Comfrey

Scientific Name(s): Symphytum officinale L., S. asperum Lepechin, S. tuberosum L. Family: Boraginaceae

Common Name(s): Comfrey , Russian comfrey , knitbone , bruisewort , blackwort , slippery root

Clinical Overview

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Uses of Comfrey

The therapeutic use of comfrey is limited because of its potential toxicity. Comfrey has antifungal and anticancer activity, and has been used topically for treating musculoskeletal and inflammatory disorders. Because of limited evidence and toxicity, comfrey is not recommended for oral use.

Comfrey Dosing

Comfrey is not currently recommended for internal or even limited topical use because of the content of hepatotoxic pyrrolizidine alkaloids (PAs). Older preparations may still be on the market in Europe and Asia. Historically, daily doses of the leaf ranged from 5 to 30 g. 1

Contraindications

Because of the content of hepatotoxic PAs, comfrey is not recommended for internal use. Patients with hypersensitivity or allergic reactions to the plant should avoid external use. It is contraindicated during pregnancy and lactation and in patients with liver or kidney disease.

Pregnancy/Lactation

Contraindicated because of documented adverse effects. PAs have abortifacient effects and increase the risk of fatal hepatic veno-occlusive disease.

Comfrey Interactions

None well documented.

Comfrey Adverse Reactions

Internal or extensive topical use of comfrey cannot be recommended because of numerous reports of toxicity, particularly to the liver. An extract of comfrey has been reported to enhance uterine tone. The action of the extract was reported to be stronger than shepherd's purse and St. John's wort, but weaker than that exhibited by German chamomile, calendula, and plantain.

Toxicology

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. Scientific evidence indicates that any form of comfrey is unsafe and has numerous toxicological effects in animals and humans.

Botany

Comfrey is a perennial plant found in moist grasslands. It grows to about 0.9 m and has lanceolate leaves and bell-shaped purple or yellow-white flowers. Comfrey is a temperate plant found in western Asia, North America, and Australia. Symphytum x uplandicum Nyman (Russian comfrey) is a hybrid of S. officinale and S. asperum .

History

Comfrey has been cultivated in Japan as a green vegetable and has been used as an herbal medicine for more than 2,000 years. 2 , 3 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. 2 , 4 Comfrey distribution is banned in Germany and Canada because of the substantial health hazard and toxicity of the plant. 4 , 5

Chemistry

Numerous hepatotoxic pyrrolizidine alkaloids (PAs) have been identified in the plant. Not all PAs have similar toxicity. Studies confirm the following structure-toxicity relationships (from most to least toxic): macrocyclic diesters > retronecine and heliotridine diesters > heliotridine monoesters > retronecine monoesters. Comfrey PAs are retronecine mono- and diesters. 1

The PAs symphytine, echimidine, and lasiocarpine have been found in S. officinale . 6 Lasiocarpine and symphytine are carcinogenic in rats. 7 , 8 Analyses of livers from rats given doses of 50 mg/kg of comfrey-derived alkaloids showed vascular congestion, as well as necrosis and hepatocyte cell membrane damage. 9 The liver damage was dose dependent. 10

Symphytine and echimidine are derivatives of retronecine and are the major alkaloids in comfrey. When administered intraperitoneally in rats, symphytine and echimidine have lethal dose 50% (LD ₅₀ ) values of 200 and 300 mg/kg. 11 The alkaloid content of S. asperum ranges from 0.14% to 0.4%. 12

Large amounts of mucilage are found in leaves and roots. 13 , 14

A pentacyclic triterpene glycoside of oleanolic acid was identified in the root. 15 , 16

The healing action of poultices of comfrey roots and leaves may be related to the presence of allantoin, an agent that promotes cell proliferation. The underground roots contain 0.6% to 0.7% allantoin and 4% to 6.5% tannin. The leaves contain a higher proportion of tannin relative to allantoin. The roots also contain rosmarinic and lithspermic acid. Roots contain 100-fold higher alkaloid content than the aerial portions. 13 , 14 , 15 , 16

Comfrey Uses and Pharmacology

The therapeutic use of comfrey is limited by its toxicity.

In a prospective, open, multicenter, observational study, comfrey was applied topically 1 to 3 times/day over a 2-week period. The duration of morning joint stiffness decreased from 20 minutes initially to 3 minutes, and many of the patients eventually discontinued their use of nonsteroidal anti-inflammatory drug therapy. 17

In an open and uncontrolled study of 105 patients, a comfrey ointment was effective in alleviating symptoms associated with muscle pain but not for muscle pain associated with degenerative diseases. The ointment was most effective in treating muscle swelling, strains, pain, vertebral syndrome, arthralgia, and enthesopathy. 18

Symphytum extracts inhibited platelet activating factor exocytosis 90% to 100% in one study of anti-inflammatory actions. 19 An aqueous extract from the roots of S. officinale initially activated the respiratory burst of mouse peritoneal macrophages and later inhibited it, thus activating synthesis of the enzymes catalase and superoxide dimutase. 20

Forty-one patients were treated topically over 4 weeks for musculoskeletal rheumatism with a PA-free ointment (n = 20) or placebo (n = 21). The musculoskeletal symptoms included epicondylitis, tendovaginitis, and peri-arthritis. Outcome measurements included evaluation of tenderness on pressure, pain at rest, and pain on exercise. Patients treated for periarthritis reported no improvement. Patients treated for epicondylitis reported improvement versus controls for weeks 1, 2, and 4. Patients treated for tendovaginitis reported improvement versus controls for weeks 1 and 2, but not at week 4. 21

Symphytum was active against Lewis lung carcinoma, adenocarcinoma 755, and Walker carcinosarcoma 256. 10 , 11 An aqueous extract and protein fraction of S. officinale stimulated the in vivo proliferation of Ehrlich ascites cells. The extract also exerted an antimitotic effect on stimulated human T lymphocytes. 22

Efficacy in wound healing may be related to the presence of allantoin, rosmarinic acid, or to another hydrocolloid polysaccharide. 23 , 24 Although the details of the study are limited, the antiphlogistic efficacy of 10 different ointments containing comfrey were evaluated. The various ointments were used to treat circular erythema created by UV-B radiation. The ratios of ingredients were not provided, but each ointment was measured for its content of allantoin, caffeic acid derivatives, PAs, and carbohydrates. Outcomes measured included changes in pain and erythema; topical application of the various ointments provided relief of these symptoms. 23

Lithospermic acid isolated from the root appears to have antigonadotropic activity. 15

Aqueous extracts from the leaves of comfrey strongly inhibited the rate of germination of Erysiphe graminis conidia and Puccinia graminis ureidospores of plant pathogenic fungi likely because of the plant's phenolic compounds. 25

The percutaneous efficacy of an ointment of S. officinale extract was examined in 140 patients in a double-blind, multicenter, randomized, placebo-controlled study of ankle sprains. Patients received 4 topical treatments daily for 8 days.The primary outcome measure was tonometrically recorded pressure pain. Secondary outcome measures included ankle-swelling, limitation of movement, physician and patient assessment of efficacy, improved visual appearance, pain-scaling using a visual analog scale, and emergency medication (acetaminophen). Statistically significant reducations in pain, ankle edema, ankle mobility, and global efficacy were observed. No adverse drug reactions were reported in patients receiving active treatment. 26

A Cochrane review evaluated a randomized controlled trial on the efficacy of topical application of a nonsteroidal anti-inflammatory drug, 1 g of piroxicam gel 0.5%, and topical homeopathic gel mixture of Symphytum officinale , Rhus toxicodendron (poison ivy), and Ledum palustre (marsh tea). The results indicated that topically applied homeopathic gel was as effective as piroxicam gel. 27

Dosage

Comfrey is not recommended for internal or even limited topical use today because of the content of hepatotoxic PAs. Older preparations may still be on the market in Europe and Asia. For informational purposes, typical historical daily doses of the leaf ranged from 5 to 30 g. 1

Pregnancy/Lactation

Avoid use because of documented adverse effects. Pyrrolizidine alkaloids have abortifacient effects and increase the risk of fatal hepatic veno-occlusive disease (VOD). 28 , 29 , 30

Interactions

None well documented.

Adverse Reactions

The internal or extensive topical use of comfrey cannot be recommended because of numerous reports of liver toxicity.

A S. officinale extract has been reported to enhance uterine tone. The action of the extract was reported to be stronger than shepherd's purse and St. John's wort, but weaker than that exhibited by German chamomile, calendula, and plantain. 31

Toxicology

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. 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, further requiring a warning on comfrey products intended for external use. 32

The alkaloids of Russian comfrey caused chronic liver damage and pancreatic islet cell tumors after 2 years of use in animal models. Eight alkaloids have been isolated from Symphytum x uplandicum . 33 Alkaloid levels ranged from 0.003% to 0.115%, with highest concentrations in small young leaves. 34

In the early 1990s, several cases of VOD were reported in humans. VOD involves the destruction or obliteration of small hepatic veins leading to cirrhosis and eventually liver failure. Human poisoning with PAs are usually accidental and may be caused by ingestion of contaminated flour, milk, certain animal products (such as goats, which are resistant to the alkaloids), honey produced by bees that have fed on pyrrolizidine-containing weeds, and consumption of certain herbal or bush teas. It also may be caused by Russian comfrey used in salads. 1 , 5

Several members of the comfrey family ( Senecio , Heliotropium ) contain related alkaloids reported to cause liver toxicity in animals and humans. Some of these compounds predispose to hepatic tumor development. The conclusion that comfrey is not safe for internal use is based primarily on toxicity studies in rodents administered high doses of purified PAs. 1

The carcinogenic potential of S. officinale was tested in rats fed 0.5% to 8% comfrey root or leaves for 600 days. 35 Signs of liver toxicity were seen within 180 days and hepatocellular adenomas were induced in all groups. Urinary bladder tumors also were induced at the lowest comfrey levels. The incidence of liver tumors was higher in groups fed a diet of roots rather than leaves.

Wheat contaminated with PAs from Heliotropium , ingested by 7,200 Afghans, resulted in a 23% rate of liver damage. An indirect estimate of alkaloid ingestion determined the consumption of toxic alkaloids to be 2 mg per 700 g flour. Based on this value, an extrapolation of 8 to 26 mg of toxic alkaloids per 237 mL comfrey root tea suggests that comfrey ingestion poses a health risk. 36

PAs in herbal teas and similar preparations of Symphytum have been shown to cause blockage of hepatic veins, leading to hepatonecrosis. 37 VOD has been reported in a woman who ingested a comfrey-pepsin preparation for 4 months. 36 Four Chinese women who self-medicated with an herbal preparation that contained PAs from an unknown plant source also developed the disease. 38 One man presented with portal hypertension and hepatic VOD and later died of liver failure. It was discovered that he used comfrey in his vegetarian diet. 39 Oral ingestion of pyrrolizidine-containing plants, such as comfrey, poses a great risk because the alkaloids are converted to toxic pyrrole-like derivatives following ingestion. 40 The alkaloids of comfrey applied to the skin of rats were detected in the urine, and lactating rats excreted PAs into breast milk. 41 If animals consume plants containing PAs, they could pass these alkaloids on to humans via milk. 42

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