What is the recommended dosing for St. John's wort (Hypericum perforatum) in the treatment of depression?

St. John's Wort Dosing for Depression

For mild-to-moderate depression, St. John's wort should be dosed at 300 mg three times daily (900 mg/day total) of a standardized extract containing 0.3% hypericin, with the option to increase to 1200 mg/day if inadequate response occurs after 4 weeks. 1, 2, 3

Standard Dosing Regimen

Initial dosing:

• Start with 300 mg of standardized extract (0.3% hypericin) three times daily, totaling 900 mg/day 1, 2
• Continue this dose for at least 4 weeks to assess response 1, 4

Dose escalation if needed:

• If inadequate response after 4 weeks, increase to 1200 mg/day (400 mg three times daily) 1, 3
• Some studies have used up to 1500 mg/day for more severe depression, though evidence is limited 5

Treatment duration:

• Acute treatment phase: 6-12 weeks minimum 1, 4
• Responders may continue for up to 26 weeks total (8 weeks acute + 18 weeks continuation) 5

Efficacy by Severity

Mild-to-moderate depression:

• St. John's wort demonstrates response rates of 54% compared to 52% for SSRIs 6
• Remission rates of 36% versus 30% for standard antidepressants 6
• At 600-1200 mg/day, responder rates range from 64-73% versus 37% for placebo 3

Severe depression:

• Evidence is insufficient for severe depression 4
• Higher doses (600 mg three times daily = 1800 mg/day) may be needed, but this lacks robust clinical trial support 2

Critical Safety Considerations Before Prescribing

Absolute contraindications:

• Concurrent use with MAOIs or SSRIs (serotonin syndrome risk) 7, 6, 8
• Patients taking oral contraceptives (reduced efficacy, pregnancy risk) 7, 6
• Patients on immunosuppressants like cyclosporine or tacrolimus (transplant rejection risk) 7, 6

Relative contraindications requiring careful consideration:

• Warfarin therapy (reduced anticoagulation) 7
• HIV medications (significantly reduced protease inhibitor levels) 7
• Cancer chemotherapy agents (unpredictable dasatinib/imatinib levels) 7, 6
• Anticonvulsants (reduced drug levels) 7
• Cardiovascular medications including statins and digoxin 7

Practical Prescribing Algorithm

Step 1: Screen for drug interactions

• Review complete medication list for CYP3A4 substrates and P-glycoprotein substrates 7, 8
• If any significant interactions exist, choose CBT or standard antidepressants instead 8

Step 2: Assess depression severity

• Use HAM-D score: if ≥20, consider standard antidepressants first 9, 5
• If HAM-D <20 (mild-to-moderate), St. John's wort is appropriate 3

Step 3: Initiate treatment

• Prescribe 300 mg three times daily with meals 2
• Warn about photosensitivity and common adverse effects (GI symptoms, dizziness, fatigue) 1, 8

Step 4: Monitor response

• Reassess at 4 weeks using HAM-D or clinical assessment 1
• If <50% improvement, increase to 1200 mg/day 1, 3
• If no response by 8 weeks, switch to standard antidepressant 4

Important Caveats

Regulatory issues:

• St. John's wort is not FDA-regulated in the United States, leading to variable potency and content across preparations 7, 6, 8
• European standardized preparations are more reliable but may not be available in the U.S. 6

Tolerability advantage:

• Discontinuation rates due to adverse events are significantly lower (4% vs 7% for SSRIs) 6
• Overall discontinuation rates are 12% versus 16% for standard antidepressants 6
• Moderate-quality evidence confirms better tolerability than second-generation antidepressants 1, 6, 8

Transition considerations:

• When switching from St. John's wort to an SSRI, allow 24-48 hours washout to prevent serotonin syndrome 7
• When switching from an SSRI to St. John's wort, follow standard SSRI discontinuation protocols first 7

Special populations:

• In older adults (60-80 years), effectiveness and adverse event rates are similar to SSRIs, though evidence quality is low 1, 7, 6