Toxicity of herbal constituents

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Chapter 10 Toxicity of herbal constituents

Most toxic effects of herbal medicines are due to the poor quality of the product. For example, herbal medicines may be adulterated with synthetic medicines and other compounds, or there may be problems in the production of such herbal medicines. However, some toxic compounds, including the pyrrolizidine alkaloids and aristolochic acids, still pose potential serious risks for a few plant-derived products.

This chapter is not about toxic plants as such (see Nelson et al 2006), but about those plants used as herbal medicines and in therapy. Most common herbal remedies are fairly safe in clinical use; not because they are ‘natural’, but because the long history of use has uncovered some of the adverse effects.

Traditional use is not always a reliable indication of safety, since toxicity which results only from chronic use, or manifests after a long interval between taking the medicine and the onset of a reaction, may make the connection difficult. Many patients do not consider phytomedicines to be ‘drugs’, therefore an association may not have been made between the remedy and an adverse reaction, so even though a herb has been used for hundreds of years there may remain cause for vigilance. Knowledge of the chemistry and metabolism of the constituents of a herb can help to predict toxicity problems.

As with all medicines, side effects and interactions with other drugs are possible; but these are a consequence of the therapeutic use of the herb and an assessment of the usual risk:benefit ratio should be made. Problems produced by misidentification, variations in composition, which may cause overdose or underdose, and contamination with microorganisms, pesticides or heavy metals are quality issues; however, there are a number of known toxic constituents, which confer no apparent health benefit, and herbs containing them should be avoided. Allergic reactions can be elicited by any drug, and idiosyncratic responses by definition cannot be foreseen; these are certainly not restricted to plant medicines, although some plant families (e.g. Asteraceae, Ranunculaceae) are notorious for their allergenicity.

Pyrrolizidine alkaloids

These have only been reported in the plant families Boraginaceae, Asteraceae, Leguminosae, Apocynaceae, Ranunculaceae and Scrophulariaceae, and not in all species. Medicinal herbs that may be affected include comfrey (Symphytum spp.), butterbur (Petasites hybridus (L.) P. Gaertn., B. Mey. & Scherb.), alkanet (Alkanna tinctoria Tausch, Boraginaceae), coltsfoot (Tussilago farfara) and hemp agrimony (Eupatorium cannabinum L., Asteraceae). Not all pyrrolizidine alkaloids are toxic, only those that are unsaturated at the 1,2-position (e.g. senecionine; Fig. 10.1). These are liver toxins and can produce veno-occlusive disease of the hepatic vein as well as being hepatocarcinogenic, and their effects are cumulative. Several documented clinical examples can be found in the literature. Although highly toxic, they are chemically rather labile and may, therefore, not present the serious risk originally thought, at least in herbal medicines that have undergone a lengthy process involving heat. For example, when six commercial samples of comfrey leaf were tested, none of these alkaloids were detectable. However, in fresh plant material, and also root samples, they may be present in significant amounts. The total recommended maximum dose of these alkaloids is less than 1 μg daily for less than 6 weeks per year. If herbal products, which may contain these, are to be employed (and some are very useful, e.g. butterbur and coltsfoot; see Chapter 16), the content must be estimated and, if necessary, the alkaloids should be removed before use.

Aristolochic acid

Most species of birthwort (Aristolochia, known as snakeroot) and related genera including Asarum, all from the family Aristolochiaceae, contain aristolochic acid and aristolactams. Aristolochia has been found as an ingredient in a slimming formula along with dexfenfluramine and in Europe, since the mid 1990s, more than one hundred cases of nephropathy caused by the systemic and long term use of Chinese snakeroot (Aristolochia fangchi Y.C. Wu ex L.D. Chow & S.M. Hwang), mainly in these weight-loss preparations, has highlighted the risk of using preparations which contain aristolochic acids. Aristolochic acid A (Fig. 10.2) is nephrotoxic and has been responsible for several deaths from renal failure. Aristolochia and other species containing these compounds are banned from sale in Europe and the USA, but may still be present in imported Chinese medicines, and A. fangchi has been found substituted for Stephania tetrandra S. Moore. Herbs containing these substances must not be used. The disastrous consequences of using them have been a wake-up call for the regulatory authorities and the herbal industry. On the other hand, in many regions of the world species from the genus are widely used as local and traditional medicines especially in the treatment of gastrointestinal complaints like diarrhoea, of snake bites and poisoning, and of gynaecological conditions, including the treatment of sexually transmitted diseases (STDs) such as syphilis and gonorrhoea (Heinrich et al 2009; Nortier et al 2000).

Aconitine and controversial claims about ‘detoxification’

Aconitum species (Ranunculaceae) are widely distributed throughout the northern hemisphere and have been used medicinally for centuries. They provide a fascinating example of a highly toxic botanical drug, which, according to claims made by some practitioners, can be detoxified by means of its method of preparation. The tubers and roots of Aconitum species such as Aconitum kusnezoffii Reichb. and Aconitum japonicum Thunb. are commonly used in Traditional Chinese Medicine in the treatment of conditions including syncope, rheumatic fever, painful joints, gastroenteritis, diarrhoea, oedema, bronchial asthma, various types of tumour and even some endocrinal disorders like irregular menstruation. However, the cardio- and neurotoxicity of this drug is potentially lethal, and the improper use of Aconitum in China, India, Japan and some other countries still results in a high risk of severe intoxication Singhuber et al 2009.

Based upon the regulations stipulated by the State Food and Drug Administration of China (SFDA), only the processed (i.e. ‘detoxified’) tubers and roots of Aconitum are allowed to be administered orally or adopted as raw materials for pharmaceutical manufacturing. To date, more than 70 traditional and modern techniques are applied for processing Aconitum roots for medicinal use. In China, only two assays are accepted for the quantitative determination of the alkaloid content in Aconitum species in the Chinese Pharmacopoeia 2005, and these allow a maximum of 0.15% and 0.20% respectively of alkaloids, calculated as aconitine. Botanical drugs which are below this threshold can be used medicinally in China but this position is not accepted in Europe.

Monoterpenes and phenylpropanoids

Most mono- and sesquiterpenes found in essential oils are fairly safe, apart from causing irritation when used undiluted and allergic reactions in susceptible individuals. However, some have been shown to be carcinogenic, for example safrole (from Sassafras bark) and β-asarone (from Acorus calamus L.) (Fig. 10.3). They do not appear to give cause for concern when present in minute amounts in other oils. Methysticin, from nutmeg, is toxic in large doses, and has been postulated as being a metabolic precursor of the psychoactive drug methylene dioxymethamphetamine. Thujone (Fig. 10.3), which is present in wormwood (Artemisia absinthium L.) and in the liqueur absinthe, is also toxic and hallucinogenic in large doses.

Urushiol derivatives

The urushiols (Fig. 10.7), anacardic acids and ginkgolic acids are phenolic compounds with a long side-chain. The uroshiols are found in poison ivy (Toxicodendron radicans (L.) Kuntze) and poison oak [T. quercifolium (Michx.) Greene] and cause severe contact dermatitis. This is a major problem in the USA, but less so in Europe where the plants are not native. The anacardic acids, which are found in the liquor surrounding the cashew nut (Anacardium occidentale L.), are less toxic. The ginkgolic acids are reputed to cause allergic reactions; however, they are present in the Ginkgo biloba seed more than in the leaf, which is the medicinal part. Ginkgo rarely causes this sort of reaction so in practice it is not regarded as a health hazard.

The examples above are not comprehensive but highlight some core problems and how this can be controlled with appropriate pharmaceutical measures.