Comfrey (Symphytum spp.), long one of the most popular herbs in European folk medicine, has become increasingly controversial because of reports that it is toxic to the liver, and perhaps carcinogenic. At issue is a class of chemicals called pyrrolizidine alkaloids (PAs). Alkaloids of this type are responsible for the toxicity of such poisonous plants as Heliotropium, Crotalaria, and Senecio. They have caused substantial losses of grazing livestock, and some human poisonings as well. The alkaloids damage the veins within the liver, causing a condition known as hepatic veno-occlusive disease (HVOD). Different PAs have different toxicities, further complicaring matters.

Comfrey has been known since at least the 1960s to contain PAs, which in sufficient doses, have caused liver damage and minors in lab animals. The risk to humans is a matter of serious debate, while international government regulation is showing a trend toward eliminating the casual consumption of comfrey. Comfrey root is much higher in alkaloids than leaf, and young leaves contain more than older leaves. The U.S. FDA has sampled a variety of comfrey products for analysis, and will ultimately make a decision about how such products are to be regulated. Australia has banned comfrey, while Canada has proposed a ban on its use in food and restricted its medicinal use. Germany and New Zealand have also restricted its use. This article details the toxicity of the comfrey alkaloids and the latest Canadian regulatory activity -- RMc.

The first Canadian action was taken in 1982, when the Health Protection Branch of Health and Welfare Canada introduced an amendment to Canada's Food and Drug Regulations which prohibits the sale, for medicinal purposes, of any products containing echimidine (Canada Gazette, 30 March 1988). Echimidine, considered to be the most toxic of comfrey PAs (Brauchli-Theotokis 1987), is not found in common comfrey (Symphytum officinale L.). However, it is present in prickly comfrey (S. asperum Lepechin) and its hybrids with S. officinale (Huizing, Gadella, and Kliphuis 1982), including Russian comfrey (S. x uplandicum Nyman), which is the most commonly encountered commercial comfrey in Britain (Clapham, Tutin and Warburg 1962). The intent of this legislation is to have more careful attention paid to identification of botanical species by the herbal industry, and to alert the Canadian public to the potential danger of PA consumption. There was no intent to underestimate the relative potent ial danger of echimidine-free S. officinale. Both root and leaf of "S. officinale" have been shown to be carcinogenic in rats (Hirono et al. 1978), though here again there is Species confusion because the authors equate common comfrey and Russian comfrey! Also, like echimidine (Mattocks 1986), most of the constituent PAs of S. officinale have responded positively in in vivo mutagenicity tests using fruit fly (Drosophila) cells (Würgler and Vogel 1986).

Examination of comfrey products available in Canada (Awang et al. 1988) revealed that none was designated or labelled as Russian comfrey or by its Latin binomial, Symphytum x uplandicum. Products were labelled as either simply "comfrey" or Symphytum officinale (common comfrey). However, just about half (6) of all products analyzed (13) were found to contain echimidine,and must therefore have derived from S. asperum or a hybrid of that species, probably S. x uplandicum. Three of the six echimidine-containing products were specifically labelled as Symphytum officinale. The PA composition of one root product was almost exclusively echimidine -- better than 85% by HPLC!

Health and Welfare Canada has for many years refused to register cormfrey root products for any medicinal application, in recognition of the much greater risk presented by root material as compared to leaf. Comfrey root has been consistently observed to contain roughly ten times the concentration of PA found in leaves (Mattocks 1986, Roitman 1981). Manufacturers have been advised that the inclusion of comfrey root in herbal preparations is no longer acceptable.

Four cases of human poisoning by comfrey have now been published. The first case (Ridker et al. 1985) involved a 49-year-old woman in Boston diagnosed as suffering from veno-occlusive disease (VOD), characteristic of PA intoxication. Chronic ingestion of a comfrey root preparation was implicated and gas chromatographic/mass spectrometric (GC/MS) analysis of the suspected product supported its identity as S. officinale since no echimidine was detected (Huxtable, Lüthy, and Zweifel 1986). The second case, reported in the British Medical Journal (Weston et al. 1987), was claimed to be "the first to result from a native British plant." However, while S. officinale is native to Britain, S. x uplandicum (earlier noted to be the most common commercial species in the UK) results from hybridization of S. officinale with S. asperum from the Caucasus -- hence its common name, "Russian comfrey" (Hills 1977). It is not clear whether this case truly involved S. officinale, since neither confirmation of botanical identity nor analysis of PA was performed on the material implicated in their case of poisoning. A third case (Bach, Thung and Schaffner 1989) described VOD in a 47-year-old woman who was consuming as many as 10 cups of comfrey tea per day in addition to taking comfrey-pepsin tablets (species unidentified) "by the handful" for more than a year. The fourth and last case (Yeong et al. 1990)reported the death from liver failure of a 23-year-old man in New Zealand. The subject had been ingesting four to five fresh young comfrey leaves daily (species undetermined).

A widespread lack of attention to proper botanical identification of Symphytum species by herbal investigators from different disciplines has led to much confusion and perpetuated serious errors in the literature. The British Medical Journal, for example, is very misleading in stating that at least nine PAs are present in the leaves and roots of S. officinale. The reference cited (Smith and Culvenor 1981),in fact, lists the tabulated results of eight investigations covering, variously, wholeplant, root, and herb, from four different geographic locations. Perhaps the most damaging account in this area is the publication from Japan which reports on the constituent of "Symphytum officinale Linn." (Furuya and Araki 1968). The authors' statement that this species "is called comfrey or Russian Comfrey" is responsible for the widespread -- and fallacious -- claim that that species contains echimidine. It is quite obvious that these workers were dealing with a S. asperum hybrid. Also wi dely circulated but never confirmed is the notion that Symphytum spp. may contain the noxious diester PA, lasiocarpine -- following a USSR report (Man'ko et al. 1970), which based identification of the alkaloid solely on paper chromatography! (See: Awang 1987 for an evaluation of the evidence).

The acetyl diesters, 7-acetylintermedine and 7-acetyllycopsamine, have been found to be the predominant PA in S. officinale root, associated with lesser amounts of their uncetylated parents, and symphytine (Branchli et al 1982).

A recent examination of commercial comfrey root sold in the United States revealed a PA profile indicative of S. officinale (Vollmer et al. 1987).

An excellent investigation of the PA constituents of S. x uplandicum (Russian comfrey) grown in Australia was published by C. C. J. Culvenor and his colleagues at the Commonwealth Scientific and Industrial Research Organization (CSIRO) in 1980 (Culvenor et al. 1980). Eight PAs, including echimidine and symphytine, the two most toxic comfrey alkaloids, were identified. These two PAs are very similar in acute toxicity (as measured by LD(50) values). One report assigned values of 200 and 300 mg/kg respectively (Hirono et al. 1978). A later report (Brauchli-Theotokis 1987)lidts comparable values of 125-200 (echimidine) and 220-300 (symphytine)mg/kg. Both studies used intraperitoneal injection in rats.

The Health Risks

Over 200 PAs have been found in plants, mainly from the borage family -- Boraginuceue (eg. Symphytum, Heliotropium); the aster family -- Compositae/Asteraceae (eg. Senecio); and the pea family -- Leguminosae/Fabaceae (eg. Crotalaria) (Cheeke 1988) and an estimated 3% of the world's flowering plants may contain them (Culvenor 1980). The most acutely toxic PAs include those in senecio and crotalaria.(1) The kinds of PAs found in comfrey are generally less toxic (Mattocks 1986). However, PAs of the type found in comfrey must also be regarded as having the potential for liver damage due to chronic toxicity at surprisingly low levels. Humans are believed to be more susceptible to PA poisoning than are the common laboratory animals (Culvenor, personal communication 1987).

Since toxicity of PA seems to result from highly reactive compounds formed during PA metabolism in the liver, external use of comfrey is considered relatively safe (Mattocks 1968).(2) Also, since as much as 90% of total plant alkaloids may be in the form of highly water-soluble N-oxides (Roitman 1983), boiling comfrey leaf as a vegetable should reduce toxicity, because most of the alkaloids would be discarded with the water. These N-oxides are metabolized differently by the liver, with less toxic by-products than the free alkaloids (Mattocks 1971).(3) However, when administered orally to rats and sheep, N-oxides are converted in the gut and rumen, respectively, to their parent alkaloids, with the resulting higher toxicity. Also, human cancer patients under intravenous treatment with indicine-N-oxide experience liver damage, likely due to the free alkaloid, which has been detected in the blood (Ames, as cited in Culvenor 1980).

While debate continues on the safety of comfrey, current evidence indicates that commercial comfrey preparations are not always derived from S. officinale. Uncertainties in the marketplace are compounded by errors in the scientific literature, further complicating safety evaluation. The presence of echimidine (likely the most toxic alkaloid) in commercial products has led the Canadian government to propose a general ban on comfrey. In the U.S. the American Herbal Products Association and the FDA are both reviewing the literature on comfrey to determine what action may be appropriate regarding marketing of comfrey products.

References

Awang, D. V. C. 1987. Comfrey. Can. Pharm. J. 125:100-104.

Awang, D. V. C., J. Fillion, M. Girard, and D. Kindack. 1988. In preparation. Presented in part to International Congress on Natural Products Research, Park City, Utah, 17-21 July 1988.

Bach, N., S. N. Thung & F.Schaffner. 1989. Comfrey Herb Tea-Induced Hepatic Veno-occlusive Disease. Amer. J. Med. 87:97-99.

Brauchli, J., J. Lüthy et al. 1982. Experientia. 38:1085-87.

Brauchli-Theotokis, J. 1987. Zur Toxikologischen Beurteilung der Pyrrolizidin-Alkaloide in den Arzneipflanzen Symphytum officinale, Borago officinalis. Ph.D. Thesis, University of Zürich, p. 11.

Canada Gazette, 30 March 1988, Part II; Vol. 122, No. 7.

Cheeke, P.R. 1988. Toxicity and Metabolism of Pyrrolizidine Alkaloids. J. Anim. Sci. 66:2342-50.

Clapham, A. R., T. G. Tutin and E. F. Warburg. 1962. Flora of the British Isles. Cambridge, England: Cambridge University Press, p. 654.

Culvenor, C. C. J. 1980. In Toxicology in the Tropics. R. L. Smith, and E. A. Bababumi (eds.). London: Taylor and Francis.

Culvenor, C. C. J. 1987. Personal communication. 24 February 1987.

Culvenor, C. C. J., J. A. Edgar et al. 1980. The Alkaloids of Symphytum x uplandicum (Russian Comfrey). Austr. J. Chem. 33:1105-13.

Furuya, T. and K. Araki. 1968. Studies on Constituents of Crude Drugs I. Alkaloids of Symphytum officinale Linn. Chem. Pharm. Bull. 16:2512-16.

Hills, L. D. 1977. Comfrey: Fodder, Food, and Remedy. New York: Universe Books.

Hirono, I., H. Mori, and M. Haga. 1978. Carcinogenic Activity of Symphytum officinale. J. Nat. Cancer Inst. 61(5): 865-68.

Huizing, H.J., T. W. J. Gadella, and E. Kliphuis. 1982. Chemotaxonomical Investigations of the Symphytum officinale polypoid complex and S. asperum (Boraginaceae): The Pyrrolizidine Alkaloids. Plant Systematics and Evolution. 140: 279-92.

Huxtable, R. J., J. Luthy, and U. Zweifel. 1986. Toxicity of Comfrey-Pepsin Preparations. New England J. Med. 315(17):1095.

Man'ko, I. V., B. K. Kotovskii et al 1970. Level of Alkaloids in Symphytum officinale Dependent on the Phase of Plant Development. Rastit. resur. 6(3):409-11. (as cited in Chem Abstr. 1971. 74:61608).

Mattocks, A. R. 1986. Toxicity of Pyrrolizidine Alkaloids. Nature 217:724.

Mattocks, A. R. 1971. Hepatotoxic Effects Due to Pyrrolizidine Alkaloid N-Oxides. Xenobiotica 1:563-66.

Mattocks, A. R. 1986. Chemistry and Toxicology of Pyrrolizidine Alkaloids. London: Academic Press.

Ridker, P. M., S. Ohkuma, et al. 1985. Hepatic Venoocclusive Disease Associated with the Consumption of Pyrrolizidine-Containing Dietary Supplements. Gastroenterology 88:1050-54.

Roitman, J. N. 1981. Comfrey and Liver Damage. Lancet 1:944.

Roitman, J. N. 1983. In Xenobiotics in Foods and Feeds. J.W. Finely and D.E. Schwass (eds.) Washington, D.C.: American Chemical Society.

Smith, L. W., C. C. J. Culvenor. 1981. The Alkaloids of Symphytum x uplandicum (Russian Comfrey). J. Nat. Prod. 44: 129-52.

Stuart, K. L. and G. Bras. 1957. Veno-occlusive disease of the Liver. Q. J. Med. 26: 291-315.

Vollmer, J. J., N. C. Steiner, et al. 1987. Pyrrolizidine Alkaloids: Testing for Toxic Constituents of Comfrey. J. Chem.Ed. 64(12): 1027-30.

Weston, C. F. M., B. T. Cooper, et al. 1987. Veno-occlusive Disease of the Liver Secondary to Ingestion of Comfrey. Br. Med. J. 295:183.

Würgler, F. E. and E. W. Vogel. 1986. pp. 30-31 In Chemical Mutagens -- Principles and Methods for Their Detection. F. J. de Sorres (ed.) Vol. 10. New York: Plenum Press.

Yeong, M. L., E. Swinbum, et al. 1990. Hepatic Veno-occlusive Disease Associated with Comfrey Ingestion. J. Gastroent. Hepatol. 5:211-14.

Toxicity Footnotes

(1) The most acutely toxic PAs are the macrocyclic diesters of unsaturated necine (aminoalcohol) bases, such as senecionine and monocrotaline. Noncyclic diesters are generally rather less toxic and monoesters notably much less so (Mattocks 1986). However, all esterified 1,2-unsaturated necines ought to be regarded as having the potential for liver damage due to chronic toxicity at surprisingly low levels.

(2) Toxicity of PA is generally regarded as due to hepatic reduction of the 1,2-unsaturated pyrrolizidine structures to highly reactive conjugated dienic pyrroles.

(3) N-oxides are relatively innocuous compared to tertiary bases, undoubtedly because N-oxides are not converted to pyrroles by liver microsomal enzymes in vitro, nor when administered intravenously to rats (Mattocks 1971).

Article copyright American Botanical Council.

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By D.V.C. Awang