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Ruta

Ruta is a of approximately 10 to 12 species of aromatic, evergreen perennial subshrubs and herbs in the family , commonly known as the rue or family, native to the Mediterranean region and . The plants are characterized by their , fern-like leaves, pungent odor, and clusters of small, yellow flowers that develop into capsule-like fruits, with (common rue) and Ruta chalepensis (fringed rue) being the most widely recognized and studied species. Historically, Ruta species have been employed in traditional Mediterranean folk since ancient times for treating a variety of conditions, including gynecological disorders, , fever, , infections, and nervous ailments, often as infusions, essential oils, or poultices. Despite these uses, the is notable for its ; it contains bioactive compounds such as , alkaloids, and volatile oils that can cause severe phototoxic , gastrointestinal irritation, , and even systemic complications like multiorgan failure upon excessive contact or ingestion. In contemporary contexts, Ruta plants are cultivated primarily as ornamentals for their attractive blue-green foliage and , particularly R. graveolens, which grows 2–3 feet tall and thrives in well-drained soils. Modern pharmacological research has highlighted the genus's potential in developing high-value products, revealing broad bioactivities such as , , antiviral, , , anticancer, and antidiabetic effects, primarily attributed to secondary metabolites like 2-undecanone and . However, due to concerns, internal use is generally discouraged without professional supervision, and external applications require caution to avoid reactions.

Taxonomy and etymology

Taxonomic classification

The genus Ruta belongs to the family , commonly known as the citrus family, within the order and class Magnoliopsida of the kingdom Plantae. More specifically, it is placed in the subfamily Rutoideae and tribe Ruteae, reflecting its systematic position among woody and herbaceous plants characterized by glandular oil cavities. The genus was initially described by in his in 1753, establishing its foundational nomenclature. Modern taxonomic revisions, including those by C. C. Townsend in 1986 for closely related genera in Ruteae and subsequent genetic analyses, have refined its boundaries. Phylogenetic studies utilizing sequences, such as matK, rpl16, and trnL-trnF regions from the 2000s onward, have demonstrated that Ruta forms a monophyletic within tribe Ruteae. These molecular analyses, complemented by rDNA data, highlight its close affinities to genera like Haplophyllum in Rutoideae, while distinguishing it from in the related subfamily and within the broader Rutoideae. Recent plastome sequencing up to 2023 further supports this positioning, underscoring the genus's evolutionary distinctiveness in the Mediterranean flora. As of November 2025, the encompasses 12 accepted , with ongoing classifications influenced by molecular revisions that account for morphological variability.

Etymology and historical naming

The name Ruta derives from the Latin rūta, which originates from the ῥυτή (rhytḗ), possibly referring to "to set free" in to the plant's traditional use as a component in antidotes against poisons. This etymological root emphasizes the herb's historical reputation for counteracting toxins and ailments, reflecting its bitter properties that were believed to purify or liberate the body. The plant's nomenclature traces back to ancient descriptions, with the Greek physician providing the earliest detailed account in his 1st-century AD work , where he described rue (Ruta) as a medicinal herb effective for treating coughs and breathing difficulties when its juice was heated. This classical reference established rue's role in , influencing its naming and use across Mediterranean cultures. In 1753, formalized the genus in , designating as the and placing it within the family under the binomial system, which standardized its taxonomic identity. Nomenclatural developments in the 19th and 20th centuries involved refinements within Rutaceae, which helped delineate Ruta's boundaries more precisely. By the 21st century, the genus has achieved stability under the International Code of Nomenclature for algae, fungi, and plants (ICN), ensuring consistent application in botanical classifications without major revisions. Culturally, the English common name "rue" evolved from Old English rūde (or rude), a direct borrowing from Latin rūta, and became associated with bitterness and remorse due to the plant's acrid taste. This symbolism appears prominently in literature, such as in William Shakespeare's Hamlet (Act 4, Scene 5), where Ophelia distributes rue as a "herb of grace" to represent regret, repentance, and sorrow, reinforcing its enduring metaphorical role in Western tradition.

Botanical description

Morphology and growth habit

Ruta species exhibit a growth habit as subshrubs or herbs, typically reaching 30-90 cm in height, with a woody base supporting herbaceous, branched shoots that form bushy, mound-like structures; they are glabrous and strongly aromatic due to glandular trichomes covering the stems and foliage. The leaves are alternate, glaucous-blue in color, and pinnately compound, usually 2-3 pinnate with a length of 3-10 cm; leaflets are oblong to ovate or linear, measuring 5-15 mm long, thick-textured, glandular-punctate, and borne on stout rachises. Flowers occur in terminal cymes forming lax inflorescences, are typically 4-merous (occasionally 5-merous), with yellow-green petals 5-10 mm long and up to 1-2 cm in diameter overall; the four sepals are lanceolate and acute, the four petals are oblong-ovate and often fringed or undulate, the eight stamens are free, and the inferior comprises 4-5 locules. The fruits are capsular, globose to ovoid, 8-12 mm in diameter, glabrous and glandular, dehiscing septicidally at the into 4-5 pyrenes or mericarps; seeds are small, to , wedge-shaped, approximately 2 mm long, and minutely tuberculate. These perennials follow a hermaphroditic , with flowering primarily in summer for Mediterranean species, insect-mediated facilitated by nectar-rich flowers and specialized movements that present in controlled doses, and natural persistence through the woody base alongside potential vegetative spread via basal shoots.

Habitat and distribution

The genus Ruta is native to the , encompassing , , and southwest Asia, with centers of diversity in regions such as , , , and . Species within the genus typically inhabit dry, rocky slopes and scrublands, including vegetation formations characteristic of the . They thrive in well-drained, calcareous soils under full sun exposure and exhibit strong , enabling persistence in arid microhabitats. Altitudinal distribution ranges from sea level to approximately 1500 m, where conditions support their adaptation to seasonal . Ecologically, Ruta species function as pioneer plants in disturbed areas, such as eroded slopes or post-fire landscapes, facilitating early through rapid . Their secondary metabolites contribute to allelopathic effects, inhibiting seed germination and of nearby via root exudates and leaf leachates rich in coumarins and ketones. Interactions with pollinators include attraction of bees, hoverflies, and —such as swallowtails, for which R. graveolens serves as a larval host—via and resources, while volatile oils deter many herbivores, reducing foliage consumption despite occasional specialist feeding. Several Ruta species have been introduced beyond their native range and are now widely naturalized in the Americas, Australia, and South Africa, often escaping from ornamental or medicinal plantings. In some arid regions of these areas, they exhibit invasive potential, forming dense stands that outcompete native flora due to their drought tolerance and allelopathic properties. Conservation concerns affect certain taxa, such as R. museocanariensis, which is assessed as Extinct (EX) under IUCN criteria as of 2023 owing to prehistoric habitat loss associated with human activity in its limited range on the Canary Islands.

Species diversity

Accepted species

The genus Ruta currently includes approximately 10 accepted , as recognized by (POWO) as of 2025. These are mostly perennial subshrubs or shrubs native to the , , and parts of southwestern , characterized by aromatic, pinnately leaves and yellow flowers in terminal inflorescences. Distinctions among them often involve leaf , petal margins, , and preferences, though some boundaries remain debated, particularly regarding the status of R. angustifolia Pers., which is sometimes treated as a of R. chalepensis L. but accepted here pending further molecular resolution. Natural hybridization is rare but documented, such as between R. graveolens L. and R. chalepensis, occurring in overlapping ranges and producing intermediate morphologies. The type species, Ruta graveolens L. (common rue), is widespread across the Mediterranean from the to , featuring broader, glaucous-blue leaflets (typically 5–15 mm wide) that are bipinnate or tripinnate with rounded segments, non-fringed petals, and capsules with blunt lobe apices; it is commonly cultivated and not currently threatened. Ruta chalepensis L. (fringed rue) extends from through the Mediterranean to southwestern , distinguished by more finely dissected, greener leaves with narrower segments (often 2–5 mm wide) and tripinnate , fringed margins, and capsules with acute lobe tips; it thrives in rocky habitats and is stable in populations. R. bracteosa DC. is treated as a of this species. Ruta montana L. is endemic to and , with compact growth, pubescent stems, and moderately dissected leaves; it inhabits montane scrub and faces minor threats from but lacks formal conservation assessment. Ruta corsica DC. is restricted to and , featuring small stature, densely glandular leaves with broad segments, and a woody base; as an island endemic, it is potentially vulnerable to and climate shifts, though populations are stable. Ruta macrolepis Boiss. is native to and adjacent areas, characterized by large, reticulate fruit lobes and coarsely toothed leaflets; it grows in phryganic vegetation and is not threatened. Ruta oreojasme Webb & Berthel. is confined to the (), with succulent leaves and reduced dissection adapted to arid cliffs; its narrow range warrants monitoring for conservation, but it is currently secure. Ruta lamarmorae Bacch., Brullo & Giusso is endemic to ( massif), a with glandular leaves similar to R. but distinguished by and ; it is potentially vulnerable due to limited range. Ruta lindsayi () Stace occurs in the Mediterranean region, with variable leaf dissection; its taxonomic status is debated but accepted in POWO, adapted to rocky slopes. Ruta microcarpa Svent. is endemic to the , a small with reduced fruits; it is rare and requires attention due to habitat loss. Ruta pinnata L.f. is a Mediterranean species with pinnate leaves and fringed petals, growing in dry scrub; populations are stable. Ruta angustifolia Pers. is accepted in western and central Mediterranean ranges (e.g., , ), with narrow, linear leaflets and sparse pubescence, though its distinction from R. chalepensis is under debate based on morphological overlap and genetic studies.

Synonyms and variability

The genus Ruta has experienced several taxonomic revisions, particularly in the , where morphological similarities led to mergers of certain taxa based on more detailed analyses. For example, R. linifolia L.f. has been treated as a of R. chalepensis L. in some classifications due to overlapping traits, though recent assessments maintain R. montana L. as distinct while noting historical confusions with genera like Hesperethusa. Similarly, R. graveolens L. has numerous synonyms, including R. glauca L. and R. divaricata Guss., reflecting past variability in species delimitation. Molecular evidence from nuclear ribosomal internal transcribed spacer (ITS) sequencing has played a key role in resolving taxonomic variability within Ruta, confirming the monophyly of the genus and distinguishing it from closely related taxa in the tribe Ruteae, such as Haplophyllum and Dictamnus. These studies, conducted in the early 21st century, have clarified phylogenetic relationships and supported the reduction of some provisional species to synonyms by highlighting genetic uniformity across populations previously considered distinct. For instance, plastome analyses have further corroborated these findings, emphasizing low interspecific divergence in the Mediterranean-centered radiation of Ruta. Intraspecific variability in Ruta is pronounced, particularly in R. graveolens, where leaf shape exhibits polymorphisms attributed to environmental stress, such as in Mediterranean habitats, leading to more dissected or forms in drier sites. Cytogenetic studies reveal a consistent diploid number of 2n=36 across most , providing a stable chromosomal base despite . Clinal variation is evident in Mediterranean populations of R. graveolens and R. chalepensis, with gradual shifts in leaf and oil content correlating with and gradients. Subspecies and varieties further illustrate this variability; for example, R. graveolens includes var. graveolens (the typical Mediterranean form) and var. angustifolia (with narrower leaves), while historical populations have been noted as var. anglica due to localized adaptations. The former R. patavina L., now reclassified as Haplophyllum patavinum (L.) G.Don fil., represents an endangered micro-endemic restricted to relic habitats in northeastern 's , where threatens its persistence.

Cultivation

Propagation techniques

Ruta plants, particularly , can be propagated through several methods, including , vegetative cuttings, division, and , to facilitate and . Seed propagation involves sowing fresh in directly into well-draining or seed trays, as viability decreases rapidly after harvest. typically occurs within 2-3 weeks at temperatures of 15-20°C, with rates around 75-85% under optimal conditions, requiring exposure so seeds should not be deeply covered. Scarification is unnecessary, though cold stratification at 4-5°C for 2-4 weeks can improve uniformity in some cases; seedlings are ready for transplanting after 8-10 weeks when they have developed true leaves. Vegetative propagation is preferred for maintaining clonal uniformity and is achieved via stem cuttings or root division. Semi-ripe stem cuttings, taken in summer from healthy shoots (4-6 inches long), root when dipped in (IBA) hormone and placed in a moist, sterile medium under high . Alternatively, established clumps can be divided in autumn, separating rooted sections with shoots and replanting immediately to minimize stress. Tissue culture techniques enable rapid multiplication and are especially useful for conserving rare Ruta species or producing disease-free stock. starts with shoot tips or nodal explants cultured on Murashige and Skoog (MS) medium supplemented with cytokinins such as (BAP) at 1-2 mg/L, yielding 4-5 shoots per explant after 4 weeks; rooting follows on hormone-free or auxin-enriched medium, with achieving over 90% survival. This method supports by maintaining genetic stability across generations. Propagation challenges include low seed viability in stored lots due to short dormancy periods and poor seed set in some species, necessitating fresh collections or vegetative alternatives. Additionally, fungal contamination risks arise during rooting of cuttings in humid environments, requiring sterile conditions and fungicide treatments to prevent damping-off.

Environmental requirements

Ruta graveolens thrives in well-drained soils, preferring sandy or loamy textures with a neutral to slightly alkaline range of 6.0 to 7.5 to support healthy root development and prevent waterlogging-induced . Moderately fertile conditions are ideal, as overly rich soils can lead to excessive vegetative growth at the expense of flowering. The plant favors Mediterranean-like climates, performing best in USDA hardiness zones 4 to 10, where it can endure full sun exposure of at least six hours daily for optimal foliage color and bloom production. It tolerates drought once established but may suffer dieback during severe winters in the coldest parts of zone 4 without winter mulching. Ideal temperatures range from 18°C to 24°C (65°F to 75°F), with good air circulation to mitigate humidity-related issues. Watering should be minimal after establishment, providing only during extended dry periods to maintain without saturation, as overwatering promotes . Fertilization is light, using low-nitrogen formulations in spring to encourage compact growth; testing can guide applications for adjustment in acidic sites. Mulching around the base helps suppress weeds and retain moisture in drier conditions. Common pests include and spider mites, which can cluster on new growth and cause distortion if populations build in hot, dry weather; organic controls like or are effective management options. Fungal diseases such as may occur in humid environments, appearing as white powdery coatings on leaves, and can be prevented through proper spacing for or treated with baking soda sprays. Overall, rue exhibits strong resistance to most and diseases when grown under suitable conditions. In ornamental contexts, Ruta graveolens adds value to herb or cottage gardens with its striking blue-green foliage and clusters of yellow flowers in summer, attracting pollinators while serving as a deer-resistant border plant.

Phytochemistry

Primary chemical constituents

The genus Ruta, particularly R. graveolens, is characterized by a diverse array of bioactive compounds, with alkaloids, coumarins, , volatile oils, , and phenolics forming the primary chemical constituents. These compounds contribute to the 's structural integrity and ecological interactions, varying in concentration across and parts. A 2024 review identified 61 alkaloids and 43 phenylpropanoids, including acridone types like arborinine and rutacridone. Alkaloids represent a major class, comprising quinoline types such as graveoline, as well as furoquinolines like skimmianine and γ-fagarine. In R. graveolens, alkaloid content typically ranges from 0.1% to 1% of dry weight, with higher levels observed in aerial parts and root cultures, reaching up to 0.16% in optimized conditions. Coumarins and are prominent phenylpropanoids, including linear psoralens such as and xanthotoxin, alongside angular forms. Furanocoumarin levels in R. graveolens average 1% of dry weight, with individual psoralens like xanthotoxin up to 0.43% and up to 0.19%, predominantly in leaves and fruits; total coumarins can reach 0.92%. Rutamarin, a linear , is also notable. These compounds show inter-origin variability, from 0.28% to 1.75% total furanocoumarins. Volatile oils constitute 0.5% to 1.5% of the material, primarily in leaves and fruits, featuring the 2-undecanone (37%–91% of oil), alongside 2-nonanone (13%–60%), (up to 8.3%), and (up to 11.9%). Yields vary by region and cultivation, from 0.06% in samples to 1.67% in Tunisian ones. and phenolics include and quercetin glycosides, with at approximately 0.05% in extracts, contributing to properties; provide astringency. Total phenolics, including , are present at levels supporting structural roles.

Biosynthesis overview

The biosynthesis of alkaloids in Ruta species, particularly quinoline alkaloids like graveoline and skimmianine in R. graveolens, originates from the pathway, which produces as a precursor to aromatic amino acids. is converted to via anthranilate synthase, a key branch-point enzyme that is upregulated in leaves under elicitor stress, directing flux toward alkaloid production rather than . Subsequent steps involve decarboxylation of derivatives and reverse prenylation with to form the quinoline ring system, as demonstrated by isotope labeling studies in R. graveolens cell cultures. Coumarin biosynthesis in Ruta, focusing on furanocoumarins such as psoralen and xanthotoxin, proceeds through the phenylpropanoid pathway starting from , which is transaminated to by . is hydroxylated to and further processed to , followed by angular closure to form the linear furan ring via a enzyme that catalyzes the cyclization of marmesin with release of acetone. The furan ring addition occurs in the , where prenyltransferases like coumarin-specific enzymes attach dimethylallyl groups to umbelliferone derivatives. Essential oil production in Ruta primarily involves aliphatic ketones and minor monoterpenes synthesized in glandular s on leaves and stems. Monoterpenes such as arise from the in the , where is converted to isopentenyl via , followed by geranyl synthase to yield C10 precursors. In contrast, the major ketone 2-undecanone is derived from elongation of , with subsequent beta-oxidation and in specialized cells, contributing up to 50-70% of the oil in R. graveolens. Environmental stresses significantly regulate biosynthesis in Ruta. and UV radiation induce furanocoumarin accumulation through activation of MYB transcription factors, which upregulate phenylpropanoid pathway genes like chalcone synthase and cytochrome P450s, enhancing levels by 2-5 fold in exposed leaves. Species variations exist, with R. montana exhibiting higher expression of furanocoumarin biosynthetic enzymes compared to R. graveolens, leading to greater yields under similar stress conditions. Analytical methods for studying these pathways include gas chromatography-mass spectrometry (GC-MS) for volatile terpenoids and ketones, which resolves components like 2-undecanone with detection limits below 0.1%, and (HPLC) coupled with UV or diode-array detection for alkaloids and coumarins, enabling quantification of derivatives at ng/g levels. Yields of secondary metabolites vary by part, with leaves typically producing 2-3 times higher concentrations of alkaloids and than flowers or roots in R. graveolens.

Uses

Medicinal applications

Ruta graveolens extracts and isolated compounds have demonstrated activity , particularly against such as and like , as well as fungi including . Graveoline, an constituent, exhibits minimum inhibitory concentrations (MICs) of 500–1000 μg/mL against S. aureus and . Essential oils from R. graveolens display potent antibacterial effects with MICs as low as 0.75–1.40 μg/mL against various pathogens and have been shown to reduce biofilms by up to 50% at sub-MIC concentrations. Compounds like and coumarins in R. graveolens contribute to and effects by reducing COX-2 expression in inflammatory models. In animal studies using carrageenan-induced paw in rats, methanolic and ethanolic extracts at 20–50 mg/kg achieved 64–91% inhibition of volume, outperforming standard drugs like in some cases. activity has been observed in models of , with extracts reducing response latency by 30–60% in and writhing tests, supporting potential for relief. The anticancer potential of R. graveolens involves graveoline, which induces in cells, triggering production and autophagic pathways. Furanocoumarins such as , , and xanthotoxin act as I inhibitors, stabilizing DNA-enzyme complexes and inhibiting cancer cell proliferation . Clinical evidence remains limited, primarily to topical applications for dermatological conditions like , with no large-scale trials for systemic anticancer use. Antioxidant activity is attributed to , a in the plant, which scavenges free radicals with an of approximately 5–10 μM in assays. Recommended dosages for extracts range from 100–500 mg/day, always under medical supervision due to potential interactions. Recent research from 2020–2025 has explored R. graveolens-derived nanoparticles for enhanced , including silver nanoparticles synthesized via leaf extracts showing improved bioavailability and targeted anticancer effects against cells. Regulatory recognition includes monographs in various jurisdictions for supportive use as a digestive , such as relief of mild gastrointestinal discomfort.

Traditional and cultural uses

In and traditions, , commonly known as rue, was valued for its medicinal properties. documented its use as an antidote to poisons, a remedy for attributed to , and a treatment for eye-related issues such as improving eyesight. praised it as one of the finest medicinal herbs, noting its ability to dispel through its heating qualities and its role as a and to promote menstrual flow. The plant also appears in biblical texts, where Luke 11:42 references rue as part of the Pharisaic alongside and other herbs, highlighting its cultural significance in ancient Judean practices. In European folk medicine, rue infusions were commonly employed to alleviate , expel intestinal worms, and soothe . It held protective symbolism, often fashioned into talismans against evil influences; in , the cimaruta—a silver amulet shaped like a sprig of rue—served to ward off the and malevolent spirits, a tradition rooted in medieval beliefs. During the Victorian period, rue earned the moniker "herb of grace" for its purifying attributes, with sprigs used in rituals to symbolize and spiritual cleansing, echoing its earlier Christian associations with sprinkling. Across the Mediterranean and , rue featured prominently in traditional healing. Historically, rue preparations were applied for various ailments, though such uses are now discouraged due to concerns. In Turkish practices, rue teas were brewed to relieve headaches and nervous . In other cultural contexts, rue found roles in Ayurvedic traditions under names like Sadapushpa or Sadapaha, where it was applied topically for skin disorders such as fungal infections and due to its properties. Following its introduction to , rue—known as ruda—integrated into syncretic spiritual practices like Mexican curanderismo, where it is burned, bathed in, or carried for energetic cleansing, protection against negativity, and fostering self-love. Symbolically, rue embodied themes of regret, repentance, and grace in literature and rituals. In Shakespeare's Hamlet, Ophelia distributes rue in her garland, calling it the "herb of grace" to signify sorrow and moral reflection. In European festivals, including some Spanish processions, rue sprigs were carried as emblems of purification and warding off misfortune.

Toxicity and safety

Toxic compounds and mechanisms

Ruta graveolens contains several toxic compounds, primarily furanocoumarins such as xanthotoxin (8-methoxypsoralen), which are responsible for phototoxicity. Upon skin contact followed by exposure to ultraviolet A (UVA) light (320-400 nm), these compounds intercalate into DNA strands and form covalent cross-links with pyrimidine bases, inhibiting mitosis and leading to cell death. This results in phytophotodermatitis, characterized by erythema, blistering, and severe burns, often appearing as linear streaks where plant sap has contacted the skin. The reaction is non-immunologic and peaks post-flowering when furanocoumarin concentrations are highest, with symptoms manifesting 24-48 hours after exposure and potentially persisting as hyperpigmentation for months. Alkaloids in Ruta, including graveoline, contribute to hepatotoxicity by inhibiting cytochrome P450 (CYP450) enzymes, disrupting and leading to in liver cells. At high doses, these alkaloids induce , manifesting as tremors, , incoordination, and hallucinations due to and interference with neurotransmitter pathways. Additionally, Ruta exhibits effects through stimulated by compounds like methyl-nonyl-ketone, causing pelvic congestion, hemorrhage, and pregnancy termination. Other risks include skin irritation from 2-undecanone, a volatile in the , which provokes direct independent of exposure. Chronic ingestion of Ruta extracts can lead to cumulative liver and damage via sustained CYP450 inhibition and nephrotoxic accumulation. In , the LD50 for aqueous extracts is approximately 620 mg/kg, indicating moderate . Mechanisms of toxicity extend to (ROS) generation by coumarins under UV activation, exacerbating cellular damage through and protein oxidation. Alkaloids also inhibit (P-gp), a key efflux transporter, potentially causing drug interactions by increasing of co-administered substrates and elevating risks. Ruta constituents may accumulate in , posing potential teratogenic risks to infants based on the plant's known embryotoxicity in and general systemic . Documented human poisonings include cases of abortion and miscarriage following consumption of Ruta teas, with reports describing severe gastrointestinal distress, hemorrhage, and fetal loss after intentional use as an abortifacient. Veterinary toxicity is evident in livestock, particularly , where oral doses of 5 g/kg body weight daily caused tremors, dyspnea, frequent urination, , recumbency, and death within 1-7 days, accompanied by hepatic and renal lesions.

Precautions and contraindications

When handling , protective measures are essential to prevent , a severe reaction triggered by contact with the plant's furocoumarins followed by . Individuals should wear gloves and long sleeves during pruning, harvesting, or any direct contact with the foliage to minimize absorption of these compounds. After any application or , avoid direct sunlight for at least 24-48 hours, as the latency period for phototoxic reactions can extend up to this duration, potentially leading to painful blisters and . Extracts and oils should be stored in opaque containers away from to preserve stability and reduce degradation of photosensitizing constituents. Ruta graveolens is contraindicated in several populations due to its potent and properties, which can induce and . Pregnant and individuals must avoid it entirely, as it poses significant risks to fetal development and may pass into , potentially causing harm to infants. Those with pre-existing liver or disorders should not use it, as it can exacerbate damage through and , leading to elevated liver enzymes or renal failure in severe cases. Use is also contraindicated in children under 12 years, given the lack of safety and reports of mutagenic and systemic toxic effects even at therapeutic doses. Individuals with photosensitive conditions, such as systemic , should avoid exposure, as the plant's furocoumarins can intensify UV-induced flares and skin damage. Dosage guidelines for are limited by insufficient clinical evidence, emphasizing caution to avoid toxicity. For internal use, traditional recommendations suggest no more than 500 mg to 1 g of dried three times daily for short-term periods, but exceeding this can cause gastrointestinal distress, spasms, and organ damage; modern sources advise against oral consumption altogether due to s. Topical applications should be highly diluted, typically in creams or oils at concentrations below 1% to reduce , and always followed by sun avoidance. Potential interactions include enhanced when combined with medications like tetracyclines, NSAIDs, or other photosensitizers, necessitating protective measures. Although no direct interactions with via inhibition are well-documented for , caution is advised with anticoagulants due to general reports of altered from emmenagogues. Regulatory bodies classify as unsafe for internal medicinal use in many contexts. The U.S. (FDA) does not approve it as a and considers it potentially hazardous, recommending external use only while urging reporting of adverse events through MedWatch; it is not classified as (GRAS) for therapeutic doses beyond food amounts. The () issues warnings against internal consumption due to risks, limiting it to traditional external applications under . As of March 2025, the Australian () requires warnings against use in pregnancy or lactation for homoeopathic preparations and notes increased risk for dermal applications. In , some EU countries prohibit grazing on for , as it causes and in animals like sheep and . In cases of phototoxicity from skin contact, immediate first aid includes washing the affected area with soap and cool water, applying cool compresses to reduce , and using topical corticosteroids if blisters form; severe reactions may require medical evaluation for systemic symptoms. For ingestion, seek emergency medical help promptly; initial management may involve activated charcoal to adsorb toxins if presentation is within 1-2 hours, followed by monitoring for gastrointestinal, hepatic, and renal effects.