What are the guidelines for using St. John's Wort (Hypericum perforatum) for depression?

St. John's Wort for Depression

Primary Recommendation

St. John's wort may be considered for mild-to-moderate major depressive disorder with comparable efficacy to SSRIs, but should NOT be used in patients taking multiple medications due to severe drug interactions, those with severe depression or high suicide risk, or when standardized dosing cannot be assured. 1

Efficacy Evidence

Effectiveness for Depression:

• Low-quality evidence demonstrates no significant difference in response or remission rates between St. John's wort and second-generation antidepressants (SGAs) for major depressive disorder after 4-12 weeks of treatment 2
• A 2017 meta-analysis of 27 trials (3,808 patients) confirmed comparable response rates (pooled RR 0.983) and remission rates (pooled RR 1.013) when compared to SSRIs 3
• Moderate-quality evidence shows St. John's wort has significantly better tolerability than SSRIs, with lower discontinuation rates due to adverse events (pooled OR 0.587) 1, 3

Critical Limitation:

• Studies comparing St. John's wort to SGAs used antidepressant doses capped below usual therapeutic ranges, which downgrades the quality of comparative evidence 2

When NOT to Use St. John's Wort

Absolute Contraindications:

• Concomitant use with SSRIs or MAOIs is contraindicated due to serotonin syndrome risk 4, 1
• Patients taking warfarin (reduced anticoagulant effect) 4
• Patients on ivabradine (specifically contraindicated) 4
• Patients taking oral contraceptives (risk of unintended pregnancy) 4

Relative Contraindications:

• Severe depression or high suicidality risk—cognitive behavioral therapy is strongly recommended instead 1
• Patients on HIV protease inhibitors or NNRTIs (significantly decreased drug levels) 4
• Patients taking immunosuppressants, anticonvulsants (carbamazepine, phenytoin, phenobarbital), or chemotherapy agents like imatinib 4
• Discontinue at least 2 weeks before surgery due to multiple drug interactions and serotonin effects 4

Mechanism of Drug Interactions

• St. John's wort is a potent inducer of CYP3A4 and P-glycoprotein, which significantly decreases plasma concentrations of numerous medications, potentially causing treatment failure 4, 1
• More frequent monitoring of drug levels or therapeutic effects is required if interactions cannot be avoided 4

Dosing and Quality Concerns

Standard Dosing:

• Mild-to-moderate depression: 300 mg standardized extract (0.3% hypericin) three times daily 5
• Severe depression may require 600 mg three times daily, though evidence is limited 5

Major Quality Issue:

• St. John's wort is NOT regulated by the FDA, with no standardization of content or potency in U.S. preparations 4, 1
• This lack of standardization creates unpredictable efficacy and safety profiles 1

Adverse Effects Profile

Common adverse effects include 1:

• Mild gastrointestinal symptoms
• Skin reactions (photosensitivity)
• Fatigue or sedation
• Dizziness or confusion
• Headache
• Dry mouth

Clinical Algorithm for Decision-Making

Use St. John's Wort ONLY if ALL criteria are met:

1. Mild-to-moderate depression (not severe)
2. Low or absent suicide risk
3. NOT taking any medications that interact with CYP3A4 or P-gp
4. NOT taking SSRIs, MAOIs, warfarin, oral contraceptives, or immunosuppressants
5. Patient can obtain standardized preparation with verified hypericin content
6. Patient discloses use to all healthcare providers 4

Choose SSRIs or cognitive behavioral therapy instead if:

• Severe depression present 1
• High suicide risk 1
• Multiple concurrent medications
• Need for reliable, FDA-regulated treatment
• Patient cannot ensure product standardization

Evidence Limitations

• All available studies range from 4-12 weeks duration; long-term efficacy and safety data are lacking 3
• Evidence for severe depression is insufficient 3
• One large U.S. trial showed complete absence of efficacy trends for moderately severe major depression, though this may reflect low assay sensitivity 6