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Rue

Scientific Name(s): Ruta bracteosa L., Ruta chalepensis L., Ruta graveolens L., Ruta montana L.
Common Name(s): Common rue, Fringed rue, Garden rue, German rue, Herb of Grace, Meadow rue, Rue

Clinical Overview

Use

Rue extract is potentially useful as a potassium channel blocker. It has been used to treat many neuromuscular problems and to stimulate the onset of menstruation. Because rue has an antispasmodic effect at relatively low doses, it should be taken with caution. However, considering rue's potential for severe adverse effects, clinical trials are limited.

Dosing

There is no recent clinical evidence to support dosing recommendations for rue. Traditional use calls for 0.5 to 1 g of the herb daily or 65 mg of the essential oil. In larger doses, rue is an emmenagogue, an aphrodisiac, and an abortifacient, and should be considered dangerous.

Contraindications

Contraindications have not yet been identified.

Pregnancy/Lactation

Documented adverse effects, including emmenagogue and abortifacient effects. Avoid use.

Interactions

None well documented.

Adverse Reactions

Rue extracts are mutagenic and furocoumarins have been associated with photosensitization. If ingested, rue oil may result in kidney damage and hepatic degeneration. Large doses can cause violent gastric pain, vomiting, and systemic complications, including death. Because of possible abortifacient effects, the plant should never be ingested by women of childbearing potential. Toxic hepatitis due to Ruta has been reported.

Toxicology

Rue should only be taken with extreme caution. A case report describes multiorgan toxicity in a 78-year-old woman ingesting R. graveolens for cardiovascular protection. After 3 days of use, the patient entered the emergency department with bradycardia, acute renal failure with hyperkalemia necessitating hemodialysis, and coagulopathy.

Botany

Rue is native to Europe but is now cultivated worldwide. It is often found growing along roadsides and in waste areas. An herbaceous evergreen half-shrub that grows to 61 cm in height, the leaves have a feathery appearance and are green or blue-green. Its flowers are yellow with petals that are 1 cm in diameter.1 The plant is ornamental and medicinal.2

History

The leaves, extracts, and other parts of rue have been used for hundreds of years as an insect repellent. In folk medicine, rue has been used as an antispasmodic, sedative, and stimulant for the onset of menses. In some cultures, rue extracts have been used as abortifacients.3

In Mediterranean traditional medicine, Ruta has been used to treat pulmonary conditions, such as tuberculosis, and to reduce swelling of the spleen, as well as externally to treat wounds.4

In New Mexico, rue has been used as a tisane (tea) for ailments such as stiff neck, dizziness, headache, tightness in the stomach, and inner ear problems. The oil has a strong, bitter taste and has been used for the treatment of intestinal worms.

Roman naturalist Pliny the Elder (23 to 79 AD) mentions 84 remedies containing rue.5 Aside from its use as an abortifacient, rue was also used in ancient Greece and Egypt to strengthen eyesight.2

Chemistry

Rue has been studied extensively.6 Common rue contains a mixture of furoquinoline alkaloids in a concentration of approximately 1.5%, the most important of which appear to be arborine, arborinine, and gamma-fagarine.7, 8

The acridone alkaloids (rutacridone epoxide, hydroxyrutacridone epoxide) are found in greatest concentration in the roots.9 Other alkaloids include graveoline, graveolinine, kokusaginine, rutacridone, and skimmianine. The flavonoid rutin is also present in the plant and is said to support and strengthen blood vessels, which reduces pressure.2, 5

A volatile oil is present in a concentration of approximately 0.1%. The oil is 90% methyl-nonylketone with the balance composed of related ketones, esters, and phenols.10

The plant and its oil are rich in coumarin derivatives, which appear to contribute to the pharmacologic activity of the plant. These furocoumarins include bergapten, psoralen, xanthoxanthin, xanthotoxin, isopimpinellin, and rutamarin.2, 5, 11 Isolation of such furocoumarins has been performed using an improved extraction technique.12 Other reports have described isolation of the alkaloid isogravacridonchlorine from rue roots13; identification of dihydropyrano- and dihydrofuro-3, 5, 6, 7, 8 quinolinium alkaloids14; and purification of acridone synthase from rue cell cultures.15

Uses and Pharmacology

Cardiovascular and antioxidant effects

R. graveolens extract has been studied as a potential potassium channel blocker of ionic currents in myelinated nerve cells.16

Animal data

In isolated rat hearts treated with R. graveolens extract, a concentration-dependent effect increase was seen in atviroventricular-conduction time, Wenckebach cycle length, and effective and functional refractory periods.17 Rats given a methanolic extract of R. graveolens 20 mg/kg/day for 90 days were found to have lower total cholesterol, low-density lipoprotein levels, and atherogenic indices. Additionally, high-density lipoprotein levels increased in rats given R. graveolens. Oxidative stress and inflammation measures were also reduced.18

Clinical data

In a study of 56 patients with colorectal cancer (34 with early stage and 22 with advanced stage), R. chalepensis was found to protect erythrocytes from oxidative stress caused by radicals. Specifically, this effect was noted in patients with early-stage colorectal cancer and was not observed with advanced disease.19

Other uses

Rue has been used to treat many ailments, including epilepsy, eye strain, multiple sclerosis, Bell palsy, and heart conditions. It has also been used as a uterine stimulant to encourage onset of menstruation.2, 5 In South Africa, it has been used to treat hysteria.20

Antispasmodic effects

The rue plant and its extracts, in particular the tea and oil, have been reported to have antispasmodic effects on smooth muscles. This pharmacologic action has been attributed to the alkaloids arborine and arborinine and to the coumarins, in particular rutamarin. While the pharmacologic half-life of arborinine is about the same as that of papaverine, the half-life of rutamarin is approximately 20 times longer. These spasmolytic effects have also been observed in isolated GI smooth muscle.6

One study found the spasmolytic effect of arborinine on pig coronary muscle to be as potent as that of papaverine, while rutamarin was 20-fold more potent than papaverine. The antispasmodic effects of these compounds were reversible.

Antifertility

The abortifacient effects of rue teas and oil are well documented. The abortifacient effect may be due to an anti-implantation action2 or to a generalized state of systemic toxicity resulting in fetal death.10

Antifertility action of R. graveolens has been reported in rats.21, 22 In 1 report, chalepensin was found to be the active component, acting at early stages of pregnancy.21

Anti-inflammatory effects

In a murine model, R. graveolens was found to exert anti-inflammatory activity as well as reduce edema in affected arthritic paws. Particularly, it was the alkaloid fraction of R. graveolens given at a dose of 10 mg/kg that demonstrated a larger anti-inflammatory effect as compared with the polyphenolic fraction and diclofenac.23

R. graveolens was found to suppress the production of nitric oxide from lipopolysaccharide in murine macrophage cells, suggesting potential anti-inflammatory activity.24

Antibacterial/Antifungal activity

More than 15 compounds in rue have been identified as having in vitro antibacterial and antifungal activity.8 The acridone alkaloids are the most potent antimicrobial compounds; the coumarins inhibit growth only at high doses. The essential oil and flavonoids tested did not show activity. One report suggests that extracts of R. graveolens demonstrated inhibitory effects against gram positive organisms such as Staphylococcus aureus, Streptococcus pyogenes, Listeria monocytogenes, and Bacillus subtilis.25 Other researchers have found that a number of components of rue interfere directly with DNA replication, thereby preventing the propagation of some viruses.26 The leaf of rue is said to alleviate cancer of the mouth, as well as tumors and warts. In Chinese medicine, rue is used as a vermifuge and for insect bites.2, 5 Experimentation in H. pylori-infected gastric epithelial cells with 24 medicinal plants indigenous to Pakistan was conducted to evaluate their effect on secretion of interleukin (IL)-8 and generation of reactive oxygen species (ROS) in order to assess anti-inflammatory and cytoprotective effects. Although no significant direct cytotoxic effects on the gastric cells or bactericidal effects on H. pylori were found, leaf extract of rue was observed to have moderate and strong inhibitory activity on IL-8 at 50 and 100 mcg/mL, respectively, in H. pylori-infected gastric cells.42

Dosing

There is no clinical evidence to support dosing recommendations for rue. Traditional use calls for 0.5 to 1 g of the herb daily or 65 mg of the essential oil. In larger doses, rue is an emmenagogue, aphrodisiac, and an abortifacient, and should be considered dangerous.27

Pregnancy / Lactation

Documented adverse effects, including emmenagogue and abortifacient effects.28, 29 Avoid use.

Interactions

None well documented.

Adverse Reactions

Because the antispasmodic effect of this plant occurs at relatively small doses, rue should only be taken with extreme caution. The safety of the plant in pregnant women has not been established, and most of the literature describing its potential abortifacient effects indicates that the plant should never be ingested by women of childbearing potential.2, 5

Psoralens from rue that have come in contact with skin and exposed to ultraviolet A light are responsible for photodermatitis.30 Several case reports of photodermatitis following R. graveolens have been reported.1, 30, 31 One case report describes the presence of blisters and erythema in a 48-year-old woman who used an infusion of R. graveolens for the management of fibromyalgia. She had been exposed to the sun and subsequently developed vesicles and erythema in the center and lateral areas of the back. She was treated with corticosteroids, antibiotics and analgesics, and the lesions disappeared within 2 weeks.31 Another case report describes a 2-year-old child with erythema and blistering of the lower half of his face and hands following exposure to rue while playing in his family's garden.1

In albino male rats, R. graveolens L. 500 mg/kg for 60 days caused a decrease in the weight of reproductive organs, sperm motility, spermatogenesis, number of spermatocytes and spermatids, and the number of impregnated female rats.32 In a study of human sperm, a dose-dependent effect was noted on the immobilization of sperm, with the minimum effective dose determined to be 100 mg/mL.33

Toxic hepatitis due to Ruta has been reported.34

The volatile oil has an irritant quality; it may result in kidney damage and hepatic degeneration if ingested.10

Toxicology

Extracts of rue have been found to be mutagenic in experimental mutagenicity screens, but the clinical importance of these findings has not been established.35, 36

The toxicity of the dried leaves is most likely less than that of the fresh leaves because of the loss of volatile oil.37, 38 A tincture of R. graveolens exhibited marked photomutagenicity of varying degrees based on various alkaloid concentrations present in the compound.39

Large doses (more than 100 mL of the oil or approximately 120 g of the leaves in 1 dose) can cause violent gastric pain, vomiting, and systemic complications, including death. A single oral dose of 400 mg/kg given to guinea pigs was fatal because of hemorrhages of the adrenal gland, liver, and kidney. However, a daily oral dose of 30 mg given to human subjects for 3 months did not result in abnormal hepatic function.40

A case report describes multiorgan toxicity in a 78-year-old woman ingesting R. graveolens for cardiovascular protection. After 3 days of use, the patient entered the emergency department with bradycardia, acute renal failure with hyperkalemia necessitating hemodialysis, and coagulopathy.41

References

1. Furniss D, Adams T. Herb of grace: an unusual cause of phytophotodermatitis mimicking burn injury. J Burn Care Res. 2007;28(5):767-769.17667834
2. Chevallier A. The Encyclopedia of Medicinal Plants. New York, NY: DK Publishing; 1996:262-263.
3. Conway GA, Slocumb JC. Plants used as abortifacients and emmenagogues by Spanish New Mexicans. J Ethnopharmacol. 1979;1(3):241-261.232204
4. Pollio A, De Natale A, Appetiti E, Aliotta G, Touwaide A. Continuity and change in the Mediterranean medical tradition: Ruta spp. (rutacecae) in Hippocratic medicine and present practices. J Ethnopharmacol. 2008;116(3):469-482.18276094
5. Duke J. CRC Handbook of Medicinal Herbs. Boca Raton, FL: CRC Press; 1989:417-418.
6. Minker E, Bartha C, Koltai M, Rózsa Z, Szendrei K, Reisch J. Effect of secondary substances isolated from the Ruta graveolens L. on the coronary smooth muscle. Acta Pharm Hung. 1980;50(1):7-11.7361557
7. Tyler VE. The New Honest Herbal: A Sensible Guide to the Use of Herbs and Related Remedies. Philadelphia, PA: GF Stickley Co; 1987.
8. Wolters B, Eilert U. Antimicrobial substances in callus cultures of Ruta graveolens. Planta Med. 1981;43(2):166-174.7312985
9. Verzár-Petri G, Csedö K, Möllmann K, Szendrei K, Reisch J. Fluorescence microscopic investigations on the localisation of acridone alkaloids in the organs of Ruta graveolens [in German]. Planta Med. 1976;29(4):370-375.959379
10. Spoerke DG. Herbal Medications. Santa Barbara, CA: Woodbridge Press; 1980.
11. Haesen JP, Vörde Sive Vörding JG, Kho KF. Isolation and identification of xanthotoxin from the underground parts of Ruta graveolens. Planta Med. 1971;19(3):285-289.5546269
12. Zobel AM, Brown SA. Determination of furanocoumarins on the leaf surface of Ruta graveolens with an improved extraction technique.J Nat Prod. 1988;51(5):941-946.21401190
13. Paulini H, Popp R, Schimmer O, Ratka O, Röder E. Isogravacridonchlorine: a potent and direct acting frameshift mutagen from the roots of Ruta graveolens. Planta Med. 1991;57(1):59-61.2062959
14. Montagu M, Petit-Paly G, Levillain P, et al. Synchronous fluorescence spectrometry and identification of dihydrofuro[2,3-b]quinolinium alkaloids biosynthesized by Ruta graveolens cultures in vitro. Pharmazie. 1989;44:342-344.
15. Baumert A, Maier W, Gröger D, Deutzmann R. Purification and properties of acridone synthase from cell suspension cultures of Ruta graveolens L. Z Naturforsch C. 1994;49(1-2):26-32.8148006
16. Bethge EW, Bohuslavizki KH, Hänsel W, Kneip A, Koppenhöfer E. Effects of some potassium channel blockers on the ionic currents in myelinated nerve. Gen Physiol Biophys. 1991;10(3):225-244.1916219
17. Khori V, Nayebpour M, Semnani S, Golalipour MJ, Marjani A. Prolongation of AV nodal refractoriness by Ruta graveolens in isolated rat hearts. Potential role as an anti-arrhythmic agent. Saudi Med J. 2008;29(3):357-363.18327359
18. Ratheesh M, Shyni GL, Sindhu G, Helen A. Inhibitory effect of Ruta graveolens L. on oxidative damage, inflammation and aortic pathology in hypercholesteromic rats. Exp Toxicol Pathol. 2011;63(3):285-290.20163942
19. Acquaviva R, Iauk L, Sorrenti V, et al. Oxidative profile in patients with colon cancer: effects of Ruta chalepensis L. Eur Rev Med Pharmacol Sci. 2011;15(2):181-191.21434485
20. Stafford GI, Pedersen ME, van Staden J, Jäger AK. Review on plants with CNS-effects used in traditional South African medicine against mental diseases. J Ethnopharmacol. 2008;119(3):513-537.18775771
21. Kong YC, Lau CP, Wat KH, et al. Antifertility principle of Ruta graveolens. Planta Med. 1989;55(2):176-178.2748734
22. Gandhi M, Lal R, Sankaranarayanan A, Sharma PL. Post-coital antifertility action of Ruta graveolens in female rats and hamsters. J Ethnopharmacol. 1991;34(1):49-59.1753787
23. Ratheesh M, Shyni GL, Sindhu G, Helen A. Protective effects of isolated polyphenolic and alkaloid fractions of Ruta graveolens L. on acute and chronic models of inflammation. Inflammation. 2010;33(1):18-24.19777330
24. Raghav SK, Gupta B, Agrawal C, Goswami K, Das HR. Anti-inflammatory effect of Ruta graveolens L. in murine macrophage cells. J Ethnopharmacol. 2006;104(1-2):234-239.16207519
25. Ivanova A, Mikhova B, Najdenski H, Tsvetkova I, Kostova I. Antimicrobial and cytotoxic activity of Ruta graveolens. Fitoterapia. 2005;76(3-4):344-347.15890462
26. Novák I, Buzás G, Minker E, Koltai M, Szendrei K. Isolation of some effective substance from the herb of Ruta graveolens L. [ in Hungarian]. Acta Pharm Hung. 1967;37(3):130-141.6062200
27. Gruenwald, et al, eds. PDR for Herbal Medicines. 2nd ed. Montvale, NJ: Medical Economics Company; 2000:649.
28. Brinker FJ. Herb Contraindications and Drug Interactions. 2nd ed. Sandy, OR: Eclectic Medical Publications; 1998.
29. Ernst E. Herbal medicinal products during pregnancy: are they safe?BJOG. 2002;109(3):227-235.11950176
30. Eickhorst K, DeLeo V, Csaposs J. Rue the herb: Ruta graveolens—associated phytophototoxicity. Dermatitis. 2007;18(1):52-55.17303046
31. Arias-Santiago SA, Fernández-Pugnaire MA, Almazán-Fernández FM, Serrano-Falcón C, Serrano-Ortega S. Phytophotodermatitis due to Ruta graveolens prescribed for fibromyalgia. Rheumatology (Oxford). 2009; 48(11):1401.19671699
32. Khouri NA, El-Akawi Z. Antiandrogenic activity of Ruta graveolens L in male albino rats with emphasis on sexual and aggressive behavior. Neuro Endorcrinol Lett. 2005;26(6):823-829.16380694
33. Harat ZN, Sadeghi MR, Sadeghipour HR, Kamalinejad M, Eshraghian MR. Immobilization effect of Ruta graveolens L. on human sperm: a new hope for male contraception. J Ethnopharmacol. 2008;115(1):36-41.18029123
34. Rabaev E, Zeller L, BIton A, Barski L. Toxic hepatitis due to the use of Ruta herbal medicine [in Hebrew]. Harefuah. 2011;150(3):235-236, 305.21574354
35. Paulini H, Eilert U, Schimmer O. Mutagenic compounds in an extract from rutae herba (Ruta graveolens L.), I: mutagenicity is partially caused by furoquinoline alkaloids. Mutagenesis. 1987;2(4):271-273.3325757
36. Paulini H, Schimmer O. Mutagenicity testing of rutacridone epoxide and rutacridone, alkaloids in Ruta graveolens L., using the Salmonella /microsome assay. Mutagenesis. 1989;4(1):45-50.2654551
37. Heskel NS, Amon RB, Storrs FJ, White CR Jr. Phytophotodermatitis due to Ruta graveolens. Contact Dermatitis. 1983;9(4):278-280.6617186
38. Ortiz-Frutos FJ, Sanchez B, Garcia B, Iglesias L, Sanchez-Mata D. Photocontact dermatitis from rue (Ruta montana L.). Contact Dermatitis. 1995;33(4):284.8654097
39. Schimmer O, Kühne I. Mutagenic compounds in an extract from Rutae Herba (Ruta graveolens L.), II: UV-A mediated mutagenicity in the green alga Chlamydomonas reinhardtii by furoquinoline alkaloids and furocoumarins present in a commercial tincture from Rutae Herba. Mutat Res. 1990;243(1):57-62.2300085
40. Leung AY. Encyclopedia of Common Natural Ingredients Used in Food, Drugs and Cosmetics. New York, NY: Wiley; 1980.
41. Seak CJ, Lin CC. Ruta graveolens intoxication. Clin Toxicol (Phila). 2007;45(2):173-175.17364636
42. Zaidi SF, Muhammad JS, Shahryar S, et al. Anti-inflammatory and cytoprotective effects of selected Pakistani medicinal plants in Helicobacter pylori-infected gastric epithelial cells. J Ethnopharmacol. 2012;141(1):403-410.22433535

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