Scientific Name(s): Symphytum officinale L., S. asperum Lepechin, S. tuberosum L., Symphytum x uplandicum Nyman. Family: Boraginaceae (Borage)
Common Name(s): Comfrey , bruisewort , blackwort , knitbone , radix consolidate , Russian comfrey , slippery root
Uses of Comfrey
Therapeutic use of comfrey is limited because of its toxicity. A limited number of clinical trials show short-term efficacy of topically applied, alkaloid-free comfrey preparations in skin abrasions and inflammatory conditions. Although not examined in clinical trials, comfrey may possess antifungal and anticancer activity.
Oral use of comfrey is not supported because of potential hepatotoxicity. Additionally, because externally applied alkaloids are well absorbed and detected in the urine, topical use of comfrey should not exceed an alkaloid exposure of 100 mcg/day. Limited trials have evaluated the efficacy of alkaloid-free preparations for topical use; however, these studies do not report on hepatic laboratory indices of study participants.
Comfrey is not recommended for internal use because of the hepatotoxic pyrrolizidine alkaloid content. Patients with hypersensitivity or allergic reactions to the plant should avoid external use. Use is contraindicated during pregnancy and lactation, in infants, and in patients with liver or kidney disease.
Contraindicated because of documented adverse effects. Pyrrolizidine alkaloids have abortifacient effects and increase the risk of fatal hepatic veno-occlusive disease. Animal experiments have detected alkaloids in breast milk.
None well documented.
Comfrey Adverse Reactions
Neither internal nor extensive topical use of comfrey is recommended because of numerous reports of liver toxicity (see Toxicology). Case reports show hepatic veno-occlusive disease and pulmonary hypertension related to comfrey use. Infants are more susceptible to pyrrolizidine-related, veno-occlusive disease; therefore, the use of comfrey in this population is contraindicated.
The Food and Drug Administration (FDA) released an advisory in July 2001 recommending that comfrey products be removed from the market because of cases of hepatic veno-occlusive disease. Comfrey is generally considered unsafe, with numerous toxicological effects in animals and humans.
Comfrey is a perennial plant found in moist grasslands in western Asia, as well as in North America. It grows to heights of 50 to 150 cm and has long, hairy lanceolate leaves and bell-shaped, red-violet or yellowish flowers. S. x uplandicum Nyman is a hybrid of S. officinale and S. asperum , and has been cultivated to contain insignificant amounts of alkaloids in the aerial parts of the plant. 1 , 2 , 3
Comfrey has been cultivated in Japan as a green vegetable and has been used as an herbal medicine for more than 2,000 years. Comfrey's original name, knitbone, derives from the external use of poultices of its leaves and roots to heal burns, sprains, swelling, and bruises. In Western Europe, comfrey has been used topically for treating inflammatory disorders such as arthritis, gout, and thrombophlebitis, and internally for treating diarrhea. Comfrey has been claimed to heal gastric ulcers and hemorrhoids, and to suppress bronchial congestion and inflammation. Comfrey distribution is restricted in Germany and Canada because of its substantial toxicity. 2 , 4
Numerous hepatotoxic pyrrolizidine alkaloids with differing toxicities have been identified in the plant, including symphytine, echimidine, intermedine, symviridine, and lasiocarpine (retronecine mono- and diester alkaloids). Roots contain a 100-fold higher alkaloid content than the aerial portions. 2 , 5 , 6
The healing action of poultices of comfrey roots and leaves may be related to the presence of allantoin. The underground roots contain allantoin 0.6% to 0.7% and tannin 4% to 6.5%; the leaves contain a higher proportion of tannin relative to allantoin. The roots also contain rosmarinic and lithspermic acid. 7 , 8 , 9 , 10
Comfrey Uses and Pharmacology
The therapeutic use of comfrey is due in part to allantoin and rosmarinic acid content, but it is limited by the toxicity of pyrrolizidine alkaloids. 4 Controlled cultivation of S. x uplandicum is said to produce a plant devoid of the toxic alkaloids in the aerial plats, enabling the production of relatively nontoxic comfrey preparations. 3 Pyrrolizidine alkaloid-free preparations of comfrey have been used in clinical studies in Germany.Inflammation
A limited number of clinical trials have been conducted to assess the efficacy of topically applied, alkaloid-free comfrey preparations in ankle sprains, osteoarthritic knee conditions, and back pain/myalgia. 13 , 14 Outcome measures include patient assessment of pain and mobility, as well as measures of ankle swelling and clinician evaluations. Most studies show a statistically significant advantage of active preparation over placebo in the short term; however, because many of these trials have been conducted by product manufacturers, the possibility of publishing bias exists. 3 , 11 , 12 , 14 , 15 , 16 Other open-label or single-blind trials with topical comfrey preparations have been conducted; however study design limits the validity of the results. 17 , 18 , 19 Preparations generally contained a 35% liquid root extract from which toxic alkaloids were removed and standardized to allantoin 0.2% to 0.5%, 11 , 12 , 15 , 19 or to a preparation with 10% extract of S. x uplandicum aerial parts. 3 , 16 Duration of use ranged from 5 days to 3 weeks in these studies. The studies report no adverse effects, although liver function test results were not reported.
The use of a dermal preparation of comfrey derived from alkaloid-free cultivars of S. x uplandicum has been studied in limited clinical trials. Applied to fresh abrasions, a 10% preparation showed faster decreases in wound size and shorter times to healing, with no cutaneous reactions to the preparation reported. 3 , 22 The preparations were applied to the skin over short time periods (days) only. Efficacy in wound healing may be related to the presence of allantoin, rosmarinic acid, or another hydrocolloid polysaccharide. 23 , 24Other effects
Aqueous extracts from comfrey leaves strongly inhibited plant pathogenic fungi, most likely because of the plant's phenolic compounds. 25Cancer
Lithospermic acid isolated from the root appears to have antigonadotropic activity. 9
The oral use of comfrey cannot be supported because of potential hepatotoxicity. Because externally applied alkaloids are well absorbed (detected in the urine), topical use of comfrey should not exceed an alkaloid exposure of 100 mcg/day. 2
Limited trials have evaluated the efficacy of alkaloid-free preparations for topical use; however, these studies do not report on hepatic laboratory indices of the participants.
Avoid use because of documented adverse effects. Pyrrolizidine alkaloids have abortifacient effects and increase the risk of fatal hepatic veno-occlusive disease. 30 , 31 , 32 An extract of S. officinale has been reported to enhance uterine tone. 33 Animal experiments have detected comfrey alkaloids in breast milk. 34 , 35
Case reports are lacking. Experimental evidence exists of the potentiation of toxicity of comfrey's alkaloids by phenobarbital via the cytochrome P450 pathway. 2
Neither internal nor extensive topical use of comfrey can be recommended because of numerous reports of liver toxicity (see Toxicology). Case reports show hepatic veno-occlusive disease and pulmonary hypertension related to comfrey use. 2 , 36 Infants are more susceptible to pyrrolizidine-related, veno-occlusive disease; therefore, the use of comfrey in this population is contraindicated. 2
The FDA released an advisory in July 2001 recommending that comfrey products be removed from the market following several cases of hepatic veno-occlusive disease in which the destruction or obliteration of small hepatic veins led to cirrhosis and, eventually, liver failure. Also in 2001, the Federal Trade Commission brought enforcement action against a company marketing comfrey-containing products. The parties agreed to a preliminary injunction that prohibited the company from marketing any comfrey-containing products intended for internal use or use on open wounds, as well as requiring a warning on comfrey products intended for external use. 37 , 38 , 39 , 40 , 41 , 42 , 43
Human poisonings with pyrrolizidine alkaloids are usually accidental and may be caused by ingestion of contaminated flour, milk, certain goat products that are resistant to the alkaloids, honey produced by bees fed on pyrrolizidine-containing weeds, and consumption of certain herbal or bush teas. It also may be caused by comfrey used in salads. 4 , 5 , 34 , 35Carcinogenicity
S. officinale extract and components lasiocarpine and symphytine are carcinogenic in rats, possibly via genotoxic mechanisms 44 , 45 , 46 , 47 ; however, an association of comfrey consumption with cancer in humans is lacking. 2
A pyrrolizidine alkaloid-free liquid extract of comfrey root was not mutagenic when tested by the bacterial reverse mutation assay. 48
Bibliography1. Symphytum officinale L. USDA, NRCS. 2007. The PLANTS Database ( http://plants.usda.gov , December 2009). National Plant Data Center, Baton Rouge, LA 70874-4490 USA.
2. Stickel F, Seitz HK. The efficacy and safety of comfrey. Public Health Nutr . 2000;3(4a):501-508.
3. Kucera M, Barna M, Horàcek O, Kàlal J, Kucera A, Hladìkova M. Topical symphytum herb concentrate cream against myalgia: a randomized controlled double-blind clinical study. Adv Ther . 2005;22(6):681-692.
4. Stewart MJ, Steenkamp V. Pyrrolizidine poisoning: a neglected area in human toxicology. Ther Drug Monit . 2001;23(6):698-708.
5. Rode D. Comfrey toxicity revisited. Trends Pharmacol Sci . 2002;23(11):497-499.
6. Furuya T, Hikichi M. Alkaloids and triterpenoids of Symphytum officinale . Phytochemistry . 1971;10(9):2217-2220.
7. Tyler VE. The Honest Herbal . 3rd ed. New York, NY: Pharmaceutical Press; 1972.
8. Mutterlein R, Arnorld CG. Investigations concerning the content and the pattern of pyrrolizidine alkaloids in Symphytum officinale L. (comfrey). Pharm Ztg Wiss . 1993;138(5/6):119-125.
9. Wagner H, Hörhammer L, Frank U. Lithospermic acid, the antihormonally active principle of Lycopus europaeus L. and Symphytum officinale 3. Ingredients of medicinal plants with hormonal and antihormonal-like effect [in German]. Arzneimittelforschung . 1970;20(5):705-713.
10. Ahmad VU, Noorwala M, Mohammad FV, Sener B. A new triterpene glycoside from the roots of Symphytum officinale . J Nat Prod . 1993;56(3):329-334.
11. Koll R, Buhr M, Dieter R, et al. Efficacy and tolerance of a comfrey root extract (Extr. Rad. Symphyti) in the treatment of ankle distorsions: results of a multicenter, randomized, placebo-controlled, double-blind study. Phytomedicine . 2004;11(6):470-477.
12. Giannetti BM, Staiger C, Bulitta M, Predel HG. Efficacy and safety of comfrey root extract ointment in the treatment of acute upper or lower back pain: results of a double-blind, randomised, placebo controlled, multicentre trial. Br J Sports Med . 2010;44(9):637-641.
13. Bleakley CM, McDonough SM, MacAuley DC. Some conservative strategies are effective when added to controlled mobilisation with external support after acute ankle sprain: a systematic review. Aust J Physiother . 2008;54(1):7-20.
14. Petersen G, Lorkowski G, Kasper FR, Gottwold R, Lucker PW. Anti-inflammatory activity of a pyrrolizidine alkaloid-free extract of roots of Symphytum officinale in humans. Planta Med . 1993;59(51):A703-A704.
15. Grube B, Grünwald J, Krug L, Staiger C. Efficacy of a comfrey root (Symphyti offic. radix) extract ointment in the treatment of patients with painful osteoarthritis of the knee: results of a double-blind, randomised, bicenter, placebo-controlled trial. Phytomedicine . 2007;14(1):2-10.
16. Kucera M, Barna M, Horácek O, Kováriková J, Kucera A. Efficacy and safety of topically applied Symphytum herb extract cream in the treatment of ankle distortion: results of a randomized controlled clinical double blind study. Wien Med Wochenschr . 2004;154(21-22):498-507.
17. Koll R, Klingenburg S. Therapeutic characteristance and tolerance of topical comfrey preparations. Results of an observational study of patients [in German]. Fortschr Med Orig . 2002;120(1):1-9.
18. Kucera M, Kálal J, Polesná Z. Effects of Symphytum ointment on muscular symptoms and functional locomotor disturbances. Adv Ther . 2000;17(4):204-210.
19. Predel HG, Giannetti B, Koll R, Bulitta M, Staiger C. Efficacy of a comfrey root extract ointment in comparison to a diclofenac gel in the treatment of ankle distortions: results of an observer-blind, randomized, multicenter study. Phytomedicine . 2005;12(10):707-714.
20. Tunón H, Olavsdotter C, Bohlin L. Evaluation of anti-inflammatory activity of some Swedish medicinal plants. Inhibition of prostaglandin biosynthesis and PAF-induced exocytosis. J Ethnopharmacol . 1995;48(2):61-76.
21. Dolganiuc A, Radu LD, Olinescu A. The effect of products of plant and microbial origin on phagocytic function and on the release of oxygen free radicals by mouse peritoneal macrophages [in Romanian]. Bacteriol Virusol Parazitol Epidemiol . 1997;42(1-2):65-69.
22. Barna M, Kucera A, Hladícova M, Kucera M. Wound healing effects of a Symphytum herb extract cream ( Symphytum x uplandicum NYMAN: ): results of a randomized, controlled double-blind study [in German]. Wien Med Wochenschr . 2007;157(21-22):569-574.
23. Andres R, Brenneisen R, Clerc JT. Relating antiphlogistic efficacy of dermatics containing extracts of Symphytum officinale to chemical profiles. Planta Med . 1989;55(7):643-644.
24. Franz G. Polysaccharides in pharmacy: current applications and future concepts. Planta Med . 1989;55(6):493-497.
25. Karavaev VA, Solntsev MK, Iurina TP, Iurina EV, Poliakova IB, Kuznetsov AM. Antifungal activity of aqueous extracts of the leaves of cowparsnip and comfrey [in Russian]. Izv Akad Nauk Ser Biol . 2001;4:435-441.
26. Yeong ML, Clark SP, Waring JM, Wilson RD, Wakefield SJ. The effects of comfrey derived pyrrolizidine alkaloids on rat liver. Pathology . 1991;23(1):35-38.
27. Awang DV. Comfrey. Can Pharm J . 1987;120:101-104.
28. Gomes MF, de Oliveira Massoco C, Xavier JG, Bonamin LV. Comfrey ( Symphytum Officinale . L.) and experimental hepatic carcinogenesis: a short-term carcinogenesis model study. Evid Based Complement Alternat Med . 2010;7(2):197-202.
29. Olinescu A, Manda G, Neagu M, Hristescu S, Dasanu C. Action of some proteic and carbohydrate components of Symphytum officinale upon normal and neoplastic cells. Roum Arch Microbiol Immunol . 1993;52(2):73-80.
30. Brinker FJ. Herb Contraindications and Drug Interactions . 2nd ed. Sandy, OR: Eclectic Medical Publications;1998.
31. Newall CA, Anderson LA, Phillipson JD, eds. Herbal Medicines: A Guide for Health-Care Professionals . London: Pharmaceutical Press; 1996.
32. Ernst E. Herbal medicinal products during pregnancy: are they safe? BJOG . 2002;109(3):227-235.
33. Shipochliev T. Uterotonic action of extracts from a group of medicinal plants [in Bulgarian]. Vet Med Nauki . 1981;18(4):94-98.
34. Schoental R. Health hazards of pyrrolizidine alkaloids: a short review. Toxicol Lett . 1982;10(4):323-326.
35. Panter KE, James LF. Natural plant toxicants in milk: a review. J Anim Sci . 1990;68(3):892-904.
36. Györik S, Stricker H. Severe pulmonary hypertension possibly due to pyrrolizidine alkaloids in polyphytotherapy. Swiss Med Wkly . 2009;139(13-14):210-211.
37. U.S. Food and Drug Administration. Center for Food Safety and Applied Nutrition. FDA advises dietary supplement manufacturers to remove comfrey products from the market. July 6, 2001. http://www.cfsan.fda.gov/~dms/dspltr06.html . Accessed January 10, 2006
38. Mattocks AR. Toxic pyrrolizidine alkaloids in comfrey. Lancet . 1980;2(8204):1136-1137.
39. Ridker PM, Ohkuma S, McDermott WV, Trey C, Huxtable RJ. Hepatic venocclusive disease associated with the consumption of pyrrolizidine-containing dietary supplements. Gastroenterology . 1985;88(4):1050-1054.
40. Larrey D. Liver involvement in the course of phytotherapy [in French]. Presse Med . 1994;23(15):691-693.
41. Kumana CR, Ng M, Lin HJ, Ko W, Wu PC, Todd D. Hepatic veno-occlusive disease due to toxic alkaloid herbal tea. Lancet . 1983;2(8363):1360-1361.
42. Yeong ML, Swinburn B, Kennedy M, Nicholson G. Hepatic veno-occlusive disease associated with comfrey ingestion. J Gastroenterol Hepatol . 1990;5(2):211-214.
43. Mattocks AR. Toxicity of pyrrolizidine alkaloids. Nature . 1968;217(5130):723-728.
44. Svoboda DJ, Reddy JK. Malignant tumors in rats given lasiocarpine. Cancer Res . 1972;32(5):908-913.
45. Hirono I, Haga M, Fujii M, et al. Induction of hepatic tumors in rats by senkirkine and symphytine. J Natl Cancer Inst . 1979;63(2):469-472.
46. Hirono I, Mori H, Haga M. Carcinogenic activity of Symphytum officinale . J Natl Cancer Inst . 1978;61(3):865-869.
47. Mei N, Guo L, Fu PP, Heflich RH, Chen T. Mutagenicity of comfrey ( Symphytum Officinale ) in rat liver. Br J Cancer . 2005;92(5):873-875.
48. Benedek B, Ziegler A, Ottersbach P. Absence of mutagenic effects of a particular Symphytum officinale L. liquid extract in the bacterial reverse mutation assay. Phytother Res . 2010;24(3):466-468.
Copyright © 2009 Wolters Kluwer Health