What is the recommended dose of St. John's Wort (Hypericum perforatum) for treating mild to moderate depression?

Recommended Dose of St. John's Wort for Mild to Moderate Depression

The recommended dose of St. John's Wort for treating mild to moderate depression is 300 mg three times daily (total 900 mg/day), using a standardized extract containing 0.3% hypericin or 0.12-0.28% hypericin, based on the dosing regimens used in clinical trials that demonstrated efficacy comparable to SSRIs. 1, 2

Dosing Specifications

Standard Dosing Regimen:

• 300 mg orally three times daily is the most commonly studied and recommended dose 1
• Total daily dose ranges from 300 mg/day to 1800 mg/day across clinical trials, though 900 mg/day (300 mg TID) represents the most frequently used effective dose 1
• Standardization should be to 0.3% hypericin (preferred) or 0.12% to 0.28% hypericin 1, 2

Alternative Formulation:

• For hypericin liquid preparations: 10 drops orally 3 times daily for adults and children above 12 years 3

Evidence Supporting This Dosing

Efficacy at Standard Doses:

• Meta-analyses of 9 trials (1,513 participants) using doses of 300-1800 mg/day demonstrated response rates of 54% with St. John's Wort versus 52% with SSRIs (RR 0.96, CI 0.83-1.11), showing comparable efficacy 1
• Remission rates were 36% with St. John's Wort versus 30% with SSRIs (RR 0.85, CI 0.70-1.04) across 5 trials with 768 participants 1
• More recent meta-analysis of 27 trials with 3,808 patients confirmed comparable response (pooled RR 0.983) and remission rates (pooled RR 1.013) to SSRIs 4

Safety Profile at Standard Doses:

• Discontinuation due to adverse events was significantly lower with St. John's Wort (4%) compared to SSRIs (7%), with RR 1.70 (CI 1.12-2.60) favoring St. John's Wort 1, 2
• Overall discontinuation rates were also lower: 12% for St. John's Wort versus 16% for antidepressants (RR 1.28, CI 1.01-1.62) 1

Treatment Duration and Monitoring

Initial Treatment Period:

• Treatment effects should be assessed after 6 to 12 weeks of therapy at the standard dose, as this was the duration used in efficacy trials 1
• If no improvement occurs after 2 to 4 weeks at the upper dosing range, consider switching to conventional SSRI or cognitive behavioral therapy 2, 5

Long-term Considerations:

• Evidence for long-term efficacy and safety beyond 12 weeks is limited, as most trials ranged from 4-12 weeks duration 4
• Patients requiring extended treatment should be monitored closely for sustained efficacy and emerging adverse effects 4, 6

Critical Contraindications and Precautions

Absolute Contraindications:

• Concomitant use with SSRIs or MAOIs due to serotonin syndrome risk 7, 8
• Severe depression, high suicide risk, or suicidal ideation (insufficient evidence in these populations) 2, 4
• Patients taking warfarin, oral contraceptives, immunosuppressants (cyclosporine, tacrolimus), HIV protease inhibitors, or ivabradine due to CYP3A4 induction reducing drug efficacy 7, 8

Important Drug Interactions:

• St. John's Wort is a potent inducer of CYP3A4 and P-glycoprotein, significantly decreasing plasma concentrations of numerous medications 7, 8
• Should be discontinued at least 2 weeks before surgery due to multiple drug interactions 7
• Reduces effectiveness of statins, anticonvulsants, digoxin, and chemotherapy agents like imatinib 7

Quality and Standardization Concerns

Regulatory Status:

• St. John's Wort is not FDA-regulated, with no standardization of content or potency in U.S. preparations 2, 8
• The American College of Physicians notes insufficient evidence about applicability, purity, and potency of preparations available in the United States 7, 8
• Prescribers should recommend pharmaceutical-grade products standardized to hypericin content to ensure consistency 1, 9

Active Constituents and Mechanism

Key Components:

• Hyperforin is the primary constituent responsible for antidepressant activity, not hypericin as originally thought 9, 10
• Hypericin and pseudohypericin (naphthodianthrones) contribute to efficacy but are present at lower plasma concentrations 9, 10
• Flavonoids (including rutin and quercetin) also participate in antidepressant effects 9, 10
• Hyperforin is the only ingredient consistently detected in brain tissue after oral administration 10

Common Adverse Effects

Expected Side Effects:

• Mild gastrointestinal symptoms 8
• Skin reactions and photosensitivity (increased risk when combined with other photosensitizing medications) 7, 8
• Fatigue or sedation 8
• Dizziness or confusion 8
• Headache and dry mouth 8

Clinical Algorithm for Implementation

Step 1: Patient Selection

• Confirm diagnosis of mild to moderate depression only 2, 5, 4
• Screen for severe depression, suicidality, or psychotic features (if present, choose CBT or SSRIs instead) 2

Step 2: Medication Review

• Obtain complete medication list including all prescription drugs, over-the-counter medications, and supplements 7
• Identify any contraindicated medications (SSRIs, MAOIs, warfarin, oral contraceptives, immunosuppressants, etc.) 7, 8
• If significant interactions exist, choose alternative treatment (CBT or conventional antidepressants) 2, 8

Step 3: Initiate Treatment

• Prescribe 300 mg three times daily of standardized extract (0.3% hypericin) 1, 2
• Counsel patient on photosensitivity risk and need to avoid sun exposure 7, 8
• Warn about potential contraceptive failure if using oral contraceptives 7

Step 4: Follow-up and Assessment

• Reassess at 2-4 weeks for early response 2, 5
• If no improvement by 2-4 weeks, consider dose optimization within the 300-1800 mg/day range or switch to SSRI/CBT 2, 5
• Full efficacy assessment at 6-12 weeks 1

Step 5: Treatment Adjustment

• If inadequate response after 6-12 weeks at optimal dose, switch to conventional SSRI or initiate cognitive behavioral therapy 2
• Do not combine St. John's Wort with SSRIs due to serotonin syndrome risk 7, 8