The botanical St. John’s wort (Hypericum perforatum) is native to Europe, West Asia, and North Africa, and has been naturalized to North and South America and Australia. The Greeks and the Romans documented its medicinal use in the treatment of nerve-related disorders. In Germany, St. John’s wort is the most commonly prescribed anti-depressant. In 1984, the German Commission E designated St. John’s wort as an approved herb,¹ and its safety and effectiveness are reevaluated periodically.

St. John’s wort has been used to treat a variety of conditions. It also has been suggested to alleviate symptoms of premenstrual syndrome² and obsessive-compulsive disorder³; however, these applications have been studied less extensively. Additional studies of St. John’s wort, funded by the National Center for Complementary and Alternative Medicine, are underway.⁴ This review focuses solely on the use of St. John’s wort for the treatment of depression.

Pharmacology

The main active components of St. John’s wort are thought to be hypericin and hyperforin.⁵ St. John’s wort also contains other common plant constituents (e.g., flavonoids and flavonoid derivatives, xanthone derivatives, amentoflavone, biapigenin, volatile oil) that may have antidepressant effects. Although additional research is needed to definitively understand the effects of these components alone and in combination, most available St. John’s wort formulations are now standardized to include hypericin (range: 0.1 to 0.4 percent) and hyperforin (range: 2.0 to 4.0 percent) because these constituents have been researched the most extensively.

Studies⁶ have suggested that St. John’s wort acts via inhibition of the reuptake of serotonin, dopamine, and noradrenaline, along with activation of gamma-amino-butyrate and glutamate receptors. At high dosages, hypericin is a monoamine oxidase inhibitor; however, these effects have not been demonstrated with the consumption of St. John’s wort at dosages recommended for the treatment of depression.⁷

The absorption and elimination of hypericin extract have been researched in healthy volunteers.⁸ After oral ingestion, plasma levels were measurable within two to three hours. A steep cumulative rise in plasma levels was seen during the first three days; however, a more gradual rise continued for several weeks. The elimination half-life was 24 to 48 hours.⁸

Effects on Depression

A Cochrane Systematic Review⁹ used specific criteria to examine the use of St. John’s wort for depression. Study limitations included heterogeneous diagnoses of depression, short trial durations, and low dosages of standard antidepressants in comparison trials. In all but one of the 27 clinical studies (n = 2,291) of different hypericum preparations, investigators concluded that St. John’s wort was either more effective than placebo or as effective as older pharmaceutical antidepressants in the treatment of mild to moderate depression.

More recently, 13 additional clinical trials have been published, some of which, along with a Cochrane review, are summarized in Table 1.^9–19 In 10 of these studies, investigators found that St. John’s wort was superior to placebo^{11,16,20–22} or as effective as standard antidepressants (e.g., amitriptyline [Elavil],¹⁰ fluoxetine [Prozac],^12,13 imipramine [Tofranil],^11,14 sertraline [Zoloft]¹⁵) in the treatment of mild to moderate depression. Two updated meta-analyses exploring the effectiveness of St. John’s wort for the treatment of depression are based on studies published between 1979 and 2003.²³ Although their results suggest the possibility that St. John’s wort may be less effective than previously assumed, the meta-analyses indicated that St. John’s wort was significantly more effective than placebo (risk ratio for first meta-analysis: 1.97, 95% confidence interval [CI], 1.54 to 2.53; risk ratio for second meta-analysis: 1.73, 95% CI, 1.40 to 2.14).

Studies^17–19 on the use of St. John’s wort in patients with major depression have had conflicting results. According to the results of one double-blind, placebo-controlled, multi-center clinical trial¹⁸ (n = 200), St. John’s wort was effective in treating outpatients with major depression. Although the number of patients achieving remission in symptoms of depression was significantly higher with St. John’s wort therapy than with placebo (P = .02), overall remission rates were low (14.3 and 4.9 percent, respectively).

The Hypericum Depression Trial Study Group conducted a double-blind, randomized controlled trial¹⁹ (n = 340) in 12 academic and community psychiatric research clinics in the United States. Investigators found that St. John’s wort and sertraline did not differ from placebo for major depression outcomes or adverse events. The authors of an earlier study¹⁷ (n = 209) concluded that St. John’s wort was equivalent to imipramine in patients with severe depression.

Taken together, the data^10–22 continue to support the overall conclusions of the Cochrane review,⁹ as well as other published reviews,^24,25 that St. John’s wort is more effective than placebo and as effective as standard antidepressants for the treatment of mild to moderate depression.

Adverse Effects, Contraindications, and Drug Interactions

In clinical trials comparing St. John’s wort with other antidepressants, the use of St. John’s wort was not associated with any serious adverse events. Authors of a systematic review²⁶ reported an overall side-effect rate of 2.4 percent, with no severe side effects and only the expected mild side effects (i.e., gastrointestinal upset, increased anxiety, minor palpitations, photosensitivity, fatigue, restlessness, dry mouth, headache, and increased depression). Transient photosensitivity is generally the most common side effect and occurs more commonly at higher dosages.²⁷ Use of St. John’s wort continues among a substantial number of persons without apparent serious adverse events.

Because of the possibility of developing serotonin syndrome, use of St. John’s wort in conjunction with selective serotonin reuptake inhibitors is not recommended. St. John’s wort should be used cautiously in patients with bipolar disorder because there have been a few case reports of St. John’s wort–related mania.²⁸

Table 2^29–40 lists the possible drug interactions that may occur with St. John’s wort. The results of one report⁴¹ suggest that induction of cytochrome (CYP) P450 3A4 activity by St. John’s wort may have a substantial impact on the effectiveness of pharmaceutical agents because at least one half of all marketed medications are metabolized via this pathway.

Given the induction of CYP 3A4, concurrent use of St. John’s wort may reduce the effectiveness of oral contraceptives. In a study³⁵ of 12 healthy premenopausal women who received an oral contraceptive along with 900 mg of St. John’s wort daily in three divided doses, researchers noted a shorter estrogen half-life and increased breakthrough bleeding. Women using oral contraceptives should be counseled regarding possible breakthrough bleeding and might consider a barrier method of contraception when taking St. John’s wort.³⁵

Additional study is needed to establish if and how St. John’s wort interacts with specific pharmaceutical agents. Experience to date suggests few clinically significant interactions. Until the results of ongoing studies on this matter have been published, the medications listed in Table 2^29–40 should be considered to have potential interactions and should be monitored when used concurrently with St. John’s wort. Family physicians should query all patients about the use of St. John’s wort and other herbal agents.

Dosage

Findings suggest that 900 mg of St. John’s wort (450 mg two times daily or 300 mg three times daily) is needed to reduce symptoms of depression.^8,10,17 Because plasma levels continue to show a gradual rise over several weeks, the full clinical effect of St. John’s wort may take two to four weeks to manifest.

Final Comment

St. John’s wort represents an effective therapy for the treatment of mild to moderate forms of depression. Standardized formulations are available for $10 to $25 for a one-month supply. It is important to emphasize that not all St. John’s wort products are systematically standardized. Drug interactions with St. John’s wort have been demonstrated in a variety of pharmacologic studies, although the clinical importance of these observations is uncertain given the widespread use of this agent. Table 3 outlines the effectiveness, safety, tolerability, dosage, and cost of standardized St. John’s wort formulations.