Hypericum perforatum (St. John's Wort) for Depression
St. John's wort is as effective as second-generation antidepressants for treating mild-to-moderate major depressive disorder and is better tolerated, but it should NOT be used as first-line therapy in the United States due to lack of FDA regulation, significant drug interactions, and contraindications with common medications. 1, 2
Efficacy Evidence
For Mild-to-Moderate Depression:
- Meta-analyses of 9 trials (1,513 participants) showed similar response rates between St. John's wort and second-generation antidepressants (54% vs. 52%; RR 0.96) after 6-12 weeks of treatment 1
- Remission rates were comparable (36% vs. 30%) with no statistically significant difference 1
- A 2017 meta-analysis of 27 trials (3,808 patients) confirmed comparable response and remission rates to SSRIs 3
Tolerability Advantage:
- Patients on St. John's wort had significantly lower treatment discontinuation rates (12% vs. 16%; RR 1.28) compared to antidepressants 1
- Discontinuation due to adverse events was notably lower (4% vs. 7%; RR 1.70) 1
- Moderate-quality evidence confirms St. John's wort is better tolerated than second-generation antidepressants 1, 2
Critical Limitations and Safety Concerns
Regulatory Issues:
- St. John's wort is NOT regulated by the U.S. Food and Drug Administration 1, 2
- No current standard exists for contents and potency of preparations in the United States 1, 2
- Patients cannot reliably obtain quality-controlled medication with similar effectiveness as those used in clinical trials 1
Serious Drug Interactions:
- St. John's wort induces cytochrome P450 isoenzyme 3A4, reducing bioavailability of multiple medications 1, 2
- May reduce efficacy of oral contraceptives and immunosuppressants 1, 2
- Contraindicated with monoamine oxidase inhibitors or serotonin reuptake inhibitors due to serotonin syndrome risk 1, 2
- Decreases dasatinib plasma concentrations unpredictably in cancer patients 1
Common Adverse Effects:
- Gastrointestinal symptoms, dizziness or confusion, fatigue or sedation 1, 2
- Skin reactions, restlessness, headache, and dry mouth 1, 2
Evidence Quality Limitations
Study Design Issues:
- Most trials compared St. John's wort with moderate- or low-dose antidepressant regimens, not fully using approved dose ranges 1
- All studies lasted only 4-12 weeks, providing no long-term efficacy or safety data 3
- Evidence is insufficient for severe depression, high suicidality, or suicide risk 3
Population-Specific Data:
- In older adults (aged 60-80 years), St. John's wort showed equal effectiveness and similar adverse event rates compared to second-generation antidepressants (low-quality evidence) 1
Clinical Recommendation Algorithm
First-Line Treatment (American College of Physicians):
- Choose between cognitive behavioral therapy OR second-generation antidepressants (strong recommendation, moderate-quality evidence) 1
- Discuss treatment effects, adverse effect profiles, cost, accessibility, and patient preferences 1
When St. John's Wort Should NOT Be Used:
- Patients taking oral contraceptives, immunosuppressants, anticonvulsants, or chemotherapy 1, 2
- Patients on any monoamine oxidase inhibitors or SSRIs 1, 2
- Patients requiring reliable, standardized dosing 1, 2
- Severe depression or high suicide risk 3
When St. John's Wort Might Be Considered:
- Mild-to-moderate depression in patients who cannot tolerate standard antidepressants 1, 3
- No contraindicated medications 1, 2
- Access to quality-controlled European preparations (not reliably available in U.S.) 1
- Patient strongly prefers herbal therapy after informed discussion of limitations 3
Common Pitfalls to Avoid
- Do not assume all St. John's wort preparations are equivalent—potency varies widely without FDA regulation 1, 2
- Do not overlook drug interaction screening before initiating therapy 1, 2
- Do not use for severe depression or patients with suicidal ideation 3
- Do not combine with standard antidepressants due to serotonin syndrome risk 1, 2