St. John's wort and S-adenosyl methionine as "natural" alternatives to conventional antidepressants in the era of the suicidality boxed warning: what is the evidence for clinically relevant benefit?

Altern Med Rev. 2011 Mar;16(1):17-39.


Introduction: A boxed-warning in antidepressant labeling now informs prescribers of the potential for treatment-emergent suicidality to occur. Consequently, alternative "natural" antidepressant therapies widely viewed to be devoid of this risk, such as St. John's wort (SJW) and s-adenosyl methionine (SAM-e), may experience a resurgence in popularity and expansion of use beyond mild forms of depressive illness. The purpose of this article is to critically assess whether the clinical evidence supports the use of SJW and SAM-e as alternatives to conventional antidepressants in the treatment of major depressive disorder (MDD). In addition, this article evaluates whether the behavioral adverse event profiles of SJW and SAM-e suggest an increased risk for suicidality, like their conventional counterparts.

Methods: A comprehensive literature review was performed (Jan 1975-July 2010) to identify all English language reports of placebo-controlled studies of SJW and SAM-e conducted for psychiatric indications. MDD studies were categorized as "positive" or "negative" based on statistical superiority to placebo on prospectively-defined, primary, clinician-rated efficacy parameters (e.g., change in Hamilton Depression scores [HAM-D] or Montgomery-Asberg Depression Rating Scale [MADRS] total). Treatment effect size (Cohen's d) was also calculated in each case to assess the clinical relevance of the findings. Behavioral-related adverse events were summarized by treatment.

Results: Ten of 14 (71%) SJW studies in mild-to-moderate MDD were positive. The mean and median effect sizes for HAM-D change in those studies were 0.64 and 0.48, respectively, indicative of a moderately-large treatment effect. In the few studies that included patients with severe symptoms, however, or which evaluated long-term maintenance of effect, SJW did not differentiate from placebo. The majority of SAM-e studies in MDD were also positive (8/14, 57%); however, most were methodologically flawed to some extent. Based on the magnitude of the treatment-effect size in a number of positive studies, SJW appears to be useful for the short-term treatment of mild-to-moderate depressive illness in adults. Existing data do not support the use of SJW in more severely depressed individuals. The SAM-e clinical data also are strongly suggestive of antidepressant efficacy; however, until more rigorously generated data become available it is not possible to reach a more definitive conclusion. There are no long-term treatment data that convincingly demonstrate long-term maintenance of effect for either product. The reviewed studies did not reveal evidence of treatment-emergent suicidality, suggesting that this risk for either product is low. However, the studies examined were not prospectively designed to detect such events and therefore were likely unable to reliably assess this risk.

Publication types

  • Review

MeSH terms

  • Adult
  • Antidepressive Agents / adverse effects
  • Antidepressive Agents / therapeutic use*
  • Depressive Disorder / drug therapy*
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Evidence-Based Medicine
  • Humans
  • Hypericum*
  • Phytotherapy / methods*
  • Psychiatric Status Rating Scales
  • S-Adenosylmethionine / therapeutic use*
  • Suicide / prevention & control*
  • Treatment Outcome


  • Antidepressive Agents
  • S-Adenosylmethionine