Is St. John's wort (Hypericum perforatum) effective for treating depression?

St. John's Wort for Depression

St. John's wort may be as effective as second-generation antidepressants for mild-to-moderate depression, but I cannot recommend it for routine use in the United States due to lack of FDA regulation, significant drug interactions, and uncertain product quality. 1, 2

Efficacy Evidence

Comparable Effectiveness to SSRIs

• Low-quality evidence from 9 trials shows no difference in response or remission rates when comparing St. John's wort to second-generation antidepressants (SGAs) in patients with major depressive disorder after 4-12 weeks of treatment 1
• A 2023 meta-analysis of 14 trials (2,270 patients) demonstrated comparable efficacy with a pooled odds ratio of 2.44 (95% CI 1.33-4.45), showing St. John's wort reduced depressive symptoms similarly to SSRIs 3
• A 2017 meta-analysis of 27 trials (3,808 patients) found comparable response rates (pooled RR 0.983,95% CI 0.924-1.042) and remission rates (pooled RR 1.013,95% CI 0.892-1.134) between St. John's wort and SSRIs 4

Important Caveat on Study Quality

• The comparative effectiveness studies used SGA dosages capped at levels lower than usual dosing ranges, which downgrades the evidence quality 1
• One high-quality U.S. trial found St. John's wort was not significantly different from placebo in moderately severe major depression, with complete absence of efficacy trends 5

Tolerability Profile

Advantages

• Moderate-quality evidence shows St. John's wort is better tolerated than SGAs with significantly lower discontinuation rates due to adverse events (pooled OR 0.587,95% CI 0.478-0.697) 4
• Common adverse effects include mild gastrointestinal symptoms, skin reactions, fatigue, sedation, dizziness, headache, and dry mouth—generally milder than SSRI side effects 1, 2

Critical Limitations and Safety Concerns

Lack of Regulatory Oversight

• St. John's wort is not regulated by the FDA, and there is no standardization of contents or potency in U.S. preparations 1, 2
• Patients cannot reliably obtain preparations with similar effectiveness as those used in clinical trials 1

Dangerous Drug Interactions

• St. John's wort is a potent inducer of cytochrome P450 3A4 and P-glycoprotein, significantly decreasing plasma concentrations of many medications 2, 6
• Absolutely contraindicated with MAO inhibitors or serotonin reuptake inhibitors due to serotonin syndrome risk 2, 6
• Reduces effectiveness of oral contraceptives (risk of unintended pregnancy), immunosuppressants (cyclosporine, tacrolimus), warfarin, HIV medications, chemotherapy agents (imatinib), and anticonvulsants 6
• Must be discontinued at least 2 weeks before surgery due to multiple drug interactions 6

Evidence Gaps

• All available studies ranged from only 4-12 weeks duration; long-term efficacy and safety data are lacking 4
• Unclear if St. John's wort benefits patients with severe depression, high suicidality, or suicide risk 4

Clinical Algorithm for Decision-Making

When St. John's Wort Should NOT Be Used:

• Patients taking any medications metabolized by CYP3A4 (statins, immunosuppressants, oral contraceptives, anticoagulants, HIV medications, chemotherapy) 6
• Patients on any antidepressants (SSRIs, MAOIs) 2, 6
• Patients with severe depression or suicidality 4
• Patients requiring standardized, quality-controlled medication 1, 2
• Patients scheduled for surgery within 2 weeks 6

Theoretical Consideration (Not Recommended):

If a patient with mild-to-moderate depression insists on St. John's wort despite counseling:

• Verify they are taking NO interacting medications 6
• Obtain complete medication and supplement history 6
• Counsel about lack of FDA regulation and product variability 1, 2
• Discuss that cognitive behavioral therapy has stronger evidence (moderate-quality) with fewer safety concerns 1

Preferred Alternative

The American College of Physicians strongly recommends selecting between cognitive behavioral therapy or second-generation antidepressants for major depressive disorder, as both have moderate-quality evidence for efficacy with better-characterized safety profiles 1