© Borgis - Postępy Fitoterapii 2/2007, s. 109-113
*Radosław J. Ekiert
Harmful constituents of herbs
Krakowskie Zakłady Zielarskie „Herbapol” w Krakowie S.A.
Prezes Zarządu: mgr inż. Alina Lekstan
Herbs are used by humans as medicines and spices for thousands years. They are used in prophylaxis and treat of many disorders. Till today, because of the availability, they form the base of medicinal systems in many countries. Despite herbs are generally considered to be safe, many of them contain harmful constituents. These compounds belong to the different chemical groups and exert different adverse effects. It is important to be conscious which herbs posses harmful potential and avoid adverse reactions.
The problem of medicines side effects becomes an essential matter after thalidomide disaster. The interest has been also focused on medicinal herbs. Many scientists have undertaken efforts to assess herbs safety and to identify hazardous substances of plant origin. Consequently the knowledge about poisonous substances is much better now. There are some elaborations that try to gather these data. We can mention among others „Adverse effects of herbal drugs” (1) and „Herbal medicines. A guide for health care professionals” (2). Health authorities (e.g. EMEA), which are very interested in the problem, issue documents concerning herbs safety too. This review tries to sum up shortly all these numerous, important informations.
The compounds comprised by herbs, which possess hazardous potential belong to many chemical groups. Among others they are anthranoids, cardiac glycosides, furanocoumarins, proteins, resins, saponins and constituents of essential oils. There is also a big, differentiated group of alkaloids. A lot of them are serious poisons, which can lead to death after ingestion even in miligram amount.
The constituents mentioned above cause many different adverse effects (Table 1). The most common are; hepatotoxicity, nephrotoxicity, mutagenicity, carcinogenicity and allergic reactions. The effects are usually dose-dependent with exclusion to hypersensitivity reactions which can be caused even by a trace amount of allergen.
Table 1. List of the most important harmful constituents occurring in herbs.
|Harmful constituents||Main Families/ Herbs||Adverse effects|
|Alkaloids||almost in all plant families, especially in Apocynaceae, Papaveraceae, Fabaceae and Ranunculaceae||miscellaneous effects, e.g. neurotoxicity, hepatotoxicity, cytotoxicity|
|Alkylphenols||Ginkgo biloba||allergen reactions|
|Amino acids||Blighia sapida, Medicago sativa||teratogenic, erythematosus syndrome|
|Anthranoids||Polygonaceae, Rhamnaceae, Rubiaceae, Scrophulariaceae and Liliaceae||mutagenecity, minerals depletion|
|Aristolochic acid||Aristolochiaceae||nephrotoxicity, genotoxicity|
|Cardiac glycosides||Scrophulariaceae, Ranunculaceae, Liliaceae, Apocynaceae||cardiotoxicity|
|Coumarin||Melilotus sp., Asperula odorata||neurotoxicity, hepatotoxicity|
|Cyanogenetic glycosides||Rosaceae||inhibiting of hemoglobin|
|Essential oils components (phenols, terpens)||Apiaceae, Asteraceae, Lamiaceae||miscellaneous actions, e.g. genotoxicity, hepatotoxicity, carcinogenicity, allergen reactions|
|Lectins||Viscum album, Phytolacca americana||haemagglutination|
|Oxalates||Polygonaceae, Oxalidaceae||oral and kidney injuries|
|Polyacetylenes||Cicuta virosa, Aethusa cynapium||neurotoxicity|
|Proteins||Ricinus communis, Viscum album||cytotoxicity, cardiotoxicity, gastrointestinal tract irritation|
|Resins||Podophyllum peltatum, Croton tiglium, Euphorbiaceae||gastrointestinal tract irritation, carcinogenicity|
|Saponins||Phytolacca americana||gastrointestinal tract irritation|
Harmful constituents and adverse effects
Almost all alkaloids exert a strong physiological effect. Many of them act in miligram doses and it is easy to overdose them. The most common alkaloid plants are: Atropa belladonna (atropine), Cephaelis ipecacuanha (emetine, cephaeline), Datura stramonium (hyoscyamine, atropine, scopolamine), Ephedra sinica (ephedrine), Hyoscyamus niger (hyoscyamine, scopolamine, atropine), Pausinystalia yohimbe (yohimbine), Rauwolfia serpentina (reserpine), Aconitum sp. (aconitine), Berberis vulgaris (berberine), Claviceps purpurea (ergot-alkaloids), Strychnos-nux vomica (strychnine) and Vinca minor containing a group of indole alkaloids (3). Benzophenanthridine alkaloids (e.g. chelidonine) comprised in prickly ash and bloodroot have exhibited cytotoxic action on animals (2). Sparteine is a cardiac depressant, lobeline cause nausea, vomiting and diarrhoea. Many others, like solanine, tomatine, solasonine, coniine, anagyrine, cytisine can exert hazardous effect too (4).
Pyrrolizidine alkaloids. A lot of herbs contain hepatotoxic unsaturated pyrrolizidine alkaloids. Some of them are used in phytotherapy; liferoot ( Senecio sp.), borage ( Borago officinalis) and comfrey ( Symphytum officinalis). A grate number of trials are performed for comfrey, they shown damage of liver in animals and humans (5, 6). At present comfrey can be only used externally on unbroken skin. Investigations with borage herb showed genotoxic, carcinogenic and hepatotoxic action. Pyrrolizidine alkaloids are also present in leaves of butterbur ( Petasites hybridus) and flowers and roots of Tussilago farfara (3).
Curare isoquinoline and indole alkaloids – tubocurarine and toxiferine C. It is worth to remember about tubocurarine, dimeric isoquinoline alkaloid, comprised in calabash curare – extract from bark, shoots and roots of same plants from Strychnos sp. and dimeric indole alkaloid – toxiferine C occuring in roots of plants in genus Chondrodendron (bamboo curare). The action of these alkaloids is based on strike skeletal muscles by inhibition of conductivity in motoric plate. It was used by South American Indian to the poisoning of arrows (7).
Ginkgo leaves contain alkylphenols; ginkgols and ginkgolic acids which are known irritants causing allergen reactions (8). Ginkgolic acids content is limited to a maximum of 5 ppm by German authorities (9).
Hypoglycin A, an amino acid from unripe Blighia sapida fruits, shown teratogenic effect in animal trials (10). Other substance – canavanine coming from Alfalfa can cause systemic lupus erythematosus syndrome.
Contained by Rubia tinctorum non laxative anthranoids posses mutagenic potential (11). It is worth to say that 1,8-anthranoids could be also dangerous. Long term use or abuse of these substances could lead to severe imbalance in homeostasis (12). The genotoxic effect is also suggested.
Beside alkylphenols there is also another harmful constituent in Ginkgo seeds and leaves, ginkgotoxin, a neurotoxin which is vitamin B6 analog. It is stated that the amounts in leaves is too small to exert an adverse effect (13).
Fruits of curly garden parsley ( Petroselinum crispum) contains apiole which is used as abotifatient (3). Apiole is also irritant and hepatotoxic, what is documented (14).
This compound could be named as the herb thalidomide. Since 1993 about 150 cases of severe nephropathy was reported. A disaster was caused by confusion, Aristolochia sp. was used instead of Stephania tetrandra because they both have the same Chinese name Fang Ji (15). Aristolochic acid, a strong carcinogen with genotoxicity potential (3,16) form hazardous DNA-adducts (17). Low levels of this compound is also found in Asarum sp. (1).
Many species of the genus Acorus and Asarum contain α- or β-asarone. The content is high in triploid and tetraploid varieties of Acorus, whereas in the diploid one they are not detected. Researches have shown the genotoxic and hepatocarcinogenic potential of those substances in rodents. The maximal daily doses of asarones for humans are 2 μg/kg bw. In order to decrease the risk of poisoning the diploid Acorus should only be used (14,18).
Adonis vernalis, Convallaria majalis, Digitalis sp., Nerium oleander, Urginea maritima, Strophantus sp. are the most important sources of well known cardiac glycosides (3). The overdosage of these compounds can lead even to death because of cardiotoxic reaction (7).
Coumarin depress central nervous system and damage many organs, especially liver. Sever poisoning symptoms occur after ingestion of 3-4 g of coumarin. Overdosage of same beverages containing this compound can cause headache and stupor. In common storage conditions coumarin comprised by Melilotus sp. turn into anticoagulant dicumarol (4).
Cyanogenetic glycosides are present in the kernels of number of well known Rosaceae family fruits; apricot, bitter almond, cherry, pear and plum. After eating they are hydrolysed to hydrogen cyanide. HCN is a very dangerous competitive inhibitor of hemoglobin that can easily lead to death; the 50 mg dose can be fatal (19).
The irritant properties of diterpens are well known. They occur especially in Asteraceae family. Extremely irritant diterpens are contained by queen´s delight (2).
Estragole occurs in essential oils of many aromatic plants including e.g. tarragon ( Artemisia dracunculus), sweet basil ( Ocimum basilicum) and fennel ( Foeniculum vulgare). Some investigations on mice showed carcinogenic effect, causing liver neoplasms. This effect is not proven on humans so the further trials are needed. It is stated that not excessive consumption of estragole, probably do not result in cancer (3, 14, 20).
These compounds are present in many plants of Apiaceae and Rutaceae families, which are very common. They are used in medicine but unfortunately they are also phototoxic. Severe effects were reported for celery and bergamot oil (21, 22). Fruits and herb of Angelica archangelica can also be dangerous (3, 23).
Kavalactones are considered to be hepatotoxic. A lot of reports says about liver damage leading even to death (24). Despite of this many scientists state that kava-kava is safety and effective herb for anxiety treatment (25).
Lectins are present especially in two medicinal plants; mistletoe and pokeroot. They can influence protein synthesis and cause haemagglutination (1, 26).
Hepatotoxic reactions associated with chaparral are caused by lignans (2).
Methyleugenol is present in many plants including among others sweet flag ( Acorus calamus), tarragon ( Artemisia dracunculus), cardamom ( Elettaria cardamomum), hyssop ( Hyssopus officinalis) and sweet basil ( Ocimum basilicum). Experiments on rodents showed a lot of adverse effects such as reduction of weight gain, increased liver weight, hepatocellular damage and liver inflammation, bile duct hyperplasia, cholestasis and many others. It is considered that this compound is a genotoxic carcinogen (27).
Hazard is attributed to crystals of calcium oxalate, which cause oral injuries (28) as well as soluble salts and oxalic acid, which forms calcium crystals in kidneys. It lead to kidney damage and calcium deficiency (29).
They are very toxic constituents of Cicuta virosa and Aethusa cynapium (4).
Mistletoe alongside hazardous lectins contain cytotoxic and cardiotoxic viscotoxins (25). On the base of the current benefit-risk assessment the herb should be withdrawn from the market (30). Another poisonous toxalbumins (phytotoxins) are ricin, crotin, robin, phasin, abrin and curcin. They act as antigens, irritate gastrointestinal tract, cause sanguinary diarrhoea and liver, kidneys and lungs swell (4). Ricin, which comes from castor beans ( Ricinus communis), is one of the most poisonous substances. Investigations with animals shows that dose of 0,0001 mg/kg (i.p.) is lethal. A lot of cases of animals poisoning were described already a long time ago (31).
Pulegone and menthofuran
Mentha species essential oils; peppermint oil, mint oil and pennyroyal oil contain pulegone and menthofuran. They both have quite similar chemical structure and menthofuran, which posses the ultimate hazardous potential is the main metabolite of pulegone. Liver toxicity has been proven for pennyroyal oil and is suspected for peppermint and mint oils. The human intoxication with pennyroyal oil results also in pulmonary edema and internal haemorrhage. There were also suggested harmful consequences for brain, but it has been not confirmed (32).
Some of resins are very strong purgative agents; podophyllin, Resina Jalape, Resina Scammoni and croton oil. The last one, as others resins from Euphorbia sp. contain carcinogenic phorbol esters (4).
Sassafras albidum root contains essential oil with genotoxic and carcinogenic safrole. (3). Studies performed on animals have shown the hepatotoxic effect of sassafras oil (14).
Some saponins can be irritant to humans. Saponins occurring in pokeroot cause gastrointestinal irritation and in consequence, abdominal cramps (1). Long-term using lead to hypotension and tachycardia (33).
Especially sesquiterpene lactones are potent allergens. They are present in almost all Asteraceae family and cause hypersensitivity reactions (2). It is possible that these compounds are responsible for mouth ulcers and swollen tongue observed after feverfew ingestion (34).
Thujone possess neurotoxic action. It is contained in Chrysantemum vulgare and in Oleum Salviae (3).
Adverse effects caused by other factors
There is need to remember, that adverse effects caused by herbs are not always caused by constituents which occurs normally in herbs. The toxicity can also result from plant identification mistake, the intentionally falsification by adding other herbs (35) or even active synthetic substances (36). Dangerous can be the high level of heavy metals such as mercury or cadmium (37), microorganisms and their products (e.g. aflatoxins). The high content of pesticides and fumigants should also be considered, as well as radionuclides content. Side effects can be caused by notable nitrates content, which becomes from the soil. Finally adverse reactions can be a result of excipients, extrahents and solvents used in production process.
Another reason of undesirable effects are interactions between herbs and other substances, particularly synthetic medicines (38, 39). The risk is also associated with patient-related features, such as genetics predispositions, age, sex, race and concomitant diseases (10).
Summarizing, herbs are mostly beneficial to humans, but they can also be harmful. According to the Paracelsus rule all substances can threat and poison, and the way of action depends on dose. There is need to remember about this fact taking herbal medicines or adding spices to meals. Data listened in this publication shows that matter of herbs safety should be treat seriously. For many years, worldwide, the International Drug Monitoring Programme is conducted under the auspices of World Health Organization. It proves the herbs safety on medicinal authorities level.
Author thanks to pharmacists ScD Halina Ekiert and late PhD Leszek J. Ekiert.
1. De Smet P.A.G.M.: Adverse effects of herbal drugs (vol.1). Springer Verlag, Berlin 1992. 2. Newall C.A., Anderson L.A., Phillipson J.D.: Herbal Medicines. A guide for health-care professionals. The Pharmaceutical Press, London 1996. 3. EMEA/HMPC/246736/05. Public statement on "CPMP list of herbal drugs with serious risks, dated 1992”. EMEA, London 2005. 4. Henneberg M., Skrzydlewska E.: Zatrucia roślinami wyższymi i grzybami. PZWL, Warszawa 1984. 5. Ridker P.M., Ohkuma S., McDermott W.V. et al.: Hepatic venocclusive disease associated with the consumption of pyrrolizidine-containing dietary supplements. Gastroenterology 1985, 88,1050. 6. Weston C.F.M., Cooper B.T., Davies J.D. et al.: Veno-occlusive disease of the liver secondary to the ingestion of comfrey. Br. Med. J. 1987, 295, 183. 7. Kohlmünzer S.: Farmakognozja. Wydawnictwo Lekarskie PZWL, 2003. 8. Siegers C.P.: Cytotoxicity of alkylphenols from Ginkgo biloba. Phytomedicine 1999, 6, 281. 9. Blumenthal M., Busse W.R., Goldberg A. et al.: The Complete German Commission E Monographs-Therapeutic Guide to Herbal Medicines. American Botanical Council, Boston 1998. 10. De Smet P.A.G.M.: Health risks of herbal remedies. Drug Safety 1995. 13. 81. 11. Kawasaki Y., Goda Y., Yoshihira K.: The mutagenic constituents of Rubia tinctorum. Chem. Pharm. Bull. 1992, 40, 1504. 12. De Smet P.A.G.M.: Towards safer herbal medicines. The European Phytojournal, 1996. 13. Ansgar A., Klein M., Fiehe K. et al.: Occurrence of neurotoxic 4´-O-methylpyridoxine in Ginkgo biloba leaves, Ginkgo medications and Japanese Ginkgo food. Planta Med. 1996, 62, 548. 14. Tisserand R, Balacs T.: Essential oil safety. Edinburgh. Churchill Livingstone, 1995. 15. EMEA/HMPC/138381/2005. Public statement on the risk associated with the use of herbal products containing Aristolochia species. EMEA, London 2005. 16. Teuscher E., Lindequist U.: Biogene Gifte. Biologie-Chemie-Pharmakologie. Akademie-Verlag, Berlin 1988. 17. Nortier J.L., Martinez M.C., Schmeiser H.H. et al.: Urothelial carcinoma associated with the use of a Chinese herb ( Aristolochia fangchi). N. Engl. J. Med. 2000, 342, 1686. 18. EMEA/HMPC/139215/05. Public statement on the use of herbal medicinal products containing asarone. EMEA, London 2005. 19. Chandler R.F., Phillipson J.D., Anderson L.A.: Controversial laetrile. Pharm. J. 1984, 232-330. 20. EMEA/HMPC/137212/05. Public statement on the use of herbal medicinal products containing estragole. EMEA, London 2005. 21. Ljunggren B.: Severe phototoxic burn following celery ingestion. Arch .Dermatol. 1990, 126, 1334. 22. Boffa M.J., Gilmour E., Ead R.D.: Celery soup causing severe phototoxicity during PUVA therapy. Brit. J. Dermatol. 1996, 135, 330. 23. EMEA/HMPC/317913/2006. Reflection paper on the risk associated with furocoumarins contained in preparations of Angelica archangelica L. EMEA, London 2007. 24. Russmann S.: Kava hepatotoxicity. Ann Int. Med. 2001, 135, 68. 25. Geier F.P., Konstantinowicz T.: Kava treatment in patients with anxiety. Phytother. Res. 2004, 18, 297. 26. Anderson L.A., Phillipson J.D.: Mistletoe- the magic herb. Pharm. J. 1982, 229, 437. 27. EMEA/HMPC/138363/05. Public statement on the use of herbal medicinal products containing methyleugenol. EMEA, London 2005. 28. Gardner D.G.: Injury to the oral mucous membranes caused by the common houseplant, dieffenbachia. Oral Surg. Oral Med. Oral Pathol. 1994, 78, 631. 29. Lindsjo M.: Oxalate metabolism in renal stone disease with special reference to calcium metabolism and intestinal absorption. Scand. J. Urol. Nephrol. Suppl. 1989, 119, 1. 30. McGuffin M., Hobbs C., Upton R. et al.: American Herbal Products Association´s Botanical Safety Handbook. Boca Raton, CRC Press, USA 1997. 31. Kingsbury J.M.: Poisonous plants of the United States and Canada. Prentice-Hall Inc., 1964. 32. EMEA/HMPC/138386/05. Public statement on the use of herbal medicinal products containing pulegone and menthofuran. EMEA, London 2005. 33. Tyler V.E.: The Honest Herbal (3rd edn.). Howarth Press, New York 1993. 34. Baldwin C.A., Anderson L.A., Phillipson J.D.: What pharmacists should know about feverfew. Pharm. J. 1987, 239, 237. 35. Slifman N.R., Obermeyer W.R., Aloi B.K. et al.: Contamination of botanical dietary supplements by Digitalis lanata. N. Engl. J. Med. 1998, 339, 806. 36. Huang W.F., Wen K.C., Hsiao M.L.: Adulteration by synthetic therapeutic substances of traditional Chinese medicines in Taiwan. J. Clin. Pharmacol. 1997, 37, 344. 37. Koh H.L., Woo S.O.: Chinese proprietary medicine in Singapore: regulatory control of toxic heavy metals and undeclared drugs. Drug Safety 2000, 23, 351. 38. Williamson E.M.: Drugs interactions between herbal and prescription medicines. Drug Safety 2003, 26, 1075. 39. Fugh-Berman A.: Herb-drug interactions. The Lancet 2000, 355, 134.