St. John’s Wort — Hypericum perforatum

Common & Latin Names

Common names: St. John’s Wort, Saint John’s Wort, Klamath weed, Tipton’s weed, Rosin rose, Goatweed, Chase-devil, Perforate St. John’s Wort Latin name: Hypericum perforatum L. (the species name “perforatum” refers to the tiny translucent oil glands in the leaves that look like perforations when held to the light) TCM name: Guan Ye Lian Qiao (贯叶连翘) — not a classical TCM herb but used in modern Chinese integrative practice German: Johanniskraut (John’s herb) French: Millepertuis (thousand holes — referring to the leaf glands)

Plant Family & Parts Used

Family: Hypericaceae (St. John’s Wort family; formerly classified within Clusiaceae/Guttiferae) Parts used: Flowering tops (aerial parts harvested during full bloom, typically around June 24 — the Feast of St. John the Baptist, hence the name). The flower buds and open flowers are richest in hypericin and hyperforin. When the flower buds are crushed, they release a characteristic blood-red pigment — this red oil was central to the plant’s ancient reputation as a wound-healing “blood” herb. Habitat: Native to Europe, western Asia, and North Africa. Naturalized extensively in North America, Australia, New Zealand, and parts of South America — in some regions considered an invasive weed (particularly in the western United States and Australia). Grows in meadows, roadsides, woodland margins, and dry, sunny locations. A perennial growing to 0.3-1 meter with distinctive yellow flowers with five petals, each dotted with tiny black glands containing hypericin.

Traditional Uses

European Folk Medicine and Herbalism (2,000+ years)

St. John’s Wort has one of the richest histories of any European medicinal plant:

Greco-Roman: Dioscorides (1st century CE) recommended Hyperikon for sciatica and “fever of the third day” (possibly malaria). Pliny the Elder described it for burns and for driving out “evil spirits.” The association with combating darkness — both literal (wounds, inflammation) and figurative (melancholy, evil spirits) — was established early.

Medieval: Paracelsus (1493-1541) used St. John’s Wort specifically for melancholy and “phantasmata” (what we might now call depression with psychotic features or severe anxiety with intrusive thoughts). He recognized that the plant’s blood-red oil corresponded to its affinity for blood-related conditions. The plant was hung over doors and windows on St. John’s Eve (June 23) to protect against evil spirits, witchcraft, and lightning — a tradition reflecting its reputation as a protector of psychological and spiritual well-being.

Eclectic Medicine: The Eclectics used St. John’s Wort primarily as a nerve tonic and wound healer. Harvey Wickes Felter wrote: “It is prominently a remedy for injuries to the spine, coccyx, and for the effects of shocks and concussions.” The Eclectics used it for neuralgia, spinal injuries, bed-wetting in children, melancholia, and hysteria. The oil infusion (Oleum Hyperici — the red oil) was a standard wound and burn treatment.

German Phytomedicine (Modern Clinical Use)

St. John’s Wort’s modern reputation was established in Germany in the 1980s-1990s, when clinical trials demonstrated its efficacy for mild-to-moderate depression. By the late 1990s, it was the most prescribed antidepressant in Germany — outselling fluoxetine (Prozac) by a factor of four. Commission E approved it for “psychovegetative disturbances, depressive moods, anxiety and/or nervous unrest” in 1984.

Wound Healing Traditions (Cross-Cultural)

In virtually every European folk tradition, the red oil of St. John’s Wort (made by infusing the fresh flowers in olive oil until the oil turns deep red) was used for:

Burns (including sunburn)
Wounds and cuts
Bruises
Nerve damage and neuralgia
Ear infections (oil drops in the ear)
Hemorrhoids
Muscle pain and inflammation

This topical use has been validated by modern research showing anti-inflammatory, antimicrobial, and wound-healing properties of the red oil.

Active Compounds & Pharmacology

Primary Phytochemicals

Naphthodianthrones:

Hypericin (0.05-0.3%): The characteristic red pigment. Used as a standardization marker (most extracts are standardized to 0.3% hypericin). Hypericin is photosensitizing and has antiviral and anti-cancer properties. However, recent research suggests hypericin is NOT the primary antidepressant compound — this role belongs to hyperforin.
Pseudohypericin: Related compound with similar properties.

Phloroglucinol derivatives:

Hyperforin (2-4%): Now recognized as the primary antidepressant compound. An acylphloroglucinol that inhibits the reuptake of serotonin, norepinephrine, dopamine, GABA, and glutamate — a “broad-spectrum reuptake inhibitor” unlike any pharmaceutical antidepressant. Hyperforin achieves this through a unique mechanism: activation of TRPC6 (transient receptor potential canonical 6) ion channels, which modulates intracellular sodium, altering neurotransmitter transport.
Adhyperforin: Related compound with similar but less potent activity.

Flavonoids (2-4%):

Quercetin, hyperoside, rutin, isoquercitrin, quercitrin: Anti-inflammatory, antioxidant. Quercetin is a MAO-A inhibitor — contributing to antidepressant effects.
Amentoflavone: A biflavone that binds to benzodiazepine sites on GABA-A receptors — contributing to anxiolytic effects.
I3,II8-biapigenin: GABA-A receptor modulation.

Xanthones: Kielcorin, norathyriol. Anti-inflammatory.

Volatile oil: Contains 2-methyloctane, alpha-pinene, myrcene, limonene. Minor contribution.

Mechanisms of Action

Broad-Spectrum Neurotransmitter Reuptake Inhibition: Hyperforin inhibits the synaptic reuptake of serotonin (5-HT), norepinephrine (NE), dopamine (DA), GABA, and L-glutamate — simultaneously. No pharmaceutical antidepressant achieves this breadth. SSRIs affect only serotonin. SNRIs affect serotonin and norepinephrine. Bupropion affects norepinephrine and dopamine. St. John’s Wort affects all five. The mechanism is unique: hyperforin activates TRPC6 channels, increasing intracellular sodium, which interferes with the transmembrane sodium gradient that neurotransmitter transporters depend upon for reuptake.
GABA-A Receptor Modulation: Amentoflavone and biapigenin bind to benzodiazepine sites on GABA-A receptors, producing anxiolytic and mildly sedative effects without the tolerance, dependence, and withdrawal risks of benzodiazepines.
MAO Inhibition: Quercetin and other flavonoids inhibit monoamine oxidase-A (MAO-A), the enzyme that breaks down serotonin, norepinephrine, and dopamine. However, this inhibition is relatively mild compared to pharmaceutical MAO inhibitors and does not require the strict dietary restrictions of pharmaceutical MAOIs.
Anti-inflammatory (Neuroinflammation): St. John’s Wort reduces neuroinflammatory markers (IL-6, TNF-alpha, NF-kB) in the CNS. This is increasingly recognized as relevant because depression is associated with neuroinflammation, and anti-inflammatory mechanisms may contribute to antidepressant effects.
HPA Axis Modulation: St. John’s Wort reduces cortisol levels and normalizes HPA axis function in depressed patients. This connects its antidepressant mechanism to the broader stress-hormone network.
Photodynamic Activity (Hypericin): Hypericin is a potent photosensitizer — when activated by light, it generates reactive oxygen species that destroy pathogens and cancer cells. This underlies both the topical antimicrobial use and the photosensitivity side effect.

Clinical Evidence

Key Clinical Trials

Linde, K., Berner, M.M., & Kriston, L. (2008). “St John’s wort for major depression.” Cochrane Database of Systematic Reviews, (4), CD000448.

Cochrane systematic review — 29 RCTs involving 5,489 patients with major depression
St. John’s Wort extracts were significantly superior to placebo (RR for response: 1.48, 95% CI: 1.23-1.77)
St. John’s Wort was similarly effective to standard antidepressants (SSRIs and TCAs) (RR: 1.00, 95% CI: 0.90-1.12)
Patients on St. John’s Wort had significantly fewer dropouts due to adverse effects compared to pharmaceutical antidepressants (OR: 0.24, 95% CI: 0.13-0.46)
The review noted that evidence was stronger for German-language studies (where standardized pharmaceutical-grade extracts were used) than for English-language studies
Concluded: “The available evidence suggests that the Hypericum extracts tested in the included trials are superior to placebo in patients with major depression, are similarly effective as standard antidepressants, and have fewer side effects”

Ng, Q.X., Venkatanarayanan, N., & Ho, C.Y.X. (2017). “Clinical use of Hypericum perforatum (St John’s wort) in depression: A meta-analysis.” Journal of Affective Disorders, 210, 211-221.

Meta-analysis of 27 clinical trials with 3,808 patients
Confirmed that St. John’s Wort is significantly more effective than placebo for depression (SMD: -0.49, 95% CI: -0.74 to -0.24)
No significant difference in efficacy compared to SSRIs (SMD: -0.03, 95% CI: -0.15 to 0.09)
Significantly lower adverse event rate than SSRIs (RR: 0.77)
Particularly effective for mild-to-moderate depression; evidence for severe depression was less convincing
Concluded: “St John’s Wort monotherapy for mild and moderate depression is superior to placebo and as effective as SSRIs”

Kasper, S., Caraci, F., Forti, B., Drago, F., & Aguglia, E. (2010). “Efficacy and tolerability of Hypericum extract for the treatment of mild to moderate depression.” European Neuropsychopharmacology, 20(11), 747-765.

Review of the clinical evidence base for Hypericum extract STW 3-VI and WS 5570
Confirmed efficacy equivalent to SSRIs (paroxetine, fluoxetine, sertraline) in head-to-head trials
Documented superior tolerability: sexual dysfunction (the most common SSRI side effect) was virtually absent with St. John’s Wort
Weight gain (another common SSRI issue) was not observed

Gastpar, M., Singer, A., & Zeller, K. (2006). “Comparative efficacy and safety of a once-daily dosage of hypericum extract STW3-VI and citalopram in patients with moderate depression: a double-blind, randomised, multicentre, placebo-controlled study.” Pharmacopsychiatry, 39(2), 66-75.

388 patients with moderate depression, St. John’s Wort extract STW3-VI (900mg/day) vs. citalopram (20mg/day) vs. placebo for 6 weeks
Both St. John’s Wort and citalopram were significantly superior to placebo
St. John’s Wort was non-inferior to citalopram (HAMD-17 response rates: SJW 54.2%, citalopram 55.9%, placebo 39.2%)
SJW had significantly fewer side effects than citalopram

Therapeutic Applications

Conditions

Mild to moderate depression: The primary evidence-based indication — efficacy equivalent to SSRIs
Anxiety (mild to moderate): GABAergic and serotonergic mechanisms
Seasonal affective disorder (SAD): The traditional “solstice herb” — light-gathering and mood-lifting
Menopausal mood disturbance: Effective for depression and mood instability during menopause
Somatoform disorders: Depression manifesting as physical symptoms
Wounds, burns, and skin inflammation (topical): Red oil application
Neuralgia and nerve pain (topical): Red oil for postherpetic neuralgia, sciatica
PMS-related mood changes: Preliminary positive evidence
OCD (adjunctive): Preliminary evidence for serotonin-modulating effects on obsessive symptoms

Dosage Ranges

Standardized extract (0.3% hypericin, 2-5% hyperforin): 300mg, 3 times daily (900mg/day total). This is the most studied dose.
Hyperforin-standardized extract (5% hyperforin): 300mg, 3 times daily
Dried herb: 2-4g daily in capsules or as tea
Tincture (1:5 in 45% alcohol): 2-4mL, 3 times daily
Red oil (Oleum Hyperici — topical): Fresh flowers infused in olive oil for 4-6 weeks. Apply to affected area 2-3 times daily.
Tea: 1-2 teaspoons dried flowering tops per cup, steep 10-15 minutes. 2-3 cups daily.

Forms and Duration

Standardized extracts (LI 160/Jarsin, WS 5570, STW 3-VI, Ze 117) have the strongest evidence base. Effects on depression typically manifest within 2-4 weeks (similar to SSRIs). Full effects at 4-8 weeks. For depression, treatment should continue for a minimum of 6 months to reduce relapse risk. Topical red oil is the preferred form for wound healing and neuralgia.

Safety & Contraindications

The Drug Interaction Issue (Critical)

St. John’s Wort is one of the safest herbs for its direct effects but one of the most problematic for drug interactions. This paradox makes it unique in herbal medicine.

CYP3A4 and P-glycoprotein Induction: Hyperforin is a potent inducer of cytochrome P450 3A4 (CYP3A4) and the drug efflux transporter P-glycoprotein (P-gp). This means St. John’s Wort ACCELERATES the metabolism and elimination of drugs cleared by these pathways — reducing their blood levels and potentially causing treatment failure.

Critical Drug Interactions (Partial List)

Oral contraceptives: Reduced efficacy — breakthrough bleeding and unplanned pregnancy documented. THIS IS THE MOST COMMON PRACTICAL CONCERN.
Cyclosporine and other immunosuppressants: Dramatically reduced levels — transplant rejection has occurred. ABSOLUTE CONTRAINDICATION in transplant patients.
HIV protease inhibitors and NNRTIs: Reduced levels — viral rebound risk. ABSOLUTE CONTRAINDICATION with antiretroviral therapy.
Warfarin: Reduced levels — loss of anticoagulation.
Digoxin: Reduced levels by up to 25%.
SSRIs and SNRIs: Risk of serotonin syndrome when combined (additive serotonergic effects). CONTRAINDICATED with serotonergic antidepressants.
Triptans (sumatriptan): Additive serotonergic effects — serotonin syndrome risk.
Benzodiazepines: Reduced levels (CYP3A4 induction).
Statins (simvastatin, atorvastatin): Reduced levels by up to 50%.
Chemotherapy agents: Reduced efficacy of many CYP3A4-metabolized chemotherapy drugs (irinotecan, imatinib, docetaxel).
Theophylline: Reduced levels.
Methadone: Reduced levels — withdrawal symptoms.

Other Contraindications

Bipolar disorder: St. John’s Wort can trigger manic episodes in patients with bipolar disorder, similar to pharmaceutical antidepressants.
Photosensitivity: Hypericin is a photosensitizer. Fair-skinned individuals should use sun protection. The risk is dose-dependent and more significant at high doses.
Pregnancy: Traditionally considered safe, but modern concerns about uterotonic effects and drug interactions advise caution. Avoid unless under practitioner supervision.
Fertility treatments/IVF: May interfere with reproductive hormones and reduce effectiveness of fertility medications.

Side Effects

Generally mild and less frequent than SSRIs: GI discomfort (nausea, diarrhea), photosensitivity (sunburn-like reaction), dry mouth, dizziness, fatigue, headache, anxiety/agitation (usually transient), and vivid dreams. Sexual dysfunction is notably ABSENT — a major advantage over SSRIs.

Energetics

TCM Classification (Modern Integration)

Temperature: Cool to neutral
Flavor: Bitter, sweet
Meridian entry: Liver, Heart, Lung
Actions: Courses Liver Qi, calms the Shen, clears heat-toxin, activates Blood (topically), dries dampness
TCM pattern correspondence: Liver Qi stagnation with constraint depression (the depressed patient who feels stuck, frustrated, and unable to express emotions), Heart-Shen disturbance (anxiety, insomnia, restlessness), damp-heat with emotional overlay

Ayurvedic Classification (Modern Integration)

Rasa (taste): Tikta (bitter), Kashaya (astringent)
Virya (energy/potency): Shita (cooling)
Vipaka (post-digestive effect): Katu (pungent)
Dosha effects: Pacifies Pitta (cooling, anti-inflammatory). Pacifies Kapha (drying, lightening). May increase Vata in excess if used long-term without balancing (bitter/dry qualities).
Dhatu affinity: Majja (nerve/marrow — primary), Rakta (blood), Mamsa (muscle)
Srotas affinity: Manovaha (mind/nervous system — primary), Raktavaha (blood), Mamsavaha (muscle)

Functional Medicine Integration

St. John’s Wort is the most evidence-based botanical antidepressant and plays a specific role in functional medicine mood support protocols — with the critical caveat that drug interactions must be thoroughly evaluated.

Depression Protocol (Mild to Moderate)

For patients with mild-to-moderate depression who are NOT on medications that interact with CYP3A4 inducers, St. John’s Wort is a first-line botanical intervention with efficacy equivalent to SSRIs and superior tolerability. In functional medicine, it is used within a comprehensive protocol that includes: root cause investigation (thyroid, nutrient deficiencies, gut-brain axis, HPA dysregulation), foundational nutrients (omega-3, vitamin D, B vitamins, magnesium), lifestyle interventions (exercise, sleep, light exposure), and herbal support (St. John’s Wort for serotonergic/dopaminergic/GABAergic modulation).

Seasonal Affective Disorder Protocol

St. John’s Wort is perhaps uniquely suited for SAD. It is traditionally harvested at the summer solstice — the day of maximum light — and was associated with capturing and preserving the sun’s healing power. Its photosensitizing properties (hypericin) may actually enhance the biological response to light therapy. Combined with light box therapy, vitamin D supplementation, and omega-3 fatty acids, St. John’s Wort addresses SAD from multiple angles.

Menopausal Mood Protocol

For menopausal women experiencing depression, irritability, and mood instability, St. John’s Wort provides antidepressant effects without the sexual dysfunction and weight gain of SSRIs — both of which are particularly unwelcome during menopause. Combined with black cohosh (for vasomotor symptoms) and maca (for libido), it addresses the mood component of the menopause triad.

Wound Healing Protocol (Topical)

The red oil of St. John’s Wort (Oleum Hyperici) is a potent topical healing agent for burns, wounds, nerve pain, and musculoskeletal inflammation. It is used in post-surgical wound care, postherpetic neuralgia, and chronic skin conditions. Applied topically, the drug interaction concerns do not apply.

The Drug Interaction Management Protocol

In functional medicine practice, the first step before prescribing St. John’s Wort is a comprehensive medication review. If the patient is on ANY drug metabolized by CYP3A4 or P-glycoprotein, St. John’s Wort is typically not used. Alternatives include saffron (Crocus sativus), SAMe, rhodiola, and high-dose omega-3 fatty acids for mood support in patients on interacting medications.

Four Directions Connection

Primary Direction: Eagle (East — Spiritual Vision)

St. John’s Wort is the Eagle’s herb — the herb of light, vision, and spiritual clarity. It is harvested at the solstice, the day the sun reaches its zenith. The Eagle sees from the highest vantage, and St. John’s Wort lifts the consciousness out of the darkness of depression and into the clarity of light. Depression is, at its core, a loss of vision — the inability to see a future, to perceive meaning, to connect with purpose. The Eagle restores this vision. St. John’s Wort, through its action on five neurotransmitter systems simultaneously, restores the neurochemical foundation for perception, meaning, and engagement with life. The blood-red oil that emerges when you crush the golden flowers is the Eagle’s alchemy: light transmuted into healing.

Secondary Direction: Jaguar (West — Emotional Healing)

Depression is the Jaguar’s territory — it is the journey through darkness, the confrontation with despair, the descent into the emotional underworld. The Jaguar teaches that we must walk through the darkness to emerge transformed. But sometimes the darkness is so deep that we cannot walk at all — we become frozen, paralyzed, unable to function. St. John’s Wort does not bypass the Jaguar’s journey (unlike SSRIs, which can blunt emotional range), but it provides enough neurochemical support to keep moving through the darkness rather than being swallowed by it. The medieval name “Chase-devil” captures this Jaguar function perfectly — the herb that chases the demons of the shadow without denying their reality.

Tertiary: Hummingbird (North — Ancestral Wisdom)

St. John’s Wort’s association with the summer solstice — the most universally celebrated astronomical event across human cultures — connects it to the deepest ancestral wisdom about light, darkness, and renewal. The Hummingbird’s long journey passes through many solstices, and at each turning point, the herbs of light are gathered to sustain the journey through the dark half of the year. This is ancestral knowledge encoded in botanical timing: harvest the light when it is strongest to sustain you when it is weakest.

References

Linde, K., Berner, M.M., & Kriston, L. (2008). St John’s wort for major depression. Cochrane Database of Systematic Reviews, (4), CD000448.
Ng, Q.X., Venkatanarayanan, N., & Ho, C.Y.X. (2017). Clinical use of Hypericum perforatum (St John’s wort) in depression: A meta-analysis. Journal of Affective Disorders, 210, 211-221.
Kasper, S., Caraci, F., Forti, B., Drago, F., & Aguglia, E. (2010). Efficacy and tolerability of Hypericum extract for the treatment of mild to moderate depression. European Neuropsychopharmacology, 20(11), 747-765.
Gastpar, M., Singer, A., & Zeller, K. (2006). Comparative efficacy and safety of a once-daily dosage of hypericum extract STW3-VI and citalopram in patients with moderate depression. Pharmacopsychiatry, 39(2), 66-75.
Müller, W.E. (2003). Current St. John’s wort research from mode of action to clinical efficacy. Pharmacological Research, 47(2), 101-109.
Russo, E., Scicchitano, F., Whalley, B.J., et al. (2014). Hypericum perforatum: pharmacokinetic, mechanism of action, tolerability, and clinical drug-drug interactions. Phytotherapy Research, 28(5), 643-655.
Schempp, C.M., Windeck, T., Hezel, S., & Simon, J.C. (2003). Topical treatment of atopic dermatitis with St. John’s wort cream — a randomized, placebo controlled, double blind half-side comparison. Phytomedicine, 10(Suppl 4), 31-37.
Butterweck, V. (2003). Mechanism of action of St John’s wort in depression: what is known? CNS Drugs, 17(8), 539-562.
Henderson, L., Yue, Q.Y., Bergquist, C., Gerden, B., & Arlett, P. (2002). St John’s wort (Hypericum perforatum): drug interactions and clinical outcomes. British Journal of Clinical Pharmacology, 54(4), 349-356.
Laakmann, G., Schüle, C., Baghai, T., & Kieser, M. (1998). St. John’s wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry, 31(Suppl 1), 54-59.

St. John's Wort — Hypericum perforatum