Is Saint John's Wort (Hypericum perforatum) effective for treating depression?

St. John's Wort for Depression

St. John's wort appears to be as effective as second-generation antidepressants (SGAs) for mild to moderate depression with fewer side effects, but lacks FDA regulation and has significant drug interaction concerns. 1, 2

Efficacy Evidence

• Meta-analyses of 9 trials (1513 participants) showed similar response rates between St. John's wort and SGAs (54% vs. 52%) after 6-12 weeks of treatment 1
• No statistically significant difference in remission rates (36% vs. 30%) between treatment groups 1
• A 2017 meta-analysis of 27 clinical trials (3808 patients) confirmed comparable response and remission rates between St. John's wort and SSRIs 3
• Patients treated with St. John's wort had significantly lower discontinuation rates (12% vs. 16%) and fewer discontinuations due to adverse events (4% vs. 7%) compared to SGAs 1

Important Limitations and Concerns

Regulatory and Quality Control Issues

• St. John's wort is not regulated by the FDA in the United States 1, 2
• No standardization of contents and potency exists 1
• Patients may not reliably obtain preparations with similar effectiveness as those used in clinical studies 1, 2

Drug Interactions

• St. John's wort induces cytochrome P450 isoenzyme 3A4, leading to significant drug-drug interactions 1, 2
• May reduce the bioavailability or efficacy of:
  • Oral contraceptives (risk of unintended pregnancy)
  • Immunosuppressants (risk of graft rejection)
  • Anticoagulants (risk of thrombosis)
  • HIV protease inhibitors
  • Digoxin 1, 2, 4
• Contraindicated with monoamine oxidase inhibitors and serotonin reuptake inhibitors due to risk of serotonin syndrome 1, 2

Adverse Effects

• Generally better tolerated than SGAs 1
• Common side effects include:
  • Mild gastrointestinal symptoms
  • Skin reactions/photosensitivity
  • Fatigue or sedation
  • Dizziness or confusion
  • Headache (more common than with placebo: 41% vs. 25%) 1, 5

Clinical Application Algorithm

1. For mild to moderate depression:

   • St. John's wort may be considered if:
     • Patient prefers a "natural" approach
     • Patient is not taking medications with potential interactions
     • Patient understands the lack of standardization and regulation
   • Typical dosage: 300-1800 mg/day of standardized extract (0.12% to 0.28% hypericin) 1

2. For moderate to severe depression:

   • SGAs or CBT are preferred over St. John's wort 2
   • Limited evidence supports St. John's wort for severe depression 4, 5

3. Contraindications for St. John's wort:

   • Concurrent use of:
     • SSRIs or MAOIs (risk of serotonin syndrome)
     • Oral contraceptives
     • Anticoagulants
     • Immunosuppressants
     • Antiretrovirals
     • Other medications metabolized by CYP3A4 1, 2, 4
   • Pregnancy or breastfeeding (insufficient safety data)
   • History of photosensitivity

Monitoring and Follow-up

• Assess response after 4-6 weeks
• Monitor for drug interactions if patient is taking other medications
• Advise patients to report any unusual symptoms or side effects
• Consider switching to SGAs or CBT if inadequate response or side effects occur

Bottom Line

While St. John's wort shows comparable efficacy to SGAs for mild to moderate depression with potentially fewer side effects, its lack of regulation, standardization issues, and significant drug interaction profile limit its clinical utility. For patients with no contraindications who prefer a "natural" approach, it remains a reasonable option with proper counseling about its limitations.