The final treatment modality is St. John’s wort (Hypericum perforatum): the most widely used herbal antidepressant in the world (Dugoua et al., 2006).  Herbalists have used St. John’s wort since the Middle Ages.  At that time, it was used to treat insanity resulting from “attacks of the devil.”  It derives its name from St. John’s Day (June 24) because it blooms near this day on the medieval church calendar.  “Wort” is the old English word for a medicinal plant.  It is native to Great Britain, Wales, and northern Europe.  Since settlers brought it to North America in the 1700s (Balch, 2002; Humphrey, 2003), it is now a common wildflower in the northeastern and north central U.S.

Efficacy of St. John’s Wort

A large body of evidence indicates that St. John’s wort effectively treats depression (Sarris, 2007; Werneke et al., 2006).  Most of the earlier research has been done in Germany, where St. John’s wort is widely used and, indeed, is the preferred treatment for depression.  Standard antidepressants are tried only after St. John’s wort has failed (Linde et al., 1996; Wurglies & Schubert-Zsilavecz, 2006).  Evidence for St. John’s wort’s effectiveness can be found in both review articles and in results of randomized clinical trials.

Review articles

In a meta-analysis of 23 randomized trials, Linde and colleagues (1996) found that hypericum extracts were superior to placebos and were as effective as antidepressants in treating depression.  Patients taking St. John’s wort were less likely to drop out of studies and reported fewer side effects than their counterparts taking antidepressants.  Placebo groups (across 13 studies) had an average response rate of 22.3%, compared with 55% of the hypericum groups. 

A review of 22 studies (Whiskey et al., 2001) and another with 27 trials (Lawvere & Mahoney, 2005) had similar findings.  The authors of both reviews found that St. John’s wort was more effective than a placebo and as effective as antidepressants.  They also concluded that side effects were more common with antidepressants than with St. John’s wort.  A final review indicated that there was “very strong evidence” of St. John’s wort’s effectiveness for mild-to-moderate depression (Duguoa et al., 2006).

Data from clinical trials

A number of clinical trials have compared the efficacy of various St. John’s wort extracts to either a placebo or an antidepressant.  In one trial (Lecrubier et al., 2002), 375 patients were randomized to receive either St. John’s wort (Hypericum perforatum Extract WS 5570) or a placebo for six weeks to treat mild-to-moderate depression.  At the end of six weeks, patients receiving St. John’s wort had significantly lower scores on the Hamilton Depression Rating Scale.  And significantly more patients were in remission or had a response to treatment than patients receiving the placebo.  Both groups had similar rates of adverse effects.  Fifty-three percent of the patients in the St. John’s wort group responded to treatment, compared with 42% of the placebo group.  The authors concluded that St. John’s wort was safe and effective for the treatment of mild-to-moderate depression. 

Two randomized trials compared St. John’s wort to the tricyclic antidepressant imipramine.  The first randomized trial compared St. John’s wort (Hypericum extract ZE 117) to imipramine for 324 outpatients with mild-to-moderate depression (Woelk, 2000). After six weeks of treatment, St. John’s wort was as effective as imipramine in lowering depressive symptoms.  However, adverse effects were significantly more likely in the imipramine group, with 63% reporting adverse effects, but only 39% reporting adverse effects in the St. John’s wort group.  In addition, only 3% in the St. John’s wort group dropped out of the study due to adverse effects versus 16% of the imipramine group.  The author concluded that St. John’s wort is therapeutically equivalent to imipramine, but is better tolerated by patients.

The second trial compared St. John’s wort (Hypericum extract STEI 300) to a placebo and imipramine.  The subjects were 263 primary-care patients with moderate depression.  The authors found that St. John’s wort was as effective as imipramine for moderately depressed patients after four, six, and eight weeks of treatment (Philipp et al., 1999).  Patients in this trial also tolerated St. John’s wort better.

Two clinical trials compared St. John’s wort to sertraline for major depression. One study had wide press coverage, but unfortunately much of it was misleading (Hypericum Depression Trial Study Group, 2002).  In this study, 340 adults with major depression were randomly assigned to receive H Perforatum, a placebo, or sertraline for eight weeks.  Subjects responding to the medication could opt to receive still-blinded treatment for another 18 weeks.  Depression was assessed at baseline and again at eight weeks.  The researchers found no significant difference in depression levels or rate of response between the placebo and St. John’s wort.  That much was widely reported.  What the media did not report was that the same was true for sertraline.  The rate of full response was almost identical for the St. John’s wort and sertraline groups (24% vs. 25%).  The low response rates for both medications suggest limitations to the study.  Eight weeks may not have been sufficient for patients with severe depression to recover. Or the dosages may have been too low.  The authors noted that their findings were not unusual in that approximately 35% of studies of standard antidepressants show no greater efficacy than the placebo. 

Another study that same year of patients with major depression had opposite findings.  This study (van Gurp et al., 2002) included 87 patients with major depression recruited from Canadian family practice physicians.  Patients were randomly assigned to receive either St. John’s wort or sertraline.  At the end of the 12-week trial, both groups improved, and there was no difference between the two groups.  But there were significantly more side effects in the sertraline group at two and four weeks.  The authors concluded that St. John’s wort, because of its effectiveness and benign side effects, was a good first choice for a primary-care population.

St. John’s wort was also compared to paroxetine in a study of 251 patients with acute, moderate-to-severe major depression (Szegedi et al., 2005).  In this study, patients were randomly assigned to receive 20 mg paroxetine or 900 mg St. John’s wort (Hypericum extract WS 5570).  After two weeks, dosages for non-responders were doubled: 1,800 mg St. John’s wort or 40 mg paroxetine.  After six weeks of treatment, the response rates were 70% for St. John’s wort and 60% for paroxetine.  The remission rates for St. John’s wort were 50% versus 35% for paroxetine.  The authors concluded that St. John’s wort was as effective as paroxetine and better tolerated.

Anghelescu and colleagues (2006) also compared the efficacy and safety of Hypericum extract WS 5570 to paroxetine for patients with moderate-to-severe depression.  The acute phase of treatment lasted for six weeks, with another four months of follow-up to prevent relapse.  The patients improved on both treatments, with no significant difference in efficacy between paroxetine and St. John’s wort.  The authors noted that St. John’s wort was an important alternative to standard antidepressants for depressed patients.