Symphytum


Common Names: Comfrey, Common Comfrey, Prickly Comfrey, Russian Comfrey, Boneset, Knitbone.

Clinical Names: Symphytum officinale, Symphytum spp.


Summary

botanical names: Symphytum officinale, Symphytum asperum, Symphytum caucasicum, Symphytum tuberosum, Symphytum x. uplandicum.

common names: Comfrey

overview of interactions:
• herb constituent potentially causing increase in drug toxicity: Hepatotoxic, Pyrrolizidine alkaloids.

• pharmacokinetic interactions: Dugs that inhibit or are substrates of cytochrome P4503A4.

AHPA Botanical Safety Rating: 2a, 2b, 2c, 2d






Clinical

botanical names: Symphytum officinale, Symphytum asperum, Symphytum caucasicum, Symphytum tuberosum, Symphytum x uplandicum.

common names: Comfrey, Common Comfrey, Prickly Comfrey, Russian Comfrey, Boneset, Knitbone.

parts used: Leaf, roots.

qualities: Sweet, bland, cool, moist.

affinities: Bones, liver, lung, skin, stomach, intestine, bladder and genitals.

actions:
• internal: Anti-inflammatory, demulcent, vulnerary, anti-ulcer (peptic).
• external: Vulnerary, anti-inflammatory, anti-ulcer (stasis), emmolient, hemostatic, astringent.

dosage:
• externally: used as poultice, salve, oil or liniment.
• internally: used as tea or tincture (2 - 4 ml.). See toxicity.
• powder: 1 - 2 g.

therapy:
• internal: Traditionally used for many conditions, including blepharitis, conjunctivitis, cough, irritable bowel syndrome and peptic ulcer disease. Currently considered as unsafe for internal use.
• external (poultice): Bruises, chronic skin ulcer, fracture, rashes, strains, sprains, thrombophlebitis, wounds.

specific indications:
• Fractures, sprains, strains, wounds.

AHPA Botanical Safety Rating: 2a, 2b, 2c, 2d

toxicity:
• Contains hepatotoxic pyrrolizidine alkaloids (PA's) which are associated with hepatic veno-occlusive disease (VOD). Comfrey root contains more PA's than leaf. For full discussion of PA's see interactions section for Comfrey and also:
Herb Groups: Metabolic: Hepatotoxic

contraindications:
• Pregnancy and lactation: Contraindicated due to hepatotoxic pyrrolizidine alkaloids. Evidence for teratogenicity or transfer across placental membranes is lacking, and this contraindication is described as speculative by Brinker.
(Brinker F. 1998, 63; McGuffin M, et al. 1997, 111.)

• Internal Use: Comfrey is not recommended for internal use by AHPA. This caution is regarded as excessively stringent by some herbalists, especially for short term use of comfrey leaf preparations. Assessment of hepatic detoxification status should be performed by a qualified practitioner familiar with the procedures before comfrey is prescribed; internal self-medication with comfrey preparations should be avoided, especially on an extended basis.
(Denham A. Eur J Herb Med 1996;2(3):27-38; McGuffin M, et al. 1997, 149-151; Whitelegg M. Eur J Herb Med 1994;1(1)11-17.)

constituents:
• Allantoin (0.6 - 2.5%).
• Pyrrolizidine alkaloids (0.02-0.07%) varying by species. [7-acetylintermedine, 7-acetyllycopsamine, symphytine: echimidine not present in S. officinale but possibly in S. uplandicum.]
• Mucilage (29%)
• Phytosterols including beta-sitosterol.
• Other: phenolics including caffeic and lithospermic acids; asparagine, pyrocatechol tannins, vitamins including riboflavin, niacin, pantothenic acid, vitamin B12 (very rare in vegetable matter); vitamin A, vitamin C and vitamin E.



Interactions

herb constituent causing increase in drug toxicity: Pyrrolizidine alkaloids

• mechanism: Pyrrolizidine alkaloids (PA's) are found in over 240 species, mostly amongst the Asteraceae (Daisy) and Boraginaceae (Borage) families. The toxicity of PA's has been known since the nineteenth century; Senecio "hepatitis" in cattle was described in 1884. The mechanisms of toxicity are well documented have been reviewed recently. See, for example, Denham A.1996. Hepatotoxicity among PA's varies with minor differences in chemical structure. It is most marked among macrocyclic diesters, these form highly reactive pyrrole intermediates upon metabolism by CYP3A4. Subsequent conjugation of the pyrroles is via glutathione. The reactive pyrrole intermediates form covalent bonds with nucleic acids and disrupt cellular protein synthesis and cell replication which initiates the pathological process. DNA crosslinking may also lead to carcinogenesis.

• herbal concern: Evaluation of the risks from ingestion of PA containing herbs is a complex, controversial and unresolved subject. PA's vary in toxicity, not only by distribution in different species of the same genera, but in their distribution in different plant parts (leaf, root, etc.) of the same species. Regulatory authorities in some countries have proscribed the use of all PA-containing herbs such as Tussilago farfara (coltsfoot) and Borago officinalis (borage) despite complete lack of any evidence for toxicity in normal usage, along with Symphytum spp. (comfrey) for which there is more compelling evidence of hepatoxicity, there being four reports world-wide associating possible veno-occlusive disease (VOD) with comfrey use at normal dose levels. In the USA, cautions are recommended by AHPA (American Herbal Products Association) to restrict use of PA-containing herbs to external use on unbroken skin and to avoid consumption during pregnancy and nursing.
(Denham A. Eur J Herb Med 1996;2(3):27-38; McGuffin M, et al. 1997, 149-151; Whitelegg M. Eur J Herb Med 1994;1(1)11-17.)

see also: Herb Groups: Metabolic: Hepatotoxic

overview of interactions: Drugs that inhibit or are substrates of cytochrome P4503A4.

• Detoxification of PA's depends initially on the CYP3A4 enzyme subsystem and subsequently on hepatic glutathione (GSH) status. Although age, genetic variation, nutritional status and other factors account for large inter-individual differences, it is known which drugs inhibit CYP3A4 and which drugs are substrates by CYP3A4. Use of these drugs would require an even greater vigilance concerning the concurrent ingestion of PA-containing herbs.

• drugs inhibiting CYP3A4: Fluoxetine, Itraconazol, Fluconazole, Ketoconazole, Erythromycin, Clarithromycin, Troleandomycin. See also Grapefruit Juice.

• drugs metabolized by CYP3A4: Quinidine, Carbamazepine, Astemizole, Terfanadine, Fluoxetine, Alprazolam, Midazolam, Triazolam, Diltiazem, Nifedipine, Cisapride, Cyclosporine, Lidocaine, Lovastatin, Hydrocortisone, Dexamethsone.
(Bland JS.1997, 17.)

Please read the disclaimer concerning the intent and limitations of the information provided here.
Do not rely solely on the information in this article.

The information presented in Interactions is for informational and educational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, case reports, and/or traditional usage with sources as cited in each topic. The results reported may not necessarily occur in all individuals and different individuals with the same medical conditions with the same symptoms will often require differing treatments. For many of the conditions discussed, treatment with conventional medical therapies, including prescription drugs or over-the-counter medications, is also available. Consult your physician, an appropriately trained healthcare practitioner, and/or pharmacist for any health concern or medical problem before using any herbal products or nutritional supplements or before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using supplements, herbs, remedies, or other forms of self-care.


References

[No authors listed] Symphytine. IARC Monogr Eval Carcinog Risk Chem Hum. 1983 Jul;31:239-245.

Abbott PJ. Comfrey: assessing the low-dose health risk. Med J Aust. 1988 Dec 5-19;149(11-12):678-682. (Review)
Abstract: The regular use of comfrey as part of the diet or for medicinal purposes may be a potential health risk as a result of the presence of naturally-occurring pyrrolizidine alkaloids. The majority of these alkaloids are hepatotoxic in both animals and humans, and some have been shown to induce tumours in experimental animals. In this article, the toxic properties of pyrrolizidine alkaloids are reviewed briefly, with particular reference to their presence in comfrey. The acute and long-term health risks at the normally-low levels of comfrey consumption are evaluated and discussed. On the basis of the data that are available currently, the small but significant long-term risk that is associated with the consumption of comfrey justifies the need to limit its intake. This is being achieved by controls under various state Poisons Acts, but also requires further education on the potential dangers of naturally-occurring chemicals of plant origin.

Anderson C. Comfrey toxicity in perspective. Lancet. 1981 Jun 27;1(8235):1424. (Letter)

Anderson PC, McLean AEM. Comfrey and liver damage. Human Toxicol 1989;8:68-69.

Bach N, Thung SN, Schaffner F. Comfrey herb tea-induced hepatic veno-occlusive disease. Am J Med. 1989 Jul;87(1):97-99.

Betz JM, Eppley RM, Taylor WC, Andrzejewski D. Determination of pyrrolizidine alkaloids in commercial comfrey products (Symphytum sp.). J Pharm Sci. 1994 May;83(5):649-653.
Abstract: The presence of hepatotoxic pyrrolizidine alkaloids in comfrey (Symphytum sp.) and the widespread use of decoctions of this plant as a beverage (herbal tea) are of increasing concern. A method for the extraction and solid-phase concentration and capillary gas chromatographic determination of these alkaloids and their N-oxides in botanical materials has been developed and was applied to eleven comfrey-containing products purchased from retail health-food outlets in the Washington, DC, area during May-June 1989. Nine of the 11 products were found to contain measurable quantities of one or more of the alkaloids, in ranges from 0.1 to 400.0 ppm. Products containing comfrey leaf in combination with one or more other ingredients were found to contain the lowest alkaloid levels. Highest levels were found in bulk comfrey root, followed by bulk comfrey leaf. The species of the bulk material was verified by thin-layer chromatography and other means.

Bland JS. The Inflammatory Disorders Gig Harbor WA: HealthComm Seminar 1997.

Brauchli J, Luthy J, Zweifel U, Schlatter C. Pyrrolizidine alkaloids from Symphytum officinale L. and their percutaneous absorption in rats. Experientia. 1982 Sep 15;38(9):1085-1087.
Abstract: An analysis of a commercial sample of Symphyti radix originating from Poland with a total alkaloid content of 0.07% revealed the presence of 7 pyrrolizidine alkaloid-N-oxides: 7-acetyl intermedine, 7-acetyl lycopsamine as the main constituents and lycopsamine, intermedine, symphytine and traces of 2 further not yet identified alkaloids. The percutaneous absorption of these alkaloids was investigated in rats, using a crude alcoholic extract of the plant corresponding to a dose of 194 mg alkaloid-N-oxides/kg b.wt. The excretion of N-oxides in the urine during 2 days was in the range of 0.1-0.4% of the dose. The dermally absorbed N-oxides are not or only to a small extent converted to the free alkaloids in the organism. The oral application led to a 20-50 times higher excretion of N-oxides and free alkaloids in the urine.

Bradley PR, ed. British Herbal Compendium, vol 1. Bournemouth, Dorset, UK: British Herbal Medicine Association, 1992.

Brinker F. Botanical Medicine Research Summaries. In: Eclectic Dispensatory of Botanical Therapeutics, vol.11. Sandy, Oregon: Eclectic Medical Publications, 1995.

Brinker F. Herb Contraindications and Drug Interactions. Second edition., Sandy, OR. Eclectic Institute Inc, 1998.

Couet CE, Crews C, Hanley AB. Analysis, separation, and bioassay of pyrrolizidine alkaloids from comfrey (Symphytum officinale). Nat Toxins. 1996;4(4):163-167.
Abstract: Pyrrolizidine alkaloids have been linked to liver and lung cancers and a range of other deleterious effects. As with many natural toxicants, major problems arise in determining the effects of the different members of the class and the importance of various forms of ingestion. In this study we have investigated the levels of pyrrolizidine alkaloids in comfrey (Symphytum officinale), determined the levels in different parts of the plant and in herbal remedies, separated the alkaloids into two main groups--the principal parent alkaloids and the corresponding N-oxides--and, finally, carried out a simple bioassay based upon the mutagenic capability of the separated compounds in a human cell line. We conclude that the part of the plant ingested is important in terms of alkaloid challenge and that the effect of two of the major groups of alkaloids individually is different from that of alkaloids in the whole plant extract.

Culvenor CC, Clarke M, Edgar JA, Frahn JL, Jago MV, Peterson JE, Smith LW. Structure and toxicity of the alkaloids of Russian comfrey (symphytum x uplandicum Nyman), a medicinal herb and item of human diet. Experientia. 1980 Apr 15;36(4):377-379.
Abstract: Eight pyrrolizidine alkaloids of hepatotoxic type have been indentified in leaves of Symphytum X uplandicum. The combined alkaloids exhibit chronic hepatotoxicity in rats.

Denham A. Using herbs that contain pyrrolizidine alkaloids. Eur J Herb Med 1996;2(3):27-38.

Duke JA. Handbook of Phytochemical Constituents of GRAS Herbs and Other Economic Plants. Boca Raton, FL: CRC Press, 1992.

Hirono I. Carcinogenicity of plant constituents: pyrrolizidine alkaloids, flavonoids, bracken fern. Prog Clin Biol Res. 1986;206:45-53.

Huxtable RJ, Wild SL. Relationship between in vitro metabolism of pyrrolizidine alkaloids and extrahepatic toxicity in vivo. Proc West Pharmacol Soc. 1994;37:109-111.

Huxtable RJ, Luthy J, Zweifel U. Toxicity of comfrey-pepsin preparations. N Engl J Med. 1986 Oct 23;315(17):1095.

Larrey D. [Liver involvement in the course of phytotherapy]. Presse Med. 1994 Apr 16;23(15):691-693. Review) [Article in French]
Abstract: The development of herbal medicine has follow in line with increased popular interest in ecology. Emphasis has been placed on the safety of natural herbs in contrast with the risks involved with "classical" medicines. But recent publications have revealed that several herbal medicines are toxic for the liver. For example, in France we have observed cases of hepatitis after ingestion of germander (Teucrium chamaedrys). Clinicians should also be aware of other well documented toxic effects of herbs used in popular medicines in Africa, Asia or Central America. The toxicity of pyrrolizidine alkaloids was recognized over 40 years ago. More than 300 plant species, including Heliotropium, Crotalaria, Senecio and Symphytum, are implicated. In Africa or Central America, intoxication is sometimes endemic since these plants are often used for making tea. In Western countries, cases of herb-induced hepatitis have been observed after use of preparations containing Symphytum or Chinese herbs. Pyrrolizidine alkaloids cause obstruction of the hepatic venous system and can lead to hepatonecrosis. Clinical manifestations include abdominal pain, ascitis, hepatomegaly and raised serum transaminase levels. Prognosis is often poor with death rates of 20 to 30% being reported. Atractylis gummifera is another example of herbal toxicity. Twenty-six species of this plant are used for medicinal purposes or for chewing gum. Intoxication usually occurs in the spring and is related to chewing the roots of these plants. Severe hepatocellular lysis may occur less than 24 hours after ingestion. Clinical manifestations are related to the induced hypoglycemia and neurovegetative disorders or subsequent renal failure. These compounds have an inhibitor effect on the Krebs cycle and can lead to severe or fatal liver failure. Other similar cases of fatal liver accidents have been reported after ingesting Callilepis laureola, a herb used by the Zoulous in Natal for medicinal purposes or after use of products containing extracts of Teucrium chamaedrys, which was nevertheless authorized in France in 1986 for use in preparations for weight loss. These examples emphasize the importance of remembering that herbal medicine is not harmless. Faced with the extensive distribution of many herbal preparations and the risk of self-medication, consumers and clinicians alike should be increasingly vigilant with these potentially hepatotoxic products.

McGuffin M, et al. (eds.) AHPA Botanical Safety Handbook .CRC Press, 1997.

Panter KE, James LF Natural plant toxicants in milk: a review. J Anim Sci. 1990 Mar;68(3):892-904. (Review)

Ridker PM, McDermott WV. Comfrey herb tea and hepatic veno-occlusive disease. Lancet. 1989 Mar 25;1(8639):657-658.

Ridker PM, Ohkuma S, McDermott WV, Trey C, Huxtable RJ. Hepatic venocclusive disease associated with the consumption of pyrrolizidine-containing dietary supplements. Gastroenterology. 1985 Apr;88(4):1050-1054.
Abstract: Venocclusive disease, a form of Budd-Chiari syndrome, was diagnosed in a 49-yr-old woman. The patient had portal hypertension associated with obliteration of the smaller hepatic venules. A liver biopsy specimen showed centrilobular necrosis and congestion. Analysis of food supplements the woman regularly consumed showed the presence of pyrrolizidine alkaloids. The major source was a powder purporting to contain ground comfrey root (Symphytum sp). We calculated that during the 6 mo before the woman was hospitalized, she had consumed a minimum of 85 mg of pyrrolizidine alkaloids (15 micrograms/kg body wt X day). The clinical and analytic findings were consistent with chronic pyrrolizidine intoxication, indicating that low-level, chronic exposure to such alkaloids can cause venocclusive disease.

Ridker PN, McDermont WV. Hepatotoxicity due to comfrey herb tea. Am J Med. 1989 Dec;87(6):701. (Letter)

Robins DJ. Pyrrolizidine alkaloids. Nat Prod Rep. 1995 Aug;12(4):413-48.. (Review)

Roeder E. Medicinal plants in Europe containing pyrrolizidine alkaloids. Pharmazie. 1995 Feb;50(2):83-98. (Review)

Roitman JN. Comfrey and liver damage. Lancet. 1981 Apr 25;1(8226):944. (Letter)

Stamford IF, Tavares IA. The effect of an aqueous extract of comfrey on prostaglandin synthesis by rat isolated stomach. J Pharm Pharmacol 1983 Dec;35(12):816-817.

Stegelmeier BL, Edgar JA, Colegate SM, Gardner DR, Schoch TK, Coulombe RA, Molyneux RJ. Pyrrolizidine alkaloid plants, metabolism and toxicity. J Nat Toxins. 1999 Feb;8(1):95-116. (Review)
Abstract: More than 350 PAs have been identified in over 6,000 plants in the Boraginaceae, Compositae, and Leguminosae families (Table 1). About half of the identified PAs are toxic and several have been shown to be carcinogenic in rodents. PA-containing plants have worldwide distribution, and they probably are the most common poisonous plants affecting livestock, wildlife, and humans. In many locations, PA-containing plants are introduced species that are considered invasive, noxious weeds. Both native and introduced PA-containing plants often infest open ranges and fields, replacing nutritious plants. Many are not palatable and livestock avoid eating them if other forages are available. However, as they invade fields or crops, plant parts or seeds can contaminate prepared feeds and grains which are then readily eaten by many animals. Human poisonings most often are a result of food contamination or when PA-containing plants areused for medicinal purposes. This is a review of current information on the diagnosis, pathogenesis, and molecular mechanisms of PA toxicity. Additional discussion includes current and future research objectives with an emphasis on the development of better diagnostics, pyrrole kinetics, and the effects of low dose PA exposure.

Summers RS. Cardiotoxic principle in comfrey. S Afr Med J. 1979 Jan 13;55(2):37. (Letter)

Weiss RF. Herbal Medicine. Beaconsfield, UK: Beaconsfield Publishers Ltd, 1988, 334-335.

Weston CF, Cooper BT, Davies JD, Levine DF. Veno-occlusive disease of the liver secondary to ingestion of comfrey. Br Med J (Clin Res Ed). 1987 Jul 18;295(6591):183.

Whitelegg M. In defence of Comfrey. Eur J Herb Med 1994;1(1)11-17.

Winship KA. Toxicity of comfrey. Adverse Drug React Toxicol Rev 1991 Spring;10(1):47-59. (Review)

Yeong ML, Wakefield SJ, Ford HC. Hepatocyte membrane injury and bleb formation following low dose comfrey toxicity in rats. Int J Exp Pathol. 1993 Apr;74(2):211-217.