Herbal Monograph
St. John's wort
Hypericum perforatum L.
Hypericaceae (formerly placed in Clusiaceae/Guttiferae)
Evidence-based nervine for mild-moderate depression; critical drug interaction profile
Overview
Plant Description
Erect, rhizomatous herbaceous perennial, 30-100 cm tall (occasionally to 150 cm in favorable conditions). Stems woody at the base, branching in the upper portion, with two distinctive raised longitudinal ridges running along their length — a key identification feature. Leaves opposite, sessile, oblong to elliptic, 1-3 cm long, with conspicuous translucent oil glands (pellucid dots) visible when held up to light — this 'perforated' appearance gives the species its name 'perforatum.' Leaf margins may also bear dark glandular dots (containing hypericin). Flowers bright golden-yellow, 2-2.5 cm diameter, in terminal corymbose cymes; petals 5, asymmetric, bearing black dots and streaks along the margins (glandular structures containing hypericin and pseudohypericin); stamens numerous, in 3 fascicles; when flowers or buds are crushed between the fingers, they release a characteristic deep red-purple pigment (hypericin). Fruit a three-celled capsule containing numerous small, dark brown, cylindrical seeds approximately 1 mm long. Flowers from June to August in the Northern Hemisphere, typically peaking around the summer solstice (St. John's Day, June 24th — the origin of the common name). The entire plant has a balsamic, turpentine-like odor when crushed.
Habitat
Open, disturbed habitats including meadows, pastures, roadsides, field margins, railway embankments, open woodlands, and waste ground. Prefers dry to mesic, well-drained soils in full sun to partial shade. Thrives in calcareous and sandy soils. Pioneer species that colonizes disturbed ground. Altitude range: sea level to approximately 1,600 m in Europe, higher in some mountainous regions.
Distribution
Native to Europe, western Asia, and North Africa. The species has become widely naturalized and is now found on every continent except Antarctica. Extensively naturalized in North America, South America (Argentina, Chile), Australia, New Zealand, and South Africa, where it is often classified as an invasive weed. In parts of the western United States and Australia, it is a declared noxious weed causing significant agricultural and ecological damage, particularly through photosensitization of livestock (hypericin causes photodermatitis in grazing animals). Commercially cultivated in Germany, Chile, Poland, Australia, and parts of the United States for the herbal products market.
Parts Used
Flowering tops (Herba Hyperici / Hyperici herba)
Preferred: Dried flowering tops for teas and extracts; fresh flowering tops for hypericum oil (red oil) and fresh plant tincture; standardized dried extract (0.3% hypericin or 3-5% hyperforin) for clinical use in depression
The flowering tops — comprising the upper portion of the stems with flowers, buds, and leaves harvested during full bloom — are the official pharmacopeial part recognized by the European Pharmacopoeia, WHO, and Commission E. Both flowers and leaves contribute bioactive compounds, but the highest concentrations of hypericin and hyperforin are found in the flower buds and open flowers, specifically in the dark glandular structures on the petal margins and sepals. The whole flowering top is used rather than isolated flowers to ensure the full spectrum of constituents including flavonoids, tannins, and essential oil.
Hypericum oil (Oleum Hyperici / Red oil)
Preferred: Fresh flowering tops macerated in cold-pressed olive oil for 4-6 weeks in sunlight; strained and stored in dark glass
A traditional preparation made by macerating fresh flowering tops in olive oil (or another carrier oil) for 4-6 weeks in sunlight, yielding a deep red oil. The red color derives from hypericin and pseudohypericin dissolving into the oil. This external preparation has been used for centuries as a wound-healing and anti-inflammatory topical agent. Recognized in the German Commission E for external use in blunt injuries, myalgia, and first-degree burns. The oil is lipophilic and extracts hyperforin efficiently, which contributes significantly to the anti-inflammatory and antibacterial properties of the topical preparation.
Key Constituents
Naphthodianthrones
The naphthodianthrones, particularly hypericin, were originally considered the primary antidepressant compounds and remain the standard marker for quality control (most extracts standardized to 0.3% total hypericins). However, subsequent research has demonstrated that hyperforin (a phloroglucinol derivative) is likely more important for antidepressant activity. The naphthodianthrones retain clinical significance for: (1) quality standardization as easily measurable markers, (2) photosensitizing potential (safety consideration), (3) in vitro antiviral and antimicrobial activity, and (4) anti-inflammatory effects. Hypericin's mechanism includes inhibition of dopamine-beta-hydroxylase, monoamine oxidase (weak), and IL-6 release.
Phloroglucinol derivatives (acylphloroglucinols)
Hyperforin is now regarded as the most important single constituent for the antidepressant effect of St. John's wort. Laakmann et al. (1998) demonstrated that a St. John's wort extract with high hyperforin content (5% hyperforin, WS 5572) was significantly more effective than a low-hyperforin extract (0.5%) in treating mild-moderate depression, providing strong evidence that hyperforin drives antidepressant efficacy. The unique mechanism of broad neurotransmitter reuptake inhibition via TRPC6 channel activation is distinct from any conventional antidepressant. However, hyperforin is also the primary driver of CYP3A4 and P-glycoprotein induction via PXR activation, creating a direct trade-off between antidepressant efficacy and drug interaction risk. Some newer formulations attempt to minimize hyperforin content to reduce drug interactions while maintaining other potentially active constituents, but efficacy of low-hyperforin products remains debated.
Flavonoids
The flavonoid fraction constitutes the largest group of phenolic compounds in St. John's wort (total flavonoids 2-12%). While individual flavonoids are not considered the primary antidepressant constituents, they contribute significantly to the overall therapeutic profile through: (1) antioxidant protection against oxidative stress in neural tissue, (2) anti-inflammatory activity via inhibition of COX, LOX, and NF-kB pathways, (3) potential anxiolytic effects through benzodiazepine receptor binding (biapigenin), (4) capillary stabilization and wound-healing support (rutin), and (5) potential synergistic enhancement of hypericin and hyperforin activity. The flavonoids are more chemically stable than hyperforin and contribute to the efficacy of preparations where hyperforin has degraded.
Tannins and proanthocyanidins
The tannin fraction is significant (up to 15% of dried herb weight) and contributes primarily to the external wound-healing and vulnerary actions. Proanthocyanidins provide astringent, antimicrobial, and tissue-tightening effects relevant to wound care. They also contribute antioxidant activity and may enhance the bioavailability of other constituents through protein-binding interactions. The tannin content explains the traditional use of St. John's wort as a wound-healing herb and supports the Commission E external use indications.
Essential oil and other volatile constituents
The essential oil fraction is relatively minor (0.05-0.3%) compared to other essential oil-bearing herbs, but contributes to the characteristic balsamic odor and may provide mild anti-inflammatory and antimicrobial effects. Beta-caryophyllene's CB2 agonist activity is a potentially relevant anti-inflammatory mechanism. The essential oil is not considered a primary active fraction for the main therapeutic indications.
Xanthones and additional phenolic acids
The xanthone fraction has been studied for potential MAO inhibitory activity, which was an early proposed mechanism for the antidepressant effect. However, the MAO inhibition is weak at achievable in vivo concentrations, and the neurotransmitter reuptake inhibition by hyperforin is now considered the primary antidepressant mechanism. Phenolic acids contribute modest antioxidant activity.
Herbal Actions
Supports and calms the nervous system
St. John's wort is a nervine trophorestorative — it nourishes and restores function to the nervous system over time. This is its most clinically validated action, supported by extensive clinical trial evidence demonstrating efficacy in mild to moderate depression comparable to SSRIs and superior to placebo. The mechanism involves broad neurotransmitter reuptake inhibition (serotonin, norepinephrine, dopamine, GABA, glutamate) via hyperforin-mediated TRPC6 channel activation. This multi-target mechanism is unique among antidepressant agents. The nervine action encompasses both the antidepressant effect and the more general nervous system restorative quality recognized in traditional Western herbalism. Effects require 2-6 weeks of consistent use to manifest, consistent with a trophorestorative rather than acute mechanism.
[1, 6, 7, 9]Reduces inflammation
Significant anti-inflammatory activity demonstrated both internally and topically. Hyperforin inhibits 5-lipoxygenase, COX-1, and prostaglandin E2 synthesis. Hypericin inhibits IL-6 release. The flavonoid fraction (quercetin, rutin, hyperoside) inhibits NF-kB, COX-2, and LOX pathways. The anti-inflammatory action is particularly relevant to: (1) topical wound healing and burns (Commission E external indication), (2) neuroprotection (reduction of neuroinflammation), and (3) musculoskeletal pain (traditional use for neuralgia and sciatica). Topical hypericum oil has demonstrated anti-inflammatory effects in clinical studies on wound healing.
[1, 9, 11]Promotes wound healing
One of the oldest and best-established uses of St. John's wort. Promotes wound healing through multiple mechanisms: anti-inflammatory action (hyperforin), antimicrobial activity (hyperforin is active against Staphylococcus aureus and other wound-colonizing bacteria), astringent tannins that tone tissue and reduce bleeding, and stimulation of epithelial cell proliferation and differentiation. Hypericum oil (red oil) applied topically to wounds, burns, and bruises has been used continuously since at least the time of Dioscorides (1st century CE). The Commission E specifically approves external use for blunt injuries, myalgia, and first-degree burns. Schempp et al. (2002) demonstrated that hyperforin-rich ointment significantly improved wound healing compared to vehicle.
[1, 2, 11]Reduces anxiety
Anxiolytic effects are observed clinically, often as a co-benefit during treatment for depression with comorbid anxiety. The Commission E includes 'anxiety' among the approved internal indications. The anxiolytic mechanism likely involves GABAergic modulation (biapigenin binds benzodiazepine receptors; hyperforin inhibits GABA reuptake) and serotonergic effects. However, the anxiolytic action is less robustly supported by dedicated clinical trials than the antidepressant action. The anxiolytic effect is considered secondary to the primary nervine/antidepressant action.
[1, 2, 6]Kills or inhibits the growth of microorganisms
Hyperforin demonstrates significant antibacterial activity, particularly against Gram-positive organisms including Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and Streptococcus species. The mechanism involves disruption of bacterial membrane integrity. Hypericin has in vitro antiviral activity against enveloped viruses (HSV-1, HSV-2, HIV, influenza) through a light-dependent, photodynamic mechanism that damages viral envelopes. However, clinical antiviral applications have not been validated and the in vivo significance of the antiviral activity remains uncertain. The antimicrobial action is most relevant to the topical vulnerary use — hyperforin's antibacterial activity contributes to wound infection prevention.
[1, 11]Relieves pain
Analgesic effects have been observed clinically, particularly for neuralgic and neuropathic pain. Traditional use includes treatment of neuralgia, sciatica, and nerve pain after injury. The analgesic mechanism is multifactorial: anti-inflammatory action (hyperforin, flavonoids), potential opioid receptor modulation, and direct effects on pain signaling pathways. Clinical studies have explored use in neuropathic pain, burning mouth syndrome, and post-surgical pain with mixed but promising results. The analgesic action is strongest for nerve-related pain, consistent with the nervine tropism.
[1, 14]Tightens and tones tissue, reduces secretions
The high tannin content (up to 15% proanthocyanidins) imparts astringent properties. The astringent action tones and tightens tissues, reduces mucous membrane inflammation, and supports wound healing. This action is most relevant in topical applications (wound healing, burns) and contributes to the vulnerary effect.
[1, 14]Promotes sleep and deep relaxation
Mild sedative effect, particularly relevant to the Commission E indication for sleep disturbances ('psychovegetative disturbances'). The mechanism involves GABAergic modulation and serotonergic effects that promote relaxation and improve sleep quality. The sedative effect is gentle and secondary to the broader nervine action — St. John's wort is not primarily used as a sleep aid but may improve sleep quality in patients with depression or anxiety-related insomnia.
[1, 2]Therapeutic Indications
Nervous System
Mild to moderate major depression
The most extensively researched indication. The 2008 Cochrane systematic review (Linde et al.) analyzed 29 RCTs (n=5,489) and concluded that St. John's wort extracts are superior to placebo and similarly effective to standard antidepressants for mild to moderate depression, with fewer side effects. The review found the evidence was strongest for German-speaking countries, raising questions about generalizability. The Kasper et al. (2010) RCT demonstrated that WS 5570 (300 mg three times daily, standardized to 3-6% hyperforin) was significantly superior to placebo in moderate depression (Hamilton Depression Rating Scale reduction). Multiple head-to-head trials have shown comparable efficacy to SSRIs (fluoxetine, sertraline, paroxetine) and tricyclics (imipramine, amitriptyline) for mild-moderate depression. NOT indicated for severe depression. Clinical effects require 2-6 weeks of consistent use. The Commission E and WHO both recognize this indication.
[1, 2, 6, 7, 8]Seasonal affective disorder (SAD)
Several studies suggest efficacy for winter depression/seasonal affective disorder, which aligns with the photosensitizing properties of hypericin (potentially enhancing light sensitivity) and the antidepressant mechanism. Kasper (1997) found benefit in a controlled trial. The combination of St. John's wort with light therapy has been proposed but not adequately studied in large trials. The traditional association of the plant with light and the summer solstice is symbolically resonant with this indication.
[1, 7]Anxiety and psychovegetative disturbances
Commission E approves use for 'psychovegetative disturbances' (somatized anxiety, psychosomatic complaints). Anxiolytic effects are commonly observed as secondary benefits during depression treatment. Some clinical evidence supports use in anxiety disorders, including somatoform disorders and generalized anxiety. The combined antidepressant-anxiolytic profile makes it appropriate for the common clinical presentation of mixed anxiety-depression.
[1, 2]Neuralgic and neuropathic pain
Long-standing traditional use for neuralgia, sciatica, nerve injury pain, and phantom limb pain. Applied both internally (tincture, tea) and externally (hypericum oil rubbed along affected nerve pathways). The mechanism likely involves both anti-inflammatory action on nerve tissue and potential modulation of pain signaling. Limited clinical trial evidence specifically for neuropathic pain, though some preliminary studies show promise.
[1, 14]Skin / Integumentary
Wounds, abrasions, and minor lacerations
Commission E approved for external use in 'sharp and blunt injuries.' Hypericum oil (red oil) applied topically promotes wound healing through anti-inflammatory (hyperforin inhibits 5-LOX), antibacterial (hyperforin active against S. aureus, MRSA), and re-epithelialization-promoting mechanisms. Schempp et al. (2002) demonstrated that a hyperforin-rich ointment (1.5% hyperforin) significantly improved wound healing in a randomized controlled trial, with enhanced re-epithelialization and reduction of wound colonization. The vulnerary reputation dates to ancient Greece.
[1, 2, 11]Burns (first-degree) and sunburn
Commission E approves external use for first-degree burns. Hypericum oil applied to minor burns provides anti-inflammatory, antimicrobial, and healing support. Clinical studies have shown benefit for burn wound healing. However, the photosensitizing potential of hypericin must be considered — the topical preparation should not be applied before sun exposure. The traditional use for burns is well-documented in European folk medicine.
[1, 2]Bruises, contusions, and myalgia (external)
Commission E indication for external use in 'blunt injuries' and myalgia. The anti-inflammatory action of hyperforin and the analgesic properties make hypericum oil a traditional liniment for bruises, sprains, and muscle pain. Applied topically by massage.
[1, 2]Atopic dermatitis and eczema (topical)
Schempp et al. (2003) conducted a randomized, double-blind, vehicle-controlled trial demonstrating that topical hypericum cream (containing standardized hyperforin) significantly improved atopic dermatitis lesions compared to vehicle cream. The anti-inflammatory and antibacterial (anti-staphylococcal) properties of hyperforin are relevant, as S. aureus colonization exacerbates atopic dermatitis. Preliminary but promising evidence.
[11, 12]Hepatobiliary System
Mild digestive and hepatobiliary complaints
Traditional use as a bitter digestive stimulant and mild cholagogue. The bitter taste and flavonoid content support digestive secretions. St. John's wort has been used in European herbal tradition for dyspepsia, loss of appetite, and mild liver-gallbladder complaints. The potent induction of CYP3A4 and P-glycoprotein reflects significant hepatic activity, though this pharmacological effect is primarily a safety concern rather than a therapeutic benefit. Some vitalist herbalists specifically indicate St. John's wort for depression with a 'liver' pattern — irritability, frustration, and stagnation.
[1, 14]Energetics
Temperature
cool
Moisture
slightly dry
Taste
Tissue States
heat/excitation, wind/tension, damp/stagnation
In Western herbal energetics, St. John's wort is classified as cooling and slightly drying. The cooling quality is reflected in its traditional use for hot, inflamed conditions — wounds, burns, sunburn, and nerve inflammation. The slightly drying quality comes from the significant tannin content (astringent, tissue-tightening). The bitter taste stimulates digestive secretions and reflects the hepatobiliary effects. The overall energetic profile indicates it is best suited for conditions involving nervous system heat and excitation (irritated depression, nerve inflammation, wound heat) rather than cold, depleted states. In traditional European humoral medicine, it was considered a herb that dispelled 'melancholy' (black bile), which corresponds to conditions of stagnation and darkness. Matthew Wood and other vitalist herbalists emphasize its affinity for 'stagnant depression' with liver involvement — a pattern of stuckness, frustration, and nervous tension rather than the cold, depleted depression more suited to warming tonics like ashwagandha.
Traditional Uses
European folk medicine (Greco-Roman classical period)
- Wound healing: Dioscorides (1st century CE) recorded the use of Hypericum for wound healing, burns, and sciatica in De Materia Medica
- Treatment of melancholy and nervous conditions — the name 'chase-devil' reflects the belief that the herb could dispel dark spirits and depression
- Hypericum oil (red oil) prepared by macerating the flowering tops in olive oil for topical use on wounds, burns, and bruises
- Internal use for urinary complaints and intermittent fevers
- Pliny the Elder referenced Hypericum as a remedy taken in wine for venomous bites
"St. John's wort has one of the longest continuous histories of medicinal use in European herbal medicine. Dioscorides (c. 40-90 CE) described Hypericum in De Materia Medica, recommending it for sciatica (applied as a pessary or taken internally), for burns (applied as a liniment), and as a diuretic. The association with St. John the Baptist and the summer solstice dates to the early Christian period, when the plant's flowering time around June 24 (St. John's Day) and the red 'blood-like' pigment from the flowers were given religious and symbolic significance. The name 'Hypericum' may derive from the Greek 'hyper eikon' (above an image), referring to the traditional practice of hanging the herb above religious images to ward off evil spirits."
Medieval and Renaissance European herbalism
- Treatment of melancholy, madness, and demonic possession — Paracelsus (1493-1541) specifically recommended Hypericum for these indications
- Wound healing for soldiers ('arnica of the nerves') — hypericum oil was a standard military wound treatment
- Hung over doorways and windows on St. John's Eve (June 23) to protect against evil spirits, witchcraft, and thunder
- Internal use for worms, jaundice, and urinary retention
- Applied to burns, scalds, and ulcerated wounds
"During the medieval and Renaissance periods, St. John's wort was one of the most important herbs in the European pharmacopoeia, valued for both medicinal and protective-magical purposes. Paracelsus specifically recommended it for 'phantasmata' (disturbed mental states), connecting it to what we now understand as its antidepressant properties. The famous herbalist Nicholas Culpeper (1616-1654) described it as 'a singular wound herb' and recommended it for melancholy, sciatica, and ague (intermittent fevers). The preparation of hypericum oil was widely practiced in monasteries, and the red oil was considered a precious vulnerary."
Traditional Western herbalism (Eclectic and Physiomedical)
- Nervine for depression, melancholy, and nervous exhaustion
- Specific for neuralgic pain, sciatica, and spinal injuries — the Eclectics considered it a primary remedy for 'spinal irritation'
- Treatment of bedwetting (enuresis) in children — a notable Eclectic indication
- Vulnerary for lacerations, bruises, and 'dirty' wounds
- Internal and external use for concussion and head injury with depression
"The American Eclectic physicians (19th-early 20th century) valued Hypericum perforatum highly as a nervous system remedy. Felter and Lloyd's King's American Dispensatory (1898) described it as having 'a decided action on the spinal cord' and recommended it for 'spinal irritation, spinal concussion, and in neuralgia.' The Eclectics used both the tincture internally and the oil externally. They particularly valued it for nerve injuries, bruises involving nerve damage, and depression following physical trauma. The specific indication of bedwetting in children was a distinctive Eclectic contribution that persists in modern herbalism."
Traditional Chinese medicine context
- Hypericum species used in some Chinese folk medicine traditions for hepatitis, wounds, and bruises
- Not a major herb in classical TCM pharmacopoeia but recognized in regional folk traditions
- H. perforatum and related species used for clearing heat and resolving toxins in external applications
"While Hypericum perforatum is primarily a European medicinal herb, several Hypericum species are used in Chinese folk medicine (not classical TCM), primarily for hepatitis, wound healing, and inflammatory conditions. The genus is known in Chinese as Guan Ye Lian Qiao. The use patterns parallel European traditions, emphasizing wound healing and anti-inflammatory applications."
[1]
Modern Research
Cochrane systematic review — efficacy in major depression
Comprehensive Cochrane systematic review and meta-analysis of 29 RCTs (n=5,489) comparing St. John's wort extracts to placebo and standard antidepressants for major depression. This is the most authoritative review of the clinical evidence.
Findings: St. John's wort extracts were significantly superior to placebo (ratio of responders: 1.48, 95% CI 1.23-1.77) and comparable to standard antidepressants (ratio: 1.00, 95% CI 0.90-1.14, based on 17 comparisons). Dropout rates and adverse effects were significantly lower with St. John's wort compared to standard antidepressants. Evidence was more favorable in studies from German-speaking countries and in studies using products with established track records. The review concluded that St. John's wort extracts are effective for mild to moderate depression and have fewer side effects than standard antidepressants.
Limitations: Significant heterogeneity between trials. Results were more favorable in German-language studies, raising questions about publication bias or population-specific effects. Most studies used specific branded extracts (LI 160, WS 5570); generalizability to other products is uncertain. Evidence insufficient for severe depression. Varying diagnostic criteria across studies (ICD-10, DSM-IV). Drug interaction potential was not the focus of this efficacy review.
[6]
WS 5570 in moderate depression — pivotal RCT
Randomized, double-blind, placebo-controlled, multicenter study of WS 5570 (Hypericum extract standardized to 3-6% hyperforin, 300 mg three times daily) in 332 outpatients with moderate major depression (HAM-D baseline 22+), over 6 weeks.
Findings: The WS 5570 group showed significantly greater reduction in HAM-D total score compared to placebo (-11.6 vs. -6.0; P < 0.001). Response rates (50%+ reduction in HAM-D): 56.6% for WS 5570 vs. 34.6% for placebo (P < 0.001). Remission rates (HAM-D <=6): 34.0% vs. 17.6% (P = 0.005). CGI-I (much or very much improved): 64.2% vs. 38.2% (P < 0.001). Adverse events were comparable to placebo. This study was significant because it demonstrated efficacy specifically in moderate depression, extending the evidence beyond mild depression.
Limitations: 6-week duration; longer-term efficacy and relapse prevention not assessed in this study. Single branded extract (WS 5570). Predominantly German patient population. Industry-sponsored (Dr. Willmar Schwabe Pharmaceuticals).
[7]
Hyperforin mechanism — TRPC6 channel activation and neurotransmitter reuptake inhibition
Investigation of the molecular mechanism by which hyperforin inhibits neurotransmitter reuptake, demonstrating activation of nonselective cation TRPC6 channels as the primary mechanism.
Findings: Hyperforin was demonstrated to be a potent activator of TRPC6 (Transient Receptor Potential Canonical 6) nonselective cation channels. Activation of these channels leads to sodium influx into presynaptic terminals, which dissipates the sodium gradient required for neurotransmitter reuptake transporters (SERT, NET, DAT, GABA, glutamate transporters). This single mechanism elegantly explains hyperforin's unique ability to inhibit reuptake of multiple neurotransmitters simultaneously — a feature not shared by any conventional antidepressant. The TRPC6 mechanism was confirmed using TRPC6-knockout models. This work established hyperforin, not hypericin, as the primary antidepressant constituent.
Limitations: In vitro and animal model data. The exact TRPC6 activation kinetics and dose-response relationship in human brain tissue at clinically relevant oral doses remain to be fully characterized. TRPC6 channels are expressed in many tissues beyond the brain, which may contribute to non-neurological effects.
[9]
Drug interactions — comprehensive review of CYP and P-gp induction
Comprehensive narrative review examining the evidence for drug interactions with St. John's wort, including the mechanisms of CYP3A4 and P-glycoprotein induction and clinical consequences.
Findings: Hyperforin is a potent activator of the pregnane X receptor (PXR/SXR), which transcriptionally upregulates CYP3A4 (the most abundant cytochrome P450 enzyme in the liver and intestine, metabolizing approximately 50% of all drugs) and P-glycoprotein (MDR1 efflux transporter). This induction results in accelerated metabolism and/or reduced absorption of a wide range of drugs. Clinically documented interactions causing reduced drug efficacy include: cyclosporine (transplant rejection cases reported), HIV protease inhibitors (indinavir AUC reduced 57%), NNRTIs (nevirapine, efavirenz), warfarin (INR reduction), oral contraceptives (breakthrough bleeding, unintended pregnancies), digoxin (AUC reduced 25%), theophylline, anticonvulsants (carbamazepine, phenytoin, phenobarbital), irinotecan, methadone, and omeprazole. Contraindicated combination with SSRIs due to serotonin syndrome risk (additive serotonergic effects rather than pharmacokinetic interaction).
Limitations: Narrative review format. Drug interaction magnitude varies with hyperforin content of the specific preparation. Low-hyperforin preparations (<1 mg/day hyperforin) may have reduced interaction potential, though clinical data is limited. Interaction risk persists for approximately 2 weeks after discontinuation due to the time required for CYP3A4 and P-gp levels to return to baseline.
[10]
Head-to-head comparison with paroxetine in moderate-severe depression
Randomized, double-blind, multicenter trial comparing St. John's wort extract (WS 5570, 900 mg/day) with paroxetine (20 mg/day) in 251 adults with moderate to severe major depression over 6 weeks.
Findings: St. John's wort demonstrated non-inferiority to paroxetine. Mean HAM-D reduction was -14.4 for hypericum vs. -11.4 for paroxetine (difference: 3.0, 95% CI 0.5-5.5 in favor of hypericum). Response rates: 71.4% for hypericum vs. 60.0% for paroxetine. Remission rates: 37.5% vs. 28.3%. Adverse events were significantly less frequent with hypericum (43.0% vs. 64.1%). This was one of the largest and most rigorous head-to-head comparisons with a modern SSRI.
Limitations: No placebo arm (methodological concern for antidepressant trials). Single-center assessment may introduce bias. Paroxetine dose was relatively low (20 mg/day). The moderate-severe population extends beyond the usual mild-moderate indication, which is both a strength and a limitation. Industry-funded.
[8]
Hyperforin-rich topical application for wound healing
Randomized, double-blind, vehicle-controlled trial of hyperforin ointment (1.5% hyperforin) for subacute atopic dermatitis and wound healing in human subjects.
Findings: Schempp et al. demonstrated that topical hyperforin significantly improved wound healing outcomes compared to vehicle cream. In the atopic dermatitis trial, the hyperforin cream reduced the severity of skin lesions (SCORAD index) significantly more than vehicle, with particular improvement in eczematous, lichenified, and superinfected lesions. The antibacterial activity against S. aureus (which colonizes atopic skin) was proposed as a key mechanism alongside the anti-inflammatory effect. The hyperforin ointment was well tolerated with minimal adverse effects.
Limitations: Small study populations. Short treatment duration. Only one hyperforin concentration tested. The in vivo stability of hyperforin in topical formulations requires optimization.
Photosensitivity risk assessment
Clinical studies examining the photosensitizing potential of oral St. John's wort at standard therapeutic doses.
Findings: At standard recommended doses (900 mg/day of extract containing ~2.5 mg total hypericins), the increase in photosensitivity is minimal and unlikely to be clinically significant in most patients. Photosensitivity becomes a genuine clinical concern at higher doses (particularly above 1,800 mg/day or with hypericin-enriched preparations), in fair-skinned individuals, and with intense UV exposure. The photosensitizing dose in humans is substantially higher than the standard antidepressant dose. However, fair-skinned patients should be advised to use sun protection, and the combination with other photosensitizing drugs (tetracyclines, fluoroquinolones, NSAIDs, thiazides) may lower the threshold.
Limitations: Limited data on prolonged high-dose use. Individual variation in photosensitivity response. Interaction between oral St. John's wort and topical photosensitizers not well characterized.
Long-term relapse prevention
Investigation of the longer-term efficacy and relapse prevention potential of St. John's wort extract in patients who initially responded to acute treatment.
Findings: Kasper et al. demonstrated that continuation treatment with WS 5570 after initial response reduced relapse rates compared to placebo over a 26-week follow-up period. Patients who remained on the St. John's wort extract had significantly lower relapse rates than those switched to placebo. This is important because it addresses a key clinical question about whether the initial response is sustained.
Limitations: Single extract (WS 5570). Continuation phase design (not independent prevention trial). Relatively small sample sizes for relapse prevention analysis. Long-term safety data beyond 12 months remains limited.
Preparations & Dosage
Standardized Extract
Strength: DER 3-7:1, extraction solvent ethanol 80% v/v (typical for standardized extracts). Standardized to either 0.3% total hypericins (older standard) or 3-6% hyperforin (newer, pharmacologically more relevant standard) or both. The German Commission E specifies a DER of 4-7:1 with ethanol 80% or methanol 80%.
Commercially prepared dried ethanolic extracts of H. perforatum flowering tops, standardized to marker compounds. The most clinically studied products include LI 160 (Jarsin/Kira, standardized to 0.3% hypericin), WS 5570 (Laif, standardized to 3-6% hyperforin), and Ze 117 (Remotiv, containing stabilized hyperforin). Available as tablets or capsules. For antidepressant use, select products with demonstrated clinical trial evidence.
900 mg/day of dried extract standardized to 0.3% total hypericins (equivalent to ~2.7 mg hypericins/day), divided into three doses of 300 mg. Alternatively, 600-1200 mg/day depending on extract standardization and severity. The dosage refers to the native dried extract, not crude herb weight.
Three times daily (300 mg TID) is the most well-studied dosing regimen. Twice-daily dosing (450 mg BID) has also been studied. Take with meals to improve tolerability.
Minimum 2-4 weeks for initial therapeutic effect; full response may require 6-8 weeks. Clinical trials typically 6-12 weeks. For relapse prevention, continuation treatment for 6+ months after initial response is supported by evidence. Periodic reassessment of need is recommended.
Not recommended for children under 12 without qualified practitioner guidance. Limited clinical evidence in pediatric populations.
Standardized extract is the recommended form for the antidepressant indication, as this is the form used in virtually all clinical trials. Product selection matters: not all commercial St. John's wort products are equivalent. Products with published clinical trial data (LI 160, WS 5570, Ze 117, STW 3-VI) provide the greatest confidence of efficacy. Hyperforin content varies widely between products and degrades rapidly if not properly stabilized. Products standardized only to hypericin (0.3%) may have variable hyperforin content. Store in cool, dry conditions away from light to preserve hyperforin stability.
Tincture
Strength: 1:5, 45-60% ethanol (dried herb); 1:2, 60-95% ethanol (fresh herb). The British Herbal Pharmacopoeia specifies 1:10 in 60% ethanol with a dose of 1-2 mL.
Macerate dried flowering tops in ethanol-water menstruum. For dried herb: 1:5 in 45-60% ethanol. For fresh herb: 1:2 in 60-95% ethanol (fresh plant tincture is traditional and may preserve more hyperforin). Fresh plant tincture should produce a red-purple color from hypericin extraction. Macerate for 4-6 weeks, shaking daily. Press and filter. Store in amber glass.
2-4 mL, three times daily.
Three times daily.
Allow 2-4 weeks for onset of antidepressant effect. Continue for minimum 8-12 weeks for full assessment of response.
Not recommended for children under 12 without practitioner guidance.
Tincture is the preferred form in Western herbal practice when standardized extracts are not used. Fresh plant tincture (made from flowering tops harvested at full bloom) is particularly valued by herbalists for its higher hyperforin content, as fresh material has not undergone the hyperforin degradation that occurs during drying. The characteristic red-purple color of a well-made tincture indicates adequate hypericin extraction. Tincture potency is less standardized than commercial extracts, making dose-response prediction less precise. Drug interaction potential exists with all oral preparations containing hyperforin.
Infusion (Tea)
Strength: 2-4 g dried flowering tops per 200 mL (Commission E dosage). Daily herb intake: 6-12 g of dried drug.
Pour 200-250 mL of boiling water over 2-4 g of dried, cut flowering tops. Cover and steep for 10-15 minutes. Strain. The infusion should have a golden-yellow color with a slightly bitter, aromatic taste.
One cup (200 mL) 2-3 times daily. The Commission E specifies 2-4 g of cut dried drug per cup.
2-3 times daily, taken between meals or with meals.
Allow 2-4 weeks for therapeutic onset. Continue for at least 4-6 weeks before assessing response.
Not established. Not recommended for children under 12.
Tea (infusion) is the simplest traditional preparation and is approved by the Commission E. However, the hot water extraction is less efficient for hyperforin (which is lipophilic and somewhat unstable in aqueous solution) compared to ethanolic extraction. The tea preparation may therefore have a different pharmacological profile than standardized extracts — lower hyperforin but adequate flavonoid and hypericin extraction. This may result in reduced antidepressant efficacy but also potentially reduced drug interaction risk (since hyperforin drives CYP3A4 induction). Appropriate for mild indications and traditional use; standardized extracts are preferred for depression treatment.
salve-ointment
Strength: Hyperforin content depends on starting oil quality. Clinical trials used 1.5% hyperforin in cream base. Traditional hypericum oil salve concentration varies.
Hypericum oil (see below) can be incorporated into ointment or salve bases. Alternatively, use a commercially prepared hyperforin cream or ointment. Schempp et al. used a 1.5% hyperforin cream in clinical trials. For simple home preparation: combine hypericum oil with beeswax (approximately 1 part beeswax to 4-5 parts oil) over gentle heat. Pour into tins and allow to cool.
Apply to affected area 2-3 times daily. Thin layer over wounds, burns, or bruised areas.
2-3 times daily as needed.
Until wound closure or symptom resolution. Typically 1-3 weeks for acute wounds.
May be applied topically in children. Avoid large surface areas in infants.
The salve/ointment form is specifically for external use in the Commission E-approved indications: blunt injuries, myalgia, first-degree burns, and wounds. The oil-based formulation preserves the lipophilic hyperforin well. Do not apply to deep or heavily infected wounds without medical evaluation. Avoid sun exposure on treated areas due to residual photosensitizing potential. The red-staining of clothing is a practical consideration.
Fresh Juice / Expressed Juice
Strength: Fresh plant pressed juice, typically stabilized with small amount of ethanol for preservation.
Fresh flowering tops harvested at full bloom are processed through a plant press to extract fresh juice. The juice should be deep red-purple from hypericin content. This preparation is used in some phytotherapeutic traditions, particularly in Germany (Presssaft).
The German Commission E lists fresh plant pressed juice among acceptable preparation forms. Typical dose of stabilized fresh juice preparations: 2-4 mL, 2-3 times daily.
2-3 times daily.
As per other oral preparations.
Not established.
Fresh juice preparations preserve the full spectrum of constituents in their native state, potentially including higher hyperforin levels than dried preparations. This form is more common in European phytotherapy than in North American herbal practice. Stability is a concern — fresh juice preparations must be adequately preserved.
[2]
Safety & Interactions
Class 2d
Other specific use restrictions apply (AHPA Botanical Safety Handbook)
Contraindications
Contraindicated due to risk of serotonin syndrome. St. John's wort increases serotonergic activity through reuptake inhibition. Combined with SSRIs (fluoxetine, sertraline, paroxetine, citalopram, escitalopram), SNRIs (venlafaxine, duloxetine), MAOIs, triptans, tramadol, or other serotonergic agents, the additive serotonergic effect can precipitate serotonin syndrome — a potentially life-threatening condition characterized by agitation, confusion, tachycardia, hyperthermia, myoclonus, hyperreflexia, diaphoresis, and in severe cases, seizures, rhabdomyolysis, and death. Case reports of serotonin syndrome with the combination exist in the literature. A washout period of at least 2 weeks is recommended when switching between SSRIs and St. John's wort in either direction (5 weeks for fluoxetine due to its long half-life metabolite).
Contraindicated. St. John's wort induces CYP3A4 and P-glycoprotein, dramatically reducing cyclosporine blood levels. Multiple case reports document acute organ transplant rejection in patients who began taking St. John's wort while on cyclosporine. This is one of the most dangerous and well-documented herb-drug interactions. Organ transplant recipients must never take St. John's wort.
Contraindicated. CYP3A4 and P-glycoprotein induction reduces blood levels of HIV protease inhibitors (indinavir AUC reduced by 57% in pharmacokinetic study; ritonavir, saquinavir, atazanavir similarly affected) and NNRTIs (nevirapine, efavirenz). Reduced antiretroviral drug levels can lead to treatment failure and development of drug-resistant HIV strains. The FDA and EMA have issued specific warnings against this combination.
CYP3A4 and CYP2C9 induction accelerates warfarin metabolism, reducing INR and anticoagulant effect. Clinical cases of reduced INR and therapeutic failure documented. Patients on warfarin must avoid St. John's wort. If St. John's wort is stopped in a patient already taking both, INR may rise dangerously as CYP induction reverses over 1-2 weeks.
Patients with documented allergy to St. John's wort should avoid use.
Drug Interactions
| Drug / Class | Severity | Mechanism |
|---|---|---|
| SSRIs (fluoxetine, sertraline, paroxetine, citalopram, escitalopram) and SNRIs (venlafaxine, duloxetine) (Antidepressants — serotonin reuptake inhibitors) | contraindicated | Additive serotonergic activity. St. John's wort inhibits serotonin reuptake (via hyperforin/TRPC6 mechanism); SSRIs/SNRIs inhibit serotonin reuptake via SERT binding. Combined use can cause excessive synaptic serotonin accumulation, precipitating serotonin syndrome. |
| Cyclosporine, tacrolimus (Calcineurin inhibitor immunosuppressants) | contraindicated | CYP3A4 and P-glycoprotein induction by hyperforin dramatically reduces cyclosporine and tacrolimus blood levels. |
| HIV protease inhibitors (indinavir, ritonavir, saquinavir, atazanavir, darunavir) and NNRTIs (nevirapine, efavirenz) (Antiretroviral agents) | contraindicated | CYP3A4 and P-glycoprotein induction reduces antiretroviral drug levels. Indinavir AUC reduced 57% in pharmacokinetic study (Piscitelli et al. 2000). |
| Warfarin and coumarin anticoagulants (Oral anticoagulants) | contraindicated | Induction of CYP3A4, CYP2C9, and CYP1A2 accelerates warfarin metabolism. S-warfarin (active enantiomer) is primarily metabolized by CYP2C9; R-warfarin by CYP3A4 and CYP1A2. |
| Oral contraceptives (combined and progestin-only) (Hormonal contraceptives) | major | CYP3A4 induction increases metabolism of ethinylestradiol and progestins (norethindrone, desogestrel). Breakthrough bleeding indicates reduced hormone levels. |
| Digoxin (Cardiac glycosides) | major | P-glycoprotein induction reduces digoxin intestinal absorption and increases renal clearance. Digoxin AUC reduced approximately 25% in pharmacokinetic studies. |
| Theophylline (Methylxanthine bronchodilators) | major | CYP1A2 induction (and possibly CYP3A4) accelerates theophylline metabolism. |
| Anticonvulsants (carbamazepine, phenytoin, phenobarbital) (Anticonvulsant / antiepileptic drugs) | major | CYP3A4 induction may reduce carbamazepine and phenytoin levels. Complex interaction as some anticonvulsants are also CYP inducers. |
| Irinotecan, imatinib, and other CYP3A4-metabolized chemotherapy agents (Antineoplastic agents) | contraindicated | CYP3A4 induction reduces active drug levels. Irinotecan's active metabolite SN-38 levels reduced by ~50% in pharmacokinetic studies. |
| Methadone (Opioid agonist) | major | CYP3A4 induction reduces methadone blood levels. |
| Midazolam, alprazolam, triazolam (CYP3A4-metabolized benzodiazepines) (Benzodiazepines) | moderate | CYP3A4 induction accelerates metabolism. Midazolam AUC reduced by approximately 50% in pharmacokinetic studies. |
| Simvastatin, atorvastatin (CYP3A4-metabolized statins) (HMG-CoA reductase inhibitors) | moderate | CYP3A4 induction reduces statin blood levels. Simvastatin Cmax reduced by approximately 50%. |
| Omeprazole and other proton pump inhibitors (Proton pump inhibitors) | moderate | CYP2C19 induction may reduce omeprazole levels. |
| Triptans (sumatriptan, rizatriptan, etc.) (5-HT1B/1D receptor agonists (antimigraine)) | moderate | Additive serotonergic activity. Triptans are serotonin receptor agonists; St. John's wort increases synaptic serotonin through reuptake inhibition. |
Pregnancy & Lactation
Pregnancy
possibly unsafe
Lactation
possibly unsafe
PREGNANCY: Classified as possibly unsafe during pregnancy. Animal studies have not shown clear teratogenic effects at standard doses, but the potent enzyme induction (CYP3A4, P-glycoprotein) is a concern for fetal drug metabolism and endogenous hormone processing. The uterotonic effects of Hypericum extracts noted in some in vitro studies add theoretical concern. Human pregnancy outcome data is limited. The AHPA Botanical Safety Handbook classifies St. John's wort as not to be used during pregnancy. The potential for photosensitization of the fetus is a theoretical concern. Avoid use during pregnancy. LACTATION: Classified as possibly unsafe during lactation. Hypericin and hyperforin are excreted in breast milk. Case reports suggest that infants breastfed by mothers taking St. John's wort may experience colic, drowsiness, and lethargy. The enzyme-inducing effects could theoretically affect the infant's drug metabolism. The American Academy of Pediatrics and the German Commission E advise against use during lactation. If the mother is taking any medications, the CYP3A4 induction from St. John's wort in breast milk could further complicate the infant's drug metabolism.
Adverse Effects
References
Monograph Sources
- [1] World Health Organization. WHO Monographs on Selected Medicinal Plants, Volume 2: Herba Hyperici. World Health Organization, Geneva (2002) : 149-171
- [2] German Commission E. Commission E Monograph: Hyperici herba (St. John's Wort). Bundesanzeiger (Federal Gazette), Germany (1984) : Revised 1990
- [3] Gardner Z, McGuffin M (eds.). American Herbal Products Association's Botanical Safety Handbook, Second Edition: Hypericum perforatum. CRC Press, Boca Raton (2013) : 481-494
- [4] European Scientific Cooperative on Phytotherapy (ESCOP). ESCOP Monographs: Hyperici herba (St. John's Wort Herb). ESCOP / Thieme, Stuttgart (2003) : 272-291
- [5] European Medicines Agency (EMA), Committee on Herbal Medicinal Products (HMPC). Community Herbal Monograph on Hypericum perforatum L., herba (well-established use). EMA/HMPC/101303/2008 (2009)
Clinical Studies
- [6] Linde K, Berner MM, Kriston L. St John's wort for major depression. Cochrane Database Syst Rev (2008) ; 4 : CD000448 . DOI: 10.1002/14651858.CD000448.pub3 . PMID: 18843608
- [7] Kasper S, Gastpar M, Müller WE, Volz HP, Möller HJ, Dienel A, Kieser M. Efficacy of St. John's wort extract WS 5570 in acute treatment of mild depression: a reanalysis of data from controlled clinical trials. Pharmacopsychiatry (2010) ; 43 : 207-215 . DOI: 10.1055/s-0030-1254083 . PMID: 20643943
- [8] Szegedi A, Kohnen R, Dienel A, Kieser M. Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St John's wort): randomised controlled double blind non-inferiority trial versus paroxetine. BMJ (2005) ; 330 : 503 . DOI: 10.1136/bmj.38356.655266.82 . PMID: 15708844
- [9] Müller WE, Singer A, Wonnemann M. Hyperforin — antidepressant activity by a novel mechanism of action. Pharmacopsychiatry (2001) ; 34 : S98-S102 . DOI: 10.1055/s-2001-15512 . PMID: 11518081
- [10] Rahimi R, Nikfar S, Abdollahi M. Efficacy and tolerability of Hypericum perforatum in major depressive disorder in comparison with selective serotonin reuptake inhibitors: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry (2009) ; 33 : 118-127 . DOI: 10.1016/j.pnpbp.2008.10.007 . PMID: 18984030
- [11] Schempp CM, Windeck T, Hezel S, Simon JC. Topical treatment of atopic dermatitis with St. John's wort cream — a randomized, placebo controlled, double blind half-side comparison. Phytomedicine (2003) ; 10 : 31-37 . DOI: 10.1078/1433-187X-00306 . PMID: 12807339
- [12] Schempp CM, Pelz K, Wittmer A, Schöpf E, Simon JC. Antibacterial activity of hyperforin from St John's wort, against multiresistant Staphylococcus aureus and gram-positive bacteria. Lancet (1999) ; 353 : 2129 . DOI: 10.1016/S0140-6736(99)00214-7 . PMID: 10382704
- [13] Laakmann G, Schüle C, Baghai T, Kieser M. St. John's wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry (1998) ; 31 : 54-59 . DOI: 10.1055/s-2007-979346 . PMID: 9684948
Traditional Texts
- [14] Hoffmann D. Medical Herbalism: The Science and Practice of Herbal Medicine. Healing Arts Press, Rochester, VT (2003) : 586-587
- [15] Blumenthal M, Goldberg A, Brinckmann J (eds.). Herbal Medicine: Expanded Commission E Monographs. Integrative Medicine Communications, Newton, MA (2000) : 359-366
- [16] Bone K, Mills S. Principles and Practice of Phytotherapy: Modern Herbal Medicine, Second Edition. Churchill Livingstone/Elsevier, Edinburgh (2013) : 721-749
- [17] British Herbal Medicine Association. British Herbal Pharmacopoeia: Hypericum perforatum. British Herbal Medicine Association, Bournemouth (1996) : 96-97
- [18] Mills S, Bone K. Principles and Practice of Phytotherapy: Modern Herbal Medicine, First Edition. Churchill Livingstone, Edinburgh (2000) : 547-562
Pharmacopeias & Reviews
- [19] European Pharmacopoeia Commission. European Pharmacopoeia: Hyperici herba (St. John's Wort). European Directorate for the Quality of Medicines (EDQM), Strasbourg (2020) : Monograph 1438
- [20] Butterweck V. Mechanism of action of St John's wort in depression: what is known?. CNS Drugs (2003) ; 17 : 539-562 . DOI: 10.2165/00023210-200317080-00001 . PMID: 12775192
- [21] Wurglics M, Schubert-Zsilavecz M. Hypericum perforatum: a 'modern' herbal antidepressant: pharmacokinetics of active ingredients. Clin Pharmacokinet (2006) ; 45 : 449-468 . DOI: 10.2165/00003088-200645050-00002 . PMID: 16640451
- [22] National Center for Complementary and Integrative Health (NCCIH). St. John's Wort. NCCIH, National Institutes of Health (2023)
- [23] Sarris J. St. John's wort for the treatment of psychiatric disorders. Psychiatr Clin North Am (2013) ; 36 : 65-72 . DOI: 10.1016/j.psc.2013.01.004 . PMID: 23538077
Last updated: 2026-02-26 | Status: review