Essentials of Complementary and Alternative Medicine (June 1999)

Spindle tree, European (Euonymus europaeus)
The fruit is said to have cathartic and emetic activity.
Squirting cucumber (Ecabalium elaterium)
The fruit juice can cause severe skin irritation, inflammation, and Quincke's edema (
205
), and has also been associated with a fatal case of cardiac and renal failure 
(
206
). Among the isolated constituents is cucurbitacin B (
207
).
St. Mary's thistle fruit (Silybum marianum = Carduus marianus)
Occasionally slight laxative effect. A case of anaphylactic shock following the use of a herbal tea containing an extract of the fruit has been reported (
208
).
St. John's wort (Hypericum perforatum)
Gastrointestinal symptoms, allergic reactions, and fatigue (
209
). Ingestion of this herb by grazing animals can cause photosensitization, which effect is generally 
ascribed to the red-colored pigment hypericin.
Sunflower seed (Helianthus annuus)
Anaphylactic reactions have been recorded (
210
).
Sweet flag (Acorus calamus)
Mutagenic and carcinogenic b-asarone in volatile oil (high levels in tetraploid Indian plants, low levels in triploid Eastern European plants, and no detectable level in 
diploid North American plants) (
82
).
Tansy, common (Chrysanthemum vulgare = Tanacetum vulgare)
Contains essential oil with neurotoxic thujone in such amounts that normal doses may already be toxic.
Tea tree oil (Melaleuca alternifolia)
Topical use of the undiluted essential oil from the leaves can result in an allergic contact eczema, which is most commonly caused by the constituent d-limonene 
(
211
, 
212
). Internal use of half a teaspoonful of the oil may result in a dramatic rash (
213
), whereas half a tea cup may induce a coma followed by a semiconscious 
state with hallucinations (
214
). Less than 10 mL is sufficient to produce serious signs of toxicity in small children.
Temu lawak rhizome (Curcuma xanthorrhiza)
Gastrointestinal irritation from continued use.
Tobacco (Nicotiana tabacum)
The leaves contain the toxic alkaloid nicotine as major constituent and several other pyridine alkaloids as minor constituents. Although tobacco enemas have been 
abolished in official medicine because of their life-threatening toxicity, self-medication has not completely died out. A case report in the 1970s described nausea and 
confusion, followed by hypotension and bradycardia, due to an enema prepared apparently from 5 to 10 cigarettes (
215
).
Tobacco, Indian (Lobelia inflata)
Because this herb contains the toxic alkaloid lobeline and other pyridine alkaloids, overdosing can result in serious toxicity. Lobeline has similar peripheral effects as 
nicotine, whereas its central activity may be different. Its use has been associated with nausea, vomiting, headache, tremors, and dizziness. Symptoms caused by 
overdosage include profuse diaphoresis, paresis, tachycardia, hypotension, Cheyne-Stokes respiration, hypothermia, coma, and death. Large doses are convulsant.
Tropane alkaloids
Tropane alkaloids occur naturally in various plants, such as  Atropa belladonna (deadly nightshade), Datura stramonium (jimson weed), Hyoscyamus niger 
(henbane), Mandragora officinarum (European mandrake), and Scopalia carniolica. These alkaloids are powerful anticholinergic agents and can elicit peripheral 
symptoms (e.g., blurred vision, dry mouth) as well as central effects (e.g., drowsiness, delirium).
Valerian root (Valeriana spp.)
The valepotriates that occur in valerian roots have alkylating properties. Valtrate/isovaltrate and dihydrovaltrate are mutagenic in bacterial test systems in the 
presence of a metabolic activator, and their degradation products baldrinal (from valtrate) and homobaldrinal (from isovaltrate) are already mutagenic without 
metabolic activation. These latter compounds also show direct genotoxic activity in SOS-chromotesting. As far as is known, decomposition of didrovaltrate does not 
yield baldrinals.
The levels of valepotriates and baldrinals in valerian extracts depend on the botanical species: root extracts of  Valeriana officinalis contain up to 0.9% of 
valepotriates, compared with 2–4% and 5–7% of valepotriates in root extracts of  Valeriana wallichii and Valeriana mexicana, respectively. Another relevant 
parameter is the dosage form:
Herbal tea. When prepared by hot extraction from valerian root, up to 60% of the valepotriates remains in the root material, and only 0.1% can be recovered from 
the tea.
Tincture. A freshly prepared tincture contains 11% of the valepotriates originally found in the root material. Storage at room temperature rapidly reduces this level to 
3.7% after one week and 0% after three weeks. In view of this rapid degradation, it is not surprising that commercially available tincture samples yield baldrinals 
when analyzed.
Tablets and capsules. Valerian-containing tablets and capsules may provide up to 1 mg of baldrinals per piece.
Valepotriates show poor gastrointestinal absorption, but 2% is degraded in vivo to baldrinals following the oral application of valtrate/isovaltrate to mice. In other 
words, a tablet with 50 mg of valepotriates may add 1 mg of baldrinals to the amount of baldrinals, which are already present before ingestion. In contrast to the 

when analyzed.
Tablets and capsules. Valerian-containing tablets and capsules may provide up to 1 mg of baldrinals per piece.
Valepotriates show poor gastrointestinal absorption, but 2% is degraded in vivo to baldrinals following the oral application of valtrate/isovaltrate to mice. In other 
words, a tablet with 50 mg of valepotriates may add 1 mg of baldrinals to the amount of baldrinals, which are already present before ingestion. In contrast to the 
valepotriates, the degradation product homobaldrinal is absorbed fairly well following oral application to mice. As much as 71% of the administered dose can be 
recovered from the urine in the form of baldrinal glucuronide. Because no unchanged homobaldrinal can be demonstrated in body fluids or liver samples following 
oral administration, the compound appears to undergo substantial first-pass metabolism. Because this glucuronidation leads to loss of the mutagenic properties, the 
primary target organs that may be at risk from valepotriates and baldrinals are the gastrointestinal tract and the liver (
216
).
The toxicological significance of these data is still not sufficiently clear because the carcinogenic potential of valerian preparations and their constituents has not yet 
been evaluated.
Vervain, European (Verbena officinalis)
Allergic contact dermatitis (
217
).
Wahoo bark (Euonymus atropurpureus)
Said to have cathartic and emetic activity.
Wall germander (Teucrium chamaedrys)
In France, numerous cases of hepatitis have been associated with the normal use of this herb. The frequency of this adverse effect has been estimated at 1 case in 
about 4000 months of treatment (
218
). Two additional cases were reported from Canada (
219
). Although most cases were not very serious, fatal outcome has been 
reported (
220
), and progression to liver cirrhosis has also been described (
220
). According to animal studies, the hepatotoxicity resides in one or more reactive 
metabolites of its furanoditerpenoids (
221
, 
222
).
The risk of Teucrium-induced hepatitis does not seem to be restricted to the single species  T. chamaedrys because the related T. canadense (see the entry on 
skullcap
) and Teucrium polium (
223
) have also been associated with this adverse effect.
Walnut fruit-shell (Juglans regia)
Fresh shells contain the naphthoquinone constituent juglone, which is mutagenic and possibly carcinogenic. The juglone content of dried shells has not been 
studied adequately.
Willow (Salix species)
The bark of various Salix species contains glycosides of saligenin (= salicylalcohol), namely the simple O-glycoside salicin and more complex glycosides like 
salicortin. When taken orally, these glycosides may undergo intestinal transformation to saligenin, which in its turn may be rapidly absorbed and then converted by 
the liver to salicylic acid. When willow bark preparations are used according to current dosage recommendations, they will not provide sufficient salicylic acid to 
produce acute salicylate poisoning. However, the risk of an idiosyncratic response (skin reactions, bronchospasm) in sensitive individuals cannot be excluded.
Witch hazel (Hamamelis virginiana)
Contact allergy has been reported (
224
).
Wolf's foot (Lycopus europaeus)
An increase in the size of the thyroid gland is possible, as is an initial increase of hyperthyreotic symptoms (e.g., nervousness, tachycardia, and loss of body weight). 
Interference with the thyroidal uptake of radioactive iodine has also been reported (
225
).
Wormwood (Artemisia absinthium)
The volatile oil is used to flavor the alcoholic liqueur absinthe, which can damage the nervous system and cause mental deterioration. This toxicity is attributed to 
thujone (a mixture of a- and b-thujone), which constitutes 3 to 12% of the oil, which in its turn reaches concentrations of 0.25 to 1.32% in the whole herb. Alcoholic 
extracts and the essential oil are forbidden in many countries.
Yohimbe bark (Pausinystalia johimbe)
A major alkaloid in yohimbe bark is yohimbine, which has a
2
-adrenoreceptor antagonistic properties and can thereby counteract the effects of certain 
antihypertensives (e.g., guanabenz, the methyldopa metabolite a-methylnorepinephrine) An oral dose of 15 to 20 mg can increase blood pressure and induce 
anxiety in healthy volunteers, and hypertension may already be induced by 4 mg taken three times daily in patients on tricyclic antidepressants. The toxicity of 
yohimbine can also be enhanced by other drugs, such as phenothiazines. A dose of 5 mg is sufficient to produce adverse effects in patients with autonomic failure, 
and 10 mg can elicit maniclike symptoms in patients with bipolar depression. Bronchospasm and a lupuslike syndrome have also been reported (
15
, 
16
).
Yohimbine also occurs in other species of  Pausinystalia (P. angolensis and P. trillesii) (
226
) and in the bark of Corynanthe paniculata (
227
).
Recreational Herbs
Western customers may purchase bioactive herbs not only for medicinal uses, but also for other purposes, such as mind-altering effects. Reported adverse reactions 
to some major source plants are reviewed below. The recreational use of botanical hallucinogens (other than marijuana) is showing signs of revival after a distinct 
decline during the 1970s and 1980s. Important examples are listed in 
Table 6.3
 (
228
, 
229
 and 
230
) on the basis of their hallucinogenic constituents. In addition to the 
general risk that consumers may overestimate their own abilities (
233
), specific toxic effects can result from plants such as  Datura (
234
, 
235
, 
236
 and 
237
) and 
Myristica fragrans (
238
), which have a strong vegetative component besides their hallucinogenic activity.
Table 6.3. Botanical Hallucinogens and their Most Important Source Plants

The next page shows a summary of the known and reported adverse effects of recreational herbs and products.
When faced with a patient using these products, the practitioner can find information on that product here. This section provides an indication of the adverse effects 
known for that plant and help guide the practitioner in monitoring for possible adverse effects in that patient. It will also help the practitioner inform the patient about 
possible risks.
Areca nut (Areca catechu)
A substantial part of the world's population chews betel nut quid, a combination of areca nut, betel pepper leaf (from  Piper betle), lime paste, and tobacco leaf. The 
major alkaloid of the areca nut, arecoline, can produce cholinergic side effects such as bronchoconstriction (
239
) as well as antagonism of anticholinergic agents 
(
240
). Under the influence of the lime in the betel quid, arecoline hydrolyzes into arecaidine, a central nervous system stimulant which accounts, together with the 
essential oil of the betel pepper, for the euphoric effects of betel quid chewing. The use of the areca nut is widely implicated in the development of oral cancers, and 
it has been documented that the saliva of betel nut chewers contains nitrosamines derived from areca nut alkaloids (
241
).
Coca leaf (Erythroxylum spp.)
Coca leaves contain cocaine as the principal alkaloid and a variety of other minor alkaloids. Only decocainized coca products are legal in the United States, but 
some commercially available tea products were found to have a cocaine level normally found in coca leaves (about 5 mg of cocaine per tea bag of 1 gram). This 
level results in mild symptoms when package directions to drink a few cups per day are followed, but massive overdosing may result in severe agitation, tachycardia, 
perspiration, and elevated blood pressure (
242
).
Kava-kava rhizome (Piper methysticum)
South Pacific natives prepare a ceremonial beverage from this rhizome. The major constituents are nonalkaloidal pyrone derivatives, which produce sedation and 
centrally induced muscle relaxation in laboratory animals. This suggests that one should be aware of a potential effect on driving ability. Western case reports have 
described allergic skin reactions, yellow discoloration of the skin, sensory disturbances, sleepiness, and ataxia (
243
, 
244
 and 
245
). Heavy chronic consumption of 
kava-kava can lead to a pellagroid dermopathy that appears to be unrelated to niacin deficiency (
246
).
Khat leaves (Catha edulis)
The chewing of khat leaves results in subjective mental stimulation, physical endurance, and increased self-esteem and social interaction. Until recently, this habit 
was confined to Arabian and East African countries, because only fresh leaves are active, but due to increased possibilities of air transportation, khat is now also 
chewed in other parts of the world. Tachycardia and increased blood pressure, irritability, psychosis, and psychic dependence have been described as adverse 
effects. Although cathine (= norpseudoephedrine) is quantitatively the main alkaloid, the amphetaminelike euphorigenic and sympathicomimetic cardiovascular 
effects of khat are primarily attributed to cathinone (
247
). Khat chewing by a breast-feeding mother can lead to the presence of cathine in the urine of the suckling 
child (
248
).
Ma Huang (Ephedra spp.)
The major alkaloid in commercial samples of Ma Huang and in its usual source plants is either the R(–)-isomer ephedrine or the S(+)-isomer pseudoephedrine (
249
, 
250
 and 
251
). In high doses, ephedrine can produce serious peripheral and central adrenergic effects, such as palpitations, tachycardia, hypertension, coronary 
spasm, psychosis, convulsions, respiratory depression, coma, and death (
47
). The occurrence of pressor effects depends on factors such as specific isomer, dose, 
and consumer. In normotensive subjects, ephedrine can produce significant blood pressure elevation at oral doses of 60 mg or more. Infants and elderly patients are 
more susceptible, and the risk may also be greater in hypertensive patients. At oral doses of 60 mg, pseudoephedrine is considered to give a low incidence of blood 
pressure elevation in normotensive subjects. If blood pressure elevation does occur, this is likely to be due to idiosyncrasy (
252
).
Ma Huang and other ephedrine-containing dietary supplements have been associated in recent years with numerous adverse events, particularly in the United 
States. These products were marketed as legal producers of a “high,” enhancers of sexual sensations, and increasers of energy and provided up to 45 mg of 
ephedrine and 20 mg of caffeine per tablet (
47
, 
253
). Among the reported effects were erythroderma (
254
), mania (
255
), psychosis (
256
), seizures, acute myocardial 
infarction, and fatal coronary artery thrombosis (
47
). The use of Ma Huang was also associated with a case of acute hepatitis, but given the lack of published cases 
of hepatotoxic reactions to Ma Huang or ephedrine, the reporting physicians rightly questioned whether the patient took a contaminated or misidentified product 
(
257
).
Poppy seed (Papaver somniferum)
The ingestion of poppy seeds can result in detectable urinary levels of morphine and codeine (
258
). There are rare cases of poppy dependence due to the frequent 
sucking of poppy seeds (
259
) or to the regular drinking of a tea infusion from poppy heads (
260
).
Traditional Chinese Medicines
The availability of traditional Chinese medicines for Western consumers appears to be increasing. Although herbal ingredients with potent pharmacological activity 
have become less and less common in Western phytotherapeutic medicines, a variety of potent herbs can still be encountered in traditional Chinese medicines (
261
, 
262
, 
263
 and 
264
). First, the Chinese materia medica comprises well-known toxic herbs, such as  Ephedra and Aconitum. The latter continues to be associated with 
cases of serious heart failure (
265
, 
266
), although its cardiotoxicity can be substantially reduced by decocting the raw root (
267
). Second, there are familiar toxic 
constituents under the guise of unfamiliar Chinese or botanical names (
Table 6.4
) (
268
, 
269
, 
270
 and 
271
). Third, adverse effects can be produced by numerous 
unfamiliar Chinese herbs or their less familiar constituents. Finally, traditional Chinese medicines can contain, besides herbs, ingredients of animal and mineral origin, 
some of which make significant contributions to the adverse reaction potential of these medicines.
Table 6.4. Familiar Toxic Agents Contained in Unfamiliar Chinese Names
Botanical Quality
A potentially toxic Chinese herb that has drawn much attention in recent years is  Aristolochia fangchi. In 1993 and 1994, Belgian researchers reported a human 
outbreak of nephropathy in more than 70 users of a slimming preparation that supposedly contained the Chinese herbs  Stephania tetrandra and Magnolia officinalis 

(
272
 and 
273
). Analysis of the incriminated material showed that the root of  Stephania tetrandra (Chinese name “Fangji”) had in all probability been substituted or 
contaminated with the root of Aristolochia fangchi (Chinese name “Guang fangji”) (
274
). In most cases, renal failure progressed despite the withdrawal of the slimming 
preparation, and 35 patients required renal replacement therapy. Renal biopsies showed extensive interstitial fibrosis with atrophy and loss of tubules (
272
, 
273
, 
275
, 
276
). The supposition that the renal interstitial fibrosis was immune-mediated was supported by the finding that the progression of the renal failure could be slowed by 
steroid therapy with prednisolone (
277
). At least two of the patients exposed to the slimming preparation rapidly developed urothelial malignancy (
278
, 
279
). This did 
not come as a great surprise, because the aristolochic acids in  Aristolochia plants are extremely potent rodent carcinogens (
88
). Further evidence of the implication of 
aristolochic acid was provided by a report on aristolochic acid DNA adducts in renal tissue samples of some victims. The demonstration of the deoxyadenosine adduct 
of aristolochic acid I conclusively showed that aristolochic acid had been ingested in amounts sufficient to alter cellular DNA (
280
). Another Aristolochia species in 
traditional Chinese medicine is  Aristolochia manshuriensis, which also provides toxic aristolochic acids (
88
). Because there is evidence that these compounds pass 
into human breast milk following maternal use (
88
), it is of concern that this herb is recommended for the improvement of mammary gland growth and function (
281
).
The Stephania/Aristolochia problem in Belgium illustrates that botanical quality assurance is as relevant for traditional Chinese medicines as it is for Western herbal 
products. A pharmacognostic study of crude materials imported into the United Kingdom suggests that there still is much room for improvement (
Table 6.5
) (
282
). 
Besides the presence of Aristolochia fangchi in Fang Ji (Stephania tetrandra), there was also the disturbing finding that  Akebia quinata (“Mutong”) had been 
substituted by Aristolochia manshuriensis (“Guanmutong”) (
283
). Among the unexpected toxic botanicals that have been discovered in Chinese herbal medicines are 
also Podophyllum emodi, Datura metel, and Mandragora officinarum (
284
, 
285
). Not all practitioners of traditional Chinese medicine in the United Kingdom are 
experts in herb recognition (
286
).
Table 6.5. Botanical Quality Problems with Certain Crude Chinese Plant Drugs Imported into the United Kingdom
Other Quality Issues
Quality control of traditional Chinese medicines is also important to exclude other contaminants (
9
), such as pathogenic microorganisms (
287
). Some recent chemical 
findings and toxicological observations concerning the presence of toxic metals in traditional Chinese medicines are provided in 
Table 6.6
 (
288
, 
289
 and 
290
) and 
Table 6.7
 (
291
, 
292
 and 
293
), respectively. Not all of these data may refer to accidental contamination, because certain traditional Chinese herbal formulas 
intentionally contain toxic arsenic and/or mercury salts as ingredients (see the section on toxic metals in 
Chapter 7
, “The Safety of Nonherbal Complementary 
Products”). Another concern involves the deliberate adulteration of certain traditional Chinese herbal medicines with conventional Western pharmaceuticals, such as 
corticosteroids, nonsteroidal anti-inflammatory agents, and benzodiazepines (
83
). Although this type of malpractice has been frequently denounced in the past 
decades (
9
), it continues to cause occasional problems (
Table 6.8
).