What are the precautions and dosage guidelines for using St. John's wort (Hypericum perforatum) for mild depression or anxiety?

St. John's Wort for Mild Depression or Anxiety: Precautions and Dosage Guidelines

St. John's wort should be used with extreme caution due to its numerous significant drug interactions, and is only recommended for mild to moderate depression at a dosage of 300-1800 mg/day of standardized extract (0.12% to 0.28% hypericin) when patients are not taking interacting medications. 1

Efficacy and Safety Profile

St. John's wort has demonstrated comparable efficacy to second-generation antidepressants (SGAs) for mild to moderate depression:

• Meta-analyses show similar response rates between St. John's wort and SGAs (54% vs. 52%) after 6-12 weeks of treatment 1
• Lower discontinuation rates (12% vs. 16%) and fewer discontinuations due to adverse events (4% vs. 7%) compared to SGAs 1
• Generally better tolerated than conventional antidepressants 1, 2

Dosage Guidelines

• Recommended dosage: 300-1800 mg/day of standardized extract containing 0.12% to 0.28% hypericin 1
• Treatment duration: If no clear improvement after 4-6 weeks at a sufficient dose (900 mg daily), consider switching to a conventional antidepressant 3
• Treatment should continue for at least 6-12 weeks based on available clinical studies 2

Major Precautions and Contraindications

Drug Interactions (CRITICAL)

St. John's wort is a potent inducer of cytochrome P450 enzymes and P-glycoprotein, leading to significant drug interactions:

1. Anticoagulants: Reduces warfarin efficacy by increasing clearance and reducing INR by approximately 20% 4
2. Oral contraceptives: May reduce effectiveness, leading to unintended pregnancy 1
3. Immunosuppressants: Decreases blood levels, potentially causing transplant rejection 1
4. Antiretrovirals: Contraindicated with HIV protease inhibitors, cobicistat-based regimens, efavirenz, delavirdine, etravirine, nevirapine, and ritonavir 4, 1
5. Antidepressants: Contraindicated with SSRIs and MAOIs due to risk of serotonin syndrome 1
6. Other medications: Reduces efficacy of digoxin and other drugs metabolized by CYP3A4 1

Other Contraindications

• Pregnancy or breastfeeding 1
• History of photosensitivity (St. John's wort can cause photosensitivity reactions) 1
• Severe depression or high suicide risk (evidence is limited to mild-moderate depression) 2

Common Side Effects

• Gastrointestinal symptoms 1, 3
• Skin reactions and photosensitivity 1
• Fatigue or sedation 1
• Dizziness or confusion 1
• Headache (more common than with placebo: 41% vs. 25%) 1

Regulation and Standardization Issues

A major concern with St. John's wort is its lack of FDA regulation in the United States:

• No standardization of contents and potency 1
• Variable effectiveness between different preparations 1
• Patients may not reliably obtain preparations with similar effectiveness as those used in clinical studies 1

Clinical Decision Algorithm

1. Assess depression severity:

   • For mild to moderate depression only
   • Not recommended for severe depression or patients with suicidality

2. Review medication list for potential interactions:

   • If patient is taking any medications metabolized by CYP3A4, P-gp substrates, anticoagulants, oral contraceptives, immunosuppressants, or antidepressants → Do NOT use St. John's wort

3. Discuss regulation/standardization issues:

   • Explain lack of FDA oversight and potential variability in products
   • Recommend products standardized to 0.12%-0.28% hypericin content

4. If appropriate, prescribe:

   • Starting dose: 300 mg three times daily (900 mg/day)
   • Duration: Evaluate response after 4-6 weeks
   • If no response after 6 weeks at 900 mg/day, switch to conventional antidepressant

5. Monitor for side effects:

   • Advise sun protection due to photosensitivity risk
   • Watch for gastrointestinal symptoms, headache, dizziness