St. John's Wort Dosing for Depression
Start with 300 mg of standardized extract (0.3% hypericin) three times daily for a total of 900 mg/day, and if response is inadequate after 4 weeks, increase to 1200 mg/day (400 mg three times daily). 1
Standard Dosing Protocol
- Initial dose: 300 mg of standardized extract (0.3% hypericin) three times daily, totaling 900 mg/day 1
- Duration before dose adjustment: Continue initial dose for at least 4 weeks to assess response 1
- Dose escalation: If inadequate response after 4 weeks, increase to 1200 mg/day (400 mg three times daily) 1
- Acute treatment phase: Minimum 6-12 weeks required to establish efficacy 1
The American College of Physicians provides this specific dosing framework based on the standardized extracts used in clinical trials demonstrating efficacy comparable to second-generation antidepressants 1. This dosing applies specifically to mild-to-moderate depression, where St. John's wort shows similar response rates (54% vs. 52%) and remission rates (36% vs. 30%) compared to SSRIs 1.
Critical Safety Considerations Before Prescribing
Absolute contraindications:
- Concurrent use with monoamine oxidase inhibitors (MAOIs) or serotonin reuptake inhibitors (SSRIs) due to serotonin syndrome risk 2, 3
- Patients taking oral contraceptives (reduces effectiveness, risking unintended pregnancy) 2, 3
- Patients on immunosuppressants like cyclosporine or tacrolimus (may cause transplant rejection) 2, 3
Relative contraindications requiring careful consideration:
- Warfarin therapy (reduces anticoagulant effectiveness) 2
- Cancer chemotherapy, particularly dasatinib or imatinib (unpredictably decreases plasma concentrations) 2
- HIV medications (significantly decreases protease inhibitor levels) 2
- Anticonvulsants (may reduce carbamazepine, phenytoin, phenobarbital levels) 2
St. John's wort is a potent inducer of cytochrome P450 3A4 and P-glycoprotein, causing clinically significant drug interactions 2, 3. The American College of Physicians emphasizes that St. John's wort is not FDA-regulated in the United States, with no standardization of content or potency 1, 3.
Efficacy and Tolerability Profile
- Better tolerability than SSRIs: Discontinuation rates due to adverse events are significantly lower (4% vs. 7%) 1
- Overall discontinuation rates: 12% for St. John's wort vs. 16% for antidepressants 1
- Comparable efficacy: Moderate-quality evidence confirms similar effectiveness to second-generation antidepressants 4, 1
Special Population Considerations
- Older adults (60-80 years): Equal effectiveness and similar adverse event rates compared to SSRIs, though evidence quality is low 1, 2
- Severe depression or high suicidality: St. John's wort is not appropriate; cognitive behavioral therapy or standard antidepressants are strongly recommended 3, 5
Clinical Decision Algorithm
St. John's wort is appropriate when ALL of the following criteria are met:
- Diagnosis of mild-to-moderate depression (not severe) 1, 5
- No concurrent medications with CYP3A4 interactions 2, 3
- Not taking oral contraceptives, immunosuppressants, or anticoagulants 2
- Patient cannot tolerate standard antidepressants OR prefers herbal treatment 1
- Access to quality-controlled European preparations (if possible, given lack of U.S. standardization) 1
If any criterion is not met: Choose cognitive behavioral therapy or second-generation antidepressants as first-line treatment per American College of Physicians strong recommendation 2, 3.
Common Pitfalls to Avoid
- Assuming all St. John's wort preparations are equivalent: Lack of FDA regulation means significant variability in U.S. products 1, 3
- Failing to screen for drug interactions: Always obtain complete medication list including over-the-counter drugs before prescribing 2
- Inadequate treatment duration: Must continue for minimum 6-12 weeks before declaring treatment failure 1
- Transitioning directly from SSRIs: Allow 24-48 hours washout period to avoid serotonin syndrome 2