Medicinal use of St. John's wort dates back to ancient Greece. The renowned physicians Dioscorides and Hippocrates used this herb to treat a variety of illnesses, and it was long believed to rid the body of evil spirits. Belief in the herb's powers continued through the Middle Ages, but by the end of the 19th century, interest in St. John's wort—and most other medicinal plants—had waned. Recent research on St. John's wort has refocused attention on the herb, and it has become extremely popular with consumers in the United States. In Europe, where St. John's wort has a longer history of use, it is used to treat wounds, gastritis, kidney and lung disorders, insomnia, and depression.

Most clinical studies of St. John's wort have focused on its use in treating mild to moderate depression. In a 1996 meta-analysis, researchers examined 23 randomized trials of St. John's wort in a total of 1,757 patients with mild to moderate depression. Acknowledging the limitations of using pooled data from studies using different preparations and dosages, varying experimental designs and patient populations, the researchers still concluded that St. John's wort is better than placebo in treating mild to moderate depression. However, from the trials reviewed, they could not draw firm conclusions about whether St. John's wort is as effective as standard antidepressants. The analysis did suggest that St. John's wort causes fewer side effects than standard antidepressants.

The National Institute of Mental Health (NIMH) does not currently recommend the use of St. John's wort for treatment of depression and has called for more rigorous research on the herb. Along with two other branches of the National Institutes of Health—the Office of Alternative Medicine and the Office of Dietary Supplements—NIMH has funded a three-year controlled clinical study of the herb in clinically depressed patients. Patient enrollment for the study began in the spring of 1999.

In at least one controlled trial, patients with seasonal affective disorder (SAD) responded well to treatment with St. John's wort, and the herb seems to be even more effective when used in combination with light therapy.

Studies from the early 1990s revealing antiretroviral activity of St. John's wort had raised hopes for using this herb to treat human acquired immunodeficiency virus (HIV). Results of small pilot studies have been promising, with patients showing stable or increased helper T cell counts, improved helper-to-suppressor T cell ratios, and low incidence of opportunistic infection, but larger and longer-term studies are still needed. However, recent data suggest a potential interaction with protease inhibitors; please refer to the section entitled "Interactions" for more information.

Topical preparations of St. John's wort have shown antibacterial and wound-healing activity and have been used to treat burns, muscle pain, and hemorrhoids. Topical preparations also have been used to reduce pain, inflammation, and to promote nerve-tissue regeneration. Interestingly, debate continues over the most active ingredient in St. John's wort.

St. John's wort is a shrubby perennial with flat-topped clusters of bright yellow flowers. The plant is native to Britain and Europe but now grows wild in many other parts of the world, including the United States. It grows best in sunny sites with dry, gravelly, or chalky soil.

• Leaves
• Flowering tops

The best-studied active components are hypericin and pseudohypericin, found in both the leaves and the flowers. There has been recent research, though, to suggest that these best-studied components may not be the most active in the plant, with significant debate ensuing within the industry. Other components include flavonoids, xanthones, phenolic carboxylic acids, essential oils, carotenoids, alkanes, phloroglucinol derivatives, phytosterols, and medium-chain fatty acid alcohols.

St. John's wort is available in various forms, including dried herb (chopped or powdered), capsule, liquid extract, tincture, infused oil, and tea infusion.

The recommended preparation of St. John's wort currently accepted by the industry is an extract standardized to contain 0.3% hypericin.

• Anxiety, depression, apathy, anorexia, and feelings of worthlessness
• Sleep disturbances including insomnia and hypersomnia
• Wounds and burns; topical application promotes healing
• Antimicrobial
• Possible adjunctive therapy for viral infections such as herpes simplex, influenza, mononucleosis, and HIV, (See Overview and Interactions sections for controversial issues)
• Hemorrhoids (topically) 

• Antidepressant activity. Early studies suggested that hypericin may act as monoamine oxidase inhibitor (MAOI) but more recent evidence suggests that it has weak MAOI activity. It has also been suggested that the antidepressant activity of St. John's wort may mimic that of a selective serotonin reuptake inhibitor (SSRI); however, the actual mechanism of antidepressant action remains unclear and controversial. Xanthones and flavonoid components may also be responsible for the antidepressant activity of this herb; most recent studies indicate that hypertorin, a phoraglucinal, is partly responsible for the antidepressant activity.
• Antibacterial activity. Extracts show broad-spectrum antimicrobial activity against such organisms as Escherichia coli, Staphylococcus aureus, Streptococcus mutans, Pseudomonas aeruginosa, and Proteus vulgaris in vitro, but the specific ingredients responsible for this action have not been isolated.
• Antiviral activity. Active components hypericin and pseudohypericin show antiviral activity against herpes simplex virus types 1 and 2, Epstein–Barr virus, and influenza types A and B. These components have also demonstrated activity against a number of retroviruses, including the human immunodeficiency virus (HIV).

As an antidepressant, the recommended amount is 300 to 500 mg (standardized to 0.3% hypericin extract), tid with meals, for a minimum of four to six weeks.

St. John's wort causes severe photosensitivity in grazing animals that eat large amounts of the plant. Such reactions are rare in humans and have been seen only in people taking very large doses for HIV infection. However, as a precaution, people with fair skin and people taking other medications such as tetracycline or piroxicam that can also cause photosensitivity should use a sunscreen with a skin protection factor (SPF) of at least 15; they should also not use sun-lamps, tanning beds or booths while taking St. John's wort.

Other side effects are usually mild. They may include:

• Abdominal pain, bloating, constipation
• Nausea, vomiting
• Dizziness
• Dry mouth
• Itching, hives, skin rash
• Sleep problems
• Elevated blood pressure
• Unusual tiredness

• Take with food to reduce chances of gastric upset.
• Do not take during pregnancy or while breast-feeding.

Two cases of heart transplant rejection in patients who took St. John's wort while being treated with cyclosporin have been reported (Ruschitzka et al. 2000). One patient had been maintained uneventfully on a regimen of cyclosporin (125 mg bid), azathioprine, and corticosteroids for 11 months. The other patient had also been stable on an immunosuppressive regimen that included cyclosporin (125 mg bid). Although cyclosporin levels had been within the therapeutic range for both patients, ingestion of St. John's wort (300 mg tid) for three weeks diminished blood concentrations of cyclosporin to subtherapeutic levels and prompted episodes of rejection in each of these patients. Cyclosporin concentrations returned to therapeutic range with discontinuation of St. John's wort in both of these cases.

Additional reports of 30 interactions between cyclosporin A and St. John's wort in kidney transplant recipients were recently described (Breidenbach et al. 2000). After beginning St. John's wort therapy, cyclosporin blood levels fell by an average of 47%; cyclosporin dosages were increased 46% to account for this drop. Upon discontinuation of St. John's wort, cyclosporin blood levels increased by an average of 187%. While the mechanism for this interaction is not entirely clear, St. John's wort may either decrease cyclosporin absorption, induce cytochrome P-450 in the liver and/or small intestine, or induce P-glycoprotein (a drug transporter) in the small intestine. Because cyclosporin has a narrow therapeutic range, the researchers caution against concomitant use of St. John's wort.

The interaction between the hypericum extract of St. John's wort (900 mg/day) and digoxin (0.25 mg/day) was investigated in a single-blind, placebo-controlled parallel study in 25 healthy volunteers (Johne et al. 1999). The combination resulted in decreased plasma concentrations of digoxin over the 10-day period. This interaction was thought to involve induction of transport proteins, specifically P-glycoprotein.

There is a report in the literature of a possible interaction between loperamide and St. John's wort (Khawaja et al. 1999). A 39-year-old woman was admitted to the hospital in a state of delirium. She had been taking St. John's wort and valerian for 6 months, and she had recently ingested loperamide for diarrhea. Because the patient's clinical condition resembled a MAOI reaction, this interaction was thought to occur as a result of a MAOI-induced mechanism, possibly associated with an interaction either between the herbal agents or the herbal agents and loperamide.

Research regarding interactions between St. John's wort and MAOIs remains incomplete and controversial. A recent report suggested that St. John's wort and phenelzine, a MAOI, should not be used concomitantly (Miller 1998).

Eight women between the ages of 23 and 31 who had used St. John's wort while taking oral contraceptives reported breakthrough bleeding or changes in menstrual bleeding (Yue et al. 2000). There have been additional reports cited in the literature of breakthrough bleeding in women taking oral contraceptives with St. John's wort (Ernst 1999). Because oral contraceptives are metabolized via the cytochrome P450 pathway, enzyme induction is thought to be the mechanism behind this interaction.

The Food and Drug Administration (FDA) has issued a public health advisory concerning an interaction between indinavir and St. John's wort that resulted in significantly decreased plasma concentrations of this protease inhibitor (FDA 2000). This advisory warning was based on results of an NIH-conducted open-label study of eight healthy volunteers receiving indinavir (800 mg) and later indinavir with St. John's wort (300 mg tid standardized to 0.3% hypericin) for 14 days (Piscitelli et al. 2000). Plasma concentrations of indinavir dropped significantly from levels obtained prior to the introduction of St. John's wort. This interaction may be secondary to induction of the cytochrome P450 metabolic pathway.

The FDA recommends against concomitant administration of St. John's wort with antiretroviral medications that are protease inhibitors or nonnucleoside reverse transcriptase inhibitors because this interaction could lead to subtherapeutic plasma concentrations of these medications with the potential for lack of efficacy and/or resistance (FDA 2000).

St. John's wort antagonized the effect of the sympatholytic agent reserpine in animal studies (Okpanyi and Weischer 1987).

In five cases, elderly patients receiving St. John's wort and prescription antidepressants (SSRIs) developed symptoms of serotonergic syndrome, including headache, dizziness, nausea, agitation, and anxiety (Lantz et al. 1999). A washout period of two weeks has been recommended when switching between SSRIs and St. John's wort because the combination of St. John's wort (600 mg) and paroxetine (20 mg) reportedly resulted in symptoms of incoherence and lethargy in a patient (Gordon 1998). Concomitant use of SSRIs with St. John's wort is not recommended. If these agents are used concomitantly, patients should be monitored very closely. Patients must be carefully weaned from one before starting on the other.

Use of St. John's wort supplement (300 mg bid standardized to 0.3% hypericin) decreased a patient's theophylline concentration, requiring an increase in dosage to 800 mg bid (Nebel et al. 1999). Discontinuation of St. John's wort caused the theophylline concentration to more than double in this individual case. St. John's wort may enhance hepatic enzyme (CYP1A2) activity, leading to increased theophylline clearance.

Unpublished data suggest that St. John's wort may lower plasma concentrations of amitriptyline (De Smet and Touw 2000). This lends support to the possibility that the mechanism of drug interactions with St. John's wort involves induction of hepatic enzymes that are part of the cytochrome P450 system.

There have been seven case reports filed with the Medical Products Agency (MPA) in Sweden involving reduced effectiveness of warfarin when taken concomitantly with St. John's wort as evidenced by clinically significant decreases in INR values (Yue et al. 2000). Adjustments in warfarin doses or discontinuation of St. John's wort resulted in a return of INR values to desired levels. This interaction may be due to induction of hepatic enzymes, specifically cytochrome P450 2C9. In addition, there was a literature report of lower serum concentrations of warfarin in a 75-year-old woman who also took St. John's wort (Ernst 1999).

St. John's wort is labeled as a dietary supplement by the U.S. Food and Drug Administration.

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