A number of controlled human studies and subsequent meta-analyses have indicated that St. John's wort is a well-tolerated and effective treatment for mild to moderate depression.  Several randomized controlled trials have concluded that St. John's wort is more effective than placebo in the treatment of mild to moderate major depression, and as effective as several tricyclic antidepressants or SSRIs.  The antidepressant efficacy of St. John's wort in patients with more severe depression has long been disputed.  Some of the most recent literature available continues to support the efficacy of St. John's wort in the treatment of all degrees of major depressive disorder.

A study of St. John's wort published in the British Medical Journal in March, 2005.  In  "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," authors A. Szegedi, R. Kohnen, A. Dienel, and M. Kieser investigated the efficacy of St. John's wort compared with paroxetine (Paxil) in patients with moderate to severe depression.  This study, conducted in Germany, involved 21 psychiatric primary care practices, and 251 adult outpatients with acute major depression with a total score of greater than 22 on the 17-item Hamilton depression scale.  The interventions were either 900mg/day of St. John's wort or 20mg/day of paroxetine for six weeks.  In initial non-responders, doses were increased to 1800mg/day of St. John's wort and 40mg/day of paroxetine after two weeks.  The primary outcome measured was the change in score on the Hamilton depression scale between baseline and at 6 weeks of treatment.  The Hamilton depression scale total score decreased by 56.6% in the St. John's wort group and by 44.8% in the paroxetine group.  The authors concluded that St. John's wort is at least as effective as paroxetine and better tolerated in the treatment of moderate to severe major depression.

Another study in 2007, "Comparison of Hypericum Extract WS^® 5570 and Paroxetine in Ongoing Treatment after Recovery from an Episode of Moderate to Severe Depression: Results from a Randomized Multicenter Study" found that an extract of St. John's Wort performed similarly to paroxetine in both acute treatment (at 6 weeks) and maintaining remission (at 16 weeks).

However, emerging evidence suggests that the effectiveness of St. John's wort may have been overestimated in the past.  Criticism of the literature available has come from sources claiming that there has been a great deal of publication bias and undersized studies when conducting meta-analyses.  In a May 2004, article from the Journal of Clinical Psychiatry, a meta-analysis was performed to re-evaluate the effectiveness of St. John's wort as an antidepressant.  This analysis evaluated 18 studies examining the antidepressant effects of St. John's wort.  Their results showed that much of the increase in effect of St. John's wort was associated with a decrease in sample size, suggesting that many of these studies have not had adequate power for their results to be accepted as proof of efficacy.  While they did conclude that the studies they evaluated showed St. John's wort to be effective in the treatment of depression, they predicted that it will ultimately prove to be ineffective if more properly conducted studies are performed.

Regardless of the literature available at this time, it is clear that more studies are needed to evaluate many of the "alternative" therapies available to patients.