One of the most researched herbs for mild-to-moderate depression, with evidence comparable to SSRIs but ten-fold better tolerability. The catch: serious drug interactions make it incompatible with many medications.
Traditions: European herbalism, Greek medicine, Medieval medicine
Multiple traditions agree on use.
Documented by Dioscorides and Hippocrates for wound healing and nerve pain.
Named after St. John the Baptist (flowers bloom around St. John's Day, June 24th). Used for melancholy, wounds, and protection against 'evil spirits' - the historical term for what we might now call severe depression or mental disorders.
Official approval for depression (900mg/day) and topical use for wounds, muscle pain, and burns.
Recognized for depression, wound healing, antibacterial, antiviral, and anti-inflammatory effects.
St. John's Wort has exceptional evidence for mild-to-moderate depression - 27 trials with 3,808 patients show comparable efficacy to SSRIs with 41-53% fewer dropouts due to side effects. The evidence stops working for severe/major depression. The primary active constituent is hyperforin, which broadly inhibits reuptake of serotonin, norepinephrine, dopamine, GABA, and glutamate - unlike SSRIs which only target serotonin.
27 trials, n=3,808. Response rate equivalent to SSRIs (RR 0.983, p>0.05). Discontinuation rate 41% lower (OR 0.587, p<0.001). Comparable efficacy with significantly better tolerability.
14 RCTs, n=2,270. Odds ratio of 2.44 favoring St. John's Wort over SSRIs with fewer adverse events.
13 trials comparing to SSRIs. Clinical response equivalent (RR 0.99). Adverse events causing withdrawal 53% lower (RR 0.53, p<0.05).
16 studies, n=34,804. Adverse event rates 0.1-2.4% in large studies. At least ten-fold lower than synthetic antidepressants.
37 RCTs. Marked effects in mild-to-moderate depression. Minimal effects over placebo in severe/major depression restricted trials.
Most studied preparations. Standard extracts (0.3% hypericin, 2-4% hyperforin) for depression. Low-hyperforin (≤1mg/day) minimizes CYP3A4 induction and drug interactions while maintaining efficacy.
Traditional: 1:5 at 40-60% alcohol. Commercial: 1:2 (more concentrated). Some standardized to 0.3% hypericin. Less standardized than clinical extracts.
Taste: Mildly bitter, slightly astringent, pleasant herbal flavor.
Traditional preparation. Significantly less concentrated than standardized extracts - suitable for very mild symptoms, not equivalent to clinical doses. Cover while steeping to retain volatile compounds.
Traditional wound oil. Made by macerating fresh flowers in olive oil for 3-6 weeks until deep red. For burns, wounds, bruises, muscle pain, nerve pain. CRITICAL: Never apply before sun exposure - severe photosensitivity risk.
St. John’s Wort is one of the most researched herbs in existence, and the evidence is clear: it works for mild-to-moderate depression, with efficacy comparable to SSRIs and dramatically better tolerability.
Strong evidence (multiple meta-analyses):
The severity boundary is real: A 2005 meta-analysis of 37 trials found St. John’s Wort highly effective in older trials with mild-to-moderate depression, but showed only minor effects over placebo in larger, recent trials restricted to severe/major depression [5]. A 2001 trial in 200 adults with major depression found remission rates of 14.3% (St. John’s Wort) vs 4.9% (placebo) - both remained low [6].
What’s actually happening: The primary active constituent is hyperforin, which non-competitively inhibits reuptake of serotonin, norepinephrine, dopamine, GABA, and glutamate - a broader mechanism than SSRIs which only target serotonin [7]. This shows up in bioavailability studies where hyperforin achieves the highest plasma concentrations (~83.5 ng/ml) despite low overall bioavailability (15-20%) [7].
Regulatory recognition: German Commission E approved it for depression in 1984 at 900mg/day [8]. WHO recognized it in 2002 for depression, wound healing, and antimicrobial effects [9]. The European Medicines Agency classifies it as “well-established use” for mild-to-moderate depression [10].
Ancient Greece (1st century CE): Dioscorides and Hippocrates documented St. John’s Wort for wound healing and nerve pain [11].
Medieval Europe (5th-15th century): Named after St. John the Baptist because the bright yellow flowers bloom around St. John’s Day (June 24th, midsummer). Used for melancholy (depression), wounds, and as protection against “evil spirits” - the historical term for severe mental disturbances [11].
The name tells the story:
Geographic spread: Native to Europe, Western Asia, and North Africa. Brought to North America by European settlers. Used by 19th-century Eclectic physicians for melancholy, nervous disorders, spinal injuries, and wounds [11].
Traditional preparations:
The consistency across ancient Greek medicine, medieval European herbalism, German regulatory approval (1984), and modern RCTs is notable. When multiple unrelated traditions and modern science independently arrive at the same use, it’s worth paying attention.
Standardized extracts (evidence-based, most studied):
| Extract | Standardization | Best For | Dose |
|---|---|---|---|
| WS 5570 / LI 160 | 0.3% hypericin, 2-4% hyperforin | Depression (no drug interaction concerns) | 900mg/day |
| WS 5572 | 0.3% hypericin, ≤1mg/day hyperforin | Depression WITH drug interaction concerns | 900mg/day |
| Ze 117 | Standardized for long-term use | Long-term treatment (up to 1 year) | 500mg/day |
Traditional preparations (less standardized, mild symptoms only):
Week 1-8: 900mg/day standardized extract (300mg three times daily)
If inadequate response at week 4-6: May increase to 1200-1800mg/day (maximum studied dose)
Don’t expect immediate results. Effects build over time. If it doesn’t work by week 6, it probably won’t work.
This is the primary safety concern. Hyperforin (the active antidepressant constituent) induces CYP3A4 and P-glycoprotein enzymes, accelerating metabolism of many medications [13].
Critical interactions (NEVER combine):
Important interactions (requires monitoring or alternative):
Solution if on interacting medications: Use low-hyperforin extract (≤1mg/day hyperforin, like WS 5572) which maintains antidepressant efficacy while minimizing CYP3A4 induction [13]. Still avoid critical combinations (immunosuppressants, antiretrovirals, SSRIs).
Baseline (week 0 before starting):
During trial (weeks 1-8): Track the same markers. Compare:
RED FLAGS - Stop immediately:
You may notice: Gradual improvement in mood over 2-4 weeks, better stress response, improved sleep, reduced emotional reactivity. In trials, 1.5-2.4 times more people responded compared to placebo [3,4].
Action if contraindicated: Consult healthcare provider for safer alternatives. For mild-to-moderate depression with contraindications, consider therapy (CBT), exercise, light therapy, or synthetic antidepressants with medical supervision.
Traditional St. John’s Wort oil (Oleum Hyperici) is made by macerating fresh flowers in olive oil for 3-6 weeks until the oil turns deep red from hypericin extraction [11]. The red color is the quality marker - it should be visibly red.
Traditional uses:
Application: Apply to affected area 2-3 times daily. For muscle/nerve pain, massage into skin.
CRITICAL warning: Never apply before sun exposure. Hypericin causes photosensitivity - you can develop severe sunburn-like reactions. Apply in evening or cover treated areas during day [14].
The problem: Not all St. John’s Wort products are equivalent. Hypericin and hyperforin content varies widely in unstandardized products.
What to look for:
For traditional preparations (tinctures, tea, oil):
Avoid: Unstandardized capsules with vague “St. John’s Wort extract” labeling, unbranded products without third-party testing, products that don’t specify hypericin/hyperforin content.
This is a powerful antidepressant with exceptional clinical evidence - comparable efficacy to SSRIs with ten-fold better tolerability. But it comes with a serious caveat: drug interactions make it incompatible with many medications.
When it works: Gradual improvement in depression over 2-4 weeks, better stress response, improved sleep. In trials, 1.5-2.4 times more people responded compared to placebo, with equivalent efficacy to SSRIs but 41-53% fewer dropouts due to side effects [1,3,4].
When it doesn’t: Severe/major depression shows minimal effects over placebo [5,6]. Drug interactions eliminate it as an option for transplant recipients, HIV/AIDS patients, cancer patients, and those on SSRIs.
The decision tree:
Start at clinical dose (900mg/day), track honestly for 6 weeks, use sun protection, screen for drug interactions, and prioritize quality. If it works, it works profoundly. If it doesn’t work by week 6, try a different approach.
Duration: Minimum 4-6 weeks. Onset takes 2-4 weeks (same as SSRIs). If effective, continue for at least 6 months to prevent relapse. Long-term use (up to 1 year) is safe based on clinical trials.
What to notice:
Start at 900mg/day standardized extract (300mg three times daily) with food to reduce GI symptoms. This is not a 'start low, titrate up' herb - 900mg is the standard studied dose. May increase to 1200-1800mg after 4 weeks if inadequate response. Effects build over 2-4 weeks - no immediate results expected. Individual variation exists but is lower than adaptogens. If it doesn't work by week 6, it probably won't work.
Generally considered: caution
Contraindications:
Pregnancy/Nursing: Contraindicated in pregnancy (insufficient safety data, possible effects on fetal development). Avoid during breastfeeding (unknown excretion in breast milk, potential effects on nursing infant).
Generally safe for healthy adults short-term (≤3 months) and long-term (up to 1 year) with adverse event rates ten-fold lower than SSRIs. The PRIMARY safety concern is drug interactions via CYP3A4 induction (caused by hyperforin). Affects: immunosuppressants (cyclosporine, tacrolimus), antiretrovirals (indinavir), cardiovascular drugs (warfarin, digoxin, statins), oral contraceptives, benzodiazepines (alprazolam), chemotherapy agents. Low-hyperforin extracts (≤1mg/day) minimize interactions while maintaining efficacy. Most common side effects: GI symptoms (nausea, diarrhea), mild dizziness, headache. Photosensitivity is dose-dependent - use sun protection (SPF 30+), avoid tanning beds, limit sun exposure. No significant withdrawal syndrome (unlike SSRIs). Can generally stop without tapering. Allow 1-2 week washout when switching to/from SSRIs to reduce serotonin syndrome risk. Discontinue 2 weeks before surgery due to potential anesthesia interactions.