Hypericum

Other Names

AmberAmber Touch-and-HealAsinszāles lakstiBarbe de Saint-JeanBassantBinbirdelikotuBlutkrautCandollCantwllCasse-diableChasse-diableCommon St. John's WortCommon St. JohnswortCorazoncilloDemon ChaserDziurawiecEala bhuidheEchtes JohanniskrautEnola WeedEurinllys TrydwllEurinllys TyllogFuga DaemonumGammockGemeines JohanniskrautGoat WeedGoatsbeardGoatweedGospina travaHardhayHartheuHerb JohnHerba HypericiHerbe à la BrûlureHerbe à Mille TrousHerbe Aux FéesHerbe Aux Mille VertusHerbe Aux PiqûresHerbe de la Saint-JeanHerbe de Saint ÉloiHerbe de Saint-JeanHerbe du CharpentierHerbe PercéeHierba de San JuanHipéricoHypereikonHyperici HerbaHypericum nachitschevanicumHypericum officinaleHypericum officinarumHypericum perforatumHypericum perforatum f. floribundumHypericum perforatum L.Hypericum perforatum subsp. songaricumHypericum perforatum var. confertiflorumHypericum perforatum var. microphyllumIpericoJohannesblödaJohanneskrautJohanneskruidJohanniskrautJonažolių žolėKlamath WeedKlamathweedLule gjakuLulebasanLulemajiMäkikuismaMansblodMillepertuisMillepertuis PerforéMillepertuis PerforeNaistepunaürtOrbáncfűPenny JohnPerforate St. John's WortPerikonRacecourse WeedRandpirkRosin RoseSaint John's WortSaynt Johannes WortSint JanskruidSJWSt. John's GrassSt. John's WortSunătoareTipton WeedTodabuenaTouch-and-HealTüpfel-HartheuUnserer Frauen BettstrohY FendigedigŽuti kantarion

Synopsis

Hypericum (Hypericum perforatum L.): A Comprehensive Reference

1. Identity and Botanical Description

Scientific and Common Names

Hypericum perforatum, commonly known as St. John's wort (sometimes perforate St. John's wort or common St. John's wort), is a flowering plant in the family Hypericaceae. Other widely used common names include Klamath weed, Tipton's weed, Rosin-rose, and Goat weed. In Chinese it is known as Guan Ye Lian Qiao. The epithet perforatum refers directly to the plant's visible anatomy: the species name perforatum refers to the presence of small oil glands on the leaves that look like windows when held against the light — light perforating the leaves.

The genus name carries its own etymology. The genus name Hypericum is possibly derived from the Greek words hyper (above) and eikon (picture), in reference to the tradition of hanging the plant over religious icons in the home.

Botanical Description and Geographic Distribution

Hypericum perforatum is an erect perennial herb with golden yellow flowers, classified within the family Hypericaceae and growing to a height of 50–60 cm. The plant is widely distributed in Europe, Asia, Northern Africa, and North America, and its leaves contain oil glands that appear as pellucid dots. It is a hairless, perennial herb with woody roots, yellow flowers marked by black glands, and leaves that appear perforated due to translucent glands, producing thousands of seeds per plant.

It is native to much of Europe, West and Central Asia, and parts of Africa and China, and has been widely introduced elsewhere, thriving in well-drained, temperate habitats such as meadows, hillsides, and open woods with moderate rainfall and mild temperatures. Probably a hybrid between the closely related H. attenuatum and H. maculatum (imperforate St. John's wort) that originated in Siberia, the species has spread worldwide.

The dark-colored dots on the leaf margins and petals, when rubbed between the fingers, produce a red stain which is rich in the bioactive compound hypericin. The genus Hypericum contains, by the most recent count, 469 species that have been classified into 36 taxonomic sections.

Pharmacopoeial and Regulatory Status

Hypericum perforatum, monographed for quality reasons also in the European Pharmacopoeia for medicinal use, contains high amounts of condensed tannins from the procyanidin group in addition to flavonoids, phloroglucinols, and naphthodianthrones. St. John's wort is a nutraceutical, phytopharmaceutical, and cosmetic ingredient. In Germany, standardized H. perforatum extracts are sold as prescription phytopharmaceuticals for mild to moderate depression.

Common Forms and Preparations

Commercial products are derived from the dried flowering tops or aerial parts of the plant; these parts are harvested shortly before or during the flowering period. Hypericum preparations include the dried herb (chopped or powdered), alcoholic extract, oil, and tincture. The plant used to be harvested immediately before or during the bloom. After harvesting, the plant must be dried immediately to avoid degradation of its bioactive compounds, especially the unstable hyperforin.

In contemporary clinical contexts, several well-characterized pharmaceutical-grade extracts have been developed. The LI 160, produced by Lichtwer Pharma, is standardized to contain 0.3% hypericin derivatives, and normally comes in 300-mg capsules. Another product, Ze 117, produced by Zeller AG, Switzerland, is a 50% ethanolic extract with an herb-to-extract ratio of between 4:1 and 7:1. The hyperforin content of Ze 117 is 0.2%, lower than that of LI 160, whose hyperforin content ranges between 1% and 4%. The dosage of Ze 117 is 500 mg/day. Hypericum perforatum extract WS® 5570 has been studied at doses of 600 mg/day (once daily) and 1200 mg/day (600 mg twice daily).

2. Traditional and Historical Use

Ancient Greek and Roman Traditions

St. John's wort (SJW), known botanically as Hypericum perforatum, is a sprawling, leafy herb that grows in open, disturbed areas throughout much of the world's temperate regions. The use of this species as an herbal remedy to treat a variety of internal and external ailments dates back to the time of the ancient Greeks. Since then, it has remained a popular treatment for anxiety, depression, cuts, and burns.

The ancient Greeks were aware of the medicinal properties of this genus. St. John's wort was recognized by Hippocrates, Pliny, and Dioscorides. Since ancient times, Hypericum plants have been used as herbal treatments for a variety of medical problems including externally for wounds, inflammations, burns, skin disorders, and nerve pain, and internally for anxiety, depression, and insomnia. The Greek physicians of the first century, Galen, Dioscorides, Pliny, and Hippocrates, recommended SJW as a diuretic, wound-healing herb.

European Folk and Monastic Medicine

St. John's wort is a plant with yellow flowers that has been widely used in various systems of traditional medicine, including Greek, Islamic, and Chinese medicine. The name St. John's wort apparently refers to John the Baptist, as the plant blooms around the time of the feast of St. John the Baptist in late June. Historically, St. John's wort has been used for a variety of conditions, including depression, stomach ulcers, and colds, and to aid wound healing.

In European folk traditions, the plant carried significant ritual as well as medicinal associations. The herb would be hung on house and stall doors on St. John's Feast Day to ward off evil spirits and to safeguard against harm and sickness to people and livestock. In other traditions it was burned in bonfires for the protection of crops, along with other herbs believed to be magical. It was commonly referred to as "Fuga daemonum" (the devil's scourge) since it was used to protect against demonic possession and "evil spirits."

One of the earliest references to the name St. John's wort is noted in a Gaelic legend from the sixth century, where the missionary St. Columba carried a piece of St. John's wort because of his high regard for St. John. During the Middle Ages, it was used to heal sword wounds as far back as the Middle Ages. The herb was closely associated with healing both spiritual afflictions and physical injuries, and was a staple in monastic gardens and folk medicine.

In the 19th century, Eclectic physicians in the U.S. used St. John's wort for nerve pain, spinal irritation, depression, and trauma recovery. It remained a popular nerve tonic and was also used in poultices and salves for bruises, sprains, and wounds.

Traditional Uses in Chinese and Islamic Medicine

Hypericum perforatum has been used in different systems of traditional medicine such as Chinese traditional medicine, Greek traditional medicine, and Islamic traditional medicine. Hypericum species have been used traditionally as astringent, antipyretic, diuretic, antiphlogistic, analgesic, and antidepressant in Europe, America, Africa, and Asia.

Hypericum species are abundant throughout China, including 30 used as ethnomedicines. There are limited publications describing the ethnobotanical uses and biological activities associated with Hypericum species in China. Some reported activities include the treatment of wounds and bruises, irregular menstruation, dysentery, hepatitis, mastitis, jaundice, hemoptysis, and epistaxis.

In traditional medicine systems generally, SJW has been applied to a wide range of conditions including skin problems such as wound healing in burns, stomach ulcers, biliary disorders, inflammation of the bronchi and genitourinary system, colds, migraines, headache, diabetes mellitus, and obesity. In folk medicine, the plant is used as an antidepressant, to aid in wound healing, and to treat liver disorders and rheumatism.

Topical Traditional Applications

Various dosage forms of Hypericum have been used topically as an astringent and to treat injuries or conditions such as blisters, burns, cuts, hemorrhoids, inflammation, insect bites, itching, redness, sunburns, and wounds. H. perforatum oleums are used to treat burns and wounds including boiling water burns in children, and surgical wounds from excision of scalp neoplasms, cesarean sections, and episiotomies.

3. Key Constituents and Active Compounds

Overview of Chemical Diversity

H. perforatum extracts have been partially chemically characterized, and more than 150 compounds have been identified. Hypericum perforatum extracts contain many different classes of constituents including flavonoids and biflavonoids, phloroglucinols, naphthodianthrones, caffeic acid derivatives, and unknown and/or unidentified compounds. Species of Hypericum contain many bioactive constituents, including proanthocyanins, flavonoids, biflavonoids, xanthones, phenylpropanes and naphthodianthrones that are characterized by their relative hydrophilicity, as well as acylphloroglucinols and essential oil components that are more hydrophobic in nature.

Naphthodianthrones: Hypericin and Pseudohypericin

Crude extracts of the flowers and leaves contain the naphthodianthrones hypericin (0.03–0.3%) and pseudohypericin at 2–10 times the level of hypericin. Hypericin is the red-pigment compound that stains fingers when the plant's glands are ruptured. Early in vitro research suggested an antidepressant activity due to hypericin, through the inhibition of the monoamine oxidase (MAO) enzyme. However, according to pharmacokinetic data and binding studies, it appears that the antidepressant effect of Hypericum extract is unlikely to be due to an interaction of hypericin with central neurotransmitter receptors. Hypericin is also associated with the plant's light-activated properties. Electrophysiological studies showed that hypericin reduced GABA-activated chloride currents, while pseudohypericin did the opposite. Furthermore, both hypericin and pseudohypericin inhibited the activation of NMDA receptors.

Acylphloroglucinols: Hyperforin and Adhyperforin

Hyperforin is identified as the most important compound in the phloroglucinol group, exhibiting antidepressant activity through a novel mechanism of action, as well as antibiotic activity against Gram-positive bacteria and antitumoral activity in vivo. Clinical data indicate that hydroalcoholic extracts of Hypericum perforatum might be as valuable as conventional antidepressants in mild-to-moderate depression, with fewer side effects. One clinical trial using two extracts with different hyperforin contents indicated it as the main active principle responsible for the antidepressant activity. A hydroalcoholic extract lacking hyperforin also lacks the antidepressant-like effect.

Hyperforin's mechanism is also centrally involved in pharmacokinetic drug interactions: Preparations of SJW are potent activators of PXR and hence inducers of cytochrome P450 enzymes (most importantly CYP3A4) and P-glycoprotein. The degree of CYP3A4 induction correlates significantly with the hyperforin content in the preparation.

Flavonoids and Related Phenolics

The largest chemical group belongs to the flavonol glycosides (up to 4%). The major flavonoids are rutin, hyperoside, isoquercitrin, quercitrin, miquelianin, and quercetin. Many constituents may be responsible for the anti-inflammatory activity of Hypericum including quercetin and derivatives, hyperforin, pseudohypericin, and amentoflavone. Amentoflavone and hypericin have anti-inflammatory activities and hyperforin has antibacterial potential.

Essential Oil Components

Essential oil and volatile constituents that have been most frequently reported from Hypericum include the aliphatic hydrocarbons n-nonane and n-undecane; the monoterpenes α- and β-pinene; and the sesquiterpenes β-caryophyllene and caryophyllene oxide. Studies on the chemical composition of the H. perforatum essential oils indicate that oxygenated sesquiterpenes (41.4%) and caryophyllene oxide (31.0%) are the main constituents.

4. Mechanisms of Action

Neurotransmitter Reuptake Inhibition

Although the exact mechanism behind the antidepressant activity of H. perforatum is not fully understood, it appears to involve multiple pathways. These pathways are primarily attributed to its bioactive compounds, such as hyperforin, hypericin, and various flavonoids. In general terms, these mechanisms include the inhibition of neurotransmitter reuptake, which affects neurotransmitters like serotonin, noradrenaline, dopamine, GABA, and L-glutamate. This inhibition leads to increased levels of these neurotransmitters in the synaptic cleft, potentially contributing to its antidepressant effects by acting similarly to selective serotonin reuptake inhibitors (SSRIs).

Hyperforin inhibits serotonin reuptake via TRPC6 channel activation, a mechanism distinct from conventional antidepressants. Hypericum perforatum also inhibits TRPM2 channels in sciatic nerve and dorsal root ganglion neurons, contributing to its anti-neuropathic pain effects. The main in vitro effects of hyperforin (at concentrations of 0.1–1 μM) are non-specific presynaptic effects, resulting in the non-selective inhibition of the uptake of many neurotransmitters.

MAO Inhibition and Receptor Modulation

Hypericum perforatum is known to contain active compounds such as hypericin, hyperforin, and dimeric flavones that exert antidepressive and anxiolytic activities on animals and humans. The mechanisms of action of these compounds are different and include anti-MAO action, action on serotonin release, and activity on benzodiazepine receptors. In line with antidepressant data, it appears that the interactions of constituents may be important for the anti-inflammatory activity of Hypericum.

Anti-inflammatory and Wound-healing Mechanisms

Studies on wound healing activity of HP extract on chicken embryonic fibroblasts showed that fibroblast percentage, collagen synthesis stimulation, and epithelial cell proliferation were increased in the presence of flavonoids and xanthones. Wound healing activity has been attributed to fibroblast migration and the stimulation of collagen synthesis, and it was speculated that it was not solely dependent on the hypericin content.

Pregnane-X-Receptor (PXR) Activation

The drug-interaction profile of SJW is driven primarily by a distinct molecular mechanism. These interactions were caused by pregnane-X-receptor (PXR) activation. Preparations of SJW are potent activators of PXR and hence inducers of cytochrome P450 enzymes (most importantly CYP3A4) and P-glycoprotein. The degree of CYP3A4 induction correlates significantly with the hyperforin content in the preparation.

5. Scientific Evidence by Area of Use

5.1 Depression (Mild to Moderate)

The most extensively studied application for Hypericum is the treatment of depression, and this is the area with the strongest body of clinical evidence.

The available evidence from Cochrane-reviewed trials suggests that the Hypericum extracts tested are superior to placebo in patients with major depression, are similarly effective as standard antidepressants, and have fewer side effects than standard antidepressants.

A key 2017 meta-analysis reviewed 27 clinical trials with a total of 3,808 patients, comparing the use of St. John's wort and SSRIs. In patients with depression, St. John's wort demonstrated comparable response (pooled RR 0.983, 95% CI 0.924–1.042) and remission rates, and significantly lower discontinuation/dropout rates (pooled OR 0.587, 95% CI 0.478–0.697) compared to standard SSRIs.

An earlier systematic review and meta-analysis examined 37 double-blind randomised controlled trials that compared clinical effects of Hypericum monopreparation with either placebo or a standard antidepressant in adults with depressive disorders. Larger placebo-controlled trials restricted to patients with major depression showed only minor effects over placebo, while older and smaller trials not restricted to patients with major depression showed marked effects. Compared with standard antidepressants, Hypericum extracts had similar effects. Current evidence regarding Hypericum extracts is inconsistent and confusing.

A specific pivotal randomized, double-blind, placebo-controlled trial using the standardized extract WS® 5570 found that Hypericum perforatum extract WS® 5570 at doses of 600 mg/day (once daily) and 1200 mg/day (600 mg twice daily) were safe and more effective than placebo, with comparable efficacy of both WS® 5570 doses for the treatment of mild to moderate major depression.

Evidence strength: H. perforatum has substantial scientific evidence that standardized extracts are efficacious for mild to moderate depression. However, evidence for severe or melancholic major depression remains substantially weaker, and larger trials targeting that population have yielded less consistent results. The overall evidence base is qualified as supportive for mild-to-moderate presentations but uncertain for major depression without that qualification.

Patients receiving Hypericum extracts were less likely to withdraw from studies because of adverse effects compared to those receiving older standard antidepressants.

5.2 Anxiety Disorders

Evidence also supports the use of Hypericum perforatum in mild to moderate anxiety disorders. However, the clinical trial database for anxiety as a primary indication is substantially smaller than for depression.

Animal research has shown that the total extract of H. perforatum increases locomotor activity in the open field and exerts anxiolytic activity in the light-dark test, whereas single components did not show any effect. The anxiolytic activity of the total extract was blocked by pretreatment with the benzodiazepine antagonist Flumazenil, suggesting an implication of benzodiazepine receptor activation in the anxiolytic effect of H. perforatum extract.

Evidence strength: Preliminary. Clinical data are limited in scope. Most evidence comes from animal models or from depression trials in which anxiety was a secondary endpoint.

5.3 Obsessive-Compulsive Disorder (OCD)

Evidence supports the use of Hypericum perforatum as complementary therapy for obsessive-compulsive disorder (OCD), with open-label and randomized controlled trials reporting significant symptom improvements.

In an early open-label trial, 12 subjects were evaluated with a primary DSM-IV diagnosis of OCD of at least 12 months' duration. Treatment lasted for 12 weeks, with a fixed dose of 450 mg of 0.3% hypericin twice daily (extended-release formulation). In this trial, a significant change from baseline to endpoint was found, with a mean reduction on the Y-BOCS of 7.4 points (p = 0.001). This change occurred at 1 week and continued to week 12. However, the fact that significant change was found as early as 1 week into treatment suggests a possible initial placebo response, although improvement grew larger over time. Results warranted a placebo-controlled study of Hypericum in OCD.

Evidence strength: Very limited. The open-label design of the key positive study precludes definitive conclusions. A subsequent placebo-controlled trial produced mixed results. Further adequately powered RCTs are needed.

5.4 Premenstrual Syndrome and Premenstrual Dysphoric Disorder (PMS/PMDD)

In a pilot study involving women with premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD), treatment with 300 mg of hypericin standardized to 0.3% hypericin resulted in a 51% reduction in symptom scores, with over two-thirds experiencing at least a 50% decrease in severity. H. perforatum extracts are also used to treat premenstrual and menopause syndromes.

Evidence strength: Preliminary. Results from a single pilot study cannot be considered conclusive; this area requires replication in larger, controlled trials.

5.5 Menopause Symptoms

A 2014 meta-analysis concluded that H. perforatum preparations are more effective than placebo in alleviating the complaints associated with menopause. A double-blind, randomized, placebo-controlled trial conducted in 80 postmenopausal women showed improvements in hot flush frequency and intensity. This study also reported a significant reduction in depression intensity for those taking hypericum; after the intervention, 80% vs 5.7% reported no depression in the treatment group vs control, respectively (P<0.001).

One trial showed evidence supporting the efficacy of H. perforatum in alleviating menopausal symptoms and depression with very low doses of the preparation.

Evidence strength: Moderate for some climacteric symptoms (particularly hot flushes and mood symptoms), but the number of well-controlled trials remains limited. Effects on depression scores in menopause are more consistently reported than vasomotor outcomes in some analyses.

5.6 Attention-Deficit/Hyperactivity Disorder (ADHD)

A randomized double-blind placebo-controlled trial of 54 children aged 6–17 years meeting DSM-IV criteria for ADHD was conducted. Participants were randomized to receive 300 mg of Hypericum perforatum or a matched placebo three times daily for eight weeks. No significant difference in the change of ADHD Rating Scale-IV score from baseline to week 8 was found between treatment and placebo groups.

Evidence strength: Negative from the key RCT. Although H. perforatum had no additional benefit beyond that of placebo for treating ADHD symptoms in this trial, the product used contained only 0.13% hypericin and 0.14% hyperforin. The evidence does not currently support use for ADHD.

5.7 Wound Healing and Skin Conditions (Topical Use)

According to current literature, some influences of Hypericum such as anti-inflammatory, antioxidant, antimicrobial, and antiviral activities are already reported, as well as a fibroblast proliferation-inducing effect. In previous in vitro and in vivo studies, impacts of Hypericum have been demonstrated on the wound healing process.

A study in diabetic rats examined wound healing using standardized topical gels. Forty-eight female diabetic rats were randomly divided into four groups: gel base treated, HP 5% gel treated, HP 10% gel treated, and a no-treatment control. A circular 1 cm² full-thickness wound was created and measured every three days. Based on the results, HP treated groups showed faster wound closure rate in comparison with control and vehicle groups (P < 0.05).

A niosomal gel study demonstrated a significant decrease in inflammatory cell count and induced a marked regression in the inflammatory phase and enhanced the early beginning of the proliferative phase of wound healing. After 21 days, it showed complete re-epithelization, formation of new matrix fibers and significant reduction in wound size, compared to control and Panthenol® 2% cream treated groups.

A randomized placebo-controlled study on an H. perforatum ointment, extracted with grape seed oil and applied to cesarean section wounds, found a significant reduction in pain and itching.

Evidence strength: Predominantly preclinical (animal and in vitro). The few available clinical studies in wound healing (surgical wounds, cesarean incisions) are small and limited. This remains a promising but insufficiently validated area in human clinical research.

5.8 Antibacterial Activity

The sole antibacterial principle isolated to date is the tetraketone hyperforin, also thought to be responsible for the antidepressant activity of the herb. The available literature indicates that it has a higher antibacterial activity against Gram-positive than Gram-negative bacteria, and alcoholic extracts (methanolic/ethanolic) were shown to possess more pronounced activity than aqueous extracts.

Hyperforin has shown significant antimicrobial effects against Staphylococcus aureus strains. The plant has exerted not only antibacterial but also anti-fungal and anti-yeast activities.

Evidence strength: Primarily in vitro. Clinically, the antibacterial potential has not been rigorously validated in human infection trials. This is considered a supporting rationale for topical wound-healing use rather than a standalone clinical indication.

5.9 Antiviral Activity

Hypericum perforatum has been investigated for its antiviral activity against SARS-CoV-2. It possesses anti-depressant, anti-cancer, anti-oxidative and neuro-protective, wound-healing, anti-inflammatory, and antimicrobial properties. Evidence was obtained that Hypericum perforatum and hypericin may hold a direct virus-blocking effect against SARS-CoV-2 virus particles. Additional antiviral studies found that H. perforatum extracts also contain light-independent anti-HIV-1 activity.

Evidence strength: Antiviral data are predominantly in vitro and preclinical. No adequately powered human clinical trials have confirmed antiviral efficacy. This area is exploratory.

5.10 Pain and Neuroprotection

Several studies in recent years have described the antinociceptive and analgesic properties of SJW that validate the traditional uses of the plant in pain conditions. Emerging preclinical evidence indicates analgesic effects of Hypericum perforatum and hypericin in neuropathic pain models, including HIV-induced and chemotherapy-induced neuropathies. These antinociceptive effects are attributed to hypericin's inhibition of PKC isoforms PKC-γ and PKC-ε, which play roles in neuropathic pain mechanisms.

H. perforatum extracts are used in pain management and likely act synergistically with morphine, including reduction of morphine tolerance.

It has been demonstrated that H. perforatum extracts and several of its major molecular components have the ability to protect against toxic insults, either directly, through neuroprotective mechanisms, or indirectly, through antioxidant properties.

Evidence strength: Predominantly preclinical (animal models). Human clinical trial data for pain as a primary outcome are limited, and no robust RCTs specifically address neuropathic pain in humans.

6. Body Systems and Health Areas Associated with Hypericum

Central Nervous System: Depression (mild to moderate), anxiety, OCD, seasonal affective disorder, mood regulation, neuroprotection.
Integumentary System: Wound healing, burns, surgical incisions, eczema, skin inflammation, topical antimicrobial action.
Endocrine/Reproductive System: Premenstrual syndrome, premenstrual dysphoric disorder, menopausal symptoms including vasomotor complaints and mood disturbance.
Immune/Antimicrobial: Antibacterial activity (particularly Gram-positive organisms), antiviral research (HIV, SARS-CoV-2 — preclinical), antifungal.
Musculoskeletal and Peripheral Nervous System: Nerve pain, neuropathic pain (preclinical), anti-inflammatory activity.
Gastrointestinal: Traditional use in stomach ulcers, biliary disorders, and gastrointestinal inflammation, though clinical evidence is sparse.

H. perforatum has recently been shown to have antioxidant, anticonvulsant, analgesic, anti-inflammatory, cytotoxic, and antidiabetic activities.

7. Dosage Forms and Dosages Reported in Studies

The most common preparations, made from the flowering aerial parts (Hyperici herba), are extracts and oleums. The method and solvent determine the phytochemicals that are extracted from H. herba.

LI 160 (Lichtwer Pharma): Standardized to contain 0.3% hypericin derivatives; normally comes in 300-mg capsules.
Ze 117 (Zeller AG): A 50% ethanolic extract with an herb-to-extract ratio of between 4:1 and 7:1. Hyperforin content is 0.2%. The dosage studied is 500 mg/day.
WS® 5570 (Dr. Willmar Schwabe Pharmaceuticals): Studied at doses of 600 mg/day (once daily) and 1200 mg/day (600 mg twice daily).
OCD open-label trial: A fixed dose of 450 mg of 0.3% hypericin twice daily (extended-release formulation) over 12 weeks.
ADHD pediatric RCT: 300 mg of Hypericum perforatum three times daily for eight weeks.
PMS pilot study: 300 mg of hypericin standardized to 0.3% hypericin.
SSRI interaction case reports: Dosages of St. John's wort in cases involving serotonin syndrome were typically between 600 mg to 900 mg per day.

It is important to note that standardization between different commercial products varies considerably, and the safety-relevant recommendation to declare hyperforin content is rarely followed even for herbal medicinal products, and is completely neglected in botanicals and food/dietary supplements. In clinical pharmacokinetic studies and case reports, administered SJW products often lack sufficient specifications, especially regarding the hyperforin content.

8. Safety Considerations and Drug Interactions

General Safety Profile

A review of safety shows that the overall incidence of adverse reactions associated with SJW is low. Patients receiving Hypericum extracts were less likely to withdraw from studies because of adverse effects compared to those receiving older standard antidepressants.

Pharmacokinetic Drug Interactions: CYP450 and P-glycoprotein Induction

This is the most clinically significant safety concern with SJW. A number of clinically significant interactions have been identified with prescribed medicines including warfarin, phenprocoumon, cyclosporin, HIV protease inhibitors, theophylline, digoxin, and oral contraceptives, resulting in a decrease in concentration or effect of the medicines. These interactions are probably due to the induction of cytochrome P450 isoenzymes CYP3A4, CYP2C9, CYP1A2 and the transport protein P-glycoprotein by constituent(s) in SJW. The degree of induction is unpredictable due to factors such as the variable quality and quantity of constituent(s) in SJW preparations.

Specific documented clinical consequences include: In 2000, a pharmacokinetic interaction between SJW and cyclosporine caused acute rejection in two heart transplant patients. Subsequent research has shown that SJW altered the pharmacokinetics of drugs such as digoxin, tacrolimus, indinavir, warfarin, alprazolam, simvastatin, and oral contraceptives.

St. John's wort decreased the plasma concentration of the active metabolite SN-38 in cancer patients receiving irinotecan treatment. St. John's wort did not alter the pharmacokinetics of tolbutamide, but increased the incidence of hypoglycaemia. Several cases have been reported that St. John's wort decreased cyclosporine blood concentration leading to organ rejection. St. John's wort caused breakthrough bleeding and unplanned pregnancies when used concomitantly with oral contraceptives.

Hypericum perforatum significantly affects drug metabolism by inducing the Cytochrome P450 enzyme system, particularly the CYP3A4 enzyme. This interaction can alter the metabolism of various medications, including oral contraceptives, cancer drugs, HIV antiretrovirals, and antidepressants.

St. John's wort affects the metabolism of several antidepressants, primarily through the CYP3A4, CYP2C9, and CYP2C19 enzymes. SSRIs such as citalopram, escitalopram, and sertraline, metabolized by CYP2C19, are more likely to interact with St. John's wort than those metabolized by CYP2D6, such as paroxetine, fluoxetine, and fluvoxamine.

Serotonin Syndrome

Possible pharmacodynamic interactions with selective serotonin reuptake inhibitors and serotonin (5-HT1d) receptor-agonists such as triptans used to treat migraine have been identified. These interactions are associated with an increased risk of adverse reactions.

SJW and SSRIs together result in symptoms characteristic of central serotonin excess. Serotonin syndrome is characterized by at least three of the following: confusion, agitation, hyperreflexia, diaphoresis, shivering or tremor, nausea, diarrhoea, lack of co-ordination, fever, coma, flushing or rhabdomyolysis. The excess serotonin is believed to be due to common pharmacological mechanisms of action on serotonin, particularly in the brain, of both SJW and conventional antidepressants.

Serotonin syndrome may first cause tachycardia, increased blood pressure, mydriasis, and sweating. Some may have a fever, and temperatures can rise above 106 degrees F. Treatment can include serotonin antagonists and a benzodiazepine to target GABA receptors. Increased blood pressure can be treated with short-acting antihypertensives.

Photosensitivity

Analysis of available epidemiological data showed that, although photosensitisation had the highest incidence of adverse drug reaction reports, severe phototoxic reactions comparable to cases documented for certain pharmaceutical drugs were rare. Excessive use of H. perforatum can cause photosensitization. Hypericin, particularly when activated by light, is considered the constituent primarily responsible for this effect.

Hyperforin Content as a Determinant of Interaction Risk

The hyperforin-dependent induction of PXR-related metabolic enzymes and transport systems is the mechanistic basis for most pharmacokinetic interactions. As recommended by the EMA in 2009, the amount of hyperforin should be declared for medicinal products containing SJW. Low-hyperforin preparations (such as Ze 117) may theoretically carry a lower interaction risk, but this has not eliminated the clinical concern.

Psychiatric Cautions

It has been suggested in the literature that SJW should not be used with psychoactive or psychotropic drugs, as the potential for adverse effects may be increased. The positive effects of St. John's wort can be negated when used in conjunction with other medications; sometimes, the effects of drug interactions can be life-threatening. Drugs that also utilize the cytochrome P450 system, specifically CYP3A4, or are substrates of P-glycoproteins in metabolism, can have reduced efficacy and produce adverse effects when taken in conjunction with St. John's wort.

References

Health Conditions

Health conditions that Hypericum may help support.

DermatitisScientific
Hypericum perforatum (St. John's Wort) has RCT evidence for atopic dermatitis via its hyperforin-rich extract showing 80% improvement vs. 10% in placebo in a double-blind half-side comparison. It has traditional recognition for dermatitis and inflammatory skin disorders across European and official monographs.
Nervous System HealthScientific
Hypericum (St. John's Wort) is one of the most extensively studied herbal medicines for nervous system conditions, particularly mild-to-moderate depression. Multiple Cochrane meta-analyses confirm superiority to placebo and comparable efficacy to antidepressants.
Bites and StingsTraditional
Hypericum (St. John's Wort) is listed in traditional homeopathic preparations for insect bites and stings, specifically for pain relief from bite injuries. DailyMed-registered homeopathic insect bite products include Hypericum perforatum as an active ingredient for relieving soreness and pain from bites. It is also cited in herbal literature for bite-related skin inflammation.

Body Systems

Body systems that Hypericum may help support.

No body systems available.