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Hypericum perforatum

Hypericum perforatum, commonly known as common St. John's wort, perforate St. John's wort, or Klamath weed, is a perennial herbaceous flowering plant in the family Hypericaceae. Native to temperate and subtropical regions of Europe, western Asia, North Africa, and the Middle East, it features upright branched stems growing 30–100 cm tall, with opposite, oblong-elliptical leaves (1–3 cm long) that are dotted with translucent glands and black marginal dots. The plant produces showy, star-shaped yellow flowers (2 cm wide) with five petals, numerous stamens, and black-glandular margins, blooming from May to August in sunny, disturbed habitats such as roadsides, meadows, and open woodlands. Introduced to in the 1700s as an ornamental and medicinal herb, H. perforatum has become widely naturalized across the , , , and , where it is frequently listed as an due to its ability to form dense stands that displace native vegetation and reduce forage quality in pastures. The spreads aggressively via rhizomes and produces up to 100,000 seeds per annually, which remain viable in soil for over a decade, contributing to its invasiveness in grasslands and rangelands. Ecologically, it provides for pollinators but poses risks to and light-colored animals, causing severe upon sun exposure due to accumulation. Historically used in traditional since ancient times for , anxiety, and disorders—earning its name from associations with St. John the Baptist's feast day—H. perforatum is now one of the most studied herbal remedies, particularly for mild to moderate . Its aerial parts contain key bioactive compounds, including (a derivative responsible for effects via inhibition) and (a naphthodianthrone with antiviral and photodynamic properties), alongside like and . Clinical meta-analyses, such as those from Cochrane Reviews, support its efficacy comparable to standard for short-term use at doses of 300–1,800 mg/day of standardized extract, with generally mild side effects like gastrointestinal upset. However, it induces enzymes (e.g., ) and , leading to significant interactions with drugs such as oral contraceptives, anticoagulants, and antiretrovirals, necessitating caution in .

Description

Physical characteristics

Hypericum perforatum is a that grows upright to a height of 30–100 , with a spread of 20–60 , forming dense clumps through vegetative . It emerges from a woody, branched and exhibits a many-branched , particularly in the upper portions of the . The overall appearance is glabrous, lacking hairs on stems and leaves, which contributes to its smooth texture. The stems are erect, terete to slightly two-ridged, and often develop a reddish or rust-colored tint as they mature, especially at the woody base. They are branched above the , supporting the leafy foliage, and measure 2–5 mm in . This ridged structure and branching pattern aid in distinguishing the species within its . Leaves are arranged oppositely along the stems, sessile or clasping, and measure 1–3 cm long by 0.3–1 cm wide, with an oblong to elliptic shape and rounded . They are entire-margined, glabrous, and feature numerous translucent glandular dots (pellucid glands) scattered across the lamina, creating a characteristic "perforated" appearance when held to light; additionally, black marginal glands line the edges. These glandular structures are integral to the plant's , though their contents are addressed elsewhere. The root system includes a deep taproot extending up to 1.5 m, complemented by woody rhizomes and fibrous lateral roots that facilitate extensive vegetative spread and persistence in various soils. These underground structures produce adventitious shoots, allowing the plant to form colonies over time.

Flowering and fruiting

The flowers of Hypericum perforatum are borne in terminal corymbose clusters, typically comprising 25 to 100 blooms per stem, with each flower measuring 1.5 to 2.5 cm in diameter. These flowers feature five bright yellow petals, each 8 to 12 mm long and approximately twice the length of the sepals, often with black glandular dots along the margins. Flowering occurs from June to September in the Northern Hemisphere, varying slightly by region and climate, with first-year plants generally not producing flowers. The floral structure includes numerous stamens arranged in three distinct bundles, creating a prominent star-like appearance at the center of the flower. The superior develops into a three-lobed structure topped by three recurved styles, facilitating . Following , the plant produces ovoid capsules as fruits, each 5 to 8 mm long and three-celled, maturing from green and moist in mid-summer to dry and dehiscent by late autumn. These capsules contain numerous small , approximately 1 mm long, that are dark brown with a reticulate (net-like) surface ornamentation. Seed dispersal is primarily achieved through wind, which can carry lightweight seeds up to 30 feet, and by animals via the sticky capsules that adhere to fur or ; seeds ingested by animals may also pass through digestive tracts intact. Viability persists in the for up to 10 years, contributing to the plant's persistence in disturbed habitats.

Similar species

_Hypericum perforatum can be distinguished from morphologically similar congeners primarily through its combination of densely distributed translucent (pellucid) dots on the leaves and prominent black marginal on the petals and edges. These features aid in field identification, as other species in section exhibit variations in gland distribution, stem structure, and pubescence. One close relative is Hypericum maculatum (spotted St. John's wort), which lacks the numerous translucent dots characteristic of H. perforatum and instead has few or no such glands, with leaves showing elongated yellow channels along the veins and rare black nodules. Additionally, H. maculatum features a quadrangular with four pronounced ridges, contrasting the two-ridged, rounded of H. perforatum, and its petals are often broader. This species is native to , where it shares similar habitats but differs in these diagnostic traits. Hypericum hirsutum (hairy St. John's wort) differs markedly from H. perforatum in its pubescent stems and leaves, covered with dense trichomes and papillae, whereas H. perforatum is entirely glabrous. The leaves of H. hirsutum are ovate-oblong to elliptical with numerous small translucent dots but no black nodules, and its sepals are linear-lanceolate with yellow secretory channels along the veins. In contrast, Hypericum tetrapterum (square-stalked St. John's wort) has distinctly four-winged stems, forming a square cross-section, unlike the two small-winged, rounded stems of H. perforatum. It also possesses fewer stamens, typically 30–40 (up to 60) in three fascicles, compared to the 50–100 stamens in H. perforatum, and its leaves, while bearing translucent dots, are rounded to oval with the margins not incurved at the base. Among common congeners, the pellucid dots densely scattered across and the black marginal glands on petals and sepals remain unique identifiers for H. perforatum, facilitating accurate differentiation in the field.

Phytochemical overview

_Hypericum perforatum is characterized by a diverse array of , primarily naphthodianthrones, derivatives, , and essential oils, which are distributed across different parts such as flowers, leaves, and petals. These compounds contribute to the distinctive pigmentation and aroma, with many localized in specialized glandular structures. Naphthodianthrones, notably and pseudohypericin, are present at concentrations of 0.1-0.3% in the flowers and are responsible for the red pigmentation observed when the plant material is crushed. These pigments accumulate primarily in the dark glands of the flowers and stems. derivatives, including and adhyperforin, can reach up to 5% in the flowers and are known for their instability when exposed to light and heat. These compounds are concentrated in the glandular trichomes of the floral parts. Flavonoids such as , , and their glycosides constitute approximately 6–9% of the dry weight and are predominantly found in the leaves. These polyphenolic compounds provide structural and protective functions within the tissues. Essential oils, comprising 0.1-0.2% of the plant material, include monoterpenes like alpha-pinene and are housed in pellucid glands visible in the leaves and petals, contributing to the plant's volatile profile. These translucent dot-like glands are a key anatomical feature linked to oil secretion.

Taxonomy

Etymology and common names

The genus name derives from the words hyper (meaning "above") and eikon (meaning "picture" or "icon"), referring to the traditional practice of hanging the plant's flowers above religious icons or images as a protective against spirits. The specific perforatum originates from the Latin term for "pierced" or "perforated," describing the translucent glandular dots on the leaves that create the illusion of small holes when held against light. The most common English name, St. John's wort, stems from its flowering peak around June 24, the feast day of St. John the Baptist, when the plant was traditionally harvested for midsummer rituals and medicinal preparations believed to ward off malevolent forces. Other English vernacular names include goatweed, reflecting its unpalatability to livestock, and Klamath weed, a regional term from tied to its invasive spread in the Klamath River area. In the United States, it is also known as Tipton weed. Regional variations highlight its ties to healing and protection: in , it is called Johanniskraut (St. John's herb), emphasizing its saintly and medicinal heritage; in , names such as millepertuis (thousand perforations) or herbe de Saint-Jean (St. John's herb) echo the structure and seasonal associations. These names often arose from historical beliefs in the plant's supernatural powers, such as repelling demons or aiding , influencing its adoption across cultures.

Phylogenetic position

Hypericum perforatum belongs to the family , within the order , and is classified in the genus , which comprises approximately 500 divided into 36 . It is placed in (also known as section 9, Hypericum sensu stricto), a group characterized by herbaceous habit, dark glands, and a primarily Palaearctic . This is part of the broader "core " , which receives strong support (posterior probability 1.00, bootstrap 99) in phylogenetic analyses and includes sections 9–9e, 10–19, 23, 24, 26, and 27. The genus itself is embedded within the tribe Hypericeae and shows close relationships to genera like Triadenum, Santomasia, and Thornea, rendering Hypericum non-monophyletic in some reconstructions. Phylogenetic studies based on nuclear internal transcribed spacer (ITS) regions and plastid markers such as trnL-trnF and psbA-trnH place H. perforatum in a well-supported Eurasian subclade within the Old World lineage of Hypericum. Its closest relatives include H. maculatum (including subspecies maculatum and immaculatum), H. attenuatum, and H. tetrapterum, forming a tight complex that reflects shared evolutionary history across temperate Eurasia. These relationships highlight a common ancestry among Eurasian species, with H. perforatum diverging from diploid progenitors like H. maculatum subsp. immaculatum (Balkans) and H. attenuatum (western Siberia to China). The species' Euro-Mediterranean origin is inferred from this distribution, aligning with the temperate Hypericum s.l. radiation. The evolutionary divergence of , including , traces back to the Eocene (approximately 35–41 million years ago) from tropical ancestors within , with the family emerging in the Holarctic region. The crown node of is estimated at around 35 million years ago, based on fossil-calibrated molecular clocks, marking a shift from shrubby ancestors to herbaceous forms adapted to temperate climates. This timeline positions H. perforatum's lineage within a broader diversification event during the –, driven by cooling climates and niche expansion. H. perforatum exhibits significant hybridization potential with other members of section Hypericum, such as H. maculatum (yielding hybrids like H. × desetangii) and H. tetrapterum (H. × medium), often resulting in variants. Predominantly tetraploid (2n = 4x = 32), it arose via allotetraploidy from diploid hybrids, with diploid (2n = 16) and hexaploid (2n = 48) forms also documented. This , coupled with , has facilitated recurrent and the establishment of cryptic gene pools across its range, enhancing within the section.

Classification history

The plant now known as Hypericum perforatum was referenced in ancient texts, with Dioscorides describing it in the AD in under names such as Askuron, likely referring to this or closely related species for its medicinal properties. Formal taxonomic description came in 1753 when named it Hypericum perforatum in the second volume of , placing it within the genus based on its five-petaled flowers and numerous stamens, establishing the binomial that persists today. Linnaeus's classification built on earlier European herbal traditions, recognizing its perforated leaves and hypericin glands as diagnostic traits. In the 19th century, botanists like Pierre Edmond Boissier subdivided H. perforatum into varieties within broader sectional frameworks, such as in his Flora Orientalis (1867), where it was placed under section Euhypericum subsection Milleporum (later adjusted to subsection Perforata), reflecting observed morphological variations across its Eurasian range. These subdivisions accounted for differences in leaf punctation, stem pubescence, and capsule form, leading to recognition of several varieties by contemporaries, though many were later synonymized. Key modern revisions occurred through Norman K.B. Robson's monographic work on the genus , beginning with his 1977 publication "Studies in the Genus Hypericum L. (Guttiferae) 1. Infrageneric Classification," which placed H. perforatum as the of section Hypericum (formerly section 13 in preliminary schemes), encompassing about 48 north temperate with similar floral and foliar traits. Subsequent parts of Robson's series (1977–2010) refined this, emphasizing H. perforatum as a single polymorphic with four accepted —subsp. perforatum, subsp. microphyllum, subsp. veronense, and subsp. songaricum—to accommodate intraspecific variation without elevating variants to rank. This treatment, widely adopted in contemporary , prioritizes morphological and geographical coherence over earlier fragmented varietal schemes.

Intraspecific variation

Hypericum perforatum displays considerable intraspecific variation, primarily through recognized that differ in morphological traits such as leaf attachment, texture, and gland coloration on petals. The nominate , H. p. subsp. perforatum, represents the typical form with shortly petiolate, oblong to ovate leaves and petal glands ranging from pale to black; it predominates across much of the species' native range from to central and . In southern regions, H. p. subsp. veronense occurs, characterized by sessile, narrow leaves and uniformly pale petal glands; this variant extends from through to . The Asian variant, H. p. subsp. songaricum, features sessile, subcoriaceous leaves and pale petal glands, primarily found in Central Asian areas including , , (), and . These reflect continuous morphological gradients rather than sharp discontinuities, with distinctions often based on shape, density, and features. Genetic diversity within H. perforatum is pronounced, marked by variable levels; while tetraploidy (2n=32) is most common, diploid (2n=16) and hexaploid (2n=48) cytotypes also appear, correlating with reproductive modes such as sexuality in diploids and in polyploids. Populations exhibit substantial biochemical variation, particularly in content, which ranges from 0.05% to 0.5% dry weight depending on , with higher levels often in polyploid individuals from temperate zones. This intraspecific heterogeneity contributes to the species' adaptability and its utility in medicinal applications, where chemotype selection is critical. Ecotypic differentiation further underscores this variability, with plants showing adaptive morphological responses to local conditions; for instance, individuals in moist habitats tend to achieve greater heights (up to 1 m) with elongated stems, whereas those in dry, sandy dune environments develop more compact, prostrate forms (30-50 cm) to withstand wind and nutrient-poor soils. Such differences are influenced by edaphic factors like and texture, as well as climatic variables including and UV exposure, leading to clinal shifts in growth habit across gradients. Molecular studies using (AFLP) markers have illuminated patterns of genetic structure, revealing clinal variation that aligns with geographic distribution; for example, distinct gene pools show a north-south cline in , with northern populations exhibiting greater diversity and southern ones more uniformity, extending into Asian ranges where from ancestral diploids shapes local adaptations. These AFLP analyses, scoring hundreds of fragments across populations, confirm low inter-subspecies but highlight cryptic polyploid gene pools that influence overall intraspecific .

Distribution and habitat

Native range

Hypericum perforatum is native to temperate regions across and , with its original distribution extending from the and western Europe—including the and —through and the to eastern Asia in areas such as , , and the , and southward into from to . This broad native range, spanning approximately the temperate zones of the , reflects the species' adaptation to mild climates and well-drained soils. Core areas of abundance include the , , and the Eurasian steppes, where the plant thrives in open, sunny habitats but is absent from arid deserts and high-elevation alpine zones such as the upper reaches of the . The species' historical spread occurred primarily through post-glacial colonization following the , originating from multiple refugia in and western via long-distance , as inferred from phylogeographic analyses of genetic variation. Within its native range, H. perforatum shows highest densities in temperate grasslands and meadows.

Introduced distributions

Hypericum perforatum, native to , western , and , has been widely introduced to temperate regions worldwide through human-mediated dispersal. It was first brought to in the 1700s, likely via contaminated fodder and ship ballast used by European settlers, with the earliest recorded occurrence in in 1793. By the early , it had established dense populations in western states, and today it occurs across 49 U.S. states and 9 Canadian provinces, particularly in disturbed habitats like pastures, roadsides, and rangelands. The species arrived in during the mid-19th century, initially as an ornamental or curiosity plant in botanical gardens, and spread rapidly, especially in where it became a significant issue in dryland pastures and forests. It was also introduced to around the same period for similar purposes and has since naturalized on both the North and South Islands. In , introductions occurred in and , where it now invades open woodlands and grasslands. More recent expansions include , with established populations in and since the , and , particularly where it was introduced in 1942 through contaminated vetch seed. Overall, these introductions—both accidental via transport vectors like and intentional for medicinal or ornamental uses—have resulted in the species occupying extensive introduced areas.

Habitat preferences

_Hypericum perforatum prefers open, sunny sites that receive abundant for optimal growth, commonly occurring in disturbed grasslands, roadsides, meadows, and edges. It thrives in full sun to partial shade but does not tolerate dense shade. The plant is frequently found in well-drained areas, tolerating conditions while being sensitive to waterlogging. The species favors well-drained, coarse-textured soils such as sandy loams, gravelly silt loams, or poor, nutrient-deficient substrates, including sandy, loamy, or clayey types. It performs best in neutral to slightly acidic conditions with a range of 5 to 6.5, showing reduced vigor on alkaline soils. Hypericum perforatum is adapted to low-nutrient environments, often establishing in impoverished or disturbed soils. In terms of climate, Hypericum perforatum is suited to temperate regions with hot, dry summers and mild, rainy winters, requiring a long of 160 to 220 days. It occurs from to altitudes of up to 1,500 and tolerates annual precipitation from 250 to 1,020 mm. The is frost-tolerant down to -15°C.

Ecology

Reproduction and life cycle

Hypericum perforatum is a that completes its over multiple years, exhibiting vegetative growth in when shoots emerge from root crowns, followed by flowering from mid-summer ( to September) and seed set in autumn (late August to November). The plant overwinters through persistent root systems, including taproots and lateral roots, which allow resprouting the following season, and requires a moderately warm, long for optimal development. Sexual reproduction in H. perforatum occurs primarily through facultative , with populations in exhibiting up to 97% apomictic formation, though and via also contribute to production. A single mature plant can produce 15,000 to 33,000 annually, with each capsule releasing 400 to 500 . require 4 to 6 months after harvest to become germinable, achieving optimal rates (up to 70%) under constant 15°C temperatures, light exposure, and after removal of chemical inhibitors through washing; typically occurs in autumn, winter, or on disturbed, moist soils. Asexual reproduction is facilitated by vegetative spread through short rhizomes and sprouts, which extend horizontally up to 1 meter per year and produce new root crowns, particularly in and fall. Root fragments remain viable and can regenerate into new plants when disturbed, such as by grazing, fire, or tillage, contributing to 46% to 50% of new crowns in established stands. Individual plants of H. perforatum persist for 10 to 20 years, forming expansive colonies through combined sexual and mechanisms, with banks maintaining viability for 6 to 30 years to support long-term .

Pollinators and herbivores

Hypericum perforatum flowers attract a variety of pollinators, primarily through and rewards. Honeybees ( mellifera) and s, such as the common eastern () and brown-belted bumblebee (Bombus griseocollis), are frequent visitors, along with sweat bees ( spp.). Hoverflies and also contribute to , with the plant supporting generalist taxa in habitats. Field observations in regions like , document up to seven species interacting with the flowers, though pollinator preferences vary and occurs alongside animal-mediated transfer. Regarding pollinators, Hypericum perforatum provides and resources that attract bees. Herbivory on H. perforatum is limited by its , particularly to mammalian browsers, due to compounds like that cause photosensitization. In native European ranges, goats and sheep occasionally graze the plant in pastures, but consumption is minimal and often used strategically for , as avoid dense stands. Specialized , however, thrive on it; leaf-feeding beetles such as Chrysolina quadrigemina and Chrysolina hyperici (St. Johnswort beetles) are key herbivores, with larvae consuming foliage and adults defoliating shoots. These beetles, native to , have been introduced as biocontrol agents in invasive areas like to target H. perforatum specifically, reducing plant biomass without broad ecological harm. The plant's chemical defenses, including , deter generalist herbivores while tolerating s. Damage from generalist insects like armyworms (Spodoptera exigua) induces 30-100% increases in and levels, enhancing resistance and reducing subsequent herbivory by grasshoppers and leafminers in field trials. In contrast, Chrysolina feeding causes less but more physical damage. Some populations exhibit mutualistic interactions, such as tending (Aphis chloris) on H. perforatum stems, indirectly protecting the plant by deterring other herbivores through ant presence.

Diseases and pests

Hypericum perforatum is susceptible to several fungal diseases, with rust caused by Melampsora hypericorum being one of the most notable pathogens. This rust fungus produces orange uredinia on leaves and stems, leading to defoliation and reduced vigor, particularly in regions with cool, moist conditions favorable for spore dispersal. Another significant fungal issue is anthracnose and leaf spot caused by Colletotrichum species, such as C. gloeosporioides and C. cigarro, which form sunken lesions on stems and leaves, potentially causing wilting and dieback; these diseases are more severe in humid climates where high moisture promotes infection and spread. Insect pests primarily include leaf-feeding and sap-sucking insects that damage foliage and reproductive structures. The Klamathweed beetle, Chrysolina quadrigemina, is a key that defoliates by consuming leaves, often introduced as a biocontrol agent but capable of significant damage in high populations. , particularly Aphis chloris, feed on sap from stems and leaves, causing distortion, yellowing, and stunted growth, with heavy infestations potentially killing young . Flower damage occurs from weevils like Anthonomus rutilus, whose larvae develop within inflorescences and feed on developing seeds, reducing seed production and plant fitness. Viral infections are rare in H. perforatum, but the plant can serve as a host for (Cucumovirus), which may cause symptoms on leaves and overall weakening, though impacts are typically minor compared to fungal or threats. Bacterial diseases, such as wilts in wet soils, are uncommon but can exacerbate issues in poorly drained habitats. Abiotic stressors also affect H. perforatum, with drought conditions reducing plant growth, flower dry weight, and overall biomass accumulation by limiting water availability and . In invasive populations, management challenges arise from variable responses to control measures, though specific has not been widely documented.

Toxicity to wildlife

Hypericum perforatum poses significant toxicity risks to primarily through photosensitization induced by the compound . When animals ingest the plant, hypericin accumulates in the skin and reacts with sunlight to produce , leading to severe in unpigmented areas. Symptoms include intense itching, , , sloughing of skin, and in severe cases, blindness due to retinal damage; affected such as sheep and may also experience abortions if pregnant. White-skinned are particularly susceptible, developing symptoms after consuming as little as 1% of their body weight in fresh plant material, while sheep require about 4%. In settings, acute oral of Hypericum perforatum extracts in rats is relatively low, with LD50 values exceeding 20 g/kg body weight for mixtures containing the extract, indicating limited immediate lethality from single high doses. At elevated doses, the plant's constituents can influence the , potentially through weak inhibition of enzymes, which may alter levels and contribute to behavioral effects such as reduced locomotor activity observed in models. The plant exhibits repellent properties against non-adapted herbivores due to its bioactive compounds, including and , which deter mammalian grazing and reduce herbivory damage in introduced ranges compared to native habitats. Specialized have evolved adaptations to feed on it, but generalist herbivores avoid consumption to prevent and digestive irritation. Toxins from , such as , demonstrate limited environmental persistence in , with minimal leaching and negligible impacts on soil microbial communities, as evidenced by stable microbiomes across varied habitats. The active compounds primarily affect aboveground interactions rather than altering significantly.

Invasiveness impacts

Hypericum perforatum, commonly known as St. John's wort, significantly reduces in invaded ecosystems by forming dense stands that outcompete native , particularly in grasslands and pastures. This aggressive growth displaces forage species such as Idaho fescue and bluebunch wheatgrass, leading to decreased plant diversity and altered community structures. In rangelands, it suppresses native emergence, with studies showing up to 100 times higher rates for natives when H. perforatum neighbors are removed, thereby diminishing habitat quality for wildlife and reducing overall ecosystem resilience. The economic consequences of H. perforatum invasions are substantial, particularly in regions where it impacts production. In , annual losses from pasture infestations, including reduced and issues in grazing animals, were estimated at $22.5 million in alone during the 1990s, with control efforts adding further costs averaging $85,000 per year in prior to widespread biocontrol adoption. In the United States, historical infestations covered over 2.5 million acres in by 1945, severely limiting due to the plant's , which causes photosensitization in upon ingestion, resulting in skin lesions, , and occasional fatalities that exacerbate economic burdens on ranchers. Beyond and economic effects, H. perforatum induces changes by depleting upper through its deep , which hinders the establishment of other vegetation and delays recovery in disturbed areas. Its dry accumulation increases hazard in invaded forests and grasslands, contributing to higher fuel loads and potentially more intense burns, as observed in and Australian woodlands. Effective management has relied on biological control, notably the introduction of Chrysolina quadrigemina beetles in Australia and the U.S., which have reduced H. perforatum populations by over 90% in targeted areas by defoliating plants and limiting seed production, thereby restoring ecological balance and minimizing ongoing impacts.

Pharmacology

Active compounds

_Hyperforin is a key non-polar phloroglucinol derivative found in Hypericum perforatum, recognized for its role in the plant's pharmacological profile. In standardized extracts, hyperforin concentrations typically range from 2% to 6%, varying based on extraction methods and plant material used. Hypericin, a polar naphthodianthrone, serves as a prominent photosensitizing compound in H. perforatum and is commonly used as a quality marker for extracts. Its content in standardized preparations is generally around 0.3%, though its oral remains low at less than 1%. Flavonol glycosides, including and , contribute properties and are abundant in the leaves and flowers of H. perforatum. These compounds collectively comprise 8-12% of the dry weight in aerial parts, with and being the predominant forms. Trace amounts of , ranging from 0.1 to 1 µg/g dry weight, are also present in H. perforatum, potentially influencing sleep-related regulation.

Mechanisms of action

, a key derivative in Hypericum perforatum, acts as a non-selective of , primarily affecting , , and transporters in the . This inhibition occurs through a mechanism involving elevation of intracellular sodium levels, which disrupts the sodium gradient required for transporter function, leading to increased synaptic availability of these monoamines. The potency of is evidenced by values ranging from 0.05 to 0.8 μg/ml (approximately 0.1–1.5 μM) across these transporters, comparable to some synthetic antidepressants but with broader specificity. The anti-inflammatory effects of H. perforatum extracts and their constituents involve multiple pathways, including inhibition of cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-κB) signaling. Hyperforin suppresses COX-2 activity indirectly by inhibiting microsomal prostaglandin E2 synthase-1 (mPGES-1), a downstream enzyme in the arachidonic acid pathway, thereby reducing prostaglandin E2 production and associated inflammation. Meanwhile, hypericin, a naphthodianthrone, acts as a non-antioxidant inhibitor of NF-κB activation, preventing its translocation to the nucleus and subsequent transcription of pro-inflammatory genes. This results in decreased production of cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Antioxidant properties of H. perforatum are largely attributed to its flavonoids, such as and , which scavenge (ROS) and free radicals, mitigating in cellular systems. These compounds donate electrons to neutralize radicals, preventing and DNA damage. Additionally, extracts of the plant upregulate (BDNF) expression in the , promoting neuronal survival and plasticity through enhanced protein levels observed in preclinical models of stress. Induction of 3A4 () by H. perforatum occurs via activation of the X receptor (PXR), a that regulates drug-metabolizing enzymes. serves as a potent PXR with a Ki of 27 , leading to transcriptional upregulation of and increased metabolism of co-administered drugs, which can result in reduced plasma levels of substrates like oral contraceptives and immunosuppressants. This herb-drug interaction mechanism underscores the need for caution in .

Clinical efficacy

Hypericum perforatum, commonly known as St. John's wort, has been extensively studied for its clinical in treating , particularly mild to moderate cases. A 2017 systematic and of randomized controlled trials (RCTs) found that extracts of H. perforatum are superior to and comparable in efficacy to selective serotonin inhibitors (SSRIs) for mild to moderate , with pooled response rates of approximately 60-70% for St. John's wort versus 50% for . This equivalence is supported by earlier meta-analyses, which reported absolute response rate improvements of 23-55% over in short-term trials. However, evidence indicates limited efficacy for severe or major , where St. John's wort performs no better than in RCTs involving moderate to severe cases. For anxiety and sleep disorders, clinical evidence is more limited, with few dedicated RCTs. Available trials suggest mild benefits for anxiety symptoms, particularly when comorbid with ; for instance, standardized extracts at 300 mg/day have been associated with reductions in (HAM-A) scores by 10-15 points in small studies, though larger trials are needed to confirm these effects. Similarly, preliminary data from open-label and small RCTs indicate potential improvements in sleep quality as a secondary outcome in patients with mild anxiety or , but robust evidence is lacking. Topical applications of H. perforatum extract show promise for , especially in diabetic ulcers. In a 2015 rat model of full-thickness excisional diabetic wounds, topical H. perforatum significantly accelerated regeneration, with higher volume densities of re-epithelialization and deposition compared to controls, leading to approximately 20% faster closure rates. A more recent 2025 study in streptozotocin-induced diabetic s confirmed these findings, demonstrating improved scores with topical H. perforatum over controls, though trials remain limited. Regarding other conditions, H. perforatum has shown no efficacy in , with clinical trials reporting no tumor regression or antitumor effects in patients. In contrast, a 2010 double-blind RCT suggested potential benefits for (PMS), where H. perforatum at 900 mg/day reduced physical and behavioral symptoms by about 40% more than , though effects on mood symptoms were less pronounced. These findings align with its mechanisms involving serotonin modulation, as discussed in the pharmacology section.

Recent research findings

Recent research on Hypericum perforatum has explored its interactions with the gut microbiome, revealing potential enhancements to its established properties. A 2024 study in mice subjected to chronic restraint stress found that H. perforatum extract restores gut microbial dysbiosis by enriching beneficial bacteria such as , which contributes to increased serotonin synthesis and reduced inflammation via the NFκB-NLRP2-Caspase1-IL1β pathway, thereby alleviating -like behaviors. This modulation supports prior clinical evidence on its efficacy for mild to moderate by linking gut-brain axis mechanisms. Advancements in systems have focused on improving the of H. perforatum for topical applications. In a 2025 study, a nanoemulsion formulation incorporating H. perforatum macerate achieved 99.83% encapsulation efficiency and sustained release of over 80 hours, demonstrating enhanced in rat models by reducing wound size to 2.92 mm by day 12 compared to 4.58 mm with the extract alone, alongside upregulated expression of TGF-β1 and VEGF for better re-epithelialization and synthesis. This approach also showed strong activity against pathogens like MRSA (MIC 12.5 µg/mL), suggesting doubled efficacy in managing inflammation-related skin conditions relative to conventional extracts. Quality assessments of commercial H. perforatum supplements have highlighted significant variability. Testing conducted by NOW Foods in 2025 on 44 samples from 22 brands sold on revealed widespread potency failures, with only one standardized product (claiming 0.3% ) meeting HPLC-verified criteria; 18% of samples contained no detectable , often due to adulteration with synthetic dyes like Brilliant Blue that falsely inflate readings and stem from inadequate sourcing and controls. Applications in animal agriculture have shown promise for H. perforatum in . A 2025 trial supplementing diets with 0.5% ethanolic extract of H. perforatum reduced markers, such as in breast muscle (P=0.001), while boosting overall capacity and immunity, including elevated at higher doses like 1.5%, positioning it as a potential alternative to mitigate and enhance performance. Protective effects against environmental toxins have been demonstrated in genotoxicity models. A 2024 Allium cepa assay exposed to vanadium chloride (200 µg/L) showed that H. perforatum extract at 187.5–375 mg/L counteracted DNA damage by reducing micronuclei formation, chromosomal aberrations, and oxidative stress indicators like MDA and enzyme activities (SOD, CAT), attributing protection to its phenolic antioxidants that scavenge ROS and chelate metals.

Uses

Traditional applications

Hypericum perforatum, commonly known as St. John's wort, has been utilized in since ancient times. In the 5th century BC, recommended it as a remedy for wounds, inflammation, menstrual disorders, intestinal worms, and snakebites, highlighting its role in early practices. , in the 1st century AD, documented its applications for treating wounds, promoting , and addressing conditions associated with madness, reflecting its early recognition for both physical and mental ailments. These ancient uses established the plant as a versatile healer in classical Mediterranean cultures. During the medieval period in , St. John's wort gained prominence for its protective and therapeutic properties. It was employed to ward off evil spirits and demons, often incorporated into rituals and charms due to its mystical associations, with the name "" derived from words meaning "over an apparition." Herbalists like in the 16th century prescribed it for and , while it was commonly used for , as a , and in oil infusions to treat burns and scalds. , in his 1652 herbal, further endorsed its external application for bruises, venomous bites, and , solidifying its place in European folk medicine. Indigenous peoples in North America adopted Hypericum perforatum for various ailments after its introduction. Tribes such as the Cherokee used it as a febrifuge, emmenagogue, and treatment for sores and venereal diseases, while the Iroquois and Montagnais applied it for fevers, coughs, and bowel complaints, akin to remedies for colds and respiratory issues like tuberculosis. In Asia, related variants like Hypericum sampsonii have been employed in traditional Chinese medicine for gastrointestinal diseases and digestive disturbances. Beyond medicinal applications, St. John's wort held cultural and practical significance. In , it was fashioned into amulets to protect against strikes and malevolent forces, a belief persisting from ancient times into the . Additionally, since Roman antiquity, the plant's flowers have been crushed to yield a for fabric, valued for its vibrant hue in .

Modern medicinal uses

Hypericum perforatum, commonly known as St. John's wort, is primarily utilized in modern medicine as an herbal supplement for mild to moderate , with standardized extracts containing 0.3% being the most common form. Typical oral dosages range from 900 to 1800 mg per day, divided into two or three doses, administered for 4 to 6 weeks to assess initial response. These extracts are derived from the aerial parts of the plant and are available over-the-counter in regulated markets, building on historical folk uses for mood support. Topically, extracts of H. perforatum are applied as ointments or creams for minor wounds, burns, and lesions, often in formulations containing 10% extract to promote healing and reduce inflammation. Such preparations leverage the plant's antiviral and wound-healing properties, particularly for herpes-related skin sores. Adjunctive applications include support for menopausal symptoms, such as hot flashes, and , where oral extracts may help alleviate associated mood disturbances. A 2025 review examined the putative antidiabetic effects of St. John's wort, suggesting potential benefits as an adjunct therapy for diabetes mellitus. A prospective (data collected 2005–2007; published 2025) investigated fresh plant tinctures for , evaluating their tolerability and symptom relief in mild to moderate cases. Common encompass tablets and capsules for oral use, herbal teas prepared from dried herb, and tinctures or liquid extracts, with fresh plant tinctures gaining attention in recent formulations.

Drug interactions

Hypericum perforatum, commonly known as St. John's wort, exhibits significant pharmacokinetic interactions with various primarily through induction of () and (), as well as pharmacodynamic effects on serotonin systems. These interactions can reduce or increase risks, necessitating caution in concurrent use. One prominent interaction involves induction, which accelerates the metabolism of substrates like oral contraceptives, leading to decreased hormone levels and reduced contraceptive efficacy. Clinical reports have documented breakthrough bleeding and unplanned pregnancies in women using both, with the failure rate potentially increasing 2-3 times compared to oral contraceptives alone. St. John's wort also acts as an inducer of , a drug efflux transporter, resulting in lowered plasma concentrations of substrates such as , cyclosporine, and protease inhibitors by 20-50%. For instance, levels may decrease by up to 36% after 10-14 days of St. John's wort use, potentially compromising therapeutic effects in or transplant patients. Similar reductions have been observed with cyclosporine, increasing rejection risk in organ transplant recipients, and with indinavir or other antiretrovirals, which could impair treatment outcomes. Pharmacodynamic interactions arise from St. John's wort's serotonergic effects, heightening the risk of when combined with selective serotonin reuptake inhibitors (SSRIs) or inhibitors (MAOIs). Case reports describe symptoms including agitation, confusion, and in such combinations, underscoring the need for monitoring or avoidance. These effects stem from mechanisms involving reuptake inhibition and activity, as detailed in the pharmacology section. Additionally, St. John's wort decreases the anticoagulant effect of via and , potentially requiring dosage adjustments to maintain therapeutic international normalized ratio (INR) levels. It also interacts with statins like , reducing their plasma concentrations and cholesterol-lowering efficacy through metabolism; 2025 data from clinical guidelines reaffirm this interaction, advising against concurrent use without monitoring.

Adverse effects and safety

Hypericum perforatum, commonly known as St. John's wort, is generally well-tolerated when used orally at recommended doses for short periods, with most adverse effects being mild and transient. Common side effects include gastrointestinal disturbances such as , upset stomach, , and dry mouth; ; or tiredness; trouble sleeping; ; and restlessness. These effects occur in approximately 20% of users in clinical trials, compared to over 50% with conventional antidepressants, and are typically self-limiting. A notable adverse effect is photosensitivity, which can manifest as severe skin reactions, including rash or sunburn-like symptoms upon sun exposure, particularly in fair-skinned individuals or with higher doses. This reaction is infrequent, affecting less than 1% of users in most studies, but can be dose-related and more pronounced with topical application or large oral doses. Allergic reactions, such as rash or itching, are also possible but uncommon. Contraindications include use during , where it is considered possibly unsafe due to potential risks of birth defects based on limited from animal studies and case reports. It is also contraindicated in individuals with , as it may induce or exacerbate psychotic symptoms by switching mood states. Patients undergoing phototherapy or those with conditions requiring avoidance of sunlight should avoid it due to the heightened risk of photosensitization reactions. Breastfeeding is not recommended, as it may cause , drowsiness, or in infants. For long-term use, St. John's wort appears safe for up to 12 weeks in most adults not taking interacting medications, with some clinical trials supporting tolerability for up to one year in treating mild to moderate , where only about 6% of adverse events were possibly related to the herb. Rare cases of liver enzyme elevation have been reported, but it is not convincingly linked to clinically apparent . Abrupt discontinuation after prolonged use may lead to mild symptoms such as , , chills, or fatigue lasting up to a week. Overdose with St. John's wort is typically mild, presenting with symptoms like , , or , and no fatalities have been reported in the literature. Management involves supportive care, and serious toxicity is rare even at high doses.

Regulation and quality

In the United States, Hypericum perforatum (St. John's wort) is regulated as a under the Dietary Supplement Health and Education Act of 1994, rather than as a pharmaceutical , allowing over-the-counter sales without pre-market approval for efficacy claims. In the , the (EMA) recognizes well-established use of standardized dry extracts for the short-term treatment of symptoms in mild to moderate depressive episodes, based on clinical evidence from products like LI 160 and WS 5570, with preparations typically standardized to 0.10-0.30% total hypericins. However, due to concerns over drug interactions, banned the sale of all products containing St. John's wort in 2005, classifying it as a medicinal product requiring strict oversight. Standardization efforts aim to ensure consistent potency, with specific extracts like WS 5570—a hydroalcoholic dry extract (drug-to-extract ratio 4–7:1)—formulated to contain 3-6% and 0.12-0.28% for therapeutic reliability in treatment. The (USP) monograph for St. John's wort flowering top dry extract requires not less than 0.2% combined hypericin and pseudohypericin, alongside specifications for other markers like , to support quality in dietary supplements and extracts. Quality control remains a significant challenge, as testing in August 2025 of 22 St. John's wort products sold on revealed that 95% failed potency assays for labeled content (e.g., only one met the 0.3% claim), with several containing synthetic dyes indicative of adulteration. Wild-harvested materials are particularly prone to , including like and lead exceeding guidelines in some samples, underscoring the need for rigorous testing. Pharmaceutical-grade cultivation occurs primarily in and the to meet regulatory demands, with practices enforced to minimize residues and ensure compliance with pharmacopeial standards. In , producers adhere to Good Agricultural and Collection Practices (GACP) outlined by the , facilitating the production of high-quality extracts for licensed medicines.

Non-medicinal applications

Hypericum perforatum flowers have been utilized historically for production, yielding yellow to red pigments primarily from and other naphthodianthrones, which are applied to textiles such as , , and . These dyes produce shades like on and golden beige or on plant fibers when mordanted with or metal salts, offering both aesthetic and functional properties such as UV protection. In medieval and , the plant served as a native source for and dyes in traditional textiles, including tartans, reflecting its role in regional practices. As an , Hypericum perforatum is employed in garden borders, woodland margins, slopes, and naturalized meadows due to its showy star-shaped yellow flowers blooming from June to and its tolerance for and poor soils. It grows 1-3 feet tall with a spread of up to 2 feet, making it suitable for low-maintenance areas in full sun to part shade, though its invasive potential limits widespread use. Cultivars such as 'Citrinum' offer compact growth for edging and ground cover, featuring enhanced floral displays while requiring good air circulation to prevent . In biological control programs, Hypericum perforatum acts as a host for specific introduced to manage its spread as an invasive , such as the leaf-feeding beetle Chrysolina quadrigemina and the gall midge Zeuxidiplosis giardi, which target foliage and seedlings to reduce populations. These agents, established since the mid-20th century in regions like and the western U.S., help suppress the plant without broad chemical use, though establishment success varies by . The extracted from Hypericum perforatum flowers, via or CO₂ methods, possesses a herbaceous, floral aroma with notes of , , and β-caryophyllene, finding application in perfumery for blending with , spices, and florals. Yields range from 0.35% to 1% during peak bloom, contributing to fragrance formulations in clean perfumery concepts. Hypericum perforatum shows potential as a low-yield feedstock in marginal lands, with dry matter productivity around 1.5 Mg/ha/year in mixed successional systems suitable for production. Field trials in Mediterranean environments report total peaks of approximately 5 tons/ha fresh weight in the second year, though declines occur subsequently, limiting commercial viability compared to dedicated energy crops.