Plant Poisons and Traditional Medicines

Plant Poisons and Traditional Medicines

76  Plant Poisons and Traditional Medicines JEFFREY K. ARONSON KEY POINTS • The recreational use of plants for their stimulant, aphrodisiac, or hall...

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76 

Plant Poisons and Traditional Medicines JEFFREY K. ARONSON

KEY POINTS • The recreational use of plants for their stimulant, aphrodisiac, or hallucinogenic effects is ancient, and throughout the ages plants have been used as poisons. • Many plants that are regarded as poisonous have been used for their supposed therapeutic properties, but while many can still be found in herbals, not all have found their way into modern formularies. In contrast, many tropical plants are used herbally, although evidence of efficacy is often poor or lacking. • Traditional medicines exist in many forms and lack standardization; very few have been rigorously tested for toxicity, especially for their long-term effects. • Traditional medicines are often prescribed as complex mixtures with uncertain pharmacology, or are prepared and taken by patients themselves. Poisoning occurs because the herb is itself toxic, has been mistaken for another plant, mislabelled, mixed accidentally or deliberately with other, poisonous, plants and medicines, contaminated with insecticides or herbicides, or, as in the Asian kushtays, mixed with appreciable amounts of heavy metals. Herbal medicines are also used in combination with allopathic drugs, and the often unpredictable effects of such combinations add to the hazards. • Plant poisoning can occur as a result of accidental, unknowing, or deliberate poisoning from contaminated foodstuffs or from toxic seeds and fruits; from the misuse of traditional or herbal medicines; or from the deliberate use of plants for their psychotropic or supposedly aphrodisiac properties.

Introduction Since ancient times, people have used plants as sources of chemicals, for therapeutic and recreational purposes and for poisoning.1 Curare (from Chondodendron tomentosum Figure 76.1), a toxin used by South American Indians as an arrow poison (the word toxin comes from a Greek word meaning ‘a bow’), is a good example of a poison that has been harnessed therapeutically.2 Its pharmacological action on skeletal muscle was demonstrated by Claude Bernard in 1856,3 and curare was introduced into anaesthetic practice in 1942.4 Many plants that are regarded as poisonous have been used for their supposed therapeutic properties, but while many can still be found in herbals, not all have found their way into 1128

modern formularies. Some therapeutically useful chemicals found in plants are listed in Table 76.1. However, the list is relatively short and although ethnopharmacology aims to remedy that, there are difficulties.5 There have been few successes. When the US National Cancer Institute, in collaboration with the US Department of Agriculture initiated a plant screening programme for anticancer drugs from 1960 to 1981, over 114 000 plant extracts from an estimated 15 000 species were screened, representing about 6% of the world’s plant species; only about 4% of the extracts had any activity and of those, only taxol eventually got beyond phase II studies.6 In contrast, many tropical plants are used herbally, although evidence of efficacy is often poor or lacking. Recent harnessing of ancient remedies has also been singularly unimpressive, a rare exception being the development of artemisinin derivatives from qinghao (Arte­ misia annua; Figure 76.2).7 The recreational use of plants for stimulant, aphrodisiac, or hallucinogenic effects is also ancient.1,8,9 In contrast to most of the therapeutic plants listed in Table 76.1, many of these plants are native to the tropics. Examples include absinthe (Artemisia absinthium);10 ayahuasca (a combination of Banisteriopsis spp. and a plant such as Psychotria viridis or Diplopterys cabrerana, as a source of dimethyltryptamine, a 5-HT2A, 5-HT2C and 5-HT1A receptor agonist;11 betel leaves (Piper betle) taken with areca (betel) nuts (Areca catechu); cannabis; cocaine; Jimson weed (Datura stramonium); kava (Piper methysticum); khat (Catha edulis); mescalin or peyotl (Lophophora williamsii); morning glory (Ipomoea tricolori); nicotine (from many plants, including Nicotiana tabacum); nutmeg (Myristica fragrans; Figure 76.3); ololiuqui (Rivea corymbosa); opioids; and pituri (Duboisia hopwoodii). The ascomycete Ophiocordyceps sinensis (or Cordyceps sinensis),12 also called Chinese caterpillar fungus and more recently Himalayan Viagra, is a parasitic fungus that grows in symbiosis with the ghost moth genus Thitarodes in the mountains of Tibet and Nepal, where it is called ‘yarchagumba’; it is a prized Chinese traditional medicine and a Tibetan folk remedy and has been used as an aphrodisiac. Plants are also sometimes used for culinary purposes; examples include Papaver rhoeas, whose seeds are used to decorate bread and as a filling in the delicious Jewish pastry called Hamantaschen (literally Haman’s ears), eaten in remembrance of the events in Persia that are recounted in the book of Esther; tansy (Tanacetum vulgare) used to make tansy cakes, for consumption at Easter time; cannabis in hashish fudge (a recipe for which can be found in The Alice B Toklas Cook Book13), space cakes or hash brownies (which featured in the 1968 movie I Love You, Alice B Toklas); and a wealth of vegetables (such as cassava and yams) and culinary herbs and spices, too numerous to be listed.



76  Plant Poisons and Traditional Medicines

TABLE 76.1 

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Some Commonly Used Therapeutic Agents that Originally Derived from Plants (see also Tables 76.2 and 76.3)

Drug

Example of Medical Use

Plant of Origin

Artemisinin derivatives Atropine Cannabinoids Capsaicin Cephaeline Cocaine Colchicine Curare Digoxin/digitoxin Ephedrine Gamolenic acid Hyoscine (scopolamine) Ispaghula Opioid alkaloids Physostigmine Pilocarpine Quinine Salicylates

Malaria Anticholinergic Palliative care Painful neuropathies [Emetogenic] Local anaesthetic Gout, Familial Mediterranean Fever Anaesthesia Atrial fibrillation and heart failure Sympathomimetic Mastodynia Anticholinergic Laxative Analgesia Myasthenia gravis Glaucoma Malaria Analgesics

Sennosides Taxanes Theophylline Topoisomerase inhibitors Vinca alkaloids

Purgative Cytotoxic Asthma Cancers Cytotoxic

Artemisia annua (qinghao) Atropa belladonna (deadly nightshade) Cannabis sativa (cannabis) Capsicum spp. (peppers) Cephaelis ipecacuanha (ipecacuanha) Erythroxylon coca (coca) Colchicum autumnale (autumn crocus) Chondodendron tomentosum (pareira) Digitalis lanata/purpurea (foxgloves) Ephedra sinica (sea-grapes) Oenothera biennis (evening primrose) Datura stramonium (thorn apple) Plantago ovata (ispaghula) Papaver somniferum (poppies) Physostigma venenosum (Calabar bean) Pilocarpus jaborandi (jaborandi) Cinchona pubescens (cinchona) Spiraea ulmaria (meadowsweet) Salix alba (willow) Gaultheria procumbens (wintergreen) Cassia acutifolia (senna) Taxus spp. (yew trees) Camellia sinensis (tea plant) Camptotheca acuminata (cancer tree) Catharanthus rosea (Madagascar periwinkle)

And, of course, throughout the ages plants have been used as poisons. Socrates, for example, executed himself at the behest of the state, supposedly using hemlock (Conium maculatum), although the exact poison that was used is disputed.14 We do not know what the hebenon was that Hamlet’s uncle poured in the elder Hamlet’s ear, but it may have been from henbane (Hyoscyamus niger; Figure 76.4) or some form of yew (Taxus; German Eibenbaum). And aconite (from Aconitum napellus; Figure 76.5) is a toxin that has been used as an arrow poison and was a favourite of professional poisoners in the Roman empire; it is still to be found in some Chinese herbs15 and has

been used as a homicidal poison in modern times.16 Poisons were so commonly used as weapons of assassination that Mithridates, King of Pontus (120–63 bc), tried to prepare a universal antidote for poisoning (hence called a ‘mithridate’) by combining many substances in a single formulation, which he then took in increasing doses, in an attempt to achieve immunity to their toxic effects.17 Traditional medicines exist in many forms and lack standardization; very few have been rigorously tested for toxicity, especially for their long-term effects. They are often prescribed as complex mixtures with uncertain pharmacology or are

Figure 76.1  Chondodendron tomentosum (curare).

Figure 76.2  Artemisia absinthium (wormwood).

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Figure 76.3  Myristica fragrans (nutmeg).

prepared and taken by patients themselves. Poisoning occurs because the herb is itself toxic, has been mistaken for another plant, mislabelled, mixed accidentally or deliberately with other, poisonous, plants and medicines, contaminated with insecticides or herbicides, or, as in the Asian kushtays, mixed with appreciable amounts of heavy metals.18 Herbal medicines are also used in combination with allopathic drugs, and the often unpredictable effects of such combinations add to the hazards.19

Figure 76.4  Hyoscyamus niger (henbane).

Figure 76.5  Aconitum napellus (monkshood).

Plant poisoning can occur as a result of accidental, unknowing, or deliberate poisoning from contaminated foodstuffs or from toxic seeds and fruits; from the misuse of traditional or herbal medicines; or from the deliberate use of plants for their psychotropic or supposedly aphrodisiac properties. Contact dermatitis can occur from contact with irritant plants.20 A report from the Uppsala Monitoring Centre of the WHO has summarized all suspected adverse reactions to herbal medicaments reported from 55 countries worldwide over 20 years.21 A total of 8985 case reports were on record. Most originated from Germany (20%), followed by France (17%), the USA (17%), and the UK (12%). Allergic reactions were the most frequent serious adverse events and there were 21 deaths. The relative lack of reports from tropical countries may have been because of poor reporting. Not all parts or constituents of a poisonous plant are poisonous. The stalks of rhubarb can be eaten, but the leaves contain toxic oxalates; all parts of the yew are poisonous except the fleshy red aril. The purgative castor oil is expressed from the beans of Ricinus communis, but the beans also contain the highly toxic alkaloid ricin. Ackee fruit is poisonous only when unripe. Furthermore, the amount of toxic ingredient in a single part of a plant varies from season to season. Nor are all poisonous plants poisonous to all species. Goats, for example, can eat foxgloves and nightshade with impunity, since they eliminate their toxic ingredients rapidly; bees can harvest pollen from poisonous plants, such as rhododendrons, which contain grayanotoxins, and the honey so produced may be poisonous to humans (see below).22 One should not be misled by seeing an animal feed on a plant, into thinking that it is safe for human consumption. The frequency of exposure to poisonous plants is difficult to assess. Many reports are anecdotal. In one series of 912 534 plant exposures in the USA, Philodendron spp. were the most commonly implicated, followed by Dieffenbachia, Euphorbia, Capsicum, and Ilex.23 In a series of 135 cases of severe plant poisonings (23 children, 112 adults) in Switzerland, including

five deaths, 12 plants were the most commonly involved: Atropa belladonna (n = 42); Heracleum mantegazzianum (18); Datura stramonium (17); Dieffenbachia (11); Colchicum autumnale (10); Veratrum album (8); Aconitum napellus (4); Aesculus hip­ pocastanum (3); Hyoscyamus niger (3); Ricinus communis (3); Oenanthe crocata (2); and Taxus baccata (2).24 Of 277 cases of acute poisoning in South Africa during 12 months, 18% were due to ingestion of traditional medicines; 26% were fatal.25 In 1306 cases of acute poisoning during 5 years, 16% were due to traditional medicines; 15% of these were fatal and poisoning with traditional medicines resulted in the highest mortality, accounting for 52% of all deaths due to acute poisoning.26 In a review of the American Association of Poison Control Centers (AAPCC) 1983–2009, there were 668 111 reported exposures to plants during 2000–2009, of which 621 109 were exposures to single substances.27 In all, 8.9% of all exposures involved plants in 1983, 6.0% in 1990, 4.9% in 2000, and 2.4% in 2009. Male subjects accounted for 52% of ingestions and over 60% of the moderate and major outcomes; children aged 5 years or under accounted for 81% of plant exposures. Only 45 deaths were recorded between 1983 and 2009; Datura and Cicuta species were responsible for 36%. There is no simple way of classifying poisonous plants, other than by the scientific names of their genera and species and even those change from time to time. Furthermore, many disparate plants contain compounds with similar effects. This chapter contains a mixture of headings, using either the names of the plants or their chief constituents; or terms that describe their chemical or pharmacological characteristics or their clinical effects. The following discussion will not be restricted to plants that are found only in tropical areas.

Alcohol The history of alcohol is as ancient as human history, and plants play a central part in its production. Rum (65–72% alcohol) is distilled from fermented molasses in the West Indies and South America; arrack or sake (50–60%) is manufactured from fermented rice in India, China, Java, and Japan. Toddy, made from the sweet sap of various palms, such as coconut, is drunk in India, Sri Lanka, and West Africa. A potent drink, pulque, is made in South America from the juice of agaves. The main medical and psychiatric problems caused by alcohol are: • acute alcohol intoxication; • chronic alcoholism associated with chronic organ damage (e.g. cirrhosis, cardiomyopathy); • alcohol withdrawal reactions (delirium tremens). In the brain, alcohol acts as a dose-dependent depressant, producing the well-known features of intoxication. At plasma concentrations of around 40 mg/dL (400 mg/L or 8.7 mmol/L) learned skills are impaired, including the ability to maintain self-restraint. Other early effects include loss of attentiveness, loss of concentration, and impaired memory, and there may be lethargy. At progressively higher concentrations, there are further changes in mood, behaviour, and a variety of sensory and motor functions. The effects on mood depend on the individual’s personality, mental state, and social environment. Commonly, there is euphoria, but any kind of mood change can occur. Libido is often enhanced, but sexual performance is impaired. Alcohol generally increases confidence, often

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resulting in aggressive or silly behaviour; loss of self-restraint leads to increased loquacity with immoderate speech content, such as swearing or the use of lewd language. Unsteadiness of gait, slurred speech, and difficulty in carrying out even simple tasks, with impaired coordination, become obvious at plasma concentrations of about 80 mg/dL (the concentration above which driving is illegal in many countries). Driving skills are therefore impaired and are affected even at concentrations below 80 mg/dL. Recovery from dazzle is delayed, which can impair night-time driving. Visual acuity, peripheral vision, colour vision, and visual tracking are impaired. Hearing and taste may also be impaired. The pain threshold is increased. At high concentrations, there may be vertigo and nystagmus. Alcohol causes acute drowsiness and deep sleep; in high concentrations it causes coma and respiratory depression. In some individuals, sleep may later be impaired. On waking, there is the characteristic ‘hangover’, which usually consists of irritability, headache, thirst, abdominal cramps, and bowel disturbance. The cause of hangover is not known. Delirium tremens is an acute withdrawal reaction that can be fatal. The symptoms come on within a few hours after the last drink and mount over the next 2–3 days. At first, there is anxiety, agitation, tremulousness, and tachycardia. These are later accompanied by confusion, severe agitation, and hallucinations (often visual). The patient is tremulous, sweating, and tachypnoeic and may be pyrexial, dehydrated, hypoglycaemic, and vitamin-deficient. The blood pressure may be high, low or normal. Nausea and vomiting are common. Seizures can occur and can be prolonged and potentially life-threatening. The medical management of alcohol withdrawal (including delirium tremens) involves the maintenance of fluid and electrolyte balance, the administration of vitamins (particularly thiamine to prevent Wernicke’s encephalopathy), a highcarbohydrate and high-calorie diet, and the use of sedating drugs to suppress symptoms and prevent seizures. Treatment is with a benzodiazepine (such as chlordiazepoxide) or clomethiazole. For many years, disulfiram (Antabuse®) and calcium carbamide have been prescribed in an attempt to prevent relapse in abstinent alcoholics. They act by inhibiting the enzyme aldehyde dehydrogenase, which results in a rapid build-up of blood acetaldehyde if the subject drinks. This produces severe vomiting and diarrhoea, along with potentially dangerous alterations in blood pressure. However, adherence to therapy is usually poor and the evidence of effectiveness probably does not justify the unpleasant adverse reactions that these drugs can cause. Two newer drugs show some promise. Naltrexone is a µ-opioid (MOR or OP3) receptor antagonist, whose use was suggested by demonstrated links between alcohol and opioid receptors. Small uncontrolled and placebo-controlled trials have suggested that it significantly reduces the likelihood and severity of relapse in comparison with placebo.28,29 Acamprosate is derived from the amino acid taurine and has structural similarities to GABA. In the brain it reduces the effects of excitatory amino acids, such as glutamate, and alters GABA neurotransmission. Clinical trials have suggested that it is significantly better than placebo in preventing or delaying relapse, with a very low incidence of adverse reactions.30 It can cause diarrhoea, nausea, vomiting, or abdominal pain; occasionally it causes pruritus or a maculopapular rash. However, behavioural interventions may be at least as good as either naltrexone or acamprosate31 or even better.32

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Allergic Reactions to Plants Some people are allergic to certain fruits (avocado, banana, chestnut, fig, kiwi, lychee, mango, melon, olives, papaya, passion fruit, peach, pineapple, and tomato),33,34 nuts (such as chestnuts35), vegetables (such as celeriac, carrots, turnips,36 zucchini,36 or cassava37), or even spices.38 This is one expression of the so-called pollen–food allergy syndrome. Allergy can be acquired by either direct sensitization via the gastrointestinal tract or by primary sensitization to plant pollen or latex.39 There are at least 13 latex allergens found in the rubber tree Hevea brasiliensis and recognized by the International Union of Immunological Societies; they are known as Hev b 1, 2, 3, etc.40,41 Latex-fruit allergy may be associated with the enzyme β-1,3-glucanase (Hev b 2),42 since the glucanase in some fruits and vegetables has allergenic properties mediated by well-conserved IgE-binding epitopes on the surface of the enzyme, which might account for the IgE-binding cross-reactivity that is often reported in people with the latex–fruit syndrome.43 Other enzymes that have been implicated include UDP glucose pyrophosphorylase,44 fructosebisphosphate aldolase and glyceraldehyde-3-phosphate dehydrogenase.45 Hevein (Hev b 6.02)46 and a latex profilin (Hev b 8)47 have also been implicated. Some fruit and vegetable allergies have been related to allergens in other forms of pollen, such as birch (Betula spp.),48,49 grass,50 mugwort,51–53 and ragweed.54,55 The clinical manifestations of latex-fruit allergy range from urticaria to angio-oedema, rhinoconjunctivitis, bronchial asthma, and anaphylactic shock.56–59 The prevalence depends on the method used to identify it; in 182 children 16 of 26 latexsensitized children cross-reacted to fruits.60 Many tropical plants cause contact dermatitis, with erythema, vesiculation, or urticaria. Contact with the leaves of Toxicodendron (formerly Rhus) spp. (poison ivy, poison oak, or poison sumach) causes intense irritation and inflammation.61,62 In Japan severe dermatitis can follow contact with lacquer made from Toxicodendron vernicifluum.63 Treatment consists of thorough washing of the skin with soap and water and removal of the poison from the clothes by soaking in 1% hypochlorite solution. Dermatitis can be caused by pyrethrum in Chrysanthemum spp.64 Exposure to the leaves and flowers causes itching, usually beginning at the corners of the eyes, and lachrymation, followed by an irritating vesicular rash, peeling of the skin, and the formation of painful fissures. Sweating and exposure to sunlight exacerbate the lesions. Urticaria and photosensitivity have also been reported. Many plants and flowers, such as the Euphorbias (which contain phorbol esters), orchids, primulas, lilies, and mangos, can cause allergic dermatitis in sensitive people. The juice of some of the umbelliferae contains photosensitizing furano­ coumarin derivatives that on contact with the skin cause erythema and vesication after exposure to light. The manchineel, Hippomane mancinella (Figure 76.6), like many other members of the Euphorbiaceae, produces a highly irritant latex.65 This small tree is common along the coastlines of South and Central America, the West Indies, and India. Both varieties, one with leaves like holly and the other like laurel, are poisonous. The attractive fruit resembles a crab-apple and sensitive people who touch it develop erythema, bullae, and vesiculation. The wood and even the sawdust are irritant and can cause dermatitis, frequently of the genitalia and anus, with a vesiculopustular eruption, sometimes confined to the glans

Figure 76.6  Hippomane mancinella (manchineel).

penis. In the eye the latex causes keratoconjunctivitis, with pain, photophobia, and blepharospasm. If the fruit is eaten it causes vesiculation of the buccal mucosa, with superinfection, bloody diarrhoea, and sometimes death. Latex on the skin should be washed off at once; blisters should be protected against infection and, if extensive, treated like second-degree burns. Seaweed dermatitis has been reported from Hawaii, probably as a result of contact with an alga, Microcoleus lyngbyaceus, which produces a rash in persons bathing in the sea off windward beaches.66 The dust from certain trees, such as iroko (African teak), pine, mahogany, satinwood, and obeche, can cause skin irritation, facial oedema, blepharospasm, acute coryza, and pharyngitis.67 Asthma and rhinitis have also been reported. In 361 of 76 697 patients with rosacea, there were positive reactions to the resin of Myroxylon pereirae (balsam of Peru) in 5.9%.68 The crushed leaves of henna (Lawsonia inermis) are used as a cosmetic agent world-wide, particularly in the Middle East. It causes a red-brown coloration of the skin. The name is also used for other dyes, such as black henna or neutral henna, which do not derive from the plant. Traditionally, henna is used as a pure dye prepared from the stems and the leaves of the plant, with the addition of coffee or tea to enhance the colour. Contact allergy and immediate hypersensitivity reactions are rare and when contact dermatitis after the use of henna tattoos has been reported it has often been attributed to the sensitizer paraphenylenediamine, which is used as an anti-oxidant and favours a long-lasting effect of the henna.69 The use of paraphenylenediamine in henna is responsible for early sensitization to it in children and in some cases local hypopigmentation occurs in the tattoo.70 ARGEMONE MEXICANA AND EPIDEMIC DROPSY Epidemic dropsy is caused by sanguinarine, an alkaloid constituent of several plants, including the Mexican poppy, Arge­ mone mexicana (Figure 76.7). The small, black, oily seeds of



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Figure 76.8  Digitalis purpurea (purple foxglove).

Figure 76.7  Argemone mexicana (Mexican poppy).

Argemone resemble those of mustard and can become mixed with them accidentally or by deliberate adulteration. Village boys in India can collect up to 8 kg of Argemone seeds a day in summer and may sell them to unscrupulous dealers. As a contaminant of a widely used cooking oil derived from mustard seed, Argemone has led to outbreaks of so-called ‘epidemic dropsy’ in many tropical countries. Sanguinarine is absorbed from the gut and through the skin if oil containing it is used for massage.71 It causes capillary dilatation and increased permeability. Epidemic dropsy is seen mostly in India,72 but has also been reported in Mauritius, Fiji, South Africa, and Nepal.73 It presents with gastrointestinal symptoms a week or so before the onset of pitting oedema of the legs, fever, and darkening of the skin, often with local erythema and tenderness. Perianal itching is common and severe myocarditis and congestive cardiac failure can occur. Other features include hepatomegaly, pneumonia, ascites, alopecia, and sarcoid-like skin changes. Glaucoma can occur, as can visual field disturbances independent of any rise in intraocular pressure.74 Haemolytic anaemia occurs when oxidative stress causes methaemoglobin formation by altering pyridine nucleotides and glutathione redox potential; treatment with antioxidants has been suggested to be effective.75 A decoction of Argemone mexicana, used as a traditional medicine, has also been used in the treatment of malaria.76 CARDIOTOXIC GLYCOSIDES IN PLANTS The number of plants worldwide that contain cardiac glycosides (cardenolides or bufadienolides) is legion – one incomplete list77 runs to nearly 400 compounds and spans genera such as the Apocynaceae, Asclepiadaceae, Cruciferae, Liliaceae, Moraceae, Ranunculaceae, and Schrophulariaceae. Some examples are given in Table 76.2 and Figure 76.8.

Some cardenolides (such as digoxin and digitoxin, obtained from foxgloves; Figure 76.8) are used therapeutically, but even then adverse reactions are common, because these drugs have a low therapeutic index.78 Poisoning with plants containing cardenolides is not uncommon. One example is the current TABLE 76.2 

Some Plants that Contain Cardiac Glycosides (Cardenolides or Bufadienolides)

Scientific Name

Common Name(s)

Acokanthera ouabaio/schimperi Adenium multiflorum Adonis vernalis

Olmorijoi/ Murichu Impala lily False hellebore, yellow pheasant’s eye Upas tree Black Indian hemp Redheaded cotton-bush Balloon cotton Milkweed Climbing potato King’s crown Bushman’s poison Wintersweet Sea-mango Pong pong Lily of the valley Pig’s ears Rubber vine Woolly foxglove Purple foxglove Spindle tree Glory lily Christmas rose Homeria Oleander Silkvine Frangipani Squill Various Ordeal tree Yellow oleander Savannah flower Squill

Antiaris toxicaria Apocynum cannabinum Asclepias curassavica Asclepias fruiticosa Asclepias syriaca Bowiea kilimandscharica Calotropis procera Carissa acokanthera Carissa spectabilis Cerbera manghas Cerbera odollum Convallaria majalis Cotyledon orbiculata Cryptostegia grandiflora Digitalis lanata Digitalis purpurea Euonymus europaeus Gloriosa superba Helleborus niger Homeria pallida Nerium oleander Periploca sepium Plumeria rubra Scilla maritima Strophanthus spp. Tanghinia venenifera Thevetia peruviana Urechites suberecta Urginea maritima

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epidemic of self-poisoning with the seeds of oleander trees in South India and Sri Lanka. In one series of 300 cases of selfpoisoning with Thevetia peruviana (yellow oleander) (mostly women aged 11–20, of whom 97% took crushed seeds), the main symptoms were vomiting, palpitation, epigastric pain, a burning sensation in the abdomen, shortness of breath, and diarrhoea; sinus bradycardia, sinus arrest, sinoatrial block and heart block were common.79 In Madagascar, the ordeal tree (Tanghinia venenifera) was used to test the innocence or guilt of an accused person; death on eating it signified guilt. The odollam tree, Cerbera manghas,80 another ordeal tree of former times, which contains the card­ enolide cerberin, is responsible for about 50% of cases of plant poisoning and 10% of total poisoning cases in Kerala, India, and has been used both for suicide and homicide;81 cases have also been reported in Sri Lanka.82 Poisoning can also occur by eating crabs that have eaten Cerbera manghas fruits.83 In one series of 4556 cases of self-poisoning in Sri Lanka, 2.5% were caused by plants and mushrooms; the glory lily Gloriosa superba84 was responsible in 44% of those (i.e. 50 cases);85 the toxic effects of Gloriosa are due to both cardenolides and colchicine alkaloids. Plants containing cardenolides that have been used as arrow poisons include Acokanthera schimperi in Africa86 and the upas tree (Antiaris toxicaria; Figure 76.9) in Malaysia and China.87,88 Boophone distichia (candelabra flower), used as an arrow poison in southern Africa, may have antidepressant properties.89 Treatment of cardenolide poisoning is largely supportive, but special attention should be paid to potassium balance, since cardenolides inhibit Na/K-ATPase (the Na/K pump), inhibiting the influx of potassium into cells; the severity of toxicity and therefore the prognosis, is related to the degree of hyperkalaemia that results. Fab fragments of antidigoxin antibody are effective not only in poisoning with digoxin but also with many other cardiac glycosides;90 they have been used in oleander poisoning, but without evidence of an effect on mortality.91 In contrast, repeated doses of activated charcoal (50 g 4-hourly)

Figure 76.9  Antiaris toxicaria (upas tree).

TABLE 76.3 

Some Species that Contain Cyanogenic Glycosides

Species

Glycoside

Acacia Deidamia Gynocardia Linum Loyus Lucuma Macadamia Manihot Nandina Pangium Prunus Sambucus Sorghum Taxus Tetrapathaea Trifolium Triglochin Vicia Zieria

Acaciapetalin Deidaclin Gynocardin Linamarin Lotaustralin Lucumin Proteacin Lotaustralin Proteacin Gynocardin Amygdalin, prunasin Sambunigrin Dhurrin Taxiphyllin Tetraphyllins Linamarin Triglochinin Vicianin Zierin

reduced mortality in a large randomized study from 8.0% to 2.5%, probably by encouraging the intestinal secretion of the toxic cardenolides that oleander seeds contain.92 In another study of patients with less severe poisoning and an overall lower mortality, this treatment did not reduce mortality,93 and it is probably most effective in those with severe poisoning. CYANOGENIC GLYCOSIDES IN PLANTS Cyanogenic glycosides are found in several plants,94,95 and in certain butterflies,96 protecting them against predators. Some of their sources are listed in Table 76.3. Cassava (Manihot esculenta; Figure 76.10) is a native of South America and sub-Saharan Africa, which is widely grown in the tropics for the production of flour and tapioca. The grated roots must be thoroughly washed to remove the toxic material. Badly prepared cassava causes signs of hydrocyanic acid poisoning: nausea, vomiting, abdominal distension and respiratory difficulty. Chronic cassava ingestion can cause an ataxic neuropathy, with bilateral primary optic atrophy, bilateral perceptive deafness, myelopathy and peripheral neuropathy.97 Previous reports of goitre and pancreatitis as chronic effects have not been confirmed. Konzo (‘tired legs’), a symmetrical, non-progressive, nonremitting spastic paraparesis, which occurs in epidemic and endemic forms in several African countries,98 and is invariably associated with consumption of inadequately processed bitter cassava roots and minimal protein; it may be associated with thiamine deficiency.99 It has also been proposed that konzo, tropical ataxic neuropathy (also associated with cassava consumption), and lathyrism (associated with consumption of the grass pea, see below) are all caused by the fact that they contain cyano groups with direct neurotoxic actions not mediated by systemic cyanide release.100 The Bio Cassava Plus programme in sub-Saharan Africa aims to develop and deliver genetically engineered cassava containing increased amounts of nutrients, such as zinc, iron, protein, and vitamin A, to increase shelf-life, reduce the cyanogenic glycoside content, and improve resistance to viruses.101



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with edible varieties in order to deter theft by strangers. Deaths have occurred from the consumption of bitter yams.103 Treatment of acute cyanide poisoning includes gastric lavage with 5% sodium thiosulfate within 1 hour if possible; 300 mL of 25% sodium thiosulfate should be left in the stomach. Di­ cobalt edetate (dicobalt EDTA, 600 mg in 40 mL over 1 min) should be given intravenously as soon as possible in all cases of poisoning. If recovery does not occur within 1–2 min, another 300 mg of dicobalt edetate should be given. Oxygen (100%) should also be given and acidosis should be corrected with sodium bicarbonate. If dicobalt edetate is not available, give 10 mL of 3% sodium nitrite over 3 min intravenously, followed by 25 mL of 50% sodium thiosulfate over 10 min intravenously. ERGOT

Figure 76.10  Manihot esculenta (cassava).

The broken kernels of certain fruits also contain cyanogenic glycosides, particularly Prunus spp. (plums, peaches, cherries, apricots, almonds) and loquats (Eriobotrya japonica; Figure 76.11). The active principle, amygdalin (laetrile), has been used in patients with cancer; however, it is ineffective and adverse reactions have been not uncommon.102 Yams are the tubers of Dioscorea of many varieties, including bitter toxic species, such as D. dumetorum and D. hirsuta, which contain cyanogenic glycosides, such as diosgenin. They can be steeped and washed in water and eaten sliced, but if badly prepared they are toxic. Bitter yams are sometimes interplanted

Ergot (Claviceps purpurea) is a fungus whose sclerotia contain ergotoxine and related alkaloids that stimulate smooth muscle. It is harvested with the ears of rye and other grasses. Chronic consumption of small amounts causes uterine and vascular contraction, resulting in abortion, arterial occlusion, and painful gangrene.104 In the Middle Ages, this was called St Anthony’s fire, because it was relieved by a pilgrimage to the shrine of St Anthony, in an area that was not affected by the fungus. Acute consumption of large amounts can cause headache, vertigo, hallucinations, and convulsions; the Salem witches may have been victims of this. Ergot poisoning, although easy to prevent, still occurs from careless harvesting in times of food shortage; it can also occur with deliberate hallucinogenic or abortifacient use. Vasodilators, such as sodium nitroprusside, ease ischaemic pain and help to prevent gangrene.105 Derivatives of ergot are used therapeutically (e.g. bromocriptine in Parkinson’s disease) and as hallucinogens (e.g. LSD).

Gastroenteritis due to Compounds in Plants

Figure 76.11  Eriobotrya japonica (loquat).

Jequirity beans (Abrus precatorius; Figure 76.12) and castor oil beans (Ricinus communis; Figure 76.13)) are bright and attractive and are sometimes made into necklaces. Ricinus is the source of the purgative castor oil and Abrus has been used to treat schistosomiasis. However, these beans contain poisons that, after a delay of 1–48 hours, can cause fatal gastroenteritis; their toxic principles, abrin and ricin, are among the most poisonous substances known;106 one bean can kill a child. Acute poisoning is treated by gastric lavage, demulcents and adjustment of fluid and electrolyte balance. Abdominal pain may require analgesics. In serious cases ventilation or haemodialysis may be needed. Modeccin, a lectin found in Adenia digitata, the wild granadilla,107 may have similar properties to those of abrin and ricin.108 Abrin and ricin both consist of two components, an α chain and a β chain; the former is toxic and is carried into cells by the latter, from which it then dissociates.109 This action has been put to use therapeutically, by conjugating the β chain of ricin to monoclonal antibodies for use, for example, in the treatment of leukaemias.110 The dose is limited by the risk of a vascular leak syndrome. Because ricin is so easily prepared from castor oil beans, there has been some concern in recent years that it might be

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SECTION 13  Environmental Disorders

Figure 76.12  Abrus precatorius (jequirity).

used as a weapon of mass terror, particularly because it was supposed to have been the agent that was used to kill the Bulgarian dissident Georgi Markov, who was thought to have had it injected into his leg in a metal pellet via the medium of an umbrella tip.111 However, this fear is largely unfounded.112 Although ricin is highly toxic, oral administration results only in effects on the gut and impracticably large amounts would be needed (e.g. to contaminate water supplies); mass parenteral or inhalational delivery is unrealistic. On 15 October 2003, a metal canister was found in a package in a Post Office in Greenville, South Carolina, with a note threatening to poison water supplies if certain demands were not met; there was ricin in the canister, but the threat came to nothing.113 Many other plants can cause gastrointestinal disturbances, such as nausea, vomiting, and diarrhoea. These include the

Figure 76.13  Ricinus communis (castor bean).

Figure 76.14  Phytolacca americana (pokeweed).

Euphorbia spp., Phytolacca americana (Figure 76.14), and all plants that contain cardiac glycosides (Table 76.2) or cucurbitacins (such as Bacopa monnieri, Begonia heracleifolia, Bolbo­ stemma paniculatum, Bryonia aspera, Cayaponia racemosa, Citrullus colocynthis, Coutarea hexandra, Cucurbita pepo, Ecbal­ lium elaterium, Elaeocarpus hainanensis, Gratiola officinalis, Hemsleya endecaphylla, Kageneckia oblonga, Leucopaxillus gen­ tianeus, Luffa operculata, Momordica balsamina, Morierina montana, Neopicrorhiza scrophulariiflora, Physocarpus capitatus, Picrorrhiza scrophulariaeflora, Picria fel-terrae, Trichosanthes tri­ cuspidata, and Wilbrandia ebracteata). Severe gastrointestinal toxicity can sometimes cause heart block, secondary to vagal stimulation.114 The leaves of Dieffenbachia spp. cause damage to the mucosa of the gastrointestinal tract if chewed or swallowed; this has been attributed to their oxalate content.115 The sap can also cause corneal damage. The attractive red berries of Arum maculatum (cuckoo-pint or lords and ladies) can cause burning of the mouth, tongue, and oesophagus, followed by nausea, haematemesis, and intestinal and other smooth muscle spasm.116 However, poisoning is rarely serious. Lectins are phytohaemagglutinins that are resistant to digestion in the gut but are removed from food by proper cooking. They affect the integrity of the intestinal epithelium and the absorption of dietary antigens and cause release of allergic mediators from mast cells in vitro. Many plants, such as Jatro­ pha macrorhiza (Figure 76.15)117 and Euonymus europaeus, contain lectins,118 which, if not destroyed by cooking, can cause severe vomiting and bloody diarrhoea, in some cases followed by damage to the central nervous system, the cardiovascular system, and the kidneys. Coral plants, Jatropha curcas, J. glan­ dulifera, and J. multifida, grow rapidly and are used as hedges in Africa and the West Indies. Their fruits, physic nuts, taste like sweet almonds but have been reported to cause colic, cramps, thirst, and hypothermia. Another species, J. gossypifolia, is



76  Plant Poisons and Traditional Medicines

Figure 76.15  Jatropha gossypifolia (bellyache bush).

known in the West Indies as the bellyache bush. The potential uses of lectins, such as those found in Viscum album (mistletoe), Phaseolus vulgaris (common beans), Robinia pseudoacacia (black locust), and Agaricus bisporus (button mushrooms), in the treatment of cancers have been investigated.119 Croton spp., which are widespread in the tropics cause violent purgation. They contain phorbol esters, which activate protein kinase C,120 are carcinogenic, and can cause contact dermatitis.121 The ackee, Blighia sapida Figure 76.16; (named after Captain Bligh of the Bounty) is a native of West Africa but is common in the West Indies and South America. The fruit has a large fleshy aril and is eaten when ripe; however, the unripe fruit is poisonous and has caused ‘vomiting sickness’ in Jamaica and other islands.122 Unripe ackee fruits contain toxic hypoglycins, hypoglycin A (L-α-aminomethylenecyclopropylpropionic acid) and its γ-glutamyl conjugate, the less toxic hypoglycin B.123 Hypoglycin A is metabolized to methylenecyclopropylacetic acid, which reduces several cofactors that are essential for β-oxidation of long-chain fatty acids and inhibits the transport of long-chain fatty acids into mitochondria. Accumulation of short-chain fatty acids in the serum results from suppression of short-chain acyl-CoA dehydrogenases and β-oxidation, leading to omega-oxidation of long-chain fatty acids in the liver. Reduced fatty acid metabolism causes increased use of glucose and hypoglycaemia.124,125 Anaphylaxis and cholestatic jaundice have also been reported. Typically, poisoning presents with abdominal discomfort and vomiting, usually within 6–48 hours of ingestion, and a few hours later convulsions and coma. Extreme hypoglycaemia occurs and unless glucose is given promptly, death usually occurs within 12 hours of the initial vomiting. The liver shows fatty changes, with almost complete absence of glycogen.

bradycardia, heart block, asystole, and hypotension.126 There have been many anecdotal reports of these complications in people who have eaten honey prepared by bees from Rhododen­ dron luteum, Rhododendron mucronulatum, Rhododendron pon­ ticum, or Castanea sativa;127–142 myocardial infarction has also been reported.143 In one case, poisoning from Rhododendron simsii occurred when a baby’s grandmother prepared a decoction of the plant in milk.144 Poisoning with Agauria salicifolia has also been reported in a series of cases from Reunion Island145 and a case from the Mascarene Islands.146 In the eastern Black Sea region of Turkey, where most cases have been reported, such honey is called ‘bitter honey’ or ‘mad honey’. It is often used as a household remedy for various conditions, including stomach pains, bowel disorders, hypertension, and erectile dysfunction.147 Because of variations in the plant content of grayanotoxins, poisoning with honey made in the spring is more severe.147 However, honey poisoning is rarely fatal and the effects generally last for no more than 24 hours. Common adverse reactions that have been reported in case series include nausea, vomiting, salivation, sweating, dizziness, and weakness several hours after ingestion and in some cases hypotension, sinus bradycardia, or complete atrioventricular block.148–152 Blurring of vision and diplopia have also been reported.153 Deliberate self-poisoning has been used as a means of enhancing sexual performance.154 Muscarinic M2 receptors in the vagus are involved in the cardiotoxicity of grayanotoxins,155,156 and bradycardia and heart block in these cases respond to atropine, as in toxicity with Veratrum alkaloids. However, temporary pacing may sometimes be required.157

Haemotoxicity due to Compounds in Plants HAEMOLYSIS IN GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY Deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD) in erythrocytes results in reduced production of NADPH. Consequently, oxidized glutathione (and to a lesser and insignificant extent methaemoglobin) accumulates. If the erythrocytes are then exposed to oxidizing agents, haemolysis occurs, probably because of unopposed oxidation of sulphydryl

GRAYANOTOXINS IN PLANTS Certain species of rhododendron contain grayanotoxins (andromedotoxins), which open sodium channels. In the heart, this effect can trigger the Bezold–Jarisch reflex and cause

1137

Figure 76.16  Blighia sapida (ackee).

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SECTION 13  Environmental Disorders

groups in the cell membrane, which are normally kept in reduced form by the continuous availability of reduced glutathione. The prevalence of this defect varies with race. It is rare among Caucasians and occurs most frequently among Sephardic Jews of Asiatic origin, of whom 50% or more are affected. It also occurs in about 10–20% of Blacks. Inheritance of the defect is sex-linked but complex, the genetic basis for the abnormal enzyme being heterogeneous; most of the variations produce an unstable enzyme. In the variety that affects Blacks (but is not confined to them) G6PD production is probably normal, but its degradation is accelerated, so that only erythrocytes older than about 55 days are affected; acute haemolysis occurs on first administration of the drug and lasts for only a few days, after which continued administration causes chronic mild haemolysis. In the Mediterranean variety the enzyme is abnormal and both young and old erythrocytes are affected; in this form severe haemolysis occurs on first administration and is maintained with continued administration. Occasionally methaemoglobinaemia can also occur.158 The reaction is sometimes called favism, because it can result from eating broad beans (Vicia faba; Figure 76.17), which contain oxidant substances such as divicine and isouramil.159 In a high proportion of patients with the Mediterranean form there is a mutation in the G6PD gene, G6PD(C563T).160 The condition is rare in Thailand, probably because the G6PD mutants that occur there are different.161

Figure 76.18  Allium sativum (garlic).

IMPAIRED PLATELET AGGREGATION Some plants contain compounds that inhibit platelet aggregation,162 e.g. Ginkgo biloba, the maidenhair tree, extracts from the leaves of which are marketed in some countries for the treatment of cerebral dysfunction and of intermittent claudication,

garlic (Allium sativum; Figure 76.18) and saw palmetto (Serenoa repens; Figure 76.19). As a result, bleeding complications can occur, including strokes.

Hepatotoxicity due to Compounds in Plants HEPATITIS The number of plants that have reportedly caused acute liver damage is legion.163 The pattern is a rise in serum activities of the so-called liver enzymes (aspartate and alanine aminotransferases), which is usually rapidly reversible; occasionally death

Figure 76.17  Vicia faba (broad bean).

Figure 76.19  Serenoa repens (saw palmetto).



76  Plant Poisons and Traditional Medicines

1139

Figure 76.20  Piper methysticum (kava).

Figure 76.22  Crotalaria verrucosa (blue rattlesnake).

can occur. Plants that have been reported to cause acute liver damage include Breynia officinalis,164 Callilepis laureola (ox-eye daisy),165 Camellia sinensis (green tea),166 Chelidonium majus (celandine),167 Cimicifuga racemosa (black cohosh; Figure 76.21),168,169 Larrea tridentata (chaparral),170 Piper methysticum (kava; Figure 76.20; see below under Psychotropic drugs), Polygonum multiflorum,171 Symphytum officinale (comfrey; see below under Sinusoidal obstruction syndrome)172,173 and Teu­ crium spp.174,175 Of these, black cohosh, chaparral, comfrey, and kava are the most common culprits.

Eupatorium, Heliotropium, Petasites, Senecio (Figure 76.23), and Symphytum (Table 76.4).178 They can contaminate foodstuffs;179 examples include Senecio jacobaea in Europe and Ageratum conyzoides in Ethiopia.180 They may contaminate pollen and hence honey.181,182 They may also be found in certain plants that are used in some forms of traditional medicine.183 Certain representatives of this class and the plants in which they occur, are hepatotoxic as well as mutagenic and carcinogenic. They can cause the sinusoidal obstruction syndrome (veno-occlusive disease of the liver),184 with clinical features that

Hepatic Carcinoma Aspergillus flavus and A. parasiticus produce aflatoxins that are toxic to the liver and are carcinogenic;176 e.g. the consumption of contaminated groundnuts has been linked with hepatic carcinoma in Africa and Asia.177 Sinusoidal Obstruction Syndrome (Veno-Occlusive Disease) and Pyrrolizidine Alkaloids Pyrrolizidine alkaloids occur in a large number of plants, notably the genera Crotalaria (Figure 76.22), Cynoglossum,

Figure 76.21  Cimicifuga racemosa (black cohosh).

Figure 76.23  Senecio vulgaris (groundsel).

TABLE 76.4 

Plants that Contain Pyrrolizidine Alkaloids

Genus

Pyrrolizidine Alkaloids

Genus

Pyrrolizidine Alkaloids

Crotalaria albida Crotalaria anagyroides Crotalaria aridicola Crotalaria axillaris Crotalaria barbata Crotalaria burha Crotalaria candicans Crotalaria crassipes Crotalaria crispata Crotalaria dura Crotalaria fulva Crotalaria globifer Crotalaria goreensis Crotalaria grahamiana Crotalaria grantiana Crotalaria incana Crotalaria intermedia Crotalaria laburnifolia Crotalaria madurensis Crotalaria mitchelii Crotalaria mucronata Crotalaria nana Crotalaria novae-hollandiae Crotalaria retusa Crotalaria semperflorus Crotalaria spectabilis Crotalaria stricta Crotalaria trifoliastrum Crotalaria usaramoensis Crotalaria virgulata Crotalaria walkeri Cynoglossum amabile Cynoglossum glochidiatum Cynoglossum lanceolatum Cynoglossum latifolium Cynoglossum officinale Cynoglossum pictum Cynoglossum viridiflorum Eupatorium cannabinum Eupatorium maculatum Heliotropium acutiflorum Heliotropium arguzoides Heliotropium curassavicum Heliotropium dasycarpum Heliotropium eichwaldii Heliotropium europeum Heliotropium indicum Heliotropium lasiocarpum Heliotropium olgae Heliotropium ovalifolium Heliotropium ramosissimum Heliotropium strigosum Heliotropium supinum Heliotropium transoxanum Petasites japonicus

croalbidine anacrotine, methylpyrrolizidine various dehydropyrrolizidines axillaridine, axillarine crobarbatine croburhine, crotalarine crocandine, cropodine retusamine crispatine, fulvine crotaline fulvine crotaline, globiferine hydroxymethylenepyrrolizidine grahamine grantianine anacrotine integerrimine, usaramine crotalaburnine, hydroxysenkirkine crotafoline, madurensine retusamine mucronitine, mucronitinine crotaburnine, crotananine retusamine retusamine crosemperine retronecanol crotastrictine various alkylpyrrolizidines usaramine, usaramoensine grantaline, grantianine acetylcrotaverrine, crotaverrine amabiline, echinatine amabiline cynaustine, cynaustraline latifoline heliosupine echinatine, heliosupine heliosupine, viridiflorine echinatine, supinine echinatine, trachelantimidine heliotrine trichodesmine angelylheliotridine heliotrine angelylheliotrine acetyl-lasiocarpine, helioitrine acetylindicine, indicine, indicinine heliotrine, lasiocarpine heliotrine, incanine, lasiocarpine heliofoline heliotrine strigosine heliosupine, supinine heliotrine fukinotoxin, petasinine, petasinoside platyphylline seneciphylline macrophylline angulatine aquaticine retrorsine, senecionine floridanine, florosenine, otosenine neosenkirkine seneciphylline brasilinecine campestrine senecicannabine carthamoidine jacobine, seneciphylline senampelines jacobine doronine erucifoline, floridanine retrorsine,ionine franchetine, sarracine

Senecio fuchsii Senecio gillesiano Senecio glabellum Senecio glandulosus Senecio glastifolius Senecio hygrophylus Senecio ilicifolius Senecio illinitus Senecio incanus Senecio integerrimus Senecio isatideus Senecio jacobaea

fuchsisenecionine retrorsine, senecionine integerrimine, senecionine retrorsine, senecionine graminifoline hygrophylline, platyphylline pterophine, senecionine acetylsenkirkine, senecionine seneciphylline integerrimine, senecionine isatidine, retrorsine jacobine, jacoline, jaconine, jacozine, otosenine, renardine acetylsenkirkine, senkirkine seneciphylline senecifolidine, senecifoline retrorsine, senecionine integerrimine, longiboline, retronecanol, retrorsine, riddelline, senecionine, seneciphylline macrophylline mikanoidine nemorensine, oxynemorensine floridnine, onetine, otosenine bisline, isoline seneciphylline paucicaline bisline retrorsine, seneciphylline neoplatyphylline, platyphylline, sarracine, seneciphylline, platyphylline, seneciphylline sarracine, seneciphylline procerine seneciphylline senecionine pterophine retrorsine, senecionine, uspallatine renardine, seneciphylline, senkirkine isatidine, retrorsine neoplatyphylline, platyphylline, sarracine, seneciphylline riddelline angeloyloxyheliotrine rosmarinine ruwenine, ruzorine sarracine isatidine, scleratine senecivernine seneciphylline, spartoidine senecionine, squalidine seneciphylline seneciphylline retrorsine, senecionine swazine triangularine senecionine, uspallatine senecivernine anacrotine, neoplatyphylline senecionine senecionine asperumine, echinatine, heliosupine echinatine, heliosupine, lasiocarpine, symphytine, viridiflorine echinatine, heliosupine, lasiocarpine, symphytine, viridflorine anadoline heneicisane, tricosane acetylintermedine, acetyllycopsamine, uplandicine

Senecio adnatus Senecio alpinus Senecio amphibolus Senecio angulatus Senecio aquaticus Senecio argentino Senecio aureus Senecio auricula Senecio borysthenicus Senecio brasiliensis Senecio campestris Senecio cannabifolius Senecio carthamoides Senecio cineraria Senecio cissampelinum Senecio crucifolia Senecio doronicum Senecio erraticus Senecio filaginoides Senecio franchetti

Senecio kirkii Senecio kubensis Senecio latifolius Senecio leucostachys Senecio longibolus

Senecio macrophyllus Senecio mikanoides Senecio nemorensis Senecio othonnae Senecio othonniformis Senecio palmatus Senecio paucicalyculatus Senecio petasis Senecio phillipicus Senecio platyphylloides Senecio platyphyllus Senecio pojarkovae Senecio procerus Senecio propinquus Senecio pseudoarnica Senecio pterophorus Senecio ragonesi Senecio renardi Senecio retrorsus Senecio rhombifolius Senecio Riddellii Senecio rivularis Senecio rosmarinifolius Senecio ruwenzoriensis Senecio sarracenicus Senecio scleratus Senecio seratophiloides Senecio spartioides Senecio squalidus Senecio stenocephalus Senecio subalpinus Senecio subulatus Senecio swaziensis Senecio triangularis Senecio uspallatensis Senecio vernalis Senecio vira-vira Senecio viscosus Senecio vulgaris Symphytum asperum Symphytum caucasicum Symphytum officinalis Symphytum orientale Symphytum tuberosum Symphytum uplandicum

include abdominal pain, ascites, hepatomegaly and spleno­ megaly, anorexia, nausea, vomiting, and diarrhoea. Sometimes there is also damage to the lungs. The primary pathological change of hepatic sinusoidal obstruction syndrome is subendothelial oedema, followed by intimal overgrowth of connective tissue, with narrowing and occlusion of the central and sublobular hepatic veins. Atrophy or necrosis of liver cells, with consequent fibrosis, leads to gross changes similar to those seen in cardiac cirrhosis; portal hypertension results.163 In the West Indies185 sinusoidal obstruction syndrome is related to the consumption of bush tea made from plants such as Crotalaria and Senecio.186 Hepatotoxic compounds in Crota­ laria, Senecio, and Heliotropium, and other composite plants can also enter the diet through contamination of cereals with weed seeds. For example, 28 of 67 patients died with sinusoidal obstruction syndrome in central India after consuming a local cereal, gondii, contaminated with the seeds of Crotalaria.187 Heliotropium popovii has been implicated in outbreaks in villages in north-western Afghanistan, with high mortality.188

Nephrotoxicity due to Compounds in Plants Djenkol beans (Pithecolobium) cause poisoning in Malaysia, Java, and Thailand. Blood and casts appear in the urine and the renal tract may be blocked, causing acute kidney damage;189 crystals of djenkolic acid can form urinary calculi.190 Treatment is by alkalinizing the urine (pH 8) by giving sodium bicarbonate by intravenous infusion (250 mL of a 3.5% solution four times in a single day for a 70-kg adult). Aristolochia fangchi (Chinese snakeroot), and perhaps other constituents of Chinese herbal slimming remedies, can cause a nephropathy191 through progressive interstitial fibrosis. It may also cause urothelial carcinoma.192 Nephrotoxicity has been incorrectly attributed to Stephania tetrandra (Chinese: fang-ji) through confusion with Aristolochia (Chinese: quang-fang-ji). Other species of Aristolochia are used medicinally elsewhere.193 The active ingredient, aristolochic acid, has also been implicated in Balkan endemic nephropathy, a chronic tubulointerstitial disease associated with urothelial cancer, which affects people living in the alluvial plains along the tributaries of the River Danube.194 Oxalate-rich foods (spinach, rhubarb, beets, nuts, chocolate, tea, wheat bran, and strawberries) increase urinary oxalate excretion, predisposing to renal calculi.195 Rarely acute oxalate toxicity can occur, e.g. due to ingestion of raw rhubarb stalks or leaves.196

76  Plant Poisons and Traditional Medicines

Figure 76.24  Cycas circinalis (cycad).

increased tone in the leg muscles, causing sufferers to walk on the balls of their feet with a lurching gait. The arms can also be affected. Sensory signs are absent. Grass pea is a profitable cash crop that is used as a cheap adulterant in flour from other pulses; lathyrism is likely to occur in places remote from grass pea cultivation and follows food shortages in India and Africa. Strains with low toxin content have been developed.200 The poison-nut (Strychnos nux-vomica; Figure 76.26) is the source of poisonous alkaloids (strychnine, vomicine, icajine, brucine). Strychnine is an antagonist of the actions of the inhibitory neurotransmitter glycine in the spinal cord and causes painful convulsions.201

Neurotoxicity due to Compounds in Plants In some countries, the root stocks of cycads (Cycas and Zamia) are used as foodstuffs. The seeds of Cycas circinalis (Figure 76.24), eaten by the Chamorro people of Guam and neigh­ bouring islands197 contain a neurotoxic amino acid, β-Nmethylamino-l-alanine, which is thought to cause amyotrophic lateral sclerosis, Parkinsonism, and dementia.198 A related condition, lathyrism, is caused by Lathyrus sativus (Figure 76.25), the grass pea, which contains the neurotoxin β-N-oxalylamino-l-alanine.199 It causes a symmetrical motor spastic paraparesis, with a pyramidal pattern and greatly

1141

Figure 76.25  Lathyrus sativus (grass pea).

1142

SECTION 13  Environmental Disorders

Figure 76.26  Strychnos nux-vomica (poison-nut).

The fruit of Diospyros mollis (maklua) contains a derivative of hydroxynaphthalene and is used in Thailand for treating intestinal worms. It is oculotoxic202 and has been reported to cause optic neuritis in children. Water hemlock is the common name that is given to two genera of plants, Cicuta and Oenanthe, which contain the conjugated polyacetylenes cicutoxin and oenanthotoxin, which are non-competitive gamma-aminobutyric acid (GABA) antagonists and can cause seizures, which can be fatal.203 Other features include nausea, vomiting, diarrhoea, tachycardia, mydriasis, rhabdomyolysis, renal failure, coma, respiratory impairment, and cardiac dysrhythmias.

Figure 76.27  Datura stramonium (Jimson weed).

from millet distributed by a local branch of the National Milling Corporation.207 Jimson weed has also been used as a drug of abuse, because of its hallucinogenic properties.208,209 Other plants that can cause anticholinergic poisoning include angel’s trumpet (Brugmansia spp., now called Datura),210 found in Central and South America and prepared as a tea for its hallucinogenic effects and jessamine (Gelsemium semper­ virens; Figure 76.28),211 which is native to North and Central America.

Parasympathetic Nervous System Actions due to Compounds in Plants ANTICHOLINERGIC COMPOUNDS Anticholinergic compounds, such as atropine, hyoscine (scopolamine), and semisynthetic derivatives, are widely used therapeutically (for example, in Parkinson’s disease and as adjuncts to anaesthesia). Poisoning causes tachycardia, a dry mouth and hot dry skin, dilated pupils (mydriasis), blurred vision and loss of accommodation, difficulty in micturition, confusion, an acute psychosis with hallucinations, and convulsions; glaucoma can occur in elderly people, as can acute urinary retention in men with prostatic enlargement. Treatment of poisoning is symptomatic; although physostigmine has been used to reverse anticholinergic effects,204,205 it has a short duration of action, tolerance to its beneficial effects occurs, and it can cause adverse reactions – it should not be used except in life-threatening poisoning.206 The thorn apple or Jimson weed, Datura stramonium (Figure 76.27), grows in most parts of the world and is a frequent cause of poisoning in cereal crops. The seeds contain alkaloids of the tropane series, notably hyoscyamine. One outbreak of poisoning in Tanzania involved the consumption of porridge made

Figure 76.28  Gelsemium sempervirens (jessamine).



76  Plant Poisons and Traditional Medicines

The seeds of various species of Datura have been used in cases of criminal poisoning in tropical countries. D. fastuosa was a favourite poison of practitioners of thagi in India, D. sanguinea is used in Colombia and Peru, D. ferox and D. arborea in Brazil, and the leaves of Hyoscyamus fahezlez by the Tuareg in the Sahara. The seeds of D. stramonium with D. metel have been used in East Africa for criminal purposes, as an inebriant to facilitate robbery or to elicit confessions of witchcraft. CHOLINERGIC COMPOUNDS Drugs can cause cholinergic effects either by stimulating acetylcholine receptors or by inhibiting acetylcholinesterase. Drugs that stimulate acetylcholine receptors, of which nicotine and muscarine are the prototypes, are used therapeutically (e.g. pilocarpine in glaucoma) and are found in a wide variety of plants. The effects of poisoning are constricted pupils (miosis); hypersalivation and sweating; nausea, vomiting, and diarrhoea; bradycardia; and headache, vertigo, confusion, delirium, hallucinations, coma, and convulsions. Bronchorrhoea, bronchospasm, and pulmonary oedema produce respiratory failure, the usual cause of death. Most cases of cholinergic poisoning with flowering plants have been reported with laburnum in temperate zones; other cases have been reported with hemlock (Conium maculatum; Figure 76.29).212 Many fungi contain cholinergic compounds, and muscarinic poisoning can occur with, for example, jack o’lantern (Ompha­ lotus olearius), Clitocybe spp., and Inocybe spp. In severe cases of poisoning with Amanita spp. there may be cholinergic symptoms, but the main effects are due to the GABAergic compound muscimol.213 Anticholinesterases potentiate the actions of acetylcholine by inhibiting its breakdown. Solanine is one such compound, found in plants of the Solanum spp., including the unripe berries of the bittersweet nightshade (S. dulcamara) and greened tubers of potatoes (S. tuberosum). However, S. dulcamara

1143

poisoning can also present with anticholinergic effects.214 Accidental or suicidal poisoning can occur with anticholinesterase organophosphorus insecticides;215 treatment is with atropine216 and cholinesterase reactivators, such as pralidoxime and obidoxime.217

Psychotropic Drugs in Plants AYAHUASCA Ayahuasca218 (Quichua aya = spirit, huasca = vine) is a hallucinogenic beverage that is prepared by boiling the bark of the liana Banisteriopsis caapi, which contains the beta-carbolines harmine, harmaline, and tetrahydroharmine, with the leaves of various plants, such as Psychotria viridis (chacruna or jagé), Psychotria carthagenensis, or Diplopterys cabrerana (chagropanga), which contain N,N-dimethyltryptamine, a potent hallucinogen. Dimethyltryptamine is inactive orally, because it is metabolized by gut monoamine oxidase. However, the β-carbolines are highly active reversible inhibitors of monoamine oxidase; they inhibit the deamination of dimethyltryptamine, making it orally active. In vitro, ayahuasca inhibits monoamine oxidase in proportion to the concentrations of β-carbolines.219 Ayahuasca induces a psychedelic, visionary state of mind and is used for medical and religious purposes. Shamans may use it to inspire diagnoses. At South American shamanic ceremonies people gather to take ayahuasca and sing themselves into a collective trance. After oral administration, its dose-related hallucinogenic effects first occur after 30–60 minutes, peak at 60–120 minutes and resolve by 240 minutes.220 The experience is generally regarded as pleasant, although nausea is not uncommon and diarrhoea can occur; there are occasional dysphoric reactions, with transient disorientation and anxiety. Drug interactions are to be expected between ayahuasca and drugs that would be expected to interact with monoamine oxidase inhibitors, such as selective serotonin reuptake inhibitors (SSRIs).221 BETEL Chewing betel, the leaves of Piper betle [sic] (Figure 76.30), together with lime and areca (betel) nuts (Areca catechu) is a common practice in India, Sri Lanka, and other Eastern countries. It may act by inhibiting GABA uptake. The mouth, lips, and cheeks are stained bright red and the face is flushed; there is euphoria, heightened alertness, sweating, salivation, a hot sensation in the body, and an increased capacity to work; there are increases in heart rate, blood pressure, sweating, and body temperature.222 Betel chewers can also develop manganese toxicity through contamination of the plant.223 The presence of the codon 326 polymorphism in the hOGG1 gene may confer a greater risk of oral cancer in betel chewers.224 CANNABIS

Figure 76.29  Conium maculatum (hemlock).

Cannabis sativa (Figure 76.31), the hemp plant, yields marijuana and hashish. A cannabis smoker inhales at least 60 mindaltering chemicals, but the main psychoactive ingredient is delta-9-tetrahydrocannabinol (delta-9-THC), an antiemetic, antispasticity agent, appetite stimulant, analgesic, anxiolytic,

1144

SECTION 13  Environmental Disorders

Figure 76.30  Piper betle (betel).

hypnotic, and antipyretic, which also lowers intraocular pressure. However, its beneficial effects in terminal disease are disappointing. Marijuana (‘grass’, ‘weed’, ‘bush’, ‘herb’) is the dried mixture of crushed leaves and stalks of the plant. The flowering tops of the plant secrete a resin that can be compressed to form hashish (‘hash’, ‘blow’, ‘puff ’, ‘draw’, ‘ganja’, ‘dope’, ‘pot’) or dissolved into an oil or tincture. Marijuana is usually rolled in home-made cigarettes (‘spliffs’, ‘joints’ or, if enormous, ‘blunts’), with or without tobacco. Hashish is heated and crumbled on to tobacco in spliffs or smoked in a wide variety of pipes. In many parts of the world cannabis is an ingredient of a range of culinary preparations. Cannabis has physical and mental effects that begin within minutes.225 The physical effects include an increase in heart rate, peripheral vasodilatation, conjunctival suffusion, bronchodilatation, dryness of the mouth and, in large doses, tremor, ataxia, nystagmus, nausea, and vomiting. The mental effects

Figure 76.31  Cannabis sativa (hemp).

vary from person to person, depending on such variables as personality, mood, surroundings, expectations, and previous cannabis experience. Generally, there is a feeling of wellbeing, accompanied by feelings of enhanced sensory perception. There may be drowsiness or hyperactivity. Ideas flow rapidly and may be disconnected. Time seems to pass slowly. Motor performance may be altered, as it may be by any sedative drug, and driving skills may be impaired.226 There may be mild tolerance and a mild withdrawal syndrome, rather like a mild benzodiazepine withdrawal syndrome. Physical dependence does not seem to be a big problem, but psychological dependence does occur. Heavy use of marijuana is associated with social apathy, but this often precedes drug use and may not be an adverse effect. Adverse psychological reactions include anxiety, acute panic reactions, and paranoid ideas. Large doses can cause an acute toxic psychosis with confusion and hallucinations. There is controversy as to whether marijuana can produce a prolonged psychosis, but it can certainly aggravate pre-existing mental disease. Cannabis smoke contains more insoluble particulates and carcinogens than tobacco smoke, so lung and airways damage can be anticipated in heavy regular consumers. Birth defects occasionally follow use in pregnancy. Although cannabis causes little acute toxicity, long-term use is associated with cognitive impairment and can lead to dependence in a proportion of regular users.227 Smoking cannabis involves the additional risks of chronic lung damage and possibly cancer. COCA Erythroxylon coca (Figure 76.32) is widely grown in South America and India. The leaves are dried in the sun and are chewed with lime or, in India, with betel. Cocaine powder can be sniffed, prepared as a solution for intravenous injection, or separated from its hydrochloride and smoked as the free base or as ‘crack’ (so-called because of the popping and clicking of exploding impurities when it is burnt). Crack vaporizes at a much lower temperature than cocaine hydrochloride, so that the active ingredient escapes pyrolysis and reaches the lungs intact. Because the transfer from lung to brain is so fast, the impact of smoked cocaine gives a ‘rush’ comparable with that experienced after intravenous injection. However, the euphoriant effect also wears off quickly, producing a most unpleasant downswing of mood in many users, which they may attempt to fend off with repeatedly larger and larger doses. The clinical effects of cocaine (‘coke’, ‘snow’, ‘charlie’, or ‘crack’) include euphoria, increased drive, increased confidence, increased sociability, loquacity, and increased physical and mental capacities. After chewing there is loss of sensation in the tongue and lips. The tendency to take cocaine repeatedly to fend off rebound effects and the rapid tolerance that occurs to its euphoriant effects, combine to cause a typical pattern of escalating doses terminating in ‘crash’, characterized by exhausted sleep followed by depressed mood, which fuels the initiation of the next binge. Termination of a binge comes about either through physical or mental exhaustion or lack of money or further drug supplies. Repeated sniffing can cause perforation of the nasal septum. The use of prolonged and high dosages can lead to a cocaine-induced psychosis, not dissimilar from acute paranoid schizophrenia. There are no major physiological withdrawal



76  Plant Poisons and Traditional Medicines

1145

partly related to the fact that western formulations are prepared by lipid rather than aqueous extraction,240 although the evidence is not conclusive,241 and it has been suggested that it may be due to contamination of kava formulations with hepatotoxic moulds.242 KHAT

Ibogaine is the main active ingredient of Tabernanthe iboga, a West African shrub that grows in the Congo and Angola,233 and is isolated from the root bark. It has been used traditionally as a hallucinogen, to suppress hunger and fatigue, and as an aphrodisiac. In high doses it can cause convulsions and paralysis, and deaths have been reported. It is an indole that is an antagonist at serotonin and NMDA receptors. Another constituent, tabernanthine, is an antagonist at GABAA receptors. Taber­ nanthe iboga has been used in Gabon to induce a near-death experience for spiritual and psychological purposes.234 It has been used for anti-addictive purposes,235 leading to the development of a congener, 18-methoxycoronaridine.236

Khat or qat (cafta, miraa, muiragi) is a stimulant commonly used in East Africa, Yemen, and southern Saudi Arabia and is derived from a small tree, Catha edulis.243 The leaves and twigs are chewed while fresh, but can also be smoked, infused in tea, or sprinkled on food. The khat alkaloids are absorbed first from the oral cavity and then from the gut, justifying slow chewing.244 It produces euphoria and loquaciousness, with a misleading sensation of sharpened mental processes, because it contains cathinone (S[–]alpha-aminopropiophenone) and cathine (norpseudoephedrine), phenylalkylamines that are related to ephedrine and have amphetamine-like properties.245 Cathinone increases dopamine release and reduces dopamine re-uptake.246 Khat is often used in social gatherings called ‘sessions’, which can last 3–4 hours. They are generally attended by men, although khat use among women is growing. Men are also more likely to be daily users. Users pick the leaves, chew them on one side of the mouth, swallow only the juice and add fresh leaves periodically. About 100–300 g of khat may be chewed during each session and 100 g of khat typically contains 36 mg of cathinone. It is estimated that 10 million people chew khat worldwide and it is used by up to 80% of adults in Somalia and Yemen. It is also used by immigrant African communities in the UK and USA. It is banned in Saudi Arabia, Egypt, Morocco, Sudan, Kuwait, the USA, and European countries. However, in Australia its importation is controlled by a licence issued by the Therapeutic Goods Administration, which allows up to 5 kg of khat per month per individual for personal use. Khat has many adverse effects.247 It increases blood pressure and heart rate and may increase the risk of acute myocardial infarction. It can cause headaches. Psychosis has been reported with heavy use. Constipation is common, and anorexia, stomatitis, gastritis, and oesophagitis can also occur. Khat use can lead to dependence, and khat users may devote significant amounts of time to acquiring and using it, to the detriment of work and social responsibilities. The physical effects of early khat withdrawal are generally mild. Chronic users may experience craving, lethargy, and a feeling of warmth during early khat abstinence. Chronic consumption may be genotoxic.

KAVA

NICOTINE

The powdered root of Piper methysticum, prepared as a beverage, is drunk on festive occasions throughout Polynesia.237 Formerly, the root was prepared by mastication by selected girls, a practice that caused the spread of tuberculosis. The actions of some of its constituents include altered activity at GABAA receptors and inhibition of voltage-dependent sodium channels. Over-indulgence in kava causes a state of hyperexcitement, with loss of power in the legs. Chronic intoxication leads to weight loss, raised liver enzymes, nausea, loss of appetite and a reversible ichthyosiform eruption (kava dermopathy).238 In the west hepatotoxicity has often been reported;239 this may be

The leaves and flowers of Nicotiana spp. (Figure 76.33) have been universally smoked, snuffed, or chewed for their stimulant effects. Preparations of the leaves applied to the chest to relieve respiratory complaints have sometimes given rise to toxic effects by percutaneous absorption of nicotine. However, nicotine is much more widespread in plants and occurs in such diverse species as Acacia spp., Aesculus hippocastanum, Asclepias spp., Duboisia spp. Echeviria spp., Erythroxylon coca, Juglans regia, Mucuna pruriens, Prunus spp., Sempervivum arachnoideum, and Urtica dioica. During the nineteenth and early part of the twentieth century, Australian Aborigines used pituri, a

Figure 76.32  Erythroxylon coca (coca).

reactions, but troublesome dysphoria and craving can persist for months or even years. When it is taken during pregnancy, cocaine can cause constriction of the uterine and placental blood vessels and damage the fetus by depriving it of oxygen and other nutrients.228 Besides its adverse neuropsychiatric effects,229,230 long-term cocaine abuse also has adverse effects on other organs, including the heart and skin.231,232 IBOGAINE

1146

SECTION 13  Environmental Disorders

Figure 76.33  Nicotiana tabacum (tobacco).

nicotine-containing preparation from the cured leaves of Duboisia hopwoodii.248 Green tobacco sickness is an occupational illness reported by tobacco workers worldwide.249 It causes nausea, vomiting, headache, weakness, and dizziness.250,251 Among farm workers in shade tobacco fields in Connecticut 15% had diagnoses that could be attributed to possible green tobacco sickness (ICD9);252 using a stricter case definition, the frequency fell to 4%. Non-smokers were significantly more likely than smokers to report symptoms, particularly isolated symptoms of headache and dizziness. An unusual nostrum made by the Yoruba people of Nigeria is ‘cow’s urine mixture’, which consists of green tobacco leaves, rock salt, citron (Citrus medica), the leaves of the bush basil, Ocimum viride, and cow’s urine.253 The remedy is swallowed or rubbed into the skin for prevention and treatment of epileptic or eclamptic fits; the toxic effects are those of nicotine – central nervous excitation, with vomiting, diarrhoea, dehydration, and hypoglycaemia, followed by depression and coma, sometimes with permanent neurological damage or death. Convulsions must be controlled and glucose given intravenously. The poison is removed by gastric lavage or cleansing of the skin; blood glucose, electrolytes, and fluid balance should be monitored. OPIUM ALKALOIDS AND THEIR DERIVATIVES Opioid dependence is a worldwide public health menace associated with a great deal of criminal activity. Heroin (‘smack,’ ‘junk’, ‘gear’, ‘brown’) is the opiate chosen by 75% and heroinrelated referrals are increasing by at least 15% per year. On initial use there may be nausea, vomiting, and anxiety, but these symptoms disappear with subsequent use and euphoria becomes predominant. As tolerance develops and the cost of the habit increases, the addict may switch to the intravenous route to maximize value for money. In an attempt to retain the euphoria (the ‘rush’) that results from rapidly increased concentrations of the drug in the brain, larger and larger doses will be used.

Tolerance to constipation and pupillary constriction does not occur to any great extent. Eventually the addict becomes most concerned with combating withdrawal symptoms and needs a regular supply of the drug to avoid them. Withdrawal symptoms begin at about 8 hours after the last dose and reach a peak at about 36–72 hours. Symptoms occur in the following order: • Psychological symptoms: anxiety, depression, restlessness, irritability, drug craving • Lachrymation, rhinorrhoea, mydriasis, yawning, sweating, tachycardia, and hypertension • Restless sleep, after which the above symptoms are accompanied by sneezing, anorexia, nausea, vomiting, abdominal cramps, diarrhoea, bone pain, muscle pain, tremor, weakness, chills and goose-flesh (‘cold turkey’), twitching and jerking of the legs (‘kicking the habit’), and insomnia. Hypotension, cardiovascular collapse, and convulsions occur rarely. These symptoms gradually fade over about 5–10 days, during which time, general malaise, and abdominal cramps persist. This withdrawal syndrome is not as bad as has been widely depicted in literature and is not fatal.254 With methadone, the onset of withdrawal symptoms is delayed for 24–48 hours and peaks at 3–4 days; because of this slower effect, methadone is often used to help an addict withdraw, by substituting it for morphine or heroin. PSILOCYBIN Psilocybin was isolated in 1957 from the Psilocybe mexicana mushroom and it has since been identified as a component of over 75 distinct mushroom species.255 Psilocybin-containing mushrooms, also called ‘magic mushrooms’, are used recreationally.256 Psilocybin and psilocin are listed as Schedule I drugs under the United Nations 1971 Convention on Psychotropic Substances. Psilocybin content varies based on such factors as species and preparation. The most commonly used mushroom is Psilocybe cubensis, which contains 10–12 mg of psilocybin per gram of dried mushrooms; effective oral doses range from 6 to 20 mg and about 40 µg/kg is considered the threshold level for intoxication.257 Psilocin is a high-affinity agonist at serotonin 5-HT2A receptors, which are especially prominent in the prefrontal cortex. It increases cortical activity secondary to down-stream post­ synaptic glutamate effects. It is also active at 5-HT1A, 5-HT1D, and 5-HT2C receptors, although these are thought to play a lesser role in its effects. In the presence of the 5-HT2A antagonist ketanserin, the changes in mental state that psilocybin typically causes do not occur.258 Although psilocybin has no affinity for dopamine D2 receptors, a PET study using the D2 receptor ligand raclopride showed that psilocybin increases dopamine transmission in the striatum, probably through secondary increases in dopamine.259,260 Some psilocybin-containing mushrooms contain phenylethylamine, which may contribute to sympathomimetic effects. Psilocybin alters mood, perception and cognition. In healthy volunteers, changes in emotion, consciousness, perception, and thought begin within 20–30 min, peak at 30–50 min, persist for 2 hours, and resolve within 6 hours. Lower doses may produce shorter-lasting effects of 1–2 hours. Moderate oral doses (12–30 mg) alter consciousness, increase introspection, and



76  Plant Poisons and Traditional Medicines

induce derealization, dream-like states, illusions, complex hallucinations, synaesthesia, and altered perceptions of time and space. Muscle relaxation also occurs during intoxication. Altered attention causes difficulty in disengaging from prior stimuli and impairment in monitoring several simultaneous visual stimuli.261 Euphoria, grandiosity, and other amplifications of affective experience are common. Most psilocybin users experience a pleasant alteration in mood, but some panic or become dysphoric. A user’s expectations and environment very strongly influence the hallucinogenic effects. Settings with more interpersonal support reduce panic and paranoia and increase positive experiences.262 Adverse reactions to psilocybin include hypertension, exacerbation of pre-existing psychosis, and hallucinogen persisting perceptual disorder.263 Trauma can occur if people believe that they have superhuman powers.264

Treatment of Poisoning This is not the place for a thorough description of the treatment of poisoning,265 but a few simple principles are summarized in Table 76.5.

Drug Interactions with Compounds in Plants Drug interactions can occur between plant medicaments and allopathic medicines.266–268 Some of these are summarized in Table 76.6. Many of these interactions are poorly attested, being

TABLE 76.5 

1147

anecdotal. However, interactions with grapefruit and St John’s wort are well described and are dealt with below. PHARMACODYNAMIC INTERACTIONS If a herbal medicine shares a pharmacological action with an allopathic remedy, it may potentiate its therapeutic or adverse effects; the following are examples: • Digitalis and plant remedies containing cardioactive glycosides (Strophanthus, Convallaria, Cytisus, Scilla); furthermore, some herbal medicines can interfere with serum digoxin radioimmunoassays269–271 Antihypertensive drugs and hypotensive herbs (Rauwolfia, • Crataegus, Viscum) • Oral hypoglycaemic drugs and karela, the fruit of Momordica charantia; karela, which has a hypoglycaemic action,272 is used in curries and is a traditional Indian remedy for diabetes • Oral hypoglycaemic drugs and plants that contain alphaglucosidase inhibitory activity, such as chancapiedra (Phyllanthus niruri), zarzaparrilla (Smilax officinalis), yerba mate (Ilex paraguayensis), and huacatay (Tagetes minuta)273 • Antiasthma drugs and betel nut, which is thought to274have a bronchoconstricting effect, attributed to arecoline • ACE inhibitors and Capsicum spp. ACE inhibitors increase the amount of bradykinin in the lung and enhance the cough response to capsaicin, which acts by depleting substance P from nerve endings.

A Summary of the Management of Acute Self-Poisoning

Target

Therapeutic Action

1.

Respiratory function

2.

Circulatory function

3. 4. 5.

Renal function Consciousness Temperature

6. 7. 8. 9. 10.

Convulsions Cardiac arrhythmias Gastric lavage Activated charcoal Fluid and electrolyte balance

11. 12.

Emergency measures Chest radiography

13.

Collection of specimens

Check gag reflex Remove dentures Clear out oropharyngeal obstructions, debris, secretions Lay on the left side with head down Insert oral airway or, if cough reflex lost, an endotracheal tube Give oxygen if hypoxic Assist respiration if required Check heart rate and blood pressure If systolic blood pressure below 80 mmHg (young patients) or 90 mmHg (old patients): Raise end of bed If ineffective, give volume expanders If fluid overload and oliguria: Give dopamine and/or dobutamine Monitor urine output Assess level of consciousness (Glasgow Coma Scale) Take temperature rectally; if below 36°C reheat slowly Warm all inspired air and intravenous fluids Treat with diazepam, clomethiazole, phenytoin, or anaesthesia with assisted ventilation Treat as required Not now recommended A single dose or repeated doses for some poisons Dehydration: oral fluids usually enough Unconscious patients: use intravenous fluids and insert a central venous line Treat hypokalaemia Specific to the poison In drowsy or comatose patients who vomit After endotracheal intubation Gastric aspirate (drugs) Urine (drugs, renal function) Blood (drugs, arterial gases, electrolytes)

1148

TABLE 76.6 

SECTION 13  Environmental Disorders

Some Reported Interactions of Medicinal Compounds with Plants and Herbal Products; Many of These Associations Have been Reported Anecdotally and Some Have not been Confirmed in Small Formal Studies

Plant(s)

Drug(s)

Outcome

Areca catechu (areca nut) Berberis aristata (berberine) Citrus paradisi (grapefruit juice)

Neuroleptic drugs Tetracycline Amiodarone

Exacerbation of extrapyramidal effects Prolonged diarrhoea in cholera Risk of amiodarone toxicity (e.g. cardiac arrhythmias) Prolongation of QT interval; risk of ventricular tachycardia Risk of ciclosporin toxicity (immunosuppression) Increased drowsiness; altered psychometric tests

Antihistamines (astemizole, terfenadine) Ciclosporin Benzodiazepines (alprazolam, diazepam, midazolam, triazolam) Calcium channel blockers (felodipine, nifedipine, nisoldipine) Lovastatin Quinidine

Cyanopsis tetragonolobus (guar gum) Eleutherococcus senticosus (Siberian ginseng) Gingko biloba (maidenhair) Glycyrrhiza glabra (liquorice) Hypericum perforatum (St John’s wort)

Saquinavir Sertraline Digoxin, glibenclamide, metformin, phenoxymethylpenicillin Digoxin Thiazide diuretics Corticosteroids Spironolactone Amitriptyline, ciclosporin, digoxin, finasteride, HIV protease inhibitors, irinotecan, oral contraceptives, phenprocoumon, theophylline Digoxin, indinavir

Panax ginseng (ginseng)

Pausinystalia yohimbe (yohimbine) Plantago ovale (bran, ispaghula husk) Tamarindus indica (tamarind) Shankhapushpi (an Ayurvedic mixture of herbs) Xaio chai hu tang (sho-salko-to)

Serotonin reuptake inhibitors Antidepressants Cocaine Digoxin Metamphetamine Opioids Phenelzine Tricyclic antidepressants Digoxin, iron, lithium, lovastatin, tricyclic antidepressants Aspirin Phenytoin Prednisolone

Anticoagulants Many alternative medicines interact with oral anticoagulants (principally warfarin) and interactions with plants are listed separately in Table 76.7. Drug interactions of warfarin with herbal preparations have been reviewed.275,276 In a retrospective analysis of the pharmaceutical care plans of 631 patients, 170 (27%) were taking some form of complementary or alternative medicine and 99 were using a medicine that could interact with warfarin, the commonest being codliver oil and garlic.277 The risk of bleeding associated with the use of alternative medicines has been evaluated in 171 patients taking warfarin in a prospective study in an acute-care academic research hospital in Canada.278 The patients completed a 16-week diary by recording bleeding events; 87 (51%) reported at least one bleeding event and 73 (43%) indicated that they had used at least one alternative medicine previously reported

Reduced blood pressure, increased heart rate, headaches, flushing, light-headedness Risk of lovastatin toxicity (including rhabdomyolysis and renal insufficiency) Prolongation of QT interval; risk of ventricular tachycardia Risk of saquinavir toxicity Risk of sertraline toxicity (serotonin syndrome) Reduced absorption Increased plasma digoxin concentration Hypertension Increased risk of hypokalaemia Reduced potassium-sparing effect Induction of metabolism by CYP3A4, causing reduced effects (e.g. increased risk of transplant rejection with ciclosporin, reduced anticoagulation with warfarin); induction of P glycoprotein, increasing intestinal and renal secretion of drugs Induction of P glycoprotein, increasing clearance and reducing effects Serotonin syndrome Risk of mania Tolerance inhibited Increased plasma digoxin concentration Tolerance inhibited Reduced pharmacological effects of opioids Headache, tremulousness, hyperactivity Increased risk of hypertension Reduced absorption Increased systemic availability Decreased concentrations of phenytoin, leading to seizures Reduced effect of prednisolone

to interact with warfarin. The therapies associated with an increased risk of self-reported bleeding included cayenne, ginger, willow bark, St John’s wort, and ubidecarenone (co-enzyme Q10). Use of more than one alternative medicine while taking warfarin was also a significant susceptibility factor. In a systematic review, warfarin was the most common cardiovascular drug involved in interactions with herbal medicines.279 In a meta-analysis of interactions of warfarin with other drugs, herbal medicines, Chinese herbal drugs, and foods, 642 citations were retrieved, of which 181 eligible articles contained original reports on 120 drugs or foods.280 Of all the reports, 72% described potentiation of the effect of warfarin, and the authors considered that 84% were of poor quality, 86% of which were single case reports. The 31 incidents of clinically significant bleeding were all single case reports. Relatively few anecdotal reports of adverse event–drug associations are



76  Plant Poisons and Traditional Medicines

TABLE 76.7 

Some Reported Interactions of Warfarin and Other Coumarin Anticoagulants with Plants and Herbal Productsa

Plant

Effect on Anticoagulation

Allium sativum (garlic)

Reduced (altered platelet aggregation) Potentiated Reduced (contains vitamin K) Potentiated Potentiated (inhibition of warfarin metabolism) Potentiated (contains vitamin E) Potentiated Potentiated

Angelica sinensis (dong quai) Camellia sinensis (green tea) Carica papaya (papaya) Citrus paradisi (grapefruit juice) Cucurbita pepo Ginkgo biloba (maidenhair) Harpagophytum procumbens (devil’s claw) Hypericum perforatum (St John’s wort) Lycium barbarum (Chinese wolfberry) Mangifera indica (mango) Matricaria chamomilla (chamomile) Panax ginseng (ginseng) Panax quinquefolium (American ginseng) Peumus boldus (boldo) Punica granatum (pomegranate juice ) Salvia miltiorrhiza (danshen) Trigonella foenum graecum (fenugreek) Vaccinium macrocarpon (cranberry juice) Zingiber officinale (ginger)

Reduced (induction of warfarin metabolism) Potentiated Potentiated Potentiated Reduced platelet aggregation Reduced anticoagulation Potentiated Potentiated Potentiated (?altered pharmacokinetics) Potentiated Potentiated Potentiated

a

Many of these associations have been reported anecdotally and some have not been confirmed in small formal studies.

followed-up with formal studies,281 and reports of interactions of warfarin with herbal medicines are no exception – most are based on anecdotal reports. Medicines that resulted in increased anticoagulation include Allium sativum (garlic282–284), Angelica sinensis (dong quai285), Carica papaya (papaya), curbicin286 (from Cucurbita pepo seed and Serenoa repens fruit), Ginkgo biloba (maidenhair287–290), Harpagophytum procumbens (devil’s claw), Lycium barbarum (Chinese wolfberry291,292), Mangifera indica (mango),293 Mat­ ricaria chamomilla (chamomile294), Salvia miltiorrhiza (danshen295–297), Trigonella foenum graecum (fenugreek298), Vac­ cinium macrocarpon (cranberry299–301), and Zingiber officinale (ginger302,303). Medicines that result in reduced anticoagulation include Camellia sinensis (green tea304), Hypericum perforatum (St. John’s wort305–308), Panax ginseng (ginseng309–312), and Panax quinquefolium (American ginseng310). Other plants and herbal products that have been reported to increase or reduce the actions of warfarin313 include angelica root, anise, arnica flower, asafetida, bogbean, borage seed oil, bromelain, capsicum, celery, clove, feverfew, green tea, horse chestnut, liquorice root, lovage root, meadowsweet, melilot, onion, parsley, passion-flower, poplar, quassia, red clover, rue, sweet clover (in which coumarin anticoagulants were originally discovered), sweet woodruff, tonka beans, turmeric, vitamin E, and willow bark.

1149

The mechanisms vary: for example, garlic reduces platelet aggregation; some plants (e.g. dong quai) contain anticoagulant coumarins; and some (e.g. tonka beans) contain vitamin K, a natural antagonist of the actions of coumarin anticoagulants. Warfarin has also been reported to interact with Chinese medicines, which often contain mixtures of herbs; in such cases it is difficult or impossible to identify the precipitant plant or the mechanism. For example, Quilinggao, a mixture that contains numerous herbal ingredients (including Fritillaria cir­ rhosa and other Fritillaria species, Paeoniae rubra, Lonicera japonica, and Poncirus trifoliata, in many different brands), has been reported to enhance the actions of warfarin.314 Citrus Fruits Various isoforms of the enzyme cytochrome P450 are responsible for the oxidative metabolism of many drugs.315 One of these isoforms, CYP3A4, is responsible for the metabolism of several drugs in the gut wall while they are being absorbed after oral administration. Inhibition of the enzyme by something in grapefruits (Citrus paradisi) and Seville oranges (Citrus bigaradia) causes more of the drug to escape presystemic metabolism and enter the circulation unchanged, potentially leading to drug toxicity. The compounds in grapefruit juice and Seville oranges responsible for these interactions may be, at least in part, bergamottin and dihydroxybergamottin, which are furocoumarins.316 Lime juice, which contains bergamottin but not dihydroxybergamottin, has a smaller effect.317 In some countries, a drug label has been introduced, alerting patients to potential drug interactions with grapefruit.318 In the UK in 1997, the antihistamine terfenadine was withdrawn from over-the-counter sales because of cardiac arrhythmias,319 and a year later another antihistamine, astemizole, was withdrawn for similar reasons.320 Drugs whose effects can be increased by grapefruit juice, causing toxicity321 are listed in Table 76.6. Grapefruit juice probably also inhibits the P glycoprotein and organic anion transporting polypeptides that are responsible for the intestinal secretion and active absorption of many drugs,322 and therefore other drug interactions are to be expected. This effect is at least partly due to furocoumarins323 and partly to naringin.324 Ginseng Reported drug interactions with ginseng (Panax ginseng) are listed in Table 76.6. The root has been used in China, Korea, and Japan for centuries in the belief that it counters fatigue and stress and confers health, virility, and longevity; it is supposed to enhance immunity and to combat the effects of oxidative free radicals that cause chronic diseases and ageing.325 The pharmacological basis for its reputation is slender, but ginseng is in fashion worldwide. It is often adulterated with Eleutherococcus senticosus (Siberian ginseng, Table 76.6), Man­ dragora, Rauwolfia, and other roots of similar appearance. Ginseng contains a complex mixture of steroids and saponins; it can cause insomnia, tremor, headache, diarrhoea, hyper­ tension, and oestrogen-like effects.326 It may also increase the risk of gastric cancer.327 St John’s wort As an antidepressant, St John’s wort328 may enhance the effects of other antidepressants; since it is an inhibitor of 5-HT reuptake, combination with serotonin reuptake inhibitors can cause

1150 TABLE 76.8 

SECTION 13  Environmental Disorders

Some Adulterants and Contaminants that Have Been Found in Herbal Products

Type of Adulterant/Contaminant

Examples

Allopathic drugs

Albendazole, analgesic and anti-inflammatory agents (for example aminophenazone, cocaine, diclofenac, diethylpropion, indometacin, paracetamol, phenylbutazone), benzodiazepines, chlorphenamine, ephedrine, glucocorticoids, ketoconazole, sildenafil, sulfonylureas, tadalafil, thiazide diuretics, thyroid hormones Aristolochia spp., Atropa belladonna, Digitalis spp. (see Table 76.2), Colchicum, Rauwolfia serpentina, pyrrolizidine-containing plants (see Table 76.4) Ethylene oxide, methyl bromide, phosphine Arsenic, cadmium, lead, mercury Escherichia coli, Pseudomonas aeruginosa, Salmonella spp., Shigella spp., Staphylococcus aureus Aflatoxins, bacterial endotoxins Carbamate insecticides and herbicides, chlorinated pesticides (for example aldrin, dieldrin, heptachlor, DDT, DDE, HCB, HCH isomers), dithiocarbamate fungicides, organic phosphates, triazine herbicides 134 Cs, 137Cs, 131I, 103Ru, 90Sr

Botanicals Fumigation agents Heavy metals Microorganisms Microbial toxins Pesticides Radionuclides

the serotonin syndrome. Hyperforin, an ingredient of St John’s wort (Hypericum perforatum), is an enzyme inducer and increases the metabolism of certain drugs, principally through CYP3A4, reducing their effects; St John’s wort also induces intestinal P glycoprotein, leading to increased clearance of some drugs by intestinal and renal secretion.305 Examples of these pharmacokinetic interactions are listed in Table 76.6.

Adulteration of Herbal Products There have been many reports that Chinese herbal remedies have been adulterated or contaminated with conventional drugs, heavy metals, and even other herbal substances not announced on the label.329 Some examples are listed in Table 76.8.

BIBLIOGRAPHY Aronson JK, editor. Meyler’s Side Effects of Herbal Drugs. Amsterdam: Elsevier; 2009. Online. Available: http://www.elsevier.com/wps/find/books_ browse.cws_home. Burkill HM. The useful plants of West tropical Africa. 2nd edition. Volumes 1-6. London: Crown Agents for Oversea Governments and Administrations; 1985, 1994, 1995, 1997, 2000, 2004. Caius JF. The Medicinal and Poisonous Plants of India. Jodhpur: Scientific Publishers; 2003.

Everist SL. Poisonous Plants of Australia. 2nd ed. Sydney: Angus & Robertson; 1981. Nelson LS, Shih RD, Balick MJ. Handbook of Poisonous and Injurious Plants. 2nd ed. New York: The New York Botanical Garden/Springer; 2007. Schmidt RJ. Botanical Dermatology Database. Online. Available: http://www.botanicaldermatology-database.info. Watt JM, Breyer-Brandwijk MG. The Medicinal and Poisonous Plants of Southern and Eastern

Africa. 2nd ed. Edinburgh: E & S Livingstone; 1962. Wink M, van Wyk B-E. Mind-Altering & Poisonous Plants of the World. Portland Oregon: Timber Press; 2008.

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76  Plant Poisons and Traditional Medicines 1150.e1

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SECTION 13  Environmental Disorders

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1150.e6

SECTION 13  Environmental Disorders

305. Henderson L, Yue QY, Bergquist C, et al. St John’s wort (Hypericum perforatum): drug interactions and clinical outcomes. Br J Clin Pharmacol 2002;54(4):349–56. 306. Maurer A, Johne A, Bauer S. Interaction of St. John’s wort extract with phenprocoumon. Eur J Clin Pharmacol 1999;55:A22. 307. Jiang X, Williams KM, Liauw WS, et al. Effect of St John’s wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol 2004; 57(5):592–9. Erratum 2004;58(1):102. 308. Mills E, Montori VM, Wu P, et al. Interaction of St John’s wort with conventional drugs: systematic review of clinical trials. BMJ 2005; 329(7456):27–30. 309. Rosado MF. Thrombosis of a prosthetic aortic valve disclosing a hazardous interaction between warfarin and a commercial ginseng product. Cardiology 2003;99(2):111. 310. Yuan CS, Wei G, Dey L, et al. American ginseng reduces warfarin’s effect in healthy patients: a randomized, controlled trial. Ann Intern Med 2004;141(1):23–7. 311. Coon JT, Ernst E. Panax ginseng: a systematic review of adverse effects and drug interactions. Drug Saf 2002;25(5):323–44. 312. Janetzky K, Morreale AP. Probable interaction between warfarin and ginseng. Am J Health Syst Pharm 1997;54(6):692–3.

313. Heck AM, DeWitt BA, Lukes AL. Potential interactions between alternative therapies and warfarin. Am J Health-Syst Pharm 2000; 57:1221–7. 314. Wong ALN, Chan TYK. Interaction between warfarin and the herbal product Quilinggao. Ann Pharmacother 2003;37(6):836–8. 315. Weber WW. Pharmacogenetics. New York: Oxford University Press; 1997. 316. Malhotra S, Bailey DG, Paine MF, et al. Seville orange juice–felodipine interaction: comparison with dilute grapefruit juice and involvement of furocoumarins. Clin Pharmacol Ther 2001;69(1):14–23. 317. Bailey DG, Dresser GK, Bend JR. Bergamottin, lime juice and red wine as inhibitors of cytochrome P450 3A4 activity: comparison with grapefruit juice. Clin Pharmacol Ther 2003; 73(6):529–37. 318. Anonymous. Grapefruit warning label: now official in some countries. Drugs Ther Perspect 1998;12:12–13. 319. Committee on Safety of Medicines, Medicines Control Agency. Terfenadine: now only available on prescription. Curr Probl Pharmacovig 1997;23:9. 320. Committee on Safety of Medicines, Medicines Control Agency. Astemizole (Hismanal): only available on prescription. Curr Probl Pharmacovig 1999;25:2.

321. Aronson JK. Forbidden fruit. Nature Med 2001;7:7–8. 322. Ohnishi A, Matsuo H, Yamada S, et al. Effect of furanocoumarin derivatives in grapefruit juice on the uptake of vinblastine by Caco-2 cells and on the activity of cytochrome P450 3A4. Br J Pharmacol 2000;130:1369–77. 323. Dresser GK, Bailey DG, Leake BF, et al. Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine. Clin Pharmacol Ther 2002;71(1):11–20. 324. Bailey DG, Dresser GK, Leake BF, et al. Naringin is a major and selective clinical inhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice. Clin Pharmacol Ther 2007;81(4):495–502. 325. Kitts D, Hu C. Efficacy and safety of ginseng. Public Health Nutr 2000;3:473–85. 326. Xie J-T, Mehendale SR, Maleckar SA, et al. Is ginseng free from adverse effects? Oriental Pharm Exp Med 2002;2:80–6. 327. Ahn YO. Diet and stomach cancer in Korea. Int J Cancer 1997;(Suppl 10):7–9. 328. Di Carlo G, Borrelli F, Izzo AA, et al. St John’s wort: Prozac from the plant kingdom. Trends Pharmacol Sci 2001;22:292–7. 329. Aronson JK, editor. Meyler’s Side Effects of Herbal Drugs. Amsterdam: Elsevier, 2009. p. 5–6.