased efficacy ⁽¹³⁾.
• Irinotecan: Due to changes in hepatic metabolism caused by St. John's wort, levels of irinotecan metabolite SN-38 may be lowered by as much as 40% for up to 3 weeks following discontinuation of St. John's wort ⁽²²⁾.
• Warfarin: May increase or decrease activity when administered concomitantly. Internal normalization ratio (INR) should be monitored routinely. S-isomer may have increased metabolism due to CYP 3A4 induction. S-isomer may have decreased metabolism due to CYP 1A2 inhibition ⁽²³⁾.
• Digoxin: Prolonged concurrent administration may result in decreased absorption of digoxin with lowered plasma concentrations ⁽²⁴⁾.
• Triptans: Increased serotonergic effect and possible serotonin syndrome when combined with sumatriptan, naratriptan, rizatriptan, or zolmitriptan ⁽¹³⁾.
• SSRIs: Increased serotonergic effect and possible serotonin syndrome when combined with citalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline.
• Tricyclic Antidepressants: Increased serotonergic effect and possible serotonin syndrome when combined with nefazodone, amitriptyline, or imipramine. Possible reduction in efficacy of antidepressants due to changes in metabolism ⁽¹³⁾.
• Oral Contraceptives: May reduce blood levels resulting in decreased efficacy (i.e., breakthrough bleeding or pregnancy).
• Alcohol: May result in increased sedation ⁽¹³⁾.
• Anesthetics: Case report of cardiovascular collapse (hypotension without anaphylactic symptoms) shortly after induction of general anesthesia with fentanyl, propofol, d-tubocurarine, and succinylcholine followed by nitrous oxide, oxygen, and isoflurane.
• Chemotherapy: Due to changes in hepatic metabolism caused by St. John's wort, chemotherapy levels may be altered, resulting in increased toxicity or decreased efficacy. Caution should be exercised when administering concomitantly with chemotherapy (i.e., cyclophosphamide, paclitaxel, etoposide, irinotecan).
• Tamoxifen: Due to changes in hepatic metabolism caused by St. John's wort, levels of tamoxifen may be lowered, resulting in reduced efficacy.
• Alprazolam: May reduce blood levels, resulting in decreased efficacy ⁽²⁵⁾.
• Dextromethorphan: May reduce blood levels, resulting in decreased efficacy ⁽²⁵⁾.
• Sympathomimetics: Concomitant administration may produce increased serotonergic activity and possible serotonin syndrome ⁽²⁶⁾.
• Imatinib: Increase clearance ^(27)(28).
• Simvastatin: Increase clearance, resulting in increased LDL cholesterol ⁽³⁰⁾.
• Atorvastatin: Increase clearance, resulting in increased LDL cholesterol ⁽³¹⁾.

Cytochrome P450 2C9: St. John's wort has been shown to induce cytochrome isoenzyme 2C9, therefore affecting metabolism of certain medications and reducing serum concentrations. Drugs metabolized by 2C9 include:

• Gliclazide: Increase clearance ⁽¹²⁾.

Elevated liver function tests.

Szegedi A, et al. Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St John's Wort): randomised controlled double blind non-inferiority trial versus paroxetine. BMJ 2005;330 (7490):503.
A total of 251 patients with acute major depression were given either 900 mg/day hypericum extract WS 5570 three times a day or 20 mg paroxetine, an SSRI, once a day for six weeks. At two weeks, the doses were increased to 1800 mg/day of hypercium and 40 mg paroxetine for patients who did not respond to the treatments. Researchers found that both the treatment groups showed significant decrease in depression scores. St John's Wort appears to be as effective as paroxitene in the management of severe depression. However, care should be taken while taking St John's Wort as it can interact with other drugs.

Shelton RC, et al. Effectiveness of St. John's Wort in major depression: a randomized controlled trial. JAMA 2001;285:1978-86.
A prospective, randomized, multicenter, placebo-controlled evaluation of 900-1200 mg per day of St. John's wort or placebo for major depression. A total of 167 patients completed the 8-week trial, 87 receiving placebo and 80 receiving St. John's wort. Patients who had previously taken St. John's wort, were refractory to traditional antidepressant, or had a history of concomitant psychological disorder (i.e. panic, schizophrenia, bipolar disorder) were excluded. No significant difference was found between St. John's wort and placebo for measured outcomes including Hamilton depression scale, Hamilton anxiety scale, Beck depression inventory, and global assessment of function. This study indicates that St. John's wort should not be used as monotherapy in patients with severe depression. However, the results of this study do not represent those for patients with minor to moderate depression.

Brenner R, et al. Comparison of an extract of hypericum (LI 160) and sertraline in the treatment of depression: a double-blind, randomized pilot study. Clin Ther 2000;22:411-9.
Prospective, randomized evaluation in which patients with mild to moderate depression were given either standardized St. John's wort (900 mg/day) or sertraline (75 mg/day) for seven weeks. A total of 28 patients (13 St. John's wort and 15 sertraline) were enrolled and included in the intent-to-treat analysis. Both treatments arms had similar Hamilton depression scores greater than 17. A total of 8 patients (5 St. John's wort and 3 sertraline) withdrew from the study at week 7 due to either adverse reactions (4 patients) or withdrawn consent (4 patients). Statistical analysis of all enrolled patients demonstrated no significant difference between treatment groups, indicating that St. John's wort is as effective as sertraline for mild depression. However, the small sample size is probably inadequate for definitive conclusions to be drawn.

Schrader E. Equivalence of St. John's wort extract (ze 117) and fluoxetine: a randomized, controlled study in mild-moderate depression. Int Clin Psychopharmacol 2000;15:61-8.
A prospective evaluation of 240 patients randomized to receive 20 mg/day of fluoxetine (n=114) or 500 mg/day of St. John's wort (n=126). Both treatment arms had Hamilton depression scores of approximately 19.5. One patient in the St. John's wort group withdrew from the study immediately following baseline assessment and one patient in the fluoxetine group withdrew due to adverse effects. Following 6 weeks of therapy, St. John's wort and fluoxetine were equally efficacious with respect to change in Hamilton depression scale and clinical global impression. Adverse events associated with St. John's wort were gastrointestinal disturbance, dizziness, and fatigue. Fluoxetine and St. John's wort appear to be equally efficacious for the management of mild to moderate depression.

Stevinson C, Ernst E. A pilot study of hypericum perforatum for the treatment of premenstrual syndrome. BJOG 2000;107:870-6.
Small, prospective evaluation of women experiencing premenstrual syndrome (PMS) for at least 2 cycles prior to treatment with hypericum. A total of 96 patients were screened preliminarily, 69 patients were asked to continue into baseline evaluation, and 25 patients passed baseline screening and were enrolled into the trial. Six patients withdrew consent (3 for personal reasons, 1 had hysterectomy, 1 pregnancy, and 1 adverse reaction of "jitteriness"). Treatment dose of hypericum was 300 mg three times a day (standardized to 0.3% hypericin). Adverse events seen at initiation were gastrointestinal in nature and subsided during treatment. Following 2 cycles of therapy, a 51% improvement in self-reported Daily Symptoms Ratings score from baseline was documented. This pilot study indicates a possible role for St. John's wort in the treatment of PMS, but larger studies are needed.

Kasper S, et al. Continuation and long-term maintenance treatment with Hypericum extract WS((R)) 5570 after recovery from an acute episode of moderate depression - A double-blind, randomized, placebo controlled long-term trial. Eur Neuropsychopharmacol. Nov 2008;18(11):803-813.
To determine the long-term effects of sustained treatment with hypericum extract WS 5570 in 426 individuals with recurrent, moderate depression (defined as Hamilton Depression Rating Scale [HAMD] total score ¡Ý20 and ¡Ý3 previous episodes in 5 years), this double-blind, randomized, placebo-controlled study was performed. Participants were given WS 5570 (3˟300 mg/day) or placebo for 26 weeks during which relapse rates, time to relapse, HAMD scores, as well as adverse events were assessed. Time until relapse was significantly greater and HAMD scores were lower in the WS 5570-treated group as compared to the placebo group. Also, there was no difference in adverse events reported between the 2 groups. Thus, in individuals treated for recurrent, moderate depression, WS 5570 maintenance therapy reduced relapse; however, further studies are required to determine if WS 5570 maintenance therapy is comparable to conventional maintenance therapies.

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19. Bhopal JS. St John's wort-induced sexual dysfunction. Can J Psychiatry. Jun 2001;46(5):456-457.
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21. Imai H, Kotegawa T, Tsutsumi K, et al. The recovery time-course of CYP3A after induction by St John's wort administration. Br J Clin Pharmacol. May 2008;65(5):701-707.
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23. Jiang X, Williams KM, Liauw WS, et al. Effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol. May 2004;57(5):592-599.
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29. Schwarz UI, Hanso H, Oertel R, et al. Induction of intestinal P-glycoprotein by St John's wort reduces the oral bioavailability of talinolol. Clin Pharmacol Ther. May 2007;81(5):669-678.
30. Eggertsen R, Andreasson A, Andren L. Effects of treatment with a commercially available St John's Wort product (Movina) on cholesterol levels in patients with hypercholesterolemia treated with simvastatin. Scand J Prim Health Care. Sep 2007;25(3):154-159.
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