St. John's Wort for Depression and Anxiety
Primary Recommendation
St. John's wort is as effective as second-generation antidepressants (SSRIs) for treating mild-to-moderate depression, with better tolerability, but should only be used in carefully selected patients due to significant drug interactions and lack of FDA regulation in the United States. 1, 2
Efficacy for Depression
Comparable Effectiveness to Standard Antidepressants
St. John's wort demonstrates equivalent response rates (54% vs. 52%) and remission rates (36% vs. 30%) compared to SSRIs in patients with mild-to-moderate depression. 2
Low-quality evidence from 9 trials showed no difference in response or remission when comparing St. John's wort with second-generation antidepressants after 4 to 12 weeks of treatment. 1
A 2017 meta-analysis of 27 clinical trials involving 3,808 patients confirmed comparable response (pooled RR 0.983) and remission rates (pooled RR 1.013) between St. John's wort and SSRIs. 3
A 2023 meta-analysis of 14 trials with 2,270 patients found a pooled odds ratio of 2.44 favoring St. John's wort over placebo, with reduced Hamilton Depression Rating Scale scores. 4
Superior Tolerability Profile
Patients taking St. John's wort have significantly lower treatment discontinuation rates (12% vs. 16%) and discontinuation due to adverse events (4% vs. 7%) compared to those on standard antidepressants. 2
Moderate-quality evidence confirms St. John's wort is better tolerated than second-generation antidepressants. 1, 2, 5
The meta-analysis showed significantly lower dropout rates with St. John's wort (pooled OR 0.587) compared to SSRIs. 3
Common Adverse Effects
- Adverse effects associated with St. John's wort include mild gastrointestinal symptoms, skin reactions, fatigue or sedation, dizziness or confusion, headache, and dry mouth. 1, 5
Evidence for Anxiety
Limited evidence suggests St. John's wort may have antianxiety effects, with some studies reporting benefits in generalized anxiety disorder, though this is not as well-established as its antidepressant effects. 6
The primary evidence base focuses on depression rather than anxiety disorders specifically. 7
Critical Safety Concerns and Contraindications
Absolute Contraindications
St. John's wort is absolutely contraindicated in patients taking monoamine oxidase inhibitors (MAOIs) or serotonin reuptake inhibitors (SSRIs) due to risk of serotonin syndrome. 1, 2, 8, 5
Concomitant use with ivabradine is specifically contraindicated due to reduced effectiveness. 8
Major Drug Interactions via CYP3A4 Induction
St. John's wort is a potent inducer of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein, which significantly decreases plasma concentrations and effectiveness of many medications. 1, 8, 5
Oral contraceptives: St. John's wort reduces effectiveness, potentially leading to unintended pregnancy. 1, 2, 8
Immunosuppressants: May reduce efficacy of cyclosporine and tacrolimus, risking transplant rejection. 1, 2, 8
Anticoagulants: Reduces warfarin effectiveness, increasing thrombotic risk. 8
Cardiovascular medications: Decreases levels of statins (atorvastatin, lovastatin, simvastatin) and digoxin. 8
Cancer medications: Unpredictably decreases dasatinib and imatinib plasma concentrations. 2, 8
Anticonvulsants: May decrease levels of carbamazepine, phenytoin, and phenobarbital. 8
HIV medications: Significantly decreases plasma concentrations of protease inhibitors and non-nucleoside reverse transcriptase inhibitors. 8
Perioperative Considerations
- St. John's wort should be discontinued at least 2 weeks before surgery due to multiple potential drug interactions and effects on serotonin levels. 8
Regulatory and Quality Control Issues
FDA Regulation Concerns
St. John's wort is not regulated by the U.S. Food and Drug Administration, and there is no standardization of content or potency in preparations available in the United States. 1, 8, 5
Patients in the United States may not reliably obtain preparations with similar effectiveness as those used in clinical trials, which were primarily conducted with quality-controlled European preparations. 1, 2
Clinical Decision Algorithm
When to Consider St. John's Wort
Consider St. John's wort for patients who meet ALL of the following criteria:
Diagnosis: Mild-to-moderate depression (not severe depression or high suicidality risk). 2, 3
Medication profile: Not taking any contraindicated medications including:
Access: Can obtain quality-controlled European preparations (not readily available in U.S.). 2
Intolerance: Cannot tolerate standard antidepressants due to adverse effects. 2
When to Avoid St. John's Wort
Do NOT use St. John's wort in patients with:
- Severe depression or high suicidality risk (insufficient evidence). 3
- Any of the contraindicated medications listed above. 1, 2, 8
- Planned surgery within 2 weeks. 8
- Need for reliable, FDA-regulated treatment with standardized dosing. 1, 5
Preferred First-Line Treatment
The American College of Physicians recommends choosing between cognitive behavioral therapy (CBT) or second-generation antidepressants as first-line treatment for major depressive disorder (strong recommendation, moderate-quality evidence). 1
CBT and SSRIs are similarly effective, with CBT having no more—and probably fewer—adverse effects than SSRIs, plus lower relapse rates. 1
Special Populations
Older Adults
- In older adults (aged 60-80 years), St. John's wort shows equal effectiveness and similar adverse event rates compared to second-generation antidepressants, though this is based on low-quality evidence. 2
Evidence Limitations
Study Duration and Severity
Evidence on long-term efficacy and safety is limited, as all available studies ranged from 4 to 12 weeks. 3
It remains unclear if St. John's wort would be beneficial for patients with severe depression or high suicidality risk. 3
One notable negative trial (JAMA 2002) found no significant difference between St. John's wort, sertraline, or placebo in moderately severe major depression, though this may reflect low assay sensitivity. 9
Quality of Evidence
- The comparative effectiveness studies with St. John's wort used SGA doses capped at levels lower than usual dosing ranges, contributing to the low-quality rating of this evidence. 1
Monitoring Requirements
Patients taking St. John's wort with any interacting medications require more frequent monitoring of drug levels or therapeutic effects. 8
Monitor for at least 24-48 hours after discontinuing St. John's wort, as symptoms of serotonin syndrome can emerge during this period if transitioning to SSRIs. 8
Patients should always disclose use of St. John's wort to all healthcare providers, particularly before starting new medications or undergoing surgical procedures. 8