Comfrey

1. Comfrey Ayo adekoya Korey Phan April 21, 2008 Bsci493

2. Nomenclature [8] • Kingdom : PlantAE • Division : Magnoliophyta • Class : Magnoliopsida • Order : Lamiales • Family : Boraginaceae • Genus : Symphytum • SPECIES : Symphytum officinale common comfrey

3. Symphytum officinale (common Comfrey Plant) [9]

4. Appearance & Botanical description [10] • Perennial shrub, native to Europe and temperate parts of Asia. Grows wild across North America • Plant favors moist growing conditions • Thick, hairy stem. Grows 2 - 5 feet tall. • Flowers are dull purple or whitish, densely arranged in clusters. • Lower leaves are broad at the base and tapered at the ends while upper leaves are broad throughout and narrowed only at the ends

5. History [10] • Leaves and roots used in traditional medicine, Western and Eastern, for nearly 2000 years. Used to promote rapid wound healing, healing of broken bones • Preparations are made from the leaves or parts of the plant grown above the ground. • New leaves tend to have more of the poisonous pyrrolizidine alkaloids than older leaves. • Concerns about pyrrolizidine alkaloids (PA’s) found in comfrey root. • In July 2001, products using comfrey root meant for ingestion were banned for sale in the U.S. • Ointments and oils containing comfrey still allowed • Preliminary evidence supports traditional use of root as topical application to stop bleeding, prevent infection or relieve pain.

6. Collection and Processing • Comfrey is cultivated from rootstock. • It cannot be dried in the sun because of the high mucilage. • Processing: large dehydration facilities for drying. • i.e. hop kilns, tobacco dryers, and plywood kilns. • Storage: Poly bags, pallet load, heated storage. • The powder of comfrey leaf is green, almost odorless, and has a mucilaginous, weakly astringent taste

7. Available Forms • In July 2001, the U.S. Food and Drug Administration banned all oral comfrey products from the market. • The United Kingdom, Australia, Canada, and Germany also have banned the sale of oral products containing comfrey (FDA). • Comfrey topical ointments (containing 5 - 20% comfrey), creams, poultices, and liniments are made from the fresh or dried herb, leaf, or root of comfrey species. • Because the same toxic substances can be absorbed by the skin, topical comfrey preparations should be used for only a short time

8. Constituents • Comfrey contains allantoin, which is a cell proliferative that aids in cell regeneration. Others include : rosmarinic acid, and tannins(Herb). • Wound healing, treatment for burns • Comfrey is rich in vitamin B12, which is important to vegetarians, as very few plants have B12. • It is also rich in vitamins B1, B2, C, E, A, plus calcium, iron, manganese, and phosphorus [7]

9. Adulterants • Atropa belladonna , aka belladonna ,or deadly nightshade, is herbaceous plant with extremely toxic leaves and berries [5]. • Leaves could be mistaken for comfrey by inexperienced collectors • The species is native to: Europe, N. Africa, and Western Asia. Is also found in parts of North America. • One of the most toxic plants found in the Western hemisphere. • Children have been poisoned by eating as few as three berries. • Ingestion of a leaf of the Belladonna can be fatal to an adult. • All parts of the plant contain tropane alkaloid. • Causes disruption of the parasympathetic nervous system's ability to regulate non-volitional/subconscious activities: sweating, breathing, and heart rate. • Several cases of digitalis poisoning have resulted from mistaking foxglove (Digitalis purpurea L.) leaves for comfrey leaves. • Shows the lack of quality control in some segments of the herb industry.

10. Contraindications • There are no known scientific reports of interactions between comfrey and conventional medications. • Herbs that have also been known to cause liver problems, such as kava, scullcap, and valerian, should not be avoided • increased potential for liver damage. • Pediatric • Oral consumption should be avoided • Do not apply creams or ointments containing comfrey to a child's skin. • Adult • Oral consumption should be avoided • Use only herb and leaf ointments, creams, and other topical preparations. Toxic alkaloids can be absorbed through the skin. • Never apply comfrey to broken skin. • Use only small amounts of comfrey-containing creams for no longer than 10 days at a time. • Do not use any comfrey product for more than 4 - 6 total weeks in a year [3].

11. Adverse Effects • Herb also contains several very toxic pyrrolizidine alkaloids • Echimidine the most toxic of the alkaloids found in comfrey, is present in the so-called Russian comfrey species4. • If these alkaloids reach the bloodstream, they may damage the liver or result in liver cancer. • The alkaloids damage the veins within the liver, causing a condition known as hepatic veno-occlusive disease (HVOD) • Avoid applications to open cuts or sores and ingestion. • Comfrey root contains about 10X the concentration of PAs found in the leaves [6]

12. therapeutics • Important components of the Common Comfrey revisited Allantoin Inulin Pyrrolizidine alkaloids

13. Pharmacodynamics Pyrrolizidine alkaloids • Comfrey is known to contain 3 classes of hepatotoxic pyrrolizidine alkaloids [11]: Retronecine monoester alkaloids N-oxides alkaloids Retronecine diester alkaloids

14. Pyrrolizidine alkaloids Pharmacodynamics • Mechanism of action: Not entirely understood because of lack of clear epidemiological data but there is no doubt that these alkaloids are hepatotoxic. • Many studies have confirmed hepatoxicity of alkaloids (2 studies). • Within the subset of dangerous PA’s, many factors need to be assessed. In considering crude plant material, toxicity is species specific, and depends on many elements of the plant itself (3 studies).

15. Pyrrolizidine alkaloids Pharmacodynamics • Evidence for the toxicity of PA’s • Chou, Fu et al [12]: -Female F344 rats at eight weeks of age were orally given comfrey supplements for three consecutive days. The doses were ten-fold greater than the recommended human daily oral dose of the commercial dietary supplements based upon an estimated 60-kg human body weight. Results show that DHP-derived DNA adducts were formed both in vivo and in vitro from these comfrey supplements. These adducts are potential biomarkers of PA tumorigenicity. • Mei, Guo, Chen al [13]: The study evaluated the mutagenicity of comfrey in the liver cII gene of Big Blue rats. Results suggests that PA’s were responsible for mutation induction and tumor initiation in rat livers.

16. Pyrrolizidine alkaloids Pharmacodynamics • Evidence for the toxicity of PA’s • Oberlies, Kim et al [14]: - Comfrey proponents: “Consumers of tea made from comfrey leaves are not a risk: PA’s are not soluble in water…only the N-oxides are present…” -Consumption of teas made from comfrey leaves purchased from vendors exposes consumers to alkaloids! -These PA’s cause VOD via pyrroles transformation -Roots contain even more of this bad stuff! -It is true that N-oxides derivatives of the PA’s are more hydrophilic but in vivo, these oxides can be reduced to the native PA’s in the gut. -In as such total PA’s in comfrey tea are underestimated!

17. Pyrrolizidine alkaloids Pharmacodynamics • Evidence that it is not as bad as it seems • Grube B, Grunwald J, Krug et al [15]: -Researchers conducted a placebo-controlled, double-blind study to investigate the effect of daily comfrey application over a period of three weeks on patient suffering from osteoarthritis of the knee. 220 patients participated in the study. The results of the study demonstrated a greater decline in total pain in the comfrey group (54.7%) compared to the placebo group (10.7%). • R. Koll et al[16]: -Another randomized, placebo-controlled, double-blind study was executed on patients suffering from unilateral acute ankle sprains. Results once more confirmed that Comfrey extracts clearly superior regarding the reduction of paincompared to placebo.

18. Evidence that it is not as bad as it seems Santa Amaro, Brazil Gomes, Massoco, Xavier et al[15]: -Researchers used adult male Wistar rats weighting 200–250 g and separated them in 2 groups (control, experimental groups). The control group received diluted water and the experimental 10% comfrey extract in diluted water. Researchers harvested cells from the lateral lobe of the liver and then counted megalocytic, non-megalocytic cells as well as vacuolized cells. -Macroscopically, the number of PNLs was reduced by treatment with Comfrey extract, mainly those measuring 1 mm or less! There was a great anti-proliferation effect due to an increase in megalocytic as well as vacuolized cells. -”By inhibiting cell proliferation and modulating atypical phenotype, treatment of rats with comfrey extracts seems to protect them from early development of pre-neoplastic liver lesions. Pyrrolizidine alkaloids Pharmacodynamics

19. Pyrrolizidine alkaloids Pharmacodynamics • Evidence that it is not as bad as it seems • DrDorenaRode (U.C. Davis) [11]: • “The conclusion that comfrey is not safe for internal use in humans is primarily based on studies in which high levels of purified PA’s were administered to rodents. Systematic toxicity testing or clinical trials have not been performed. Although PA poisoning in humans can occur, this is most commonly a consequence of consumption of plants other than comfrey…” • Isolated PA might not be representative of whole plant use. • “The response of different animal species to PA’s varies tremendously. Pigs, chickens and rats are highly sensitive to poisoning by Senecio, whereas mice and sheep are resistant…” • Not all PA’s have similar toxicity. The most hepatotoxic alkaloids are macrocyclic diesters.

20. So who is right? ? Would pharmacokinetics be the answer?

21. Pyrrolizidine alkaloids Pharmacokinetics[11],[17] 1st route: Dehydrogenation to pyrroles 2nd route: Dehydrogenation to pyrroles via CP450. via CP450. Detoxification via monooxygenases. Detoxification via monoesterases.

22. Pyrrolizidine alkaloids Pharmacokinetics [17] • Conclusion: There is no doubt PA’s are toxic. However, research to date has often been flawed by the use of inappropriate animal models and faulty experimental design. Correct botanical identification and analysis of the plant material for PA content and is essential.

23. References • "FDA Advises Dietary Supplement Manufacturers to Remove Comfrey Products From the Market." U. S. Food and Drug Administration 06 July 2001.Stable URL:http://www.cfsan.fda.gov/~dms/dspltr06.html. [1] • Herb News. May2000. Prevention. Vol. 52 Issue 5, p117. [2] • Koll R, Klingenburg S. 2002.Therapeutic characteristance and tolerance of topical comfrey preparations. Results of an observational study of patients. Fortschr Med Orig .120(1):1-9.[3] • McGuffin M, et al. American herbal products association's botanical safety. New York: CRC Press, 1997:111-112,149-151. [4] • Miller, Richard December 2005.Comfrey Leaf. Stable URL: http://www.nwbotanicals.org/oak/altagri/comfrey.htm.[5] • Tyler VE, Foster S. Tyler's honest herbal: A sensible guide to the use of herbs and related remedies 4th Ed. New York: Haworth herbal press:121-124.[6] • VanSeters, Joseph: Mother Earth News Dec94/Jan95 Issue 147, p18. [7] • Canadian Poisonous Plants Information System Notes on poisoning: Symphytum officinale. StableURL:http://www.scib.gc.ca/pls/pp/ppack.info?p_psn=252&p_type=all&p_sci=sci&p_x=px.[8] • Paul L. Redfearn, Jr. Photographs of flowering plant of the ozarks and the interior highlands of North America. Accessed: April 20, 2008. Stable URL:http://biology.missouristate.edu/Herbarium/Plants%20of%20the%20Interior Flowers/Stylophorum%20diphyllum%20-%20fruit.JPG [9] • Steven D. Ehrlich, N.M.D.,Comfrey. University of Maryland Medical Center, Baltimore. Accessed: April 20, 2008. Stable URL: http://www.umm.edu/altmed/articles/comfrey-000234.htm#Overview [10] • Dorena Rode. November 2002.Comfrey Toxicity revisited. TRENDS in Pharmacological Sciences Vol.23 No.11. [11] • Miang W Chou, Peter P Fu. 2006.Formation of DHP-derived DNA adducts in vivo from the dietary supplements and chinese herbal plant extracts containing carcinogenic pyrrolizidine alkaloids. Toxicology and Industrial Health 2006; 22: 321-327.[12] • N Mei1, L Guo2, PP Fu3, RH Heflich1 and T Chen*. February, 2005. Mutagenicity of Comfrey (Symphytum officinale) in rat liver. British Journal of Cancer (2005) 92, 873 – 875.[13] • Oberlies H Nicholas, Kim Nam-Cheol, Brine Dolores, Collins J Bradley, Handy Robert, Sparacino Charles, Wani Mansukh, Wall Monroe. Mach, 2004. Analysis of Herbal teas made from the leaves of comfrey (Symphytum officinale): reduction of N-oxides results in order of magnitude increases in the measurable concentration of pyrrolizidine alkaloids. Public Health Nutrition: 7(7): 919-924. [14] • Grube B, Grunwald J, Krug L, Staiger C. 2007. 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. Phytomed..14(1):2-10.[15]

24. R. Koll, M. Buhr, R. Dieter, H. Pabst, H. -G. Predel, O. Petrowicz, B. Giannetti, S. Klingenburg and C. Staiger. February,2004. 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.Phytomedecine. Volume 11. Issue 6. 470-477. [16] • Arungundrum S. Prakash. Tamara N. Pereira. Paul E.B. Reilly.Alan A.December 1998. Seawright.Pyrrolizidine alkaloids in human diet. • Mutation Research 4431999.53–67 [17]